Electromechanical ingestible device for delivery of dispensable substance

Abstract

To disclose ingestible devices capable of delivering a dispensable substance, such as, for example, a therapeutic agent, as well as related components, systems and methods.SOLUTION: An ingestible device includes: a housing; an electronic component located within the housing; a gas generating cell located adjacent to the electronic component; a storage reservoir storing a dispensable substance, a first end of the storage reservoir being connected to the first end of the housing; an exit valve located at the first end of the housing, where the exit valve is configured to allow the dispensable substance to be released out of the first end of the housing from the storage reservoir; and a safety device placed within or attached to the housing, where the safety device is configured to relieve an internal pressure within the housing when the internal pressure exceeds a threshold level.SELECTED DRAWING: Figure 45

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is filed under 35 U.S.C. § 119 in accordance with U.S. Provisional Patent Application No. 62 / 385,553, entitled "Electromechanical Ingestible Device for Delivery of a Dispensable Substance," filed on September 9, 2016; U.S. Provisional Patent Application No. 62 / 478,955, entitled "Electromechanical Ingestible Device for Delivery of a Dispensable Substance," filed on March 30, 2017; U.S. Provisional Patent Application No. 62 / 478,753, entitled "Treatment of a Disease of the Gastrointestinal Trace with an IL-6R Inhibitor," filed on March 30, 2017; U.S. Provisional Patent Application No. 62 / 480,187, entitled "Localization Systems and Method for an Ingestible Device," filed on March 31, 2017; No. 62 / 540,873, entitled "A New Ingestible Device for Treating a Gastrointestinal Tract," filed on Aug. 14, 2017; and U.S. Provisional Patent Application No. 62 / 545,129, entitled "Treatment of a Disease of the Gastrointestinal Tract with a CD40 / CD40L Inhibitor," filed on Aug. 14, 2017.

[0002] Incorporation by Reference This application incorporates by reference the following patent applications: USSN 14 / 460,893; 15 / 514,413; 15 / 680,400; 15 / 680,430; 15 / 694,458; 62 / 376,688; 62 / 385,553; 62 / 478,753; 62 / 478,955; 62 / 434,188; 62 / 434,320; 62 / 431,297; 62 / 434,797; 62 / 480,187; 62 / 502,383; 62 / 540,873; and 62 / 545,129.

[0003] Field The present disclosure relates generally to ingestible devices capable of delivering a dispenseable substance, such as, for example, a therapeutic agent, as well as related components, systems and methods. The present disclosure also relates generally to attachable storage reservoirs configured for use with ingestible devices and capable of storing a dispenseable substance, such as, for example, a therapeutic agent, as well as related components, systems and methods. [Background technology]

[0004] The gastrointestinal (GI) tract generally provides a therapeutic medium for an individual's body. At times, a therapeutic agent may need to be dispensed to a specified location in the small intestine, which is more effective than oral administration of the therapeutic agent to treat some medical condition. For example, a therapeutic agent applied directly into the small intestine will not be contaminated in the stomach, thus allowing a higher dose to be delivered to a specific location in the small intestine. However, dispensing a therapeutic agent directly into the small intestine inside the human body may be difficult, since a device or mechanism is required to carry the therapeutic agent to the desired location in the small intestine and then automatically deliver the therapeutic agent to the desired location. Such a device or mechanism also needs to be operated in a safe manner, since it must enter the human body. Summary of the Invention [Means for solving the problem]

[0005] The present disclosure provides ingestible devices that can deliver a dispenseable substance, such as, for example, a therapeutic agent, into the GI tract of a subject. The delivery can be highly controllable. The delivery can be performed with relatively high precision to a desired location in the GI tract of the subject. Optionally, the ingestible device can include a mechanism that can be used to control / manipulate the location of the ingestible device within the GI tract of the subject. The amount of the dispenseable substance delivered, and its release profile, can be controlled to a relatively high degree of precision.

[0006] The present disclosure also provides attachable storage reservoirs configured for use with, for example, ingestible devices. The storage reservoirs can be developed such that, for example, a dispenseable substance (e.g., a therapeutic agent) can be placed in the storage reservoir before, during, or after the storage reservoir is packaged, shipped, and / or stored. In such an approach, a storage reservoir containing a desired dispenseable substance can be provided a relatively short period of time before the dispenseable substance is to be delivered. For example, the dispenseable substance can be placed at any time with the storage reservoir, and shortly thereafter, the storage reservoir containing the dispenseable substance can be attached to / within the ingestible device immediately prior to ingestion of the ingestible device.

[0007] In one aspect, the present disclosure provides an ingestible device that includes a storage reservoir configured to store a dispenseable substance and a force generator component configured such that when the force generator generates a force, the dispenseable substance exits the ingestible device through an opening in the ingestible device.

[0008] The ingestible device can include a housing.

[0009] The force generator may be disposed at least partially within the housing.

[0010] The force generator may be located entirely within the housing.

[0011] The storage reservoir may be located at least partially within the housing.

[0012] The storage reservoir may be located entirely within the housing.

[0013] The housing can include a first end, a second end, and a wall extending between the first end and the second end. The storage reservoir can be adjacent the first end.

[0014] The storage reservoir can be attachable to the ingestible device.

[0015] The storage can be an integral component of the ingestible device.

[0016] The ingestible device can further include an injection device configured such that when the force generator generates a force, the force moves the injection device to cause the dispensable substance to exit the ingestible device through the opening.

[0017] The injection device may include a syringe.

[0018] The ingestible device may further include components configured to position the injection device at the epithelial layer to spread the epithelial layer prior to delivery of the dispenseable substance.

[0019] The injection device can be configured so that the force it generates is sufficient to penetrate the mucosa.

[0020] The injection device may include a piston; a needle guide disposed within the storage reservoir and having an end attached to the piston; a spring coupled to the needle guide; and an injection needle passing through a portion of the needle guide and spring.

[0021] The spring can be configured to be compressed and the needle can be configured to extend out of the ingestible device as the piston moves.

[0022] The injection device can include a truss mechanism that supports the needle; and a balloon configured to inflate to cause the truss mechanism, along with the needle, to extend out of the storage reservoir.

[0023] The injection device can include a membrane configured such that, when the force generator generates a force, the force moves the membrane to cause the dispensable substance to exit the ingestible device through the opening.

[0024] The membrane can include a piston configured to move the membrane with a force to expel the dispensable substance from the ingestible device through the opening when the force generator generates a force.

[0025] The ingestible device may further include a light sensing unit configured to detect reflections from an environment external to the ingestible device.

[0026] The ingestible device can include a housing and a light sensing unit configured to detect reflections from an environment external to the housing.

[0027] The ingestible device can be configured to determine the position of the ingestible device based on the reflection detected by the light-sensing unit.

[0028] The force generator can generate a force based on the reflection detected by the light sensing unit.

[0029] The ingestible device can further include electronic components within the housing, the electronic components configured to actuate the force generator.

[0030] The force generator can be adjacent to the electronic component.

[0031] The ingestible device may further include a safety device configured to relieve internal pressure within the housing.

[0032] The storage reservoir is capable of storing a dispensable substance.

[0033] The ingestible device can further include an occluder. The occluder can have a first state configured to prevent the dispenseable substance from exiting the ingestible device through an opening in the ingestible device. The occluder can have a second state configured to allow the dispenseable substance to exit the ingestible device through an opening in the ingestible device.

[0034] The occluder may include a magnet.

[0035] The occluder may include a sliding pin.

[0036] The occluder may include a burst disc.

[0037] The occluder may include an enteric coating.

[0038] The occluder may include an enteric coating and a sliding pin.

[0039] The occluder may include an enteric coating and a magnet.

[0040] The occluder may include a dissolvable pin.

[0041] The occluder may include a dissolvable pin and an enteric coating.

[0042] The occluder may comprise a wax.

[0043] The wax can be formed into plugs.

[0044] The occluder may further include a lead configured to melt the wax.

[0045] The leads can be configured to be activated by a power source in response to commands from at least one computer processor.

[0046] The occluder can be positioned within the housing of the ingestible device.

[0047] The ingestible device may further include a bellows between the force generator and the storage reservoir.

[0048] The force generator can be configured to apply a force to the bellows to force the dispensable substance out of an opening in the ingestible device.

[0049] The ingestible device may further include a member within the opening of the ingestible device.

[0050] The member may be in the form of a plug.

[0051] The member may include a bioabsorbable material.

[0052] The force generator can include a gas generating cell configured to generate gas to provide the force.

[0053] The force generator may include a pressurized gas chamber.

[0054] The force generator may include a vacuum chamber.

[0055] The force generator may include a spring.

[0056] The force generator may include a compression spring and an extension spring.

[0057] The force generator may include a gear motor.

[0058] The ingestible device can include an inlet configured to draw fluid into the storage reservoir.

[0059] The ingestible device can further include an auger device disposed about a portion of the gear motor that is internal to the storage reservoir, the auger device can be configured to be driven by the gear motor to rotate and mix the dispensable substance with the fluid drawn into the storage reservoir.

[0060] The ingestible device can further include a wiper device longitudinally coupled to a portion of the gear motor that is internal to the storage reservoir, The wiper device can be configured to be driven by the gear motor to rotate and mix the dispensable substance with fluid drawn into the storage reservoir.

[0061] The ingestible device can further include a helical component disposed about a portion of the gear motor that is within the storage reservoir; and a piston disposed at one end of the helical component. The helical component is configured to be driven to rotate by the gear motor, thereby moving the piston longitudinally along the pitch of the helical component toward the outlet valve.

[0062] The ingestible device can include a housing configured to maintain the mechanical integrity of the ingestible device during use.

[0063] The ingestible device can include a housing configured to maintain its mechanical integrity when pressure inside the housing increases during use of the ingestible device.

[0064] The ingestible device can further include a mechanism configured to reduce gas pressure within the ingestible device.

[0065] The mechanism may include a gas absorbing material.

[0066] The mechanism may include an oxygen absorbing material.

[0067] The mechanism can include a relief valve configured to open when pressure within at least one region of the ingestible device reaches a threshold level.

[0068] The storage reservoir may include multiple chambers.

[0069] Each of the multiple chambers can be configured to store a different dispensable substance.

[0070] The ingestible device can be configured to simultaneously release different dispensable substances from the ingestible device.

[0071] The ingestible device can be configured to sequentially release different dispensable substances from the ingestible device.

[0072] The ingestible device can include electronic components configured to control the generation of force by the force generator to deliver a metered dose of the dispensable substance out of an opening in the ingestible device.

[0073] The dispenseable substance can include a therapeutic agent.

[0074] The therapeutic agent can be in at least one form selected from the group consisting of a powder, a granule, a liquid, and a semi-liquid gel.

[0075] The ingestible device can further include a mechanism for attaching the ingestible device to the wall of the subject's GI tract.

[0076] The mechanism may include an expandable hook.

[0077] The hook is retractable.

[0078] The hook can include a needle configured to pierce the wall of the GI tract.

[0079] The hook can be hollow and configured to deliver a dispensable substance to the wall of the GI tract.

[0080] The hooks may comprise a bioabsorbable material.

[0081] The ingestible device can further include an enteric coating supported by at least a portion of the housing of the ingestible device.

[0082] The ingestible device may further include an actuator.

[0083] The actuator may include a pump.

[0084] The actuator can include an osmotic pump.

[0085] The ingestible device can further include at least two different enteric coatings.

[0086] In one aspect, the present disclosure provides an ingestible device that includes a housing, an enteric coating supported by at least a portion of the housing, and a storage reservoir within the housing. The storage reservoir can be configured to store a dispensable substance.

[0087] The housing can have an opening. In a first state of the ingestible device, the enteric coating can cover the opening to completely prevent the dispensable substance from exiting the ingestible device through the opening. In a second state of the ingestible device, the enteric coating can at least partially dissolve such that the enteric coating at least partially allows the dispensable substance to exit the ingestible device through the opening.

[0088] The housing can include a first and a second portion. In the first state of the ingestible device, the enteric coating can hold the first and second portions together. In the second state of the ingestible device, the enteric coating can at least partially dissolve such that the enteric coating at least partially releases the first and second portions from one another.

[0089] In one aspect, the present disclosure provides an ingestible device that includes a housing; an actuator disposed within the housing; and a storage reservoir disposed within the housing. The storage reservoir can be configured to store a dispensable substance.

[0090] The actuator may include a pump.

[0091] The pump can include an osmotic pump and / or a peristaltic drive pump.

[0092] The ingestible device can further include a semi-permeable membrane; and a pressure chamber disposed adjacent to the semi-permeable membrane.

[0093] The ingestible device can include a first reagent chamber configured to store a first reagent; a second reagent chamber configured to store a second reagent; and a septum that both seals the first reagent chamber from the second reagent chamber.

[0094] The diaphragm can be configured to be ruptured by a first pressure generated by the pump, such that: a first reagent passes through the semipermeable membrane into the pressure chamber; a second reagent passes through the semipermeable membrane into the pressure chamber; and the first reagent interacts with the second reagent to create a second pressure.

[0095] The ingestible device can further include a piston adjacent to the pressure chamber, the piston configured to move under the influence of a second pressure.

[0096] The storage reservoir may include bellows configured to be compressed under the influence of the second pressure.

[0097] The actuator can include a separable portion; an osmotic pump disposed adjacent to the separable portion; and a dissolvable material that attaches the separable portion to the osmotic pump. The separable portion can be configured to separate from the osmotic pump when the dissolvable material dissolves.

[0098] The ingestible device can further include a suction device configured to suck a portion of the intestinal wall through the dispensing port and into the housing when a portion of the ingestible device contacts a wall of the GI tract of the subject.

[0099] The suction device can include a barb disc disposed inwardly within the reservoir.

[0100] The ingestible device can further include a first and a second enteric coating.

[0101] The actuator can include a first semipermeable membrane adjacent to the first enteric coating; a first chamber adjacent to the first semipermeable membrane for storing soluble particles; and a mesh at an outlet of the first chamber configured to prevent the soluble particles from exiting the first chamber.

[0102] The actuator can be configured to generate a suction force on the ingestible device when the first enteric coating dissolves.

[0103] The actuator can further include a second semipermeable membrane adjacent to the second enteric coating, a second chamber adjacent to the second semipermeable membrane for storing the soluble particles, and a piston between the second chamber and the storage reservoir. The actuator can be configured such that the piston moves when the second enteric coating dissolves.

[0104] In one aspect, the disclosure provides an ingestible device including a housing; a first operative component within the housing; a second operative component, both disposed within the housing; a first enteric coating attached to the first operative component; a second enteric coating attached to the second operative component; and a storage reservoir disposed within the housing. The storage reservoir can be configured to store a dispenseable substance, and the housing can have an opening in fluid communication with the storage reservoir. The first enteric coating can be configured to dissolve when exposed to luminal fluids within a first period of time, and the second enteric coating can be configured to dissolve when exposed to luminal fluids within a second period of time that is longer than the first period of time.

[0105] The actuator can include a first semipermeable membrane adjacent to the first enteric coating; a first chamber adjacent to the first semipermeable membrane for storing soluble particles; and a mesh at an outlet of the first chamber configured to prevent the soluble particles from exiting the first chamber.

[0106] The ingestible device can further include a suction device adjacent the opening. The actuator can be configured to generate a suction force on the ingestible device when the first enteric coating dissolves.

[0107] The actuator can further include a second semipermeable membrane adjacent to the second enteric coating, a second chamber adjacent to the second semipermeable membrane for storing the soluble particles, and a piston between the second chamber and the storage reservoir. The actuator can be configured such that when the second enteric coating dissolves, the piston moves toward the opening.

[0108] The ingestible device can further include an injection device having a first end adjacent the dispensing orifice and a second end coupled to the storage reservoir. The injection device can be configured to deliver the dispensable substance when the piston is urged towards the dispensing orifice.

[0109] The ingestible device can include multiple outlet valves.

[0110] The outlet valve may have a tapered sidewall.

[0111] The outlet valve may have a straight sidewall.

[0112] The ingestible device can include a number of dispensing ports configured to deliver the dispensable substance from the storage reservoir out of the housing.

[0113] The dispensing spout may have tapered side walls.

[0114] The dispensing spout can have straight side walls.

[0115] The method can include moving the displacement member with a second pressure to deliver the pre-loaded dispensable substance out of the ingestible device through the multiple dispensing orifices.

[0116] The ingestible device can include a plurality of openings configured such that when the force generator generates a force, the dispensable substance exits the ingestible device through the plurality of openings.

[0117] The housing can have a number of openings configured to allow the dispensable substance to exit the ingestible device through the multiple openings.

[0118] The ingestible device may further include one or more processing devices; and one or more machine-readable hardware storage devices storing instructions executable by the one or more processing devices to determine the location of the ingestible device within a portion of the subject's GI tract with at least 85% accuracy.

[0119] The ingestible device may further include one or more processing devices; and one or more machine-readable hardware storage devices storing instructions executable by the one or more processing devices to determine with at least 70% accuracy that the ingestible device is in the cecum of the subject.

[0120] The ingestible device may further include one or more processing devices; and one or more machine-readable hardware storage devices storing instructions executable by the one or more processing devices to transmit data to the implementable device to determine the location of the medical device within the portion of the subject's GI tract with at least 85% accuracy.

[0121] The ingestible device may further include one or more processing devices; and one or more machine-readable hardware storage devices storing instructions executable by the one or more processing devices to transmit data to an external device capable of implementing the data to determine with at least 70% accuracy that the ingestible device is in the cecum of the subject.

[0122] The ingestible device may further include first and second light sources, the first light source configured to emit light at a first wavelength and the second light source configured to emit light at a second wavelength different from the first wavelength.

[0123] The ingestible device may further include a first and a second detector, the first detector configured to detect light at a first wavelength and the second detector configured to detect light at a second wavelength.

[0124] The storage reservoir can contain a dispenseable substance.

[0125] The reservoir can be configured to fit partially inside the housing of the ingestible device.

[0126] The reservoir can be configured to fit completely inside the housing of the ingestible device.

[0127] The reservoir can include a housing, the housing comprising plastic.

[0128] The plastic may include at least one material selected from the group consisting of PVC, silicone and polycarbonate.

[0129] The reservoir can include a housing, the housing comprising a metal-based material.

[0130] The metallic material can include an alloy.

[0131] The metallic material may include stainless steel.

[0132] The reservoir can be configured to attach to a housing of the ingestible device.

[0133] The reservoir can be configured to frictionally fit with the ingestible device.

[0134] The reservoir can be configured to be secured to the ingestible device using a biasing mechanism.

[0135] The biasing mechanism may include at least one member selected from the group consisting of a spring, a latch, a hook, a magnet, and electromagnetic radiation.

[0136] The reservoir can be configured to fit into a groove or track in the housing of the ingestible device.

[0137] The reservoir can be configured to snap-fit ​​onto the ingestible device.

[0138] The reservoir can be configured to be pierced.

[0139] The reservoir can be configured to carry an electronic component.

[0140] The ingestible device can meet FDA requirements.

[0141] The reservoir can be adapted for use with the ingestible devices disclosed herein.

[0142] In one aspect, the present disclosure provides a kit that includes an ingestible device; and a reservoir configured for use within the ingestible device. The reservoir can be configured to hold a dispenseable substance.

[0143] The kit may further include a dispensable substance in the reservoir.

[0144] The reservoir can be a reservoir as disclosed herein.

[0145] In one aspect, the disclosure provides a method that includes delivering a therapeutic agent to a subject using an ingestible device disclosed herein.

[0146] The therapeutic agent can be delivered to a location within the GI tract of a subject.

[0147] In one aspect, the disclosure provides a method that includes attaching a reservoir as disclosed herein to an ingestible device.

[0148] The method can further include disposing a therapeutic agent in the reservoir prior to attaching the reservoir to the ingestible device.

[0149] The method can further include using the ingestible device to deliver the therapeutic agent to a subject after attaching the reservoir to the ingestible device.

[0150] The therapeutic agent can be delivered to a location within the GI tract of a subject.

[0151] The method can further include determining a location of the ingestible medical device within the portion of the subject's GI tract with at least 85% accuracy.

[0152] Determining the position of the ingestible device within the subject's GI tract includes determining a light signal reflected within the GI tract, the reflected signal including light of at least two different wavelengths.

[0153] The reflected signal can include light of at least three different wavelengths.

[0154] An electromechanical ingestible device for delivering a dispenseable substance according to some embodiments described herein provides an ingestible device having a housing, an electrical component, a gas generating cell, a storage reservoir, an exit valve, and a safety device. The housing is defined by a first end, a second end substantially opposite the first end, and a wall extending longitudinally from the first end to the second end. The electronic component is disposed within the housing. The gas generating cell is disposed within the housing adjacent to the electronic component, the electronic component configured to activate the gas generating cell to generate gas. The storage reservoir is disposed within the housing, the storage reservoir storing the dispenseable substance, the first end of the storage reservoir coupled to the first end of the housing. The exit valve is disposed at the first end of the housing, the exit valve configured to allow the dispenseable substance to be released from the storage reservoir out of the first end of the housing. A safety device is disposed within or attached to the housing, the safety device being configured to relieve internal pressure within the housing if the internal pressure exceeds a threshold level.

[0155] In some embodiments, the housing has polycarbonate walls that are substantially thick enough to withstand an internal explosion without rupturing.

[0156] In some embodiments, the safety device includes an oxygen absorbing material that absorbs oxygen inside the housing to avoid internal explosion.

[0157] In some embodiments, the safety device includes an inert non-conductive dielectric that separates the gas generating cell from other components within the housing.

[0158] In some embodiments, the safety device includes a relief valve disposed at a first end of the housing, the relief valve configured to open when internal pressure within the housing reaches a threshold level.

[0159] In some embodiments, the safety device includes a rupture disc disposed at a first end of the housing, the rupture disc configured to rupture when internal pressure within the housing reaches a threshold level.

[0160] In some embodiments, the housing is configured to rupture in a controlled manner when internal pressure within the housing reaches a threshold level.

[0161] In some embodiments, the gas generation cell is a hydrogen generation cell that is mounted on and sealed from the electronic components.

[0162] In some embodiments, the ingestible device has a piston adjacent to the gas-generating cell, the piston being urged to move toward the first end of the housing by pressure from the gas-generating cell.

[0163] In some embodiments, the piston is integrated with the gas generating cell in the form of a silicone seal that wraps around the gas generating cell, allowing the gas generating cell to move with the piston.

[0164] In some embodiments, the storage reservoir is in the form of a bellows configured to be compressed by pressure from the gas generating cell.

[0165] In some embodiments, the storage reservoir includes multiple chambers, each of the multiple chambers storing a different dispensable substance.

[0166] In some embodiments, the different dispensable substances are released simultaneously through the outlet valves.

[0167] In some embodiments, different dispenseable substances from each of the multiple chambers are delivered sequentially through the outlet valve.

[0168] In some embodiments, a different dispenseable substance from each of the multiple chambers is controlled by a different membrane, and the electronics control the gas generating cells to release gas that propels the membrane to deliver the respective dispenseable substance.

[0169] In some embodiments, the ingestible device includes a flexible diaphragm adjacent to the gas generating cell, the flexible diaphragm configured to deform toward the first end of the housing due to pressure from the gas generating cell.

[0170] In some embodiments, the ingestible device includes a capillary plate positioned between the gas generating cell and the first end of the housing, and a wax seal between the gas generating cell and the storage reservoir, the wax seal configured to melt and the dispensable substance is forced through the capillary plate by pressure from the gas generating cell.

[0171] In some embodiments, the capillary plate consists of concentric microchannels.

[0172] In some embodiments, the gas generating cell is wrapped in a folded foil that is configured to deform under pressure from the gas generating cell.

[0173] In some embodiments, the wall is configured to separate into two clamshell halves along a longitudinal axis, and the ingestible device further includes a diaphragm disposed within one clamshell half along the longitudinal axis and encasing the electronic components, the diaphragm configured to deflect toward the other clamshell half due to pressure from the gas generating cell.

[0174] In some embodiments, the outlet valve has an umbrella shape and the first end of the housing has a plurality of ports below the outlet valve for directing the dispenseable substance radially out of the housing.

[0175] In some embodiments, the outlet valve has a ring around the first end of the housing and has a plurality of ports evenly distributed on the ring for directing the dispenseable substance out of the housing.

[0176] In some embodiments, the outlet valve includes a dome slit extending out of the first end of the housing, and the dispensable substance is delivered through the dome slit.

[0177] In some embodiments, the outlet valve includes a hole in the first end of the housing, the hole being sealed by a wax or silicone material configured to break by internal pressure from inside the housing.

[0178] In some embodiments, the outlet valve is positioned at the center of gravity at the first end of the housing to reduce unbalanced forces and rotation of the capsule as the dispenseable substance is delivered through the outlet valve.

[0179] In some embodiments, the ingestible device further includes a light sensing unit disposed proximate the first end or the second end of the housing. The light sensing unit is configured to transmit illumination to an environment external to the housing and detect reflections from the environment caused by the illumination. The electronics are further configured to identify a location of the ingestible device based on the reflections; and to activate the gas generating cell to generate gas if the identified location matches a predefined location.

[0180] In some embodiments, the electronics are further configured to control the gas generating cell to generate an internal pressure to deliver a metered dose of the dispensable substance outside the housing based on the characteristic of the reflection.

[0181] In some embodiments, the electronic components include a variable resistor for controlling the amount of gas generated by the gas generating cell to meter a dose of the dispensable substance.

[0182] In some embodiments, the metered dose of the dispensable substance is a one-time dose or multiple doses for systematic delivery.

[0183] In some embodiments, the storage reservoir stores between 10 μL and 1500 μL of dispensable material.

[0184] In some embodiments, the housing includes a loading port for loading the dispensable substance into the storage reservoir.

[0185] In some embodiments, the dispensable substance comprises a therapeutic agent in the form of a powder, granules, liquid, or semi-liquid gel.

[0186] Some embodiments described herein provide an ingestible device including a housing, an electronic component, a gas generating cell, a storage reservoir, an injection device, and a safety device. The housing is defined by a first end, a second end substantially opposite the first end, and a wall extending longitudinally from the first end to the second end. The electronic component is disposed within the housing. The gas generating cell is disposed within the housing adjacent to the electronic component, the electronic component configured to activate the gas generating cell to generate gas. The storage reservoir is disposed within the housing, the storage reservoir storing a dispenseable substance, and a first end of the storage reservoir coupled to the first end of the housing. The injection device is disposed at the first end of the housing, the injection device configured to inject the dispenseable substance from the storage reservoir out of the housing. The safety device is disposed within the housing or attached to the housing, the safety device configured to relieve internal pressure within the housing.

[0187] In some embodiments, the dispensable substance is expelled through the injection device with a force substantially sufficient to penetrate the mucosa.

[0188] In some embodiments, the ingestible device further includes a component attached to the exterior of the housing, the component configured to position the injection device against the epithelial layer to spread the epithelial layer prior to delivery of the dispenseable substance.

[0189] In some embodiments, the injection device is a syringe coupled to or disposed within the housing and having an injection portion extending outside the housing.

[0190] In some embodiments, the injection device includes an injection port configured to penetrate the epithelial layer to inject the dispenseable substance.

[0191] Some embodiments described herein provide an ingestible device including a housing, a light sensing unit, an electronic component, a gas generating cell, a storage reservoir, a membrane, and a dispensing spout. The housing is defined by a first end, a second end substantially opposite the first end, and a wall extending longitudinally from the first end to the second end. The light sensing unit is disposed on one side of the housing, the light sensing unit configured to detect a reflection from an environment external to the housing. The electronic component is disposed within the housing. The gas generating cell is disposed within the housing adjacent to the electronic component. The electronic component is configured to activate the gas generating cell to generate gas in response to identifying a location of the ingestible device based on the reflection. The storage reservoir is disposed within the housing, the storage reservoir storing a dispenseable substance, and a first end of the storage reservoir coupled to the first end of the housing. The membrane is in contact with the gas generating cell and configured to move or deform within the storage reservoir due to pressure generated by the gas generating cell. A dispensing spout is disposed at a first end of the housing, the dispensing spout configured to deliver a dispensable substance from the storage reservoir out of the housing.

[0192] In some embodiments, the dispensing port includes an outlet valve disposed at the second end of the storage reservoir, the outlet valve configured to allow the dispenseable substance to be released from the storage reservoir out the first end of the housing.

[0193] In some embodiments, the dispensing spout has an umbrella shape and the second end of the housing has a plurality of ports below the outlet valve for directing the dispenseable substance radially out of the housing.

[0194] In some embodiments, the dispensing spout has a ring around the second end of the housing and has a number of ports evenly distributed on the ring for directing the dispenseable substance out of the housing.

[0195] In some embodiments, the dispensing port includes a dome slit extending out of the second end of the housing, and the dispensable substance is delivered through the dome slit.

[0196] In some embodiments, the dispensing port includes a hole at the second end of the housing, the hole being sealed by a wax or silicone material configured to break by a burst of internal pressure from within the housing.

[0197] In some embodiments, the dispensing port is located at the center of gravity at the second end of the housing to reduce unbalanced forces and rotation of the capsule as the dispensable substance is delivered through the dispensing port.

[0198] In some embodiments, the dispensing port includes an injection nozzle disposed at a first end of the storage reservoir and an injection port configured to inject the dispensable substance from the storage reservoir out of the housing.

[0199] In some embodiments, the dispensable substance is expelled through the dispensing port with a force substantially sufficient to penetrate the mucosa.

[0200] In some embodiments, the ingestible device further includes a component attached to the exterior of the housing, the component configured to position the dispensing spout against the epithelial layer and spread the epithelial layer prior to delivery of the dispensable substance.

[0201] In some embodiments, the dispensing port is coupled to a syringe coupled to or disposed within the housing and having an injection portion extending outside the housing, and the gas actuator is disposed within the housing and electronically controls the syringe to inject the dispenseable substance at a location contacted by the injection portion.

[0202] In some embodiments, the injection portion is configured to penetrate the epithelial layer to inject the dispenseable substance.

[0203] In some embodiments, the electronic components are configured to automatically activate the gas generating cell in response to identifying the location of the ingestible device without any trigger mechanism or pre-programmed activation conditions external to the ingestible device.

[0204] In some embodiments, the location of the ingestible device is identified based on a reflectance indicative of an optical characteristic of the location, without assessing the pH level of the external environment.

[0205] In some embodiments, the location includes either a first portion immediately behind the pyloric sphincter or a second portion immediately before the ileocecal valve. Effect of the Invention

[0206] It should be understood that all combinations of the above concepts and additional concepts described in more detail below (provided that such concepts are not mutually inconsistent) are contemplated as part of the inventive subject matter disclosed herein. In particular, all combinations of claimed subject matter appearing at the end of this disclosure are contemplated as part of the inventive subject matter disclosed herein. It should also be understood that the terms explicitly employed herein, which may also appear within any disclosure incorporated by reference, should be accorded the meaning most consistent with the specific concepts disclosed herein.

[0207] The drawings are primarily for illustrative purposes and are not intended to limit the scope of the inventive subject matter disclosed herein. The drawings are not necessarily drawn to scale, and in some cases, various aspects of the inventive subject matter disclosed herein may be shown exaggerated or enlarged in the drawings to facilitate understanding of different features. In the drawings, similar reference characters generally refer to similar features (e.g., functionally similar and / or structurally similar elements). [Brief description of the drawings]

[0208] [Figure 1] 1 provides example mock-up diagrams illustrating aspects of the structure of an ingestible device 100 for delivering a dispensable substance according to certain embodiments described herein. [Diagram 2] 1 provides example diagrams illustrating aspects of a mechanism for a gas generation cell configured to generate gas for dispensing a substance according to certain embodiments described herein. [Diagram 3] 1 provides example structural diagrams illustrating aspects of an ingestible device 100 having a piston for pushing to deliver a dispensable substance according to certain embodiments described herein. [Figure 4] According to some embodiments described herein, example structural diagrams are provided illustrating aspects of an umbrella-shaped outlet valve design as a dispensing spout of an ingestible device. [Diagram 5] According to some embodiments described herein, example structural diagrams are provided illustrating aspects of a ring-shaped outlet valve structure as a dispensing port of an ingestible device. [Figure 6] 10A-10C provide example structural diagrams illustrating aspects of a dome slit as a dispensing port of an ingestible device, according to some embodiments described herein. [Figure 7] According to some embodiments described herein, example structural diagrams are provided illustrating the aspect of a hole located at one end of a housing as a dispensing port for an ingestible device. [Figure 8]1A-1C provide example structural diagrams illustrating aspects of an ingestible device 100 having a bellows structure for a storage reservoir of a dispensable substance according to certain embodiments described herein. [Figure 9] 1A-1C provide example structural diagrams illustrating aspects of ingestible devices having flexible septa that deform for delivery of a dispensable substance according to certain embodiments described herein. [Figure 10] According to some embodiments described herein, example structural diagrams are provided illustrating aspects of ingestible devices having an integrated piston and gas-generating cell, such that the gas-generating cell is movable with the piston for pushing to deliver a dispenseable substance. [Figure 11] 1A-1C provide example structural diagrams illustrating aspects of ingestible devices having capillaries to direct a dispenseable substance out of a storage reservoir, according to certain embodiments described herein. [Figure 12] 10A-10C provide example structural diagrams illustrating aspects of an ingestible device having a clamshell-shaped housing and a laterally split diaphragm that deforms for dispensable substance delivery in accordance with certain embodiments described herein. [Figure 13] 1A-1C provide example structural diagrams illustrating aspects of ingestible devices having elastomeric bladders according to some embodiments described herein. [Figure 14] FIG. 1 provides example structural diagrams illustrating aspects of an ingestible device that uses an elastomeric bladder to provide pressure to deliver a dispenseable substance according to some embodiments described herein. [Figure 15] 1A and 1B provide example structural diagrams illustrating aspects of an ingestible device having a gear motor for dispensing a dispensable substance from a storage reservoir, according to certain embodiments described herein. [Figure 16] 1A and 1B provide example structural diagrams illustrating aspects of an ingestible device that uses an auger to dispense a dispensable substance from a storage reservoir, according to certain embodiments described herein. [Figure 17]10A-10D provide example structural diagrams illustrating aspects of ingestible devices that use wipers to dispense a dispensable substance out of a storage reservoir, according to certain embodiments described herein. [Figure 18] FIG. 17 provides an example structural diagram illustrating an embodiment of an ingestible device that uses a piston to drive a wiper according to some embodiments described herein. [Figure 19] 1A-1C provide example structural diagrams illustrating aspects of ingestible devices that use osmotic pressure to dispense a dispensable substance according to certain embodiments described herein. [Figure 20] 1A-1C provide example structural diagrams illustrating aspects of ingestible devices that employ diffusion of a dispenseable substance through luminal fluid, according to certain embodiments described herein. [Figure 21] 1A and 1B provide example structural diagrams illustrating aspects of ingestible devices having splittable housings according to some embodiments described herein. [Figure 22] 10A-10C provide example structural diagrams illustrating aspects of an anchoring mechanism of an ingestible device for anchoring the ingestible device to the intestine for dispensable substance delivery, according to certain embodiments described herein. [Figure 23] 10A-10C provide example structural diagrams illustrating aspects of an anchoring mechanism of an ingestible device for anchoring the ingestible device to the intestine for dispensable substance delivery, according to certain embodiments described herein. [Figure 24] 10A-10C provide example structural diagrams illustrating aspects of an anchoring mechanism of an ingestible device for anchoring the ingestible device to the intestine for dispensable substance delivery, according to certain embodiments described herein. [Diagram 25] 1 provides example structural diagrams illustrating aspects of an intestinal gripper of an ingestible device for gripping a portion of the intestinal wall for delivery of a dispenseable substance according to certain embodiments described herein. [Figure 26] 1 provides example structural diagrams illustrating aspects of an intestinal gripper of an ingestible device for gripping a portion of the intestinal wall for delivery of a dispenseable substance according to certain embodiments described herein. [Figure 27]According to some embodiments described herein, example structural diagrams are provided illustrating aspects of an expandable stent of an ingestible device for lodgement at a specific location within the GI tract for dispensing. [Figure 28] According to some embodiments described herein, example structural diagrams are provided illustrating aspects of an expandable stent of an ingestible device for lodgement at a specific location within the GI tract for dispensing. [Figure 29] According to some embodiments described herein, example structural diagrams are provided illustrating aspects of an expandable stent of an ingestible device for lodgement at a specific location within the GI tract for dispensing. [Diagram 30] According to some embodiments described herein, example structural diagrams are provided illustrating aspects of an expandable stent of an ingestible device for lodgement at a specific location within the GI tract for dispensing. [Diagram 31] 1A and 1B provide example structural diagrams illustrating aspects of ingestible devices having jet delivery mechanisms according to certain embodiments described herein. [Diagram 32] According to some embodiments described herein, alternative example configurations are provided for ingestible devices having jet delivery mechanisms with improved available amounts of dispenseable substances. [Diagram 33] 1 provides example structural diagrams for a jet delivery mechanism with multiple nozzles according to some embodiments described herein. [Diagram 34] According to some embodiments described herein, alternative example structural diagrams are provided for jet delivery mechanisms with chemical actuation. [Diagram 35] 1 provides example structural diagrams illustrating direct injection of a dispenseable substance with a needle by an ingestible device according to certain embodiments described herein. [Diagram 36] 10A-10C provide alternative example structural diagrams illustrating non-axial configurations of an infusion needle for delivery in accordance with certain embodiments described herein. [Figure 37]1 provides example structural diagrams illustrating off-axis configurations of an infusion needle driven by an osmotic cell according to certain embodiments described herein. [Figure 38] 1 provides example structural diagrams illustrating the use of osmotic pressure to adhere a suction device of an ingestible device to the intestinal wall, according to some embodiments described herein. [Figure 39] According to some embodiments described herein, an example structural diagram is provided illustrating an ingestible device employing an osmotic mechanism and a suction device as illustrated in FIG. [Diagram 40] According to certain embodiments described herein, an example structural diagram is provided illustrating aspects of tumbling suction by the ingestible device described in FIG. 39 . [Diagram 41] 1 provides example structural diagrams illustrating ingestible devices employing a combination of tumbling aspiration and needle injection, according to some embodiments described herein. [Diagram 42] 1 provides example structural diagrams illustrating ingestible devices employing a combination of tumbling aspiration and needle injection, according to some embodiments described herein. [Diagram 43] 1 provides example structural diagrams illustrating ingestible devices employing a combination of tumbling aspiration and needle injection, according to some embodiments described herein. [Diagram 44] According to some embodiments described herein, example structural diagrams are provided illustrating aspects of electronic components including a printed circuit board (PCB) within the housing of an ingestible device. [Diagram 45] According to some embodiments described herein, an ingestible device is illustrated that includes a pre-pressurized actuator chamber and a sliding piston. [Figure 46A] 1 illustrates a portion of an ingestible device that includes a burst disk along a nozzle portion according to some embodiments described herein. [Figure 46B] 1 illustrates a partial cross-sectional view of a burst disc holder according to certain embodiments described herein. [Figure 47]1 illustrates a portion of an ingestible device that includes an enteric coated closure component, according to some embodiments described herein. [Figure 48] 1 illustrates a layer stack of an enteric coating for an ingestible device according to some embodiments described herein. [Figure 49] According to some embodiments described herein, an ingestible device is illustrated that includes a magnetic closure component, a burst disk, and a pre-pressurized actuator chamber. [Figure 50] According to some embodiments described herein, an ingestible device is illustrated that includes a magnetic closure component and a pre-pressurized actuator chamber. [Figure 51] According to some embodiments described herein, an ingestible device is illustrated that includes an intestinal sliding closure component and a pre-pressurized actuator chamber and sliding piston. [Figure 52] According to some embodiments described herein, an ingestible device is illustrated that includes a dissolvable pin closure component and a pre-pressurized chamber and a sliding piston. [Figure 53] According to some embodiments described herein, an ingestible device is illustrated that includes a wax plug with a wire lead activator. [Figure 54] According to some embodiments described herein, an ingestible device is illustrated that includes a pre-pressurized chamber and a bellows. [Figure 55] According to some embodiments described herein, an ingestible device is illustrated that includes a spring-loaded actuator and a sliding piston. [Figure 56] 1 illustrates an ingestible device that includes a spring-activated slidable housing portion, according to some embodiments described herein. [Figure 57] 1 illustrates an ingestible device with an alternative spring-activated slidable housing portion, according to some embodiments described herein. [Figure 58]According to some embodiments described herein, an ingestible device is illustrated that includes a dissolve-away closure component and a pressurized chamber. [Figure 59] According to some embodiments described herein, an ingestible device is illustrated that includes a dissolvable pin closure component and a spring-activated sliding piston. [Figure 60] According to some embodiments described herein, an ingestible device is illustrated that includes a shuttle slider closure component and a pressurized chamber. [Figure 61] According to some embodiments described herein, an ingestible device is illustrated that includes a hydrogen cell actuator and a burst disk closure component. [Figure 62] 1 illustrates another ingestible device that includes a hydrogen cell actuator and a burst disk closure component, according to some embodiments described herein. [Figure 63] According to some embodiments described herein, an ingestible device is illustrated that includes a vacuum actuator chamber and an enteric coated closure component. [Figure 64] 1 illustrates an ingestible device that includes an attachable reservoir, according to some embodiments described herein. [Figure 65] 1A-1D are diagrams of example embodiments of ingestible devices, according to some embodiments of the present disclosure. [Figure 66] FIG. 66 is an exploded view of the ingestible device of FIG. 65 according to some embodiments of the present disclosure. [Figure 67] 1 is a schematic diagram of an ingestible device during an example transition through the GI tract, according to some embodiments of the present disclosure. [Figure 68] 1 is a schematic diagram of an ingestible device during an example transition through the jejunum, according to some embodiments of the present disclosure. [Figure 69] 1 is a flow diagram of exemplary steps for determining the position of an ingestible device as it passes through the GI tract, according to some embodiments of the present disclosure. [Figure 70]1 is a flow diagram of exemplary steps for detecting transitions from the stomach to the duodenum and from the duodenum back to the stomach, according to some embodiments of the present disclosure, which may be used to determine the position of an ingestible device as it passes through the GI tract. [Figure 71] 1 is a plot illustrating data collected during an example operation of an ingestible device that may be used to determine the position of the ingestible device as it passes through the GI tract, according to some embodiments of the present disclosure. [Figure 72] 11 is another plot illustrating data collected during an example operation of an ingestible device that may be used to determine the position of the ingestible device as it passes through the GI tract, according to some embodiments of the present disclosure. [Figure 73] FIG. 1 is a flow diagram of exemplary steps for detecting the duodenum-to-jejunum transition that may be used in determining the position of an ingestible device as it passes through the GI tract, according to some embodiments of the present disclosure. [Figure 74] 11A-11C are plots illustrating data collected during an example operation of an ingestible device that may be used in detecting a duodenum-to-jejunum transition, according to some embodiments of the present disclosure. [Figure 75] 1 is a plot illustrating muscle contractions detected by an ingestible device over time that may be used to determine the position of the ingestible device as it passes through the GI tract, according to some embodiments of the present disclosure. [Figure 76] FIG. 1 is a flow diagram of example steps for detecting the jejunum-to-ileum transition that may be used in determining the position of an ingestible device as it passes through the GI tract, according to some embodiments of the present disclosure. [Figure 77] FIG. 1 is a flow diagram of example steps for detecting the jejunum-to-ileum transition that may be used in determining the position of an ingestible device as it passes through the GI tract, according to some embodiments of the present disclosure. [Figure 78]FIG. 1 is a flow diagram of example steps for detecting the ileum to cecum transition that may be used in determining the position of an ingestible device as it passes through the GI tract, according to some embodiments of the present disclosure. [Figure 79] FIG. 1 is a flow diagram of example steps for detecting the cecum-to-colon transition that may be used in determining the position of an ingestible device as it passes through the GI tract, according to some embodiments of the present disclosure. [Figure 80] Illustrated is a tapered silicone bellows. [Figure 81] 1 illustrates a tapered silicone bellows in a simulated device jig. [Figure 82] A smooth PVC bellows is shown. [Figure 83] 1 illustrates a smooth PVC bellows in a simulated apparatus jig. [Figure 84] 1 illustrates the principle of the competitive assay carried out in the experiments. [Figure 85] AlphaLISA data is shown. [Figure 86] AlphaLISA data is shown. [Figure 87] AlphaLISA data is shown. [Figure 88] The test method is illustrated. [Figure 89] Illustrate the assay principle. [Figure 90] 1 illustrates an ingestible device. [Figure 91] 1 illustrates a wax valve system. [Figure 92A] 1 illustrates the wax valve system in a closed position. [Fig. 92B] 1 illustrates the wax valve system in an open position. [Figure 93] 1 illustrates an ingestible device with two outlets for dispensing. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0209] Below are more detailed descriptions of various concepts related to ingestible devices capable of delivering a dispenseable substance, such as, for example, a therapeutic agent, and exemplary embodiments of the ingestible devices, as well as related components, systems, and methods. Below are also more detailed descriptions of various concepts related to adherent storage reservoirs configured for use with ingestible devices and capable of storing a dispenseable substance, such as, for example, a therapeutic agent, and exemplary embodiments of the adherent storage reservoirs, as well as related components, systems, and methods.

[0210] Various systems, devices, and methods are described herein to provide examples of at least one embodiment for the subject matter described herein. No embodiment limits any of the subject matter described herein, and any claimed subject matter may cover systems, devices, and methods different from those described herein. It is possible that the claimed subject matter is not limited to systems, devices, and methods having all of the features of any one of the systems, devices, and methods described herein, or features common to more than one or all of the features of the systems, devices, and methods described herein. It is possible that a system, device, or method described herein is not an embodiment of any claimed subject matter. Any subject matter disclosed in the systems, devices, and methods described herein that is not claimed in this document may be the subject matter of another protected document, e.g., a continuing patent application, and the applicant, inventor, or owner does not intend to relinquish, relinquish claims, or disclose any such subject matter by its disclosure in this document.

[0211] It will be understood that for simplicity and clarity of the figures, where considered appropriate, reference numerals may be repeated among the figures to indicate corresponding or similar elements. Additionally, numerous specific details are described to provide a thorough understanding of the embodiments described herein. However, it will be understood by those skilled in the art that the embodiments described herein may be practiced without these specific details. In other instances, well-known methods, procedures and components have not been described in detail so as not to obscure the embodiments described herein. Additionally, the description should not be construed to limit the scope of the embodiments described herein.

[0212] It should be noted that terms of degree, such as "substantially," "about," and "approximately," as used herein, refer to a reasonable amount of deviation from the modified term so as not to materially alter the results. These terms of degree should be construed to include deviations from the modified term if such deviations do not negate the meaning of the term they modify.

[0213] Additionally, as used herein, the phrase "and / or" is intended to represent an inclusive OR. That is, "X and / or Y" is intended to mean, for example, X or Y or both. As a further example, "X, Y, and / or Z" is intended to mean X or Y or Z or any combination thereof.

[0214] As used herein, the term "coupled" indicates that two elements may be directly connected to one another or may be connected to one another through one or more intermediate elements.

[0215] As used herein, the term "body" refers to the body of a patient, subject, or individual receiving an ingestible device. A patient or subject is generally a human or other animal.

[0216] As used herein, the term "gastrointestinal tract" or "GI tract" refers to all parts of the organ system responsible for the consumption and digestion of food, the absorption of nutrients, and the elimination of waste products, including openings and organs such as the mouth, pharynx, esophagus, stomach, small intestine, large intestine, rectum, anus, and the like, as well as the various passageways and sphincters connecting the aforementioned sites.

[0217] As used herein, the term "reflected" refers to a value derived from light emitted by a device, reflected back to the device, and received by a detector within or on the device. For example, in some embodiments, this refers to light emitted by a device, some of the light is reflected by a surface external to the device, and the light is received by a detector located within or on the device.

[0218] As used herein, the term "illumination" refers to any electromagnetic radiation. In some embodiments, illumination may be within the infrared (IR), visible spectrum, and ultraviolet (UV) ranges, and illumination may have the majority of its output centered at a particular wavelength within the range of 100 nm to 1000 nm. In some embodiments, it may be advantageous to use illumination that has the majority of its output limited to one of the infrared (750 nm to 1000 nm), red (620 nm to 750 nm), green (495 nm to 570 nm), blue (450 nm to 495 nm), or ultraviolet (100 nm to 400 nm) spectrums. In some embodiments, multiple illuminations with different wavelengths may be used.

[0219] Various embodiments described herein generally relate to ingestible devices configured to reach a specific location in the gastrointestinal (GI) tract by oral consumption and, in some embodiments, release a substance, including drugs and therapeutics, at that specific location. In another embodiment, the ingestible device may be used to release a substance, including drugs and therapeutics, within other parts of the body, such as, but not limited to, the female reproductive tract, and / or the like. In some embodiments, release of the dispensable substance may take a form similar to a bolus dose or a burst of dispensing. In some embodiments, release of the substance may take a form similar to systemic delivery of a therapeutic. The ingestible device may include a release structure that aids in the delivery of the substance to an interior surface of the GI tract, such as, for example, on or through penetration of the mucosal layer.

[0220] 1 provides a mock-up example diagram illustrating aspects of the structure of an ingestible device 100 for delivering a dispensable substance according to some embodiments described herein. In some embodiments, the ingestible device 100 may be generally in the form of a capsule, pill, or any swallowable form that may be orally consumed by an individual. As such, the ingestible device 100 may be ingested by a patient or prescribed by a medical professional and the patient.

[0221] Ingestible device 100 includes a housing 101, which may take a shape similar to a capsule, pill, and / or the like, which may include two ends 102a-b. Housing 101 may be designed to withstand the chemical and mechanical environment of the GI tract (e.g., the forces of muscle contraction and the action of concentrated hydrochloric acid in the stomach). A wide range of materials may be used for housing 101. Examples of these materials include, but are not limited to, thermoplastics, fluoropolymers, elastomers, stainless steel, and glass that meet ISO 10993 and USP Class VI specifications for biocompatibility; as well as any other suitable materials and combinations thereof. In certain embodiments, these materials may further include liquid silicone rubber materials with hardness levels of 10-90 measured using a durometer (e.g., MED-4942™ manufactured by NuSil™), soft biocompatible polymeric materials such as, but not limited to, polyvinyl chloride (PVC), polyethersulfone (PES), polyethylene (PE), polyurethane (PU) or polytetrafluoroethylene (PTFE), and hard polymeric materials coated with soft or pliable biocompatible materials (e.g., poly(methyl methacrylate) (PMMA) materials coated with silicone polymers). Using different materials for different components may allow for the functionalization of certain surfaces for interaction with proteins, antibodies, and other biomarkers. For example, Teflon® may be used as a material in ingestible device 10 for moving components to reduce friction between these components. Other example materials may include other materials commonly used in microfabrication, such as, for example, polydimethylsiloxane (PDMS), borosilicate glass, and / or silicone. Although certain materials may be mentioned herein as being used to construct the device for illustrative purposes, the materials listed are not intended to be limiting, and one of ordinary skill in the art may readily adapt the device to use any number of different materials without affecting the overall operation or functionality of the device.

[0222] In some embodiments, the housing 101 of the ingestible device 100 may be manufactured from a type of plastic, such as a photosensitive acrylic polymer material or an inert polycarbonate material. The housing 101 may also be formed using a material that can be sterilized by a chemical. In some implementations, the walls of the housing 101 may have a thickness of 0.5 mm to 1 mm, which is sufficient to withstand an internal explosion (e.g., caused by a hydrogen ignition or excess pressure inside the housing).

[0223] The housing 101 may or may not have a pH-sensitive enteric coating to detect or otherwise be sensitive to the pH level of the environment external to the ingestible device. In some specific portions of the GI tract, such as but not limited to the portion immediately after passing the pyloric sphincter or the portion immediately before the ileocecal valve, it may be difficult to target a specific location based on pH level alone. Instead of relying on pH level, the ingestible device 100 includes a light sensing unit that transmits illumination to the environment and collects reflections, based on which a region-specific location of the ingestible device may be identified based on optical properties of the reflections. For example, the ingestible device may deliver a therapeutic agent to a specific location within the GI tract that has trauma, such as an injury. The specific location may be predetermined through a previously performed endoscopy. Further discussion regarding determining the location of the ingestible device may be found in connection with FIG. 44.

[0224] Housing 101 can be formed by joining two enclosure parts together. For example, the two enclosure parts can be mated and fused together with an adhesive, such as a cyanoacrylate variant. Housing 101 actually protects the interior of ingestible device 100 from the outside environment and protects the outside environment (e.g., the gastrointestinal tract) from the internal components of ingestible device 100.

[0225] Ingestible device 100 may include electronic components within housing 100. The electronic components may be located proximate end 102b of the housing and may include a printed circuit board (PCB), a battery, a light-sensing unit, and / or the like. Further example structures of the electronic components may be illustrated in FIG.

[0226] Ingestible device 100 further includes a gas generation cell 103 configured to generate gas, thus creating an internal pressure within housing 101. In one embodiment, gas generation cell 103 may be a hydrogen generation cell, such as, but not limited to, a Varta® hydrogen gas generation cell. In alternative embodiments, one or more other gas generation cells that generate inert gases that are harmless to humans may be used.

[0227] In some embodiments, the gas-generating cell may include or be coupled to a separate channel or valve of the ingestible device, such that gas may be released through the channel or valve to create movement to alter the position of the ingestible device within the GI tract. Such gas release may be used to position the ingestible device against the intestinal lining. In another embodiment, gas may be released through a separate channel or valve to alter the surface orientation of the intestinal tissue prior to delivery of the dispensable substance.

[0228] The movable plunger 104 may be disposed above the gas generating cell 103 inside the housing 101. The movable plunger 104 is a membrane that separates the gas generating cell 103 from a storage reservoir that stores the dispensable substance 105. In some embodiments, the movable plunger 104 may be a movable piston, as further illustrated in FIGS. 3-4. In some embodiments, the movable plunger 104 may instead be a flexible membrane, such as but not limited to a diaphragm, as further illustrated in FIG. 10. In some embodiments, the movable plunger 104, which may have the form of a flexible diaphragm, may be disposed along the axial direction of the housing 101 instead of being disposed above the gas generating cell 103, as further illustrated in FIG. 44. The movable plunger or membrane 104 may move (if the membrane 104 is a piston) or deform (if the membrane 104 is a diaphragm) toward the end 102a of the housing when the gas generating cell 103 generates gas, creating an internal pressure that pushes against the membrane 104. In this manner, the membrane or movable plunger 104 may push the dispensable substance 105 out of the housing and through the dispensing port 107 .

[0229] The housing 101 may include a storage reservoir that stores one or more dispensable substances 105 adjacent to the movable plunger 104. The dispensable substance 105 may be a therapeutic agent or drug that may take the form of a powder, compressed powder, fluid, semi-liquid gel, or any other dispensable or deliverable form. Delivery of the dispensable substance 105 may take the form of, such as, but not limited to, bolus, semi-bolus, continuous, systemic, burst therapeutic delivery, and / or the like.

[0230] In some implementations, the storage reservoir may include multiple chambers, each chamber storing a different dispensable substance. For example, the different dispensable substances may be released simultaneously from the dispensing port 107. Alternatively, the multiple chambers may take the form of different layers within the storage reservoir, such that the different dispensable substances from each chamber are delivered sequentially in sequence. In one example, each of the multiple chambers is controlled by a separate movable plunger, which may be propelled by a gas generator. The electronics may control the gas generating cell 103 to generate gas to propel a particular movable plunger, such as by a separate gas generating chamber, to deliver the respective substance. In some embodiments, the contents of the multiple chambers may be mixed or combined prior to release, for example, to activate a therapeutic agent.

[0231] Ingestible device 100 may include a dispensing port 107 at one end 102a of housing 101 for directing dispensable substance 105 out of the housing. Dispensing port 107 may include an outlet valve (as further illustrated in FIGS. 5-6), a slit or hole (as further illustrated in FIGS. 7-8), a jet injection nozzle with a syringe, and / or the like. As moveable plunger 104 moves towards end 102a of housing 101, internal pressure within the storage reservoir may increase, forcing the dispensing port open and releasing dispensable substance 105 from housing 101.

[0232] Use of a hydrogen generation cell within the ingestible device 100 may pose various safety risks that can be mitigated by proper device design. For example, hydrogen ignition / heating inside or outside the ingestible device 100, excessive pressure inside the housing 101, and hydrogen toxicity may damage the use of the ingestible device. To mitigate safety risks, safety devices such as pressure relief device 106 may be placed within or attached to the housing 101.

[0233] In some embodiments, hydrogen ignition inside the ingestible device can occur when air (containing oxygen) is present inside the ingestible device 100. For example, hydrogen requires very little energy to begin to burn, with a minimum energy for ignition in air of just 0.017 mJ, for example. If silver oxide batteries (see, for example, 131 in FIG. 3) are used within the ingestible device 100, the possibility of sparking (albeit remote) cannot be eliminated and may occur due to induced charging and introduced air gaps, or other scenarios.

[0234] For example, the pressure P1 inside the ingestible device 100 can be estimated to be about P1=1479 kPa or 215 psi based on a worst-case scenario analysis of a hydrogen-air mixture. Since the hydrogen concentration inside the ingestible device 100 is likely to increase with respect to time, it can be assumed that the sufficient concentration of hydrogen is between the lower explosive limit (LEL) and upper explosive limit (UEL) of 4% and 75%, respectively. Thus, assuming that the initial pressure inside the ingestible device may exceed 101.3 kPa due to the addition of hydrogen, the final pressure may be much higher. If we assume that the housing 101 breaks at this maximum pressure, the amount of energy E released is:

number

[0235] To mitigate hydrogen ignition, in one embodiment, the housing 101 may be made of 1.6 mm wall thickness polycarbonate, which can withstand a pressure of 410 psi and therefore can withstand the effects of an internal explosion without breaking.

[0236] In one embodiment, the inner walls of the housing 101 may be made of an oxygen absorbing material (or include a layer made of an oxygen absorbing material) to reduce the concentration of oxygen (e.g., below 2%) to avoid internal explosion.

[0237] In one embodiment, an inert non-conductive liquid dielectric (such as silicone oil, food grade castor oil, wax, and / or the like) may be applied to contain the electronic connections inside the ingestible device 100 to isolate any potential ignition from the hydrogen inside the ingestible device 100. For example, isolation may also reduce the risk of hydrogen ignition outside the ingestible device, which could result in damage to the small intestine if, for example, hydrogen generated from the gas generating cell 103 mixed with an appropriate amount of air (oxygen) contained within bubbles travels along the GI tract.

[0238] In one scenario, overpressurization may occur inside ingestible device 100 if, for example, dispensing port 107 becomes blocked or is otherwise blocked from the release of hydrogen. In this case, housing 101 may break if the hydrogen gas reaches a threshold level of pressure. For example, if an ingestible device has a volume of 500 μL (the volume hydrogen may couple) and the released hydrogen may be 40 mL, the internal pressure created by the hydrogen may be:

number

number

[0239] In one embodiment, the housing 101 can be designed to collapse or break in a controlled manner, thus relieving internal pressure. For example, if the internal pressure inside the chamber filled with gas from the gas generating cell 103 exceeds a threshold level, the walls surrounding the chamber can be designed to collapse or break to relieve the pressure.

[0240] In one embodiment, pressure relief device 106 may be disposed within housing 101, such as at end 102a of housing 101. For example, pressure relief device 106 may be a pressure relief rupture disc configured to release the contents within housing 101. Thus, when dispensing port 107 becomes clogged or blocked and pressure within the storage reservoir exceeds a threshold level, pressure relief device 106 may rupture to release the dispenseable substance outward. An advantage of pressure relief device 106 is that it may also act, in part, to prevent upstream contamination of the dispenseable substance, since internal pressure is relieved by directing the dispenseable substance out of the housing such that gas does not leak into the storage reservoir.

[0241] In some embodiments, the housing 101 may include small holes (e.g., with a diameter smaller than 2 mm), for example on the side or at end 102a of the housing 101, to facilitate loading the dispenseable substance into the storage reservoir. The holes, if three or more, may be positioned axially or radially on the housing 101. The holes may then be sealed with a UV-curable cyanoacrylate.

[0242] In some implementations, a feedback control circuit (e.g., a feedback resistor, etc.) may be added to send feedback from the gas generating cell 103 to the electronic components so that when the internal pressure reaches a threshold level, the electronic components may control the gas generating cell 103 to stop gas generation or activate other safety mechanisms (e.g., a feedback controlled release valve, etc.). For example, an internal pressure sensor may be used to measure the internal pressure inside the ingestible device and generate feedback to the feedback control circuit.

[0243] FIG. 2 provides an example schematic illustrating aspects of a mechanism for a gas generating cell 103 configured to generate gas to dispense a substance, according to some embodiments described herein. As shown in FIG. 2, the gas generating cell 103 generates gas 111, which can push the dispensable substance 105 out of the dispensing port 107. A variable resistor 108 can be connected in a circuit with the gas generating cell 103, such that the variable resistor 108 can be used to control the intensity and / or amount of gas 111 (e.g., hydrogen) generated by the cell 103. Specifically, the gas generating cell 103 can be a battery form factor cell capable of generating hydrogen when a resistance is applied. In this manner, since the gas generating cell 103 only requires the use of resistance alone, without any active power requirements, the gas generating cell 103 can be incorporated into an ingestible device, such as a capsule, with limited available energy / power. For example, the gas generating cell 103 can be compatible with a capsule sized 26 mm×13 mm or smaller.

[0244] In some embodiments, it may take time to generate enough gas 111 to deliver the substance 105 based on the rate of elution of gas from the cell and the internal volume of the ingestible device, and the time required may be 30 seconds or more. For example, the time to generate a volume of hydrogen equivalent to 500 μL of fluid would be approximately 5 minutes. A longer period may be required based on non-ideal conditions inside the ingestible device, such as friction. Thus, given that gas (e.g., hydrogen) generation may take time, gas generation may need to begin before the ingestible device reaches the delivery site in order to increase the pressure inside the ingestible device. The ingestible device may then need to know when it is approaching the delivery site. For example, the device may begin gas generation at the "entry transition," which is determined by temperature, to generate enough gas to approach a high enough pressure to deliver the dispenseable substance. The ingestible device may then only begin gas generation again when it reaches the delivery site, which causes the internal pressure inside the ingestible device to reach the required level at the dispensing port to release the dispenseable substance. Additionally, for region-specific delivery, the ingestible device may estimate the time it will take to build up sufficient pressure to deliver the dispenseable substance before the ingestible device reaches a specific location to activate gas generation.

[0245] For example, for systemic delivery, with an internal volume of the ingestible device of approximately 500 μL and a gas generation time of 2 hours, an initial pressure of approximately 300 pounds per square inch absolute (psia) may be generated, with higher or lower pressures being possible. The generated pressure may decrease as air enters the storage reservoir, which was previously loaded with the dispensable substance during the dispensing process. For systemic delivery of the dispensable substance, for example, to penetrate a mucosal or epithelial layer, a force of approximately 100-360 pounds per square inch (psi) of generated pressure may be required for skin penetration. Pressure may also vary depending on the nozzle design at the dispensing port, fluid viscosity, and the proximity and properties of the surrounding tissue.

[0246] The gas 111 that can be generated for continuous delivery of a dispensable substance (e.g., 1 cc of H2 for 4 hours, 16 breaths / min with a tidal volume of 0.5 L) can be the same as 1 cc of hydrogen in approximately 2000 L of exhaled air, or approximately 0.5 ppm of H2, which is below physiological values ​​for exhaled hydrogen. Reducing this time to 10 minutes equates to approximately 13 ppm of hydrogen. Thus, due to the length of intestine that can be covered during this period, the ingestible device can have a higher local value than physiological.

[0247] 3 provides an example structural diagram illustrating aspects of an ingestible device 100 having a piston for pushing for dispensable substance delivery according to some embodiments described herein. The ingestible device 100 may have one or more batteries 131 disposed at one end 102a of the housing 101 to provide power to the ingestible device 100. A PCB 132 may be disposed adjacent to the battery 131, and the gas generating cell 103 may be fixed on the PCB 132. The gas generating cell 103 may be sealed from a lower chamber of the ingestible device 100 (e.g., the space including 131 and 132). A movable piston 134 may be disposed adjacent to the gas generating cell 103. In this manner, gas generation from gas generating cell 103 may urge piston 134 to move toward the other end 102b of housing 101 such that the dispensable substance in storage reservoir 135 may be forced out of the housing through dispensing port 107, for example, as shown at 136 in the position where piston 134 has dispensed the substance. Storage reservoir 135 may have a volume of approximately 600 μL, or even more, of dispensable substance, which may be dispensed at one time or over a period of time.

[0248] The battery cells 131 may each have a height of 1.65 mm, and one to three batteries may be used. The height of the piston may be reduced with custom molding to about 1.5 mm to save space. If the gas generating cells 103 are integrated with the piston 134 (e.g., as further illustrated in FIG. 10), the overall length of the PCB, battery, and gas generating cells combined may be reduced to about 5 mm, thus providing more space for dispensable substance storage. For example, for an ingestible device having a length of 7.8 mm (e.g., from end 102a to the other end 102b), a storage reservoir 134 of about 600 μL may be used for delivery of the dispenseable substance. As another example, for an ingestible device having a length of 17.5 mm, a storage reservoir 134 of about 1300 μL may be used for delivery of the dispenseable substance.

[0249] FIG. 4 provides an example structural diagram illustrating aspects of an umbrella-shaped outlet valve structure as a dispensing port of an ingestible device according to some embodiments described herein. The outlet valve may be disposed at one end 102b of the housing of the ingestible device (e.g., 100 in FIG. 3). The outlet valve may include an umbrella-shaped lid 141 disposed at the top of one end 102b of the housing, below which the end 102b of the housing may include holes 142 evenly distributed radially around the center of the circular end 102b. As the dispenseable substance is forced out of the interior of the housing through the holes 142, the umbrella-shaped valve 141 may be lifted due to pressure to direct the dispenseable substance out of the holes 142 radially through notches 143 radially distributed on the edge of the circular end 102b of the housing. The umbrella-shaped valve 141, covering the delivery holes 142, may also serve to keep the dispensing port hole 142 insulated from contaminants outside the ingestible device 100. The notches 143 and holes 142 may be evenly distributed radially around the central axis of gravity based on the geometric shape of the ingestible device (e.g., cylindrical) to reduce or avoid rotation or tilting of the ingestible device under the moving force of the dispenseable substance.

[0250] 5 provides an example structural diagram illustrating aspects of a ring-shaped outlet valve structure as a dispensing port of an ingestible device, according to some embodiments described herein. The housing 101 of the ingestible device may include a ring-shaped valve 151 at a circumferential location of the housing 101, proximal to the end 102b of the housing 101. The ring-shaped valve 151 may have ports 157 evenly and radially distributed around the circumference of the ring to direct the dispenseable substance out of the housing 101. The ring-shaped valve 151 may also be designed to prevent blockage from contaminants outside the ingestible device 100. The ring-shaped valve 151 may optionally have several evenly distributed slits 153 for even distribution of the dispenseable substance to maintain balance of the ingestible device.

[0251] 6 provides an example structural diagram illustrating the aspect of a dome slit as a dispensing port of an ingestible device according to some embodiments described herein. The storage reservoir of the ingestible device may include a bellows 161 (further illustrated in FIG. 8), one end of which may include a dome slit 162 that extends out from end 102b of housing 101. Thus, when the bellows is compressed, the dispensable substance may be forced out of the bellows through dome slit 162.

[0252] In one embodiment, bellows 161 with dome slits 162 may be capable of releasing the dispenseable substance at a high velocity, thus implementing a jet delivery, as opposed to the radial distribution through the valve in Figures 4-5. The internal pressure generated to compress bellows 161 may be sufficient to cause delivery at a rate to penetrate the mucosal layer inside the small intestine.

[0253] 7 provides an example structural diagram illustrating the aspect of a hole located at one end of a housing as a dispensing port for an ingestible device according to some embodiments described herein. A delivery hole 171 may be located at end 102b of housing 101 for burst delivery. Hole 171 may be sealed with a thin wax or silicone that may be broken by a force from inside housing 101 to allow the dispensable substance to be released.

[0254] In one embodiment, an injection nozzle (not shown in FIGS. 6-7) or syringe may be positioned at one end 102b of housing 101 for jet delivery. For example, the nozzle or syringe may have an injection needle extending out of dome slit 162 or delivery hole 171. The injection nozzle may use osmotic pressure from luminal fluid inside the small intestine to drive the dispensing mechanism. The injection needle may be used to penetrate the mucosal layer inside the small intestine. The various delivery mechanisms described in FIGS. 4-7 may be configured to deliver the dispenseable substance either radially or longitudinally from the ingestible device.

[0255] FIG. 8 provides an example structural diagram illustrating an aspect of an ingestible device 100 having a bellows structure for a storage reservoir of a dispensable substance according to some embodiments described herein. A gas generating cell 103 (similar to that described in FIGS. 1-3) may be attached to a PCB 132 and a battery 131. A collapsible silicone bellows 161 is placed on top of the gas generating cell 103 with one end of the bellows 161 in contact with the gas generating cell 103 and the other end in contact with one end 102b of the housing 101. The dispensable substance may be loaded into the bellows 161, which may be compressed by the gas generated from the gas generating cell 103 to dispense the dispensable substance from the housing 101. The shape of the bellows 161 may aid in controlled delivery. The dispensing port 107 may use either an outlet valve as described in FIGS. 4-5 or a dome slit 162 as described in FIG. 6.

[0256] Figure 9 provides an example structural diagram illustrating aspects of an ingestible device having a flexible diaphragm that deforms for dispensable substance delivery according to some embodiments described herein. The ingestible device 100 may have a flexible diaphragm 165 that may deform toward the dispensing port 107 as the gas generating cell 103 generates gas. The dispensable substance may then be forced out of the housing through the dispensing port 107 by the deformed diaphragm. The dispensing port 107 shown in Figure 9 is in the form of a ring valve as described in Figure 5, although any of the outlet designs described in Figures 4-7 may be applied.

[0257] For each example ingestible device with a deformable septum having a total length of 7.8 mm, the ingestible device can store and deliver approximately 600 μL of dispensable substance. As another example, for an ingestible device having a length of 17.5 mm, the ingestible device can store and deliver approximately 1250 μL of dispensable substance.

[0258] FIG. 10 provides an example structural diagram illustrating an embodiment of an ingestible device having an integrated piston and gas generating cell such that the gas generating cell is movable with the piston to push for dispensable substance delivery, according to some embodiments described herein. The ingestible device 100 may include a piston 166 that is configured with or integrated with the gas generating cell 103. The gas generating cell 103 may be sealed with custom silicone. In this manner, the gas generating cell 103 may move with the piston 166 as it generates gas. Contacts may be embedded within the seal 166 that encapsulates the gas generating cell 103 with leads connected to the PCB 132. The moving gas generating cell structure may allow for approximately 400 μL volume for storage and delivery of the dispenseable substance.

[0259] FIG. 11 provides an example structural diagram illustrating an aspect of an ingestible device having a capillary to direct a dispenseable substance out of a storage reservoir, according to some embodiments described herein. A capillary structure 169 may be disposed between the gas generating cell 103 and the end of the housing 101. The dispenseable substance may be stored in the empty chamber 135 around the gas generating cell 103 and inside the capillary structure 169. A wax seal may be applied between the gas generating cell 103 and the capillary structure 169. At the appropriate time when the ingestible device is identified as being at a particular location inside the intestine, the wax seal may be melted, for example, by heat generated by the PCB 132 or the gas generating cell 103, and then the gas generation pressure may push the dispenseable substance in the chamber 135 through the capillary plate 169 to dispense from the housing 101 through the dispensing port 107. Optionally, an outer wax seal may be disposed between the capillary structure 169 and the dispensing port 107 to avoid leakage or premature delivery.

[0260] In one example, the capillary structure 169 may include concentric rings of capillary plates. In another example, the capillary structure 170 between the storage reservoir 135 and the end of the housing 101 may be made of folded foil. An ingestible device 100 with a capillary structure may have a capacity of approximately 450 μL of dispensable substance. In some implementations, additional capacity may be gained by reducing the size of the PCB 132, removing one or two batteries, integrating the gas generating cell 103 into the PCB 132, and / or the like. The capacity of the dispensable substance may be increased to 900 μL.

[0261] FIG. 12 provides an example structural diagram illustrating aspects of an ingestible device having a clamshell-shaped housing and a laterally split septum that deforms for dispensable substance delivery, according to some embodiments described herein. The housing 101 of the ingestible device may include two clamshell halves 101a-b along the housing's longitudinal axis. The clamshell structure may be used to open the ingestible device to load the ingestible device with a dispensable substance or to insert a separate storage reservoir into the ingestible device. In the ingestible device 100a, the septum 123 may be disposed along one clamshell half 101b and extend to encase the gas generating cell 103. In this manner, the septum 123 may act as a dam between the storage reservoir 135 storing the dispensable substance and the electronics 132 to protect the electronics 132. When gas generating cell 103 generates gas, the internal pressure can deflect septum 123 towards the other clamshell half 101a, thus pushing the dispensable substance inside storage reservoir 135 out of housing 101. Ingestible devices 100b-c provide different views of transversely split septum 123 from two different angles.

[0262] 13 provides an example structural diagram illustrating aspects of an ingestible device having an elastomeric bladder to provide pressure to deliver a dispenseable substance, according to some embodiments described herein. An elastomeric component 152 (e.g., a bladder, balloon, etc.) can be disposed within storage reservoir 135 storing a dispenseable substance such that when elastomeric component 152 expands to fill the volume of storage reservoir 135, the dispenseable substance can be forced out of the ingestible device through an outlet, e.g., one or more holes 156 on a wall of the ingestible device.

[0263] The elastomeric component 152 may be made of a flexible material that occupies a small amount of volume in its free state, but can expand to fill the volume of the storage reservoir 135. A residual volume may exist because the elastomeric component 152 in its free state still occupies space inside the storage reservoir, thus reducing the volume of dispensable substance that can be filled into the storage reservoir 135. For example, as shown in FIG. 13, even in the free state, the elastomeric component 152, e.g., a balloon, may be slightly inflated, thus occupying a volume of 57 μL.

[0264] One or more holes 156 on the outer shell of the ingestible device 100 can allow luminal fluid to be drawn into the void behind the elastomeric component 152. The ports of holes 156 on the outer wall can be shaped to prevent irritation during use of the ingestible device 100, for example, so that no edges catch tissue inside the GI tract during movement, and also to reduce fouling from backfilling of luminal fluid.

[0265] A wax plug can be used to seal one or more of the holes 156, which can be pushed out by pressure when the dispensable substance is released. An additional coating, removable cover or decal can be added, for example, to the top of one or more of the holes 156 to ensure that the dispensable substance is not dispensed during processing.

[0266] FIG. 14 provides an example structural diagram illustrating how to preload an ingestible device with an elastomeric bladder to reduce holdup, according to some embodiments described herein. To reduce holdup and load the ingestible device with the maximum possible dispensable substance, the elastomeric component 152 can be stretched and filled by rods 155 before filling the storage reservoir 154 with the dispensable substance. In this way, the free state of the elastomeric component 152 is preloaded under tension, which can reduce holdup. One or more holes 156 on the outer shell of the ingestible device 100 can allow luminal fluid to be drawn into the void behind the elastomeric component 152. The ports of holes 156 on the outer wall can be shaped to prevent irritation during use of the ingestible device 100, for example, so that no edges catch tissue inside the GI tract during movement, and also to reduce fouling from backfilling of luminal fluid.

[0267] In this way, with the residual volume reduced, the payload capacity of the ingestible device can be increased, for example, a dose of up to 800 μL can be delivered by the ingestible device. Because the payload capacity is increased, the overall dimensions of the ingestible device can be reduced as a result, which can make administration easier for the patient, and the packing density can also be increased, improving distribution logistics.

[0268] FIG. 15 provides an example structural diagram illustrating an aspect of an ingestible device having a gear motor for dispensing a dispenseable substance out of a storage reservoir, according to some embodiments described herein. A gear motor mechanism 160 may be disposed inside the ingestible device with one end connected to the battery cell 131 and the other end disposed at an opposite end of the ingestible device 100. The gear motor 160 may cause a particular motion, such as a rotation, such that the dispenseable substance in the storage reservoir may be dispensed from the ingestible device 100 by the motion. The dispenseable substance may be dispensed as a bolus dose or as incremental doses over a given period of time at various dose rates, for example, by adjusting the speed, pattern, and power of the gear motor motion. The storage reservoir 135 may carry a volume of up to 720 μL, since the gear motor mechanism may require an enhanced battery system that may limit the overall payload capacity.

[0269] 16 provides an example structural diagram illustrating an aspect of an ingestible device that uses an auger to dispense a dispensable substance out of a storage reservoir, according to some embodiments described herein. The gear motor 160 can include an auger device around an outer wall of the gear motor 160 such that the auger device can be driven to agitate or wipe the dispensable substance to be dispensed from the storage reservoir.

[0270] To avoid scratching or damage to the walls of the ingestible device 100, the diameter of the auger device 161 is smaller than the diameter of the storage reservoir so that the auger device 161 does not contact the interior walls of the ingestible device 100. A seal for the ingestible device 100 can be secured between the housing of the gear motor 160 and the body of the ingestible device 100. This can reduce the amount of torque required to drive the auger 161 and may allow a user to use a smaller gear motor 160, which can increase the payload capacity available inside the ingestible device 100.

[0271] The auger mechanism can allow the dispenseable substance to be forced out of the ingestible device 100 and become gradually diluted as luminal fluid is drawn into the storage reservoir. The dispenseable substance is then dispensed from the storage reservoir in descending concentrations. As a result, a low residual amount of the dispenseable substance can remain inside the storage reservoir, depending on the number of times the auger mechanism is instantiated to dispense the dispenseable substance.

[0272] FIG. 17 provides an example structural diagram illustrating an aspect of an ingestible device that uses a wiper to dispense a dispensable substance out of a storage reservoir, according to some embodiments described herein. A wiper device 163 can be connected to a gear motor 160 such that the gear motor 160 rotates and drives the wiper device 163 to dispense the dispensable substance. Two ports 164a-b on the outer covering of the ingestible device 100 on either side of the wiper function as an inlet or an outlet. The inlet (e.g., 164a or 164b) is configured to allow luminal fluid to fill the void created by the moving wiper 163 to regulate the resulting negative pressure. The wiper 163 is configured to be sized such that an edge of the wiper 163 substantially contacts the inner wall of the storage reservoir to maintain a seal and properly deliver the dispensable substance. As a result, a battery may need to provide higher power to maintain the rotation of the gear motor 160 against friction. A wax seal may be used to retain the dispenseable substance while not in use. The wiper mechanism in Figure 17 is effective to deliver the entire payload (low / zero residual amount) to maximize delivery of the dispenseable substance and minimize substance waste.

[0273] Figure 18 provides an example structural diagram illustrating an aspect of an ingestible device that uses a piston to drive a wiper as described in Figure 17 according to some embodiments described herein. A fine pitch helix 165 is disposed on a gear motor 160, and a piston 166 is disposed at one end of the helix 165, around a portion of the gear motor 160. Thus, as the gear motor 160 rotates, the fine pitch helix 165 is driven to rotate, moving the piston towards the opposite end of the helix 165. As a result, movement of the piston forces the dispenseable substance out of the storage reservoir.

[0274] A passive umbrella valve 167 (see also e.g. 141 in FIG. 4) can be used at the outlet of the ingestible device 100. The pitch of the helix 165 can be specified to improve long term control of the metering of the dispensed dose. Low hold-up can be achieved as the piston 166 can empty the payload volume of the storage reservoir.

[0275] FIG. 19 provides an example structural diagram illustrating aspects of an ingestible device that uses osmotic pressure to dispense a dispenseable substance, according to some embodiments described herein. In some implementations, osmosis can be used to increase the internal pressure of the ingestible device to dispense a substance. Osmotic or luminal fluid can enter the ingestible device from an inlet on the outer wall of the ingestible device through a flow channel 173. A wax plug 172 can be used to keep the luminal fluid separated from the semipermeable membrane 179, and when the ingestible device is within a desired location, for example, the wax plug can be swept away to allow the luminal fluid to enter the chamber adjacent the membrane 179. In this manner, fluid can enter the storage reservoir 135 by permeating through the semipermeable membrane 179, which is disposed at one end of the storage reservoir 15.

[0276] A volume of dry salt 180 (solute) can be placed on one side of the semipermeable membrane 179 (e.g., the storage reservoir side) so that water can be drawn from the GI fluid (solvent) and combined into a solution. The solution cannot pass through the semipermeable membrane 179 in the reverse direction. Thus, as more GI fluid is drawn into the storage reservoir 135 to form a solution, pressure can build up on one side of the membrane 179 that can be used to draw off the dispenseable substance.

[0277] Mucus and mineral "residue" (e.g., from GI fluids) may prevent water from passing smoothly through membrane 179, and a variety of different options can be employed. For example, piston 171 can be used to push the dispenseable substance out of the ingestible device. Or, as another example, as a portion of the dispenseable substance is pushed out of the ingestible device due to osmotic pressure, luminal fluid can slowly fill the cavity inside storage reservoir 135 (further described in connection with FIG. 20 ) and diffuse out the remaining dispenseable substance. The diffused mixture of dispenseable substance can then be forced out of the one-way valve.

[0278] The osmotic dispensing mechanism can be built on a housing 176 disposed inside the ingestible device. A PCB 177 can be attached to the top of the housing 176. To protect the PCB 177 from direct contact with the GI fluids, an insulator 175 can be placed between the PCB 177 and the flow channel 173. The resistor 174 can be configured to provide a low-cost heating element. When the PCB 177 generates a current to pass through the resistor 174, the resistor 174 can generate heat, such that the wax plug 172 adjacent or located closest to the resistor can heat up and transition from a solid to a liquid. Any external stomach pressure or internally generated pressure can then push the melted wax plug 172 out of its original position, allowing gastric fluid to enter the device and drive the osmotic mechanism.

[0279] Because the gas, usually hydrogen, can be a flammable gas and pose a safety hazard when administered to the body, ingestible devices that use osmotic pressure can offer an added safety advantage over gas generating cells.

[0280] FIG. 20 provides an example structural diagram illustrating aspects of an ingestible device that employs diffusion of a dispenseable substance with luminal fluid, according to some embodiments described herein. Various ports 181a-b and 182 may be added to the outer wall of the ingestible device. These ports may be temporarily sealed, for example, using a wax seal or an enteric coating. Once actuated, the ports may open and the dispenseable substance may slowly enter the GI tract and mix with the luminal fluid. An elastomeric membrane 183b filled with a dispenseable substance may be placed inside the storage reservoir 135 to utilize peristaltic pressure inside the GI tract to facilitate mixing of the luminal fluid with the dispenseable substance. For example, the port 182 may be sealed with an enteric coating or wax plug. Once the enteric coating dissolves or the wax plug is removed from its original position by peristaltic pressure, the luminal fluid may enter the storage reservoir 135 and mix with the dispenseable substance. When ports 181a-b are open, luminal fluid may also enter the storage reservoir through ports 181a-b, creating pressure that may collapse elastomeric membrane 183b to position 183a, thus dispensing the dispenseable substance mixed with the luminal fluid from storage reservoir 135 through port 182.

[0281] As the dispenseable substance is dispensed gradually from the storage reservoir 135, cavities within the storage reservoir can be flushed multiple times, for example, by drawing luminal fluid into the storage reservoir 135. As a result, a higher concentration of the dispenseable substance can be delivered to the GI tract initially, which can decrease in concentration over time.

[0282] FIG. 21 provides an example structural diagram illustrating aspects of an ingestible device having a splittable housing, according to some embodiments described herein. Instead of using a port on the outer wall of the ingestible device to allow luminal fluid to be drawn into a storage reservoir and mix with the dispensable substance, as shown in FIG. 20, a splittable housing 183 can be employed with a combination of a mechanical latch 186 and an enteric coating 187. At 191, the latch 186 is held closed by the enteric coating 187. At 192, the enteric coating can dissolve when the ingestible device enters the GI tract, and the latch 186 is released. Once the latch is released at 193, the housing 185 can split into two halves, thus releasing the dispensable substance. In this manner, the entire payload can be dispensed.

[0283] The latch release can be actuated in place, for example, by melting a wax plug to release the latch mechanism and / or by using a position confirmation system to determine the position for actuation. Further description of position confirmation of ingestible devices can be found in PCT International Application No. PCT / US2015 / 052500, filed September 25, 2015, which is expressly incorporated herein by reference. Splittable housings can also be actuated by osmotic pressure.

[0284] 22-24 provide example structural diagrams illustrating aspects of an anchoring mechanism of an ingestible device for anchoring the ingestible device to the intestine for dispensable substance delivery, according to some embodiments described herein. As shown in FIG. 22, after entering a region of interest, the ingestible device 100 can be anchored inside the intestine by extending hooks 203a-d from the ingestible device 100. At 201, as the ingestible device 100 moves along the GI tract, the hooks 203a-d are housed inside the ingestible device. At 202, once the ingestible device 100 determines that it has reached a location inside the GI tract, the hooks 203a-d can be actuated to extend outwardly of the ingestible device 100 and hook onto the intestinal wall to hold the ingestible device 100 in its respective position. The hooks 203a-d can be oriented to catch the intestinal wall regardless of the momentary orientation of the ingestible device 100. The hooks 203a-d can retract, dissolve, or detach from the intestinal wall after the dispenseable substance has been delivered at the fixed location.

[0285] As shown in Figure 23, hooks 203a-d can also extend radially from the ingestible device and pierce the intestinal wall to hold the ingestible device 100 in place. If the extending hooks (e.g., 203a-b) are hollow, as shown in Figure 24, the hooks can be used to both anchor the ingestible device and inject a dispensable substance into the intestinal wall.

[0286] 25-26 provide example structural diagrams illustrating aspects of an intestinal gripper of an ingestible device for gripping a portion of the intestinal wall to deliver a dispensable substance, according to some embodiments described herein. As shown in FIG. 25, a piston 205 is coupled, for example, at 206, to two anchoring arms 204a-b inside the ingestible device. When internally generated pressure (e.g., from a gas generating cell or osmotic pressure as described throughout this disclosure) moves the piston 205 forward, for example, at 207, the two anchoring arms 204a-b can be forced to extend outward from the ingestible device and close to grip a portion of the intestinal wall. The anchoring arms 204a-b, which can be more than two arms (two arms are shown in FIG. 25 for illustrative purposes), can be arranged in a circular pattern to form a suction-like shape in state 207. Alternatively, the anchoring arms 204a-b can be arranged in a rectangular pattern for a simpler structure (e.g., fewer anchoring arms can be used). The anchoring arms 204a-b can be made of a rigid material but with a pivot that allows the arms to close in state 207, or the anchoring arms 204a-b can be made of flexible metal elements that bend as the piston 205 moves towards the outlet of the ingestible device.

[0287] As shown in FIG. 26, after a portion of the intestinal wall has been grasped, an injection needle 206 can be used with anchor arms 204a-b to inject a dispenseable substance into the intestinal wall. For example, pressure from an actuation mechanism (e.g., gas or osmotic pressure, etc.) 211 can urge piston 205 to move toward the outlet of the ingestible device, such that storage reservoir 135 storing dispenseable substance 105, e.g., a therapeutic agent, and plunger 212 housing anchor arms 204a-b and retractable needle 206 can all move toward the outlet of the ingestible device. In state 213, plunger 212 can move to a position where anchor arms 204a-b and needle 206 extend outwardly from the ingestible device, such that anchor arms 204a-b grasp a portion of the intestinal wall and needle 206 is inserted into the grasped portion. In state 214, a flow path can be opened at one end of plunger 212 so that dispenseable substance 105 can be injected into the intestinal wall with needle 206.

[0288] Figures 27-30 provide example structural diagrams illustrating aspects of expandable stents for piercing an ingestible device to a specific location in the GI tract for dispensing, according to some embodiments described herein. Examples of cylindrical stents, such as a solid cylinder 220 or a hollow frame stent 21, are shown in Figures 27-28. The outer surface of the stent 220-221 may be covered with a patch that may diffuse the dispenseable substance into the small intestine while the stent itself protects the dispenseable substance from enzymes in the luminal fluids.

[0289] In some embodiments, the stent may be formed of a shape memory alloy that returns to an expanded state upon transition to body temperature. The stent may be formed of a pre-tensioned structure that expands upon dissolving of the enteric coating. The stent material may also dissolve or may be comprised of a material that releases a therapeutic agent. Expansion of the stent geometry, for example unraveling of a coil or other geometry that allows the device to expand along the short or long axis of the cylinder 220, may be utilized. The patch may consist of a therapeutic agent embedded in a dissolving matrix. The dissolving matrix allows for re-collapsing of the therapeutic agent or the stent material itself dissolves over time.

[0290] As shown in FIG. 29, the stent is placed by pressing or adhering a patch or other dispensing object to the surface of the mucosal layer. The intention is to allow the dispensable substance to diffuse through the front of the patch toward the epithelial cells while protecting the body of the dispensable substance from degrading agents in the luminal fluid. The outer surface of the stent may also include dissolving fine needles to facilitate delivery of the dispensable substance. The stent may be deployed by tearing open an ingestible device, allowing the mechanically driven stent to expand by spring force. The stent may also expand like a balloon once deployed. An example of an expandable stent expanded using osmotic pressure is shown in FIG. 30.

[0291] If the stent is in the form of a hollow cylinder, intestinal fluids can still pass through the center of the stent and therefore do not cause blockage while the dispensable substance is being dispensed. The surface of the stent may include needles, hooks or mucoadhesives to provide a grip against the intestinal wall to pierce the ingestible device to a location within the GI tract.

[0292] FIG. 31 provides an example structural diagram illustrating aspects of an ingestible device having a jet delivery mechanism according to some embodiments described herein. The ingestible device 100 may be a variation of the ingestible device 100 described in FIG. 1, where the outlet 107 is an injection nozzle 301. In some implementations, the gas generating cell 103 generates gas 302, propelling the piston 104 towards the nozzle 301, so that the dispensable substance 105 can be pushed under pressure to break the burst disk 106 and be injected at the nozzle 301. To generate sufficient pressure for injection inside the ingestible device, a volume of gas of 325 μL may be required to expel the dispensable substance 105. Thus, the payload of the dispensable substance 105 may be limited, for example, to a maximum of 300 μL.

[0293] The ingestible device may be pushed away from the intestinal wall prior to injection to allow the dispensable substance 105 to penetrate the tissue.

[0294] FIG. 32 provides an alternative structural diagram example for an ingestible device having a jet delivery mechanism with improved available volume of dispenseable substance according to some embodiments described herein. The nozzle 301 may be located at the center of the ingestible device. A gas channel 303 may be located longitudinally along the wall of the ingestible device to carry gas from the gas generating cell 103 to propel the piston 104, located at the end of the ingestible device. The movement direction of the piston 104 may be reversed, for example, from one end of the ingestible device towards the center of the ingestible device. In this way, a total gas space of approximately 690 μL may be available inside the ingestible device, resulting in a larger force being generated to inject the dispenseable substance and break the burst disk 106. The mechanism described in FIG. 32 with a larger pressure chamber for gas may be used for multiple jets, as shown in FIG.

[0295] 33 provides an example structural diagram for a jet delivery mechanism with multiple nozzles, according to some embodiments described herein. A three-position nozzle 304 is configured with three equally spaced jets 305a-c that can balance the reaction forces of the jet delivery to deliver a dispenseable substance at three sites 305a-c. In some implementations, a different number of nozzles, e.g., 2, 4, 5, 6, etc., can be used in a similar manner as exemplified by the three-position nozzle 304. In some implementations, a two-position nozzle is configured with nozzles 180 degrees apart.

[0296] In some embodiments, multiple nozzle outlets similar to 304 can be used to deliver the dispenseable substance at a controlled pressure based on factors such as, but not limited to, the GI tract location where the ingestible device is located, the thickness of the mucosal wall, the nature of the dispenseable substance (how deep into the wall of the GI tract the dispenseable substance should be delivered), and / or the like. For example, if the dispenseable substance is to be delivered locally, e.g., past the mucus to the first layer of cells, the ingestible device can adjust the amount of pressure generated for local delivery. As another example, if the dispenseable substance is to be delivered systemically, e.g., into the submucosa, the ingestible device can configure a relatively high amount of pressure for a high velocity jet to initiate the jet delivery.

[0297] In some embodiments, the ingestible device may deliver the dispenseable substance in a series of release events by controlling the timing and amount of pressure generated. For example, predefined delivery patterns may be stored in PCT 132 (as further illustrated in FIG. 44) to deliver the dispenseable substance in a series of delivery events, for example, intermittently (e.g., every few seconds, etc.), constantly, or continuously (e.g., delivering a full payload within a few seconds, etc.). The amount of pressure to be generated by the ingestible device is thus preprogrammed into PCT 132 based on the delivery pattern.

[0298] In some embodiments, a microcontroller within PCT 132 (as further described in FIG. 44) may control the amount of pressure generated for delivery based on a matrix of delivery variables. The delivery variables may include, but are not limited to, the number of radial nozzles (e.g., 1, 2, 3, 4, 5, etc.), the design of the nozzles (e.g., nozzle shape and geometric parameters, etc.), the number of emission events (e.g., 1, 2, 3, 4, 5, consecutive, etc.), the duration between emission events (e.g., 5 seconds, 10 seconds, 30 seconds, 2 minutes, etc.), the range of pressure the ingestible device is configured to generate (e.g., 50 psi, 150 psi, 300 psi, etc.), the amount of dispenseable substance (e.g., 10 μL to 1500 μL payload, etc.), the distance of the ingestible device from the tissue or inner wall of the GI tract (referred to as the "offset distance"), and / or the like.

[0299] FIG. 34 provides an alternative structural diagram example for a jet delivery mechanism with chemical actuation, according to some embodiments described herein. The ingestible device may use a chemical reaction to mix one or more reagents 311-312 to generate a sufficient amount of gas into a pressure chamber 315 to propel the piston 104 for dispensable substance delivery. The chemical reaction may be initiated using a compound of an enteric coating 307 on the outer wall of the ingestible device, which may dissolve and expose the pump 310 in the GI tract. Once exposed to the GI fluids, the pump 310 may be driven by osmosis (osmotically driven pump) or by peristalsis (peristaltic driven pump, such as a physiological peristaltic driven pump) and may apply sufficient pressure to break the septum seal / spring 309. Once the septum seal 309 is broken, a first reagent 311, pre-stored in a separate chamber from the second reagent 312, may come into contact with the second reagent 312 to initiate a chemical reaction. The reaction can generate gases that can pass through semi-permeable membrane 179 and enter pressure chamber 315. An integrated shear ring 308 can be positioned at one end of piston 104 to stabilize piston 104 and release stored energy from pressure chamber 315 to deliver payload material 105 through jet nozzle 301 (two nozzles are shown for illustrative purposes).

[0300] The release of gas during a chemical reaction can increase pressure inside the ingestible device, providing the desired drive mechanism. Chemical reactions between acids and bases are considered fast reactions that can generate large amounts of gas as a product. Accumulation of the product gas inside a small capsule can provide the necessary pressure for the drug delivery jet. The amount of gas and pressure can be controlled by careful selection of the reaction and process stoichiometry. An ideal chemical reaction should be fast, but should not release products that are toxic or unsafe for in vivo use.

[0301] The reaction between acetic acid and sodium bicarbonate may be implemented. The products include carbonic acid and sodium acetate. A preliminary analysis of the acid and base dissociation constants (pKa, pKb) of the chemical reaction indicates that the equilibrium favors the right side of the reaction, producing a large ratio of products to reactants. [ka] Completion of the reaction involves the dissociation of the reactants in water and the release of their ions. [ka]

[0302] In the low pressure aqueous environment, carbonic acid breaks down into water and gaseous carbon dioxide. As carbon dioxide is released into the small container, the pressure inside the container increases, providing the pressure drive necessary to push the jet of drug towards the target tissue. Initial analysis of the equilibrium constants (KC and KP) and Henry's law for gases suggests that enough carbon dioxide will be released into the closed chamber to generate enough carbonic acid and satisfy the pressure requirements. [ka]

[0303] In an aqueous environment, carbonic acid also dissociates, releasing a proton. The rate at which carbonic acid dissociates is a function of the alkalinity of the solution and the partial pressure of the released gas. [ka]

[0304] The aforementioned reaction is a reversible reaction, suggesting that the reaction rate decreases with increasing product to reactant ratio. In addition to the stoichiometric ratio, the partial pressure of the product can also affect the rate and direction of the reaction. The release of multiple ions, limitations on the ionization and solubility of reactants and products, and the effects of changes in pressure make chemically driven systems a complex environment to model. As a result, careful selection and analysis of the stoichiometric ratio, acid molarity, and chamber size are necessary before an efficient and safe chemically driven system can be implemented.

[0305] As an example, an ingestible device may have a payload 105 of 400 μL, 50% of which by volume is acetic acid in water combined with dry carbonic acid. The ingestible device may require a pressure chamber 315 of 165 μL and 30 μL of reagent 312. To move 30 μL of reagent through an osmotic pump at 100 pounds-force per square inch (PSI) may require less than 1 μL of salt for an osmotic pump 310 with a 4 mm diameter osmotic membrane.

[0306] 35 provides an example structural diagram illustrating direct injection of a dispenseable substance with a needle by an ingestible device, according to some embodiments described herein. The ingestible device may include a single needle 317, or an array of needles (as shown in FIG. 35 here), housed within a needle guide 318, which may extend from and retract back into the interior of the ingestible device. One end of the needle guide 318 is disposed within the piston 316.

[0307] In state 321, needle 317 is inside the ingestible device and piston 316 is in a home position at one end of the storage reservoir. In state 322, when the ingestible device is actuated, for example by a gas-generating cell generating gas, piston 316 moves toward the outlet of the ingestible device. Friction between piston 316 and needle guide 318 is higher than the impedance force at the inner wall of the ingestible device, so needle 317 advances out of the ingestible device. Spring 319 can be compressed at the axial end of the ingestible device to allow needle 317 to extend out of the ingestible device. In state 323, once spring 319 is fully collapsed, pressure from the gas-generating cell continues to increase to a level sufficient to overcome static friction between piston 318 and needle guide 318, so piston 316 continues to move toward the outlet of the ingestible device, thus exposing the dispenseable substance to the end of needle 317 that is still inside the ingestible device. In this manner, material can be dispensed through needle 317 (hollow) as the piston continues to move. After dispensing, the gas generating cell is turned off at state 324. A spike may be placed on the inside wall of one end 325 of the ingestible device to puncture piston 316 as it reaches end 325. After a puncture is made, the pressure on both sides of piston 316 may balance and spring 316 may return piston 316 and needle 317 to a retracted position, e.g., needle 317 inside the ingestible device.

[0308] FIG. 36 provides an alternative structural diagram illustrating a non-axial configuration of an infusion needle for delivery, according to some embodiments described herein. A radial version of the direct injection described in FIG. 35 is illustrated in FIG. 36 by using a balloon 336 (similar to a catheter balloon) filled with a dispenseable substance and placed inside the ingestible device. Flexible trusses or linkages 334a-b and 332a-b can be used to assist the needle 333 to exit the ingestible device. In state 331, when the balloon 336 is deflated, the needle and linkages 332a-b and 334a-b are inside the ingestible device. In state 332, when the balloon 336 is actuated, for example by gas generated by a gas generating cell, the two coupling points of the linkages 332a-b can be pushed closer to each other due to the deformation of the balloon 336. As a result, the trusses 334a-b with the needle 333 can be pushed out of the ingestible device. In state 333, as the balloon continues to deform 336, thus further pushing against trusses 334a-b, needle 333 may be expelled to inject the dispensable substance from the ingestible device into the GI tract.

[0309] A piston driven by either a gear motor or, optionally, an osmotic or gas cell can be used to inflate the balloon 336. Figure 37 provides an example structural diagram illustrating a non-axial configuration of an infusion needle driven by an osmotic cell, according to some embodiments described herein. The osmotic cell 337 can be used to generate pressure to inflate the balloon 336. Once the balloon 336 is inflated, the needle can deliver the substance from the ingestible device in a similar manner as described in Figure 36.

[0310] FIG. 38 provides an example structural diagram illustrating the use of osmotic pressure to attach a suction device of an ingestible device to the intestinal wall, according to some embodiments described herein. Ingestible device 100 may have an osmotic mechanism having a chamber 342 that stores salt crystals. Chamber 342 includes a mesh 341 disposed proximate to a burst valve 340 at one end of chamber 342, and a reverse osmosis (RO) membrane 343 disposed proximate to a valve 345 on the other end of chamber 342. A suction device, for example, two or more suction fingers 347a-b (two fingers are shown in FIG. 38 for illustrative purposes), is positioned outside of chamber 342 with an open outlet exposed to luminal fluid in the GI tract.

[0311] At state 351, the osmotic mechanism is deactivated, e.g., valve 345 is closed, such that luminal fluid is not drawn into permeate chamber 342. At state 352, when the osmotic mechanism is activated by opening valve 345, luminal fluid enters ingestible device 100 through outlets of suction devices 347a-b, through valve 345, and into permeate chamber 342. Salts in chamber 342 then dissolve into the fluid. RO membrane 343 prevents fluid from flowing in the reverse direction, e.g., from the interior of chamber 342 into valve 345. Fluid continues to flow, e.g., through flow path 346, until all salts contained within chamber 342 have dissolved or until intestinal tissue has been drawn into suction devices 347a-b. As luminal fluid continues to flow into chamber 342, the solution of luminal fluid with dissolved salts in chamber 342 may experience a decrease in osmotic pressure, which may decrease the suction force at 347a-b. In this way, suction of intestinal tissue can be stopped before the tissue comes into contact with valve 345 to avoid damage to the intestinal tissue. If valve 340 is a burst valve, as more and more luminal fluid enters chamber 342, the luminal fluid may eventually burst valve 340 causing osmotic flow to reverse, aggressively pushing the intestinal tissue out of suction devices 347a-b. Mesh 341 positioned proximate burst valve 340 can prevent salt crystals from exiting chamber 342.

[0312] FIG. 39 provides an example structural diagram illustrating an ingestible device employing the osmotic mechanism and suction device illustrated in FIG. 38 according to some embodiments described herein. Ingestible device 100, as shown in FIG. 39, outlet 107 is disposed at one end of ingestible device 100. A suction device, e.g., two or more suction fingers 347a-b (similar to that shown in FIG. 38), is disposed proximate outlet 107. Outlet 107 is coupled to a storage reservoir that stores a dispensable substance (e.g., therapeutic agent) 105. Storage reservoir 135 is in contact with piston 363 (similar to 104 in FIG. 1), which can be driven toward outlet 107 by pressure generated by osmotic pump 362. Osmotic pump 362 is similar to the osmotic mechanism described in FIG. 38. As further illustrated in FIG. 40, a release portion 361 is located adjacent the other end of the ingestible device 100 (opposite the end where the outlet 107 is located).

[0313] FIG. 40 provides an example structural diagram illustrating the aspect of tumbling suction by the ingestible device described in FIG. 39, according to some embodiments described herein. As shown in FIG. 39, the ingestible device 100 does not require any electronics or other actuation elements. As shown in FIG. 40, the ingestible device 100 may tumble constantly, intermittently, or periodically as it moves through the intestine 370. When the ingestible device tumbles to a position where the outlet 107 is in direct contact with the intestinal wall 371, a suction process similar to that described in FIG. 38 may occur. Additional structural elements, such as fins, flutes, or the like, may be added to the outer wall of the ingestible device 100 to promote the tumbling motion.

[0314] 40, as the ingestible device 100 tumbles from position 372a or position 372b to position 372c, the axial end, e.g., outlet 107, contacts the intestinal wall 371 with some pressure. That amount of pressure may push a small amount of tissue of the intestinal wall 371 into the outlet 107, causing the inwardly facing suction fingers 347a-b to grab the intestinal wall 371. At position 372d, the peel-away portion 361, previously secured to one end of the ingestible device using an enteric coating or glucose-based retention feature, may be removed from the ingestible device 100, exposing the osmotic pump 362, as the enteric coating or glucose can dissolve in the GI tract.

[0315] FIG. 41 provides an example structural diagram illustrating an ingestible device employing a combination of tumbling suction and needle injection, according to some embodiments described herein. As shown in FIG. 41, the ingestible device includes an inwardly facing barbed disk 347 hosting several suction fingers / barbs (similar to 347a-b shown in FIG. 39). A diaphragm spring 319 is coupled to one end of the ingestible device's storage reservoir, and one end of a needle 317 is coupled to the spring 319. The other end of the needle 317 is housed within a piston 316 at the other end of the storage reservoir. The piston is positioned adjacent to an osmotic cell 363, which is similar to the osmotic pump 362 in FIG. 39. A dissolving material 361 is similar to the abrasion device 361 in FIG. 39.

[0316] Thus, as the ingestible device enters and travels along the intestine, the dissolving material 361 may dissolve, in turn exposing the osmotic cell 362 to the luminal fluid. The osmotic cell 362 may then generate osmotic pressure, urging the piston 316 to move towards the inwardly facing barb disc 347. Meanwhile, the ingestible device may aspirate a portion of the intestinal tissue with the inwardly facing barb disc 347, for example, in the manner described in FIG. 40. The needle 317 may then extend into the intestinal tissue grasped by the inwardly facing barb disc 327 as the piston 316 continues to move due to osmotic pressure, and inject the dispenseable substance into the intestinal tissue. The needle movement and injection process may be similar to that described in FIG. 35.

[0317] 42-43 provide example structural diagrams illustrating an ingestible device employing a combination of tumbling suction and needle injection according to some embodiments described herein. The osmotic mechanism described in FIG. 38 can be combined with an osmotically driven piston 363, a statically positioned needle 317 that is hollow and exposed to the dispenseable substance stored in the storage reservoir 135, and two enteric coatings 371a-b to inject the dispenseable substance into the intestinal wall.

[0318] The ingestible device has an empty chamber 375 connected to a suction device 347 to draw in luminal fluid. The inner wall of the empty chamber 375 may be covered by a short-time delay enteric coating 371b. As shown in FIG. 43, at state 401, the ingestible device, similar to that described in FIG. 42, may enter the intestine. At state 402, the short-time delay enteric coating 371b may break, thereby allowing the luminal fluid to contact the semipermeable membrane 343b. Water is then drawn from the luminal fluid in chamber 375 into salt chamber 342b, and then released from salt chamber 342b by breaking burst valve 340. Mesh screen 341 prevents entire salt crystals from being released outside the ingestible device. In this manner, as water continues to be drawn from the luminal fluid in chamber 375, more luminal fluid is drawn into chamber 375 by osmotic actuation, and tissue of the intestinal wall may be sucked into chamber 375 by suction device 347. The suction device 347 can also anchor the ingestible device to the intestinal wall as it draws in intestinal tissue. The needle 317 can penetrate the grasped tissue of the intestinal wall.

[0319] After the intestinal wall tissue is grasped by the suction device 347 in state 403 of FIG. 43, the long-delay enteric coating 371a disposed at the end of the ingestible device may break down to allow luminal fluid to contact the semipermeable membrane 343a disposed proximate the end of the ingestible device. Water is then drawn into the salt chamber 342a, generating osmotic pressure, thereby actuating the piston 363. The piston 363 then pushes the dispenseable substance from the storage reservoir 135 with the needle 317 into the intestinal tissue grasped by the suction device 347.

[0320] Once the dispenseable substance payload is fully released from the storage reservoir 135, an osmotic pressure builds up behind the piston 363 inside the storage reservoir. This pressure can be used to retract the needle 317 or expand the suction device 347 to free the tissue of the intestinal wall. Alternatively, after a period of time, once the dispenseable substance has been delivered and the piston 363 has been pushed to the end of the storage reservoir 135, the ingestible device can naturally be pulled away from the intestinal wall and then safely terminated. The barbs of the needle 317 and suction device 347 are positioned inside the ingestible device and cannot contact the intestinal wall without a vacuum.

[0321] The example ingestible device shown in FIG. 42 can deliver a 400 μl payload of dispenseable material and has a reduced overall size compared to those with gas generation cells and gas chambers.

[0322] The hooks, stents, needles, barbs, suction devices or the like shown throughout Figures 1-43 may be made of bioabsorbable or biodegradable materials such as, but not limited to, polyglycolide, poly-L-lactic acid (PLLA), poly-LD-lactic acid (PLDA), poly-ε-caprolactone-polylactic acid (PCL-PLA) blends and alloys, polyorthoesters (POE), poly(DL-lactide) (PDLLA), poly(lactide-co-glycolide) (PLGA), polydioxanone (PDS), polycaprolactone (PCL), poly(alkyl cyanoacrylate) (PCA), polyanhydrides, poly(orthoesters) or any bioabsorbable polymer with suitable material properties such as degradation rate and stiffness to hook, grab, pierce or grasp the intestinal wall and may degrade or be absorbed within the human body after a certain period of time.

[0323] FIG. 44 provides an example structural diagram illustrating aspects of electronic components including a PCB inside the housing of an ingestible device according to some embodiments described herein. The PCB 132 may be shaped to fit into the ingestible device and encase the gas generating cell. In one example, if the PCB 132 has a separate battery cell 131, the overall height of the PCB 132 may be substantially 19 mm. In another example, the PCB 132 may achieve a reduced height of 14 mm with an integrated gas generating cell 131, which may further reduce the height of the PCB 132 to less than 10 mm. In this manner, the PCB design may conserve space for a storage reservoir.

[0324] In some embodiments, the PCB 132 may include (but is not limited to) any combination of a microcontroller, a light-sensing unit, a power source (such as a battery 131), a communication unit, communication peripherals for connecting different components, and / or the like.

[0325] In some embodiments, the microcontroller includes programming, control and memory circuitry for holding and executing firmware or software, as well as for coordinating all of the functions of the ingestible device (see, e.g., 100 in FIG. 1 ) and other peripherals embedded on PCB 132. For example, the microcontroller may be implemented using a 32-bit microcontroller, such as the STM32 family of microcontrollers from STMicroelectronics™, although any suitable microcontroller may be used.

[0326] In some embodiments, the communication unit can receive operational instructions from an external device, such as a base station (e.g., an infrared transmitter and / or receiver on a dock). The base station can be used to initially program the ingestible device (e.g., 100 in FIG. 1) with operational instructions and / or to communicate with the ingestible device 10 in real time during operation or after the ingestible device has been retrieved from the body. In some embodiments, the communication unit does not receive any instructions from an external device, and instead the ingestible device operates autonomously in vivo.

[0327] In another embodiment, endoscopic tattooing may be used to mark or identify the location of disease (e.g., luminal gastrointestinal damage) or upstream of disease. Identifying the specific location of disease may then trigger operation of the ingestible device. For example, an optical sensing unit may detect the presence of an endoscopic tattoo (e.g., green dye) applied during a previous procedure, which may trigger the release of a therapeutic agent at and near the disease site by activating gas generation of a gas generating cell.

[0328] In other embodiments, a triggering mechanism or marker, such as a stainless steel clip or magnet, may be used to mark or identify the site of disease. For example, the mechanism may trigger the operation of the ingestible device, e.g., a magnet may open a valve on the ingestible device so that a dispenseable substance may be delivered. A localized triggering mechanism (e.g., an endoscopic tattoo) may not necessarily be for area-specific delivery of a dispenseable substance, such as, for example, a therapeutic agent.

[0329] In some embodiments, the communication subunit may include an optical encoder, such as an infrared emitter and receiver. The IR emitter and receiver may be configured to operate using modulated infrared light, i.e., light in the wavelength range of steps 850 nm to 930 nm. Additionally, an IR receiver may be included within the ingestible device to receive programming instructions from an IR transmitter at the base station, and an IR transmitter may be included within the ingestible device to transmit data to the IR receiver at the base station. Bidirectional IR communication between the ingestible device and the base station may thus be provided. It will be appreciated that in some embodiments, other types of optical encoders or communication subunits may be used; for example, some communication subunits may utilize Bluetooth, radio frequency (RF) communication, near field communication, and the like, rather than (or in addition to) optical signals.

[0330] The light sensing unit can be located on a PCB at a position on the side of the housing of the ingestible device. The light sensing unit can include various sensors to obtain in vivo information while the ingestible device is moving inside the body. To help identify where the ingestible device may be inside the body, various sensors can be provided at different positions on the ingestible device, such as radial sensors around the housing of the ingestible device and axial sensors along the axis of the ingestible device. In some embodiments, the data provided by the sensors can be used to trigger the operation of the ingestible device, for example, to trigger a gas generation cell (e.g., 103 in FIG. 3) to start gas generation. Each sensor can include an illuminator that can generate illumination to an environment external to the ingestible device, and a detector that can detect reflectance from the environment in response to the generated illumination. The reflectance can be transmitted to the microcontroller via a communication peripheral on the PCB 132 to identify a specific location of the ingestible device.

[0331] For example, the light-sensing unit may include a sensor with an infrared emitting diode (IR-LED) as an illuminator and a detector sensitive to illumination in the infrared spectrum. The sensor may, in some embodiments, include a yellow-green LED as an illuminator that emits light having a wavelength of about 571 nm. In some embodiments, the sensor may include a green LED that emits light having a wavelength of about 517 nm and a red LED that emits light having a wavelength of about 632 nm. In some embodiments, the sensor may include an RGB LED package capable of emitting illumination at multiple different wavelengths.

[0332] In some embodiments, the sensor may include a collimated light source. The collimated light source may direct reflected light to maximize reflectance from certain external environments, such as circular anatomical structures. For example, illumination may be provided by a collimated light source, which may be provided using LED binning or supplemental lenses, or by a combination of collimated and non-collimated light sources.

[0333] The reflectance detected in response to the illumination may be used by the microcontroller to determine the location of the ingestible device within the GI tract. In this manner, the ingestible device may track the current region of the GI tract surrounding the device and monitor the environment around the device to determine changes from one region to another. In some embodiments, the ingestible device may autonomously identify the location of the device within the GI tract of the body by monitoring changes from one region to another. In some embodiments, the ingestible device may function as a state machine, with the state tracking the current portion of the GI tract in which the ingestible device is located. The ingestible device may distinguish between various locations, including an entry point outside the body, a stomach, a duodenum, a jejunum, a cecum, a large intestine, and an exit point outside the body. In some embodiments, the ingestible device may distinguish between only the stomach, the small intestine (e.g., the small intestine, which may include the duodenum and jejunum), and the large intestine (e.g., the large intestine, which may include the cecum and large intestine). In some embodiments, the ingestible device may distinguish between a subset of the above locations and / or a combination of the above locations and other locations, such as the mouth, ileum, or rectum.

[0334] In some embodiments, the ingestible device may transmit illumination at a first wavelength towards an environment external to the housing of the ingestible device, detect the resulting reflectance, and store the reflectance value in a data set based on the first reflectance. For example, the ingestible device may transmit illumination at a red wavelength, detect the red reflectance, and store the reflectance value in a red data set indicating how much light was measured at the red reflectance. The ingestible device may repeat this process for some other type of illumination at other wavelengths, such as blue, green, or infrared wavelengths. The ingestible device may track reflectance data collected from reflectance sensors (i.e., radial detectors) in each of the red, green, blue, and IR spectra.

[0335] This data may then be used by the on-board microprocessor to execute a localization algorithm that identifies the pylorus transition from the stomach to the duodenal portion of the small intestine; the Treitz transition from the duodenum to the jejunum; the ileocecal transition from the ileum (i.e., the region located at the end of the jejunum) to the cecum; and the cecal transition from the cecum to the remainder of the large intestine. This may be accomplished by using multiple different wavelengths of light, measuring different amounts of light reflected by the environment surrounding the device, and taking into account different light absorption characteristics of different regions of the gastrointestinal tract to determine the location of the device. The ingestible device may collect this data at periodic intervals, which in some embodiments may be between 1 second and 10 minutes apart. For example, the ingestible device may intermittently, constantly, or periodically detect the location of the ingestible device until it is determined that the ingestible device is inside the small intestine, and then the ingestible device may activate a gas generating cell to generate gas, thereby forcing the dispenseable substance out of the housing. It should be noted that in at least some embodiments, the electronics are configured to automatically activate the gas generating cell in response to identifying the location of the ingestible device, for example, based on an analysis of the reflectance obtained as described above. No external trigger outside the ingestible device is required. Alternatively, the electronics are not pre-programmed with any activation conditions, such as, but not limited to, activation after a predetermined period of time, and / or the like. In at least another embodiment, the ingestible device does not rely on a pH-sensitive enteric coating to determine location, for example, particularly within certain portions of the GI tract that are difficult to target based solely on a pH-sensitive enteric coating, such as, but not limited to, the portion immediately after passing the pyloric sphincter or the portion immediately before the ileocecal valve. Further description of ingestible device location verification may be found in PCT International Application No. PCT / US2015 / 052500, filed September 25, 2015, which is expressly incorporated herein by reference.

[0336] The memory unit may comprise memory storage components such as flash storage, EEPROM, and the like. The memory unit may be used to store instructions received from the base station, as well as to store various other operational data, such as migration data and sensor data collected by the light sensing unit. For example, the memory unit may store predefined reflectance parameters indicative of a particular location and instructions for identifying an immediate location of the ingestible device based on the measured reflectance. As another example, the memory unit may store predefined parameters and instructions for a certain amount of a dispensable substance to be delivered, as well as instructions for determining and dispensing a dispensable substance based on the obtained reflectance, if there are multiple chambers for different dispensable substances. In some embodiments, the microcontroller may operate to execute instructions stored in the memory unit, which may involve operating other components of the ingestible device, such as the light sensing unit, the communication unit, and the power source.

[0337] In some embodiments, the power source may include one or more batteries 131 formed from different chemical compositions, such as lithium polymer, lithium carbon, silver oxide, alkaline, and the like. This may help accommodate different power requirements of various components within the ingestible device. In some embodiments, the power source may include silver oxide battery cells to power various components within the ingestible device. The battery cells 131 that provide power to the power source may operate at 1.55V. For example, a silver oxide coin cell type battery, such as one manufactured by Renata™, may be used, as the silver oxide coin cell battery has discharge characteristics that are compatible with the operation of the ingestible device. In some embodiments, other types of battery cells may also be used.

[0338] In some embodiments, it may include one or more battery cells 131. For example, multiple coin cells may be used to provide a higher voltage for operation of the ingestible device. It may also be possible for the power source 131 to include one or more different types of battery cells.

[0339] The power supply may also be divided into one or more cell groups to prevent momentary interruptions or changes in the power supply from affecting the overall operation of the ingestible device. For example, an example power supply may include three cells, each operable to provide 1.55 volts. In one example embodiment, the three cells may be provided as one cell group operable to provide 4.65 volts as a total voltage. A voltage regulator may control the voltage provided by the cell group. The voltage regulator may operate to provide a regulated voltage, such as 3.3 volts, to the microcontroller while operating to provide the total voltage to the light-sensing unit. In another example embodiment, the three cells may be provided as two different cell groups, a first cell group including two cells and a second cell group including one cell. The first cell group may thus provide 3.1 volts, while the second cell group may provide 1.55 volts. The first cell group may be operable to provide 3.1 volts to the microcontroller to prevent voltage fluctuations. The first group of cells and the second group of cells can then be combined to provide 4.65 volts to the light-sensing unit.

[0340] In some embodiments, power source 131 may be removed from the ingestible device for recharging by recharging circuitry external to the ingestible device. In some embodiments, power source 131 may be recharged while within the ingestible device if recharging circuitry is included on PCB 132; for example, by providing circuitry that allows the ingestible device to be inductively coupled to a base station and wirelessly charged.

[0341] In some embodiments, the ingestible device has a drive mechanism that provides positive pressure to provide sufficient energy to deliver a bolus of a dispenseable substance (e.g., a therapeutic agent) to a desired location, such as the side wall of the small intestine, via a high velocity jet through a nozzle. Alternative application examples for the drive mechanism include providing energy to a release mechanism and providing suction to adhere the device to the intestinal wall.

[0342] FIG. 45 illustrates an ingestible device 4500 including a pre-pressurized actuator chamber 4503 and a sliding piston 4504, according to certain embodiments described herein.

[0343] The ingestible device 4500 includes a device housing 4501, which in the illustrated embodiment consists of a cap portion 4502a and a base portion 4502b. The ingestible device 4500 also includes a pre-pressurized actuator chamber 4503 that is pressurized to a target pressure, for example, during manufacture or prior to ingestion using an air inlet 4506. The capsule incorporates an active release mechanism that is activated when the capsule reaches a target location. When the release mechanism is activated, a sliding piston 4504 moves quickly to the left, pushing a high-pressure jet of a dispensable substance (e.g., a therapeutic agent) through a nozzle.

[0344] Depending on the material used to form the walls of the device housing 4501, the material may allow the compressed gas to gradually diffuse within the pre-pressurized actuator chamber 4503, decreasing the internal pressure. To ensure that pressure is maintained within the ingestible device 4500 over the period between manufacture and patient use, in certain embodiments, the packaging may be pressurized to equal the internal pressure of the pill; thus preventing permeation of the compressed gas from the ingestible device 4500. Assuming that gas expansion inside the capsule occurs so rapidly that an adiabatic polytropic process occurs, gas laws are used to correlate the initial and final pressures of the gas to its rate of volume change.

[0345] For polytropic processes

number

[0346] The delivery pressure profile for a range of initial pressures and percentage of volume change is presented in Table 1. It is seen that as the volume ratio of compressed gas increases within the pre-pressurized actuator chamber 4503, the variation in delivery pressure becomes smaller. However, the increase in volume ratio comes at the expense of a reduced dispenseable substance (e.g., therapeutic agent) volume. A compromise may be made between the two parameters to reach the desired pressure profile with sufficient dispenseable substance (e.g., therapeutic agent) volume. Table 1 below provides sample results of the implementation of compressed gas for the dispenseable substance (e.g., therapeutic agent) delivery embodiments disclosed herein. [Table 1]

[0347] In one embodiment, the ingestible device 4500 is filled with a liquid dispensable substance (e.g., a liquid therapeutic agent) in a reservoir 4505. The liquid dispensable substance is expelled from the reservoir 4505 by a piston 4504 sliding within the reservoir 4505 in response to actuation by compressed gas in a balanced pre-pressurized actuator chamber 4503. The compressed gas in the pre-pressurized actuator chamber 4503 is initially maintained under pressure using a closing component, such as a plug 4508, to prevent the dispensable substance from being expelled from the reservoir 4505. For example, the device 4500 is placed in an external pressure chamber and the chamber 4503 inside the ingestible device 4500 is raised to a target pressure. The air inlet 4506 is sealed (such as with an adhesive) within the pressure chamber 4503 and the plug 4508 is inserted into the conduit 4509. When plug 4508 is removed, for example by dissolving based on a reaction occurring at or near the target site, the pressure in chamber 4503 decreases as the volume of chamber 4503 increases as piston 4504 moves further into reservoir 4505 as the dispenseable substance is withdrawn from reservoir 4505 via outlet conduit 4509.

[0348] In an embodiment, the pressure in the chamber 4503 is generated within the chamber itself by the release of gas during the chemical reaction inside the chamber. A chemical reaction between an acid and a base is considered a fast reaction and can generate a large amount of gas as a product. The accumulation of the product gas inside the small capsule can provide the necessary pressure for the dispenseable substance (e.g., therapeutic agent) delivery jet. The amount of gas and pressure can be controlled by careful selection of the reaction and process stoichiometry. An ideal chemical reaction should be fast but should not release products that are toxic or unsafe for in vivo use. In a particular embodiment, acetic acid and sodium bicarbonate are employed for the chemical reaction. All reactants and products are considered ingestible in small amounts. Products include carbonic acid and sodium acetate. In a low pressure aqueous environment, the carbonic acid breaks down into water and gaseous carbon dioxide. As the carbon dioxide is released into the small container, the pressure inside the chamber 4503 increases, providing the force required to push the piston 4504 through the reservoir 4505 towards the outlet conduit 4509, forcing the dispenseable substance out of it.

[0349] In some embodiments, the burst disk may be purposefully broken at a target pressure to allow release of the drug, an approach commonly utilized in industrial applications as a safety mechanism in pressurized systems.

[0350] FIG. 46A illustrates a burst disk 4608 along with the nozzle 4509. FIG. 46B illustrates a partial cross-sectional view of a burst disk holder 4610 according to some embodiments described herein. The burst disk 4608 allows for the release of a dispenseable substance, such as, for example, a therapeutic agent (e.g., from a reservoir 4505), by intentionally breaking at a target pressure to expel the dispenseable substance from the nozzle 4509 to a target location within the GI tract. The burst disk 4608 can be used as the only closure component in some embodiments, or can be used to provide separation between upstream contamination and the dispenseable substance payload in embodiments that include another closure component. The burst disk 4608 can be held in place using a fixed outer ring 4611 of the disk holder 4610, as shown in FIG. 46B.

[0351] In an embodiment, a custom-made burst disk may be used. Advantages of this approach may include one or more of the following: cost reduction; more control over design and size; customization of design for operation and burst pressure characteristics; more options for material types; and quality and tolerance control. Assuming for discussion that the burst disk is designed in the form of a portion of a thin-walled spherical pressure vessel (concave inside - convex outside), as shown in FIG. 46B, an analytical approach can be taken as follows. In this approach, the shear and tensile stresses on the thin-walled pressure vessel are estimated. Mohr's Circle Theorem is used to estimate the principal stresses, including tensile and shear stresses. For a thin-walled spherical sphere, the principal stresses on the outer wall are

number

[0352] The maximum shear stress on the inner wall of the vessel is:

number

[0353] As described by the formula, the maximum stress on the burst disk is a function of pressure, diameter, and wall thickness. The effect of stress concentration on the circumference of the disk is not considered in this approach. For the burst disk to operate properly through the operating pressures encountered, the principal stresses (normal and shear stresses) on the inside and outside surfaces of the vessel are desirably less than the maximum allowable stress. The maximum allowable stress is often the ultimate tensile and shear stress of the material.

[0354] Another factor that may affect the performance of a burst disk is the elongation of the material just prior to rupture. Plastic deformation and elongation of the material prior to rupture results in a change in the equivalent diameter of the sphere under stress. This may result in a delay in rupture. It may be desirable to select a material with minimal plastic elongation prior to rupture. Design limitations, availability of materials from suppliers, and product thickness and tolerances make the process of burst disk design a complex process. A dynamic model was developed. The model takes the design characteristics as input and then calculates the minimum thickness of the material required. In addition, the effect of thickness tolerances is also investigated to estimate the pressure range for material rupture. The model compares the maximum principal stress of the system with the maximum tensile and shear stresses of each material. Table 2 lists the results for eleven different shim materials from the supplier. The definition for the operating pressure in Table 2 is the nominal pressure for the design and does not affect the results provided, while the minimum and maximum pressures are the expected pressures for rupture. This analysis does not take into account variations in the tensile strength of the substrate, which may add further spread to the minimum and maximum pressures. [Table 2]

[0355] From the analysis, several off-the-shelf available materials may be deemed suitable for use. Selection may depend on the associated pressures, material properties, and compatibility of the material with the dispenseable substance (e.g., therapeutic agent). In some embodiments, it may be desirable to use materials with similar properties to materials #3 and #4, with which chemical resistance and biocompatibility can be simulated and used. In certain embodiments, it may be desirable to use stainless steel 316L.

[0356] In some embodiments, one or more enteric coatings may be used as a triggering mechanism. FIG. 47 illustrates a portion of an ingestible device 4700 including an enteric coated closure component 4708 according to some embodiments described herein. As a cost-effective method to detect general entry into the small intestine, an enteric coating is used in certain embodiments as a closure component, or at least a portion of a closure component, that is reconfigured based on changes in local pH levels. In response, the pH level provides an effective position detection signal to reconfigure the closure component to activate or deactivate the dispensable substance actuator. In certain embodiments, pressure acts on the underside of the enteric coating 4708, and as the coating 4708 weakens due to exposure to small intestine luminal fluids, it breaks, allowing release of the dispenseable substance from the reservoir 4505. A supplemental coating for sealing or strength (e.g., wax) may be incorporated on the interior or exterior surface of the enteric coating to provide separation of the dispenseable substance (e.g., therapeutic agent) from the enteric coating (which may dissolve the coating) or to add structural support. In some embodiments, an advantage of incorporating an enteric coating on the tapered geometry of the conduit 4509 is that pressure applied on the interior surface further compresses the coating.

[0357] FIG. 48 shows a stack of enteric coating 4708 layers for an ingestible device according to some embodiments described herein. As an alternative to direct actuation on the enteric coating, concepts are disclosed that utilize the coating to expose a secondary feature that triggers the jet emission. Some of these mechanisms rely on the exposure of an osmogen layer 4708d to drive the fluid. FIG. 48 shows an embodiment of enteric coating 4708a exposing membrane 4708c and osmogen 4708d through mesh layer 4708b, which drives the flow of water into the capsule.

[0358] FIG. 49 illustrates an ingestible device 4900 including a magnetic closure component 4908b, a burst disk 4608, and a pre-pressurized actuator chamber 4903, according to some embodiments described herein. FIG. 50 illustrates an ingestible device 5000 including a magnetic closure component, a pre-pressurized actuator chamber 4903, and a bioabsorbable plug 5008, according to some embodiments described herein. The magnetic stack (shown in FIGS. 49 and 50) releases air pressure upon application of peristaltic or osmotic pressure to allow delivery of a jet of dispenseable substance through the conduit 4509. As shown by FIGS. 49 and 50, osmotic pressure can be used to configure the closure component including the magnets 4908a and 4908b in FIGS. 49 and 50. The enteric coating 4908c dissolves upon exposure to luminal fluids to expose the membrane 4908d and zymogen 4908e. Membrane 4908d and zymogen 4908e facilitate the movement of liquid creating an osmotic pressure on magnet 4908a. As the osmotic pressure increases, magnet 4908a is pushed up in close proximity to magnet 4908b. Magnet 4908b is pulled down providing flow through a pathway for gas from pressurized chamber 4905 to interact with reservoir 4905 via connecting conduit 4911. The advantage of this system is that the mechanism can be completely sealed from the exterior of the capsule allowing pressure to only launch into chamber 4905. Note that enteric coating / membrane stack 4908c, 4908d can be replaced by a method utilizing peristalsis to push magnet 4908a. FIG. 49 is implemented with a burst disk 4608 as a seal / release mechanism once chamber 4905 is exposed to pressurized chamber 4903. FIG. 50 is implemented with a bioabsorbable plug 5008 (eg, enteric coating) that dissolves and is expelled once the reservoir 4905 is exposed to the pressurized actuator chamber 4903 .

[0359] 51 illustrates an ingestible device 5100 including an intestinal sliding closure component 5102, a pre-pressurized actuator chamber 4903, and a sliding component 5108, according to some embodiments described herein. An osmotic drive 4908, including an enteric coating 5102 and a semi-permeable membrane 5104, is configured to move the sliding component 5108. The sliding component 5108, once pushed by the osmotic drive 4908, allows a flow-through port 4911 to connect the pre-pressurized actuator chamber 4903 to a reservoir 4905 to provide for dispensable substance delivery through the nozzle 5108.

[0360] FIG. 52 illustrates an ingestible device 5200 including a dissolvable pin closure component, a drug chamber 5202, a pre-pressurized chamber 5204, and a sliding piston 5206, according to some embodiments described herein. In another embodiment, the enteric coating 5208b dissolves to expose a structural pin 5208a (such as a glucose spike or hydrogel) that dissolves in the presence of intestinal fluids. In this design, as long as the pin 5208a is in place, the force applied to the piston 5206 and drug chamber 5202 is not large enough to rupture the burst disk 4608. The enteric coating 5208b and pin 5208a dissolve when the capsule 5200 is ingested, resulting in an increase in pressure on the piston 5206. The total force of the pre-pressurized chamber 5204 transferred by the piston 5206 onto the drug chamber 5202 is large enough to rupture the burst disk 4608. When the burst disc 4608 bursts, it results in a pressurized jet of liquid being delivered from the medication chamber 5202 through the nozzle 4509 .

[0361] FIG. 53 illustrates an ingestible device 5300 including a wax plug 5308a with a lead activator 5308b according to some embodiments described herein. In this method, the dispensing site is identified based on collected reflected light. The reflectance of light in the green and red spectrum is measured (with iterations of the method and algorithms being actively pursued) and an algorithm is used to correlate the measured reflectance with location within the gastrointestinal (GI) tract. The method provides a non-pH based system to determine the anatomical location of the capsule during fasted transit. Once the capsule 5300 reaches the target location, a signal is generated that is used to activate an alternative release mechanism.

[0362] A melt-wax-based approach is presented that includes a printed circuit board assembly (herein referred to as PCBA) with light-based localization technology. It works by receiving electronic signals from algorithmically defined detection points to energize a resistive heating element. This element induces a solid-to-liquid phase transition, releasing pressure and forcing a jet of the dispenseable material into the intestinal wall. One limiting factor to this approach is the additional cost associated with the PCBA.

[0363] Various embodiments disclosed herein use a nozzle, such as nozzle 4509, to generate a high-pressure jet of fluid capable of penetrating the intestinal wall. The nozzle may be directly connected to the dispenseable substance reservoir (e.g., unless a burst disk is used), and as a result, the dispenseable substance may be inadvertently dispensed if the nozzle opening is not sealed. One approach to mitigate this includes using a bioabsorbable material to seal the nozzle opening. A bioabsorbable plug refers to a plug made of a material that can be absorbed by the body when injected into the intestinal wall or luminal area. If the plug is in direct contact with the dispenseable substance, a small sealant layer can be used to separate the plug from the dispenseable substance to avoid undesired dissolution. Certain embodiments use a passive bioabsorbable plug that only functions as a sealing mechanism to close the nozzle. A passive bioabsorbable plug may be used to seal the dispenseable substance chamber to prevent undesired spillage of the dispenseable substance. In this case, the internal pressure of the dispenseable substance chamber is low and a separate mechanism is used to actuate the release of the dispenseable substance. When the capsule reaches the target location, the pressure inside the dispenseable substance chamber rises to a predetermined value. This can be done through the use of any of the release mechanisms previously mentioned. When the release mechanism is activated, the high pressure fluid removes the bioabsorbable plug from its attachment to the nozzle and pushes the plug out with a jet of fluid. In this case, the plug does not play a significant role in the activation and release of the dispenseable substance. After blocking the nozzle, the plug can either fall inside the GI tract or be injected into the intestinal wall. In either case, after a period of time, it is absorbed by the body.

[0364] An embodiment implements an active plug that functions as both a sealing mechanism and a closure component that can be configured to release the actuator mechanism. An active bioabsorbable plug functions as both a release mechanism and a sealing mechanism on the dispenseable substance chamber. In this case, the plug is used to close the opening of the nozzle. The dispenseable substance chamber is already pressurized, and as a result, the plug is under pressure. The outer body of the plug may be in contact with GI fluids or covered with an enteric coating. As the capsule passes through the GI tract, the plug begins to dissolve (in the case of an enteric covered plug, the cover dissolves before the plug begins to dissolve). Over time, the structural integrity of the plug weakens as parts of the plug dissolve. After a predetermined period of time, the structure of the plug weakens and it can no longer hold the high pressure liquid. At this point, the plug is torn away from the opening of the nozzle and pushed out with the flow of the high pressure dispenseable substance. In this case, the plug functions as both a sealing and a release mechanism, hence the use of the term "active".

[0365] FIG. 54 illustrates an ingestible device 5400 including a pre-pressurized chamber 5403 and a bellows 5404 according to some embodiments described herein. The ingestible device 5400 includes two chambers: a pressure actuator chamber 5403 and a reservoir 5404 (FIG. 11). These two chambers are separated by a bellows 5404. The pressure chamber 5403 is filled with high pressure gas to provide the drive mechanism necessary to force the dispenseable substance out of the nozzle 5411. An adhesive layer 5412 is disposed on the housing opposite the nozzle 5411. The closure component or release mechanism for this concept consists of a bioabsorbable plug 5408a (enteric coated, glucose based, along with other substrates and possible combinations, see section 5.5) separated from the liquid dispenseable substance by a protective agent layer 5408b. The plug 5408a is configured to withstand the pressure applied by the gas in the pressurized actuator chamber 5403. The force required to keep the plug 5408a in place is a function of the cross-sectional area to which the plug 5408a is attached. In this embodiment, the force applied to the plug 5408a is relatively small because the plug 5408a is placed in the small cross-sectional area of ​​the nozzle outlet 5411. As the capsule 5400 is ingested and travels through the GI tract, the bioabsorbable plug 5408a begins to dissolve (see section 5.5). After a period of time (which can be controlled by the properties of the bioabsorbable plug), the plug 5408a weakens or dissolves completely in the GI fluids. After the plug 5408a dissolves, the protective agent layer 5408b is expelled and the dispenseable substance (e.g., in the form of a jet) strikes the desired tissue, such as the inner wall of the target location (e.g., the inner wall of the small intestine).

[0366] In some embodiments, an alternative to a pre-pressurized gas chamber is to use a spring mechanism to provide the necessary pressure to the jet delivery mechanism. In certain embodiments, it may be desirable to satisfy one or more of the following: The outer diameter of the spring is smaller than the inner diameter of the capsule. The compressed length of the spring is minimized to leave more space for the medication. To ensure that an acceptable driving pressure is provided throughout all time steps of jet delivery, the free length of the spring is maximized and is greater than the free length of the capsule's internal cavity. · The spring rate should be large enough to provide acceptable pressure from the beginning to the end of drug delivery. The initial pressure delivered by the spring should be in the range of 100-250 PSI and the final pressure should not fall below 50 psi.

[0367] Based on the aforementioned factors, different springs from various suppliers may be considered. Sample results of spring analysis / selection are presented in Table 3. Optionally, custom springs may be implemented. The use of conical springs may also be implemented, potentially shortening the spring's solid length. In some embodiments, a piston may be implemented with a spring such that the piston can drive fluid from the chamber. In some embodiments, the piston may have one or more sealed mating surfaces. [Table 3]

[0368] FIG. 55 illustrates an ingestible device 5500 including a spring-loaded actuator 5503 and a sliding piston 5504, according to some embodiments described herein. The ingestible device 5500 uses potential energy stored in the spring 5503 when compressed as a drive or actuation mechanism for jet delivery of a dispenseable substance. The closure component or release mechanism consists of a bioabsorbable plug 5508a separated from a reservoir 5505 by a protective agent layer 5508b. In this embodiment, the interior volume of the capsule 5500 is divided into two sections separated by a sliding piston 5504. The left section (e.g., reservoir 5505) is filled with a dispenseable substance and a spring 5503 is mounted within the right section. The piston 5504 is free to move to the right or left depending on the resultant force applied on the piston 5504 (FIG. 55). An O-ring 5510 is used to provide the necessary seal between the two sections, with possible alternative sealing means. The compression spring 5503 applies a force to the piston 5504, which transmits this force in the form of pressure to the liquid dispensable substance. The same pressure is transmitted to the plug 5508a sealing the nozzle 5512. However, this pressure acts on a small area (the area of ​​the plug 5508a). Thus, the large force applied by the spring 5503 is translated into a small force on the sealing plug 5508a. When the capsule 5500 is ingested, it travels through the GI tract and the bioabsorbable sealing plug 5508a begins to dissolve. After a period of time, the plug weakens or dissolves completely in the GI fluid. As soon as the plug 5508a weakens to a design threshold, the pressure inside the reservoir 5503 is reduced, causing the spring 5503 to expand and deliver the dispensable substance through the opening (e.g., in the form of a high-pressure jet of fluid).

[0369] FIG. 56 illustrates an ingestible device 5600 including a spring-activated slidable housing portion 5602b, according to some embodiments described herein. The ingestible device 5600 consists of a pressure actuator 5603 chamber, a reservoir 5605 separated from the pressure actuator chamber 5603 by a deformable feature 5604, such as a bellows, and a spring / enteric coating release mechanism. A spring 5608a is attached onto a polycarbonate cap 5602a from one end to a sliding cap 5602b on the other end (FIG. 56). A stainless steel top slider 5602b can slide left and right to open and close the nozzle 5611. An enteric ring 5608b is used to hold the top slider closed. An O-ring and bioabsorbable plug 5609 are used to provide the necessary seal. An adhesive seal 5612 is placed onto the housing, on the opposite end of the capsule 5600 from the spring 5608a. The compressed gas applies a force to the bellows 5604, which transmits this force in the form of pressure to the liquid dispensable substance. The same pressure is transmitted to the slider 5602b in the form of a radial force. However, this pressure acts on a small area (the area of ​​the exit orifice 5607). Therefore, the lateral load on the slider 5602b is relatively small. When the capsule 5600 is assembled, the spring 5608a is compressed (slider 5602b in closed mode) and the enteric coating 5608b holds the slider 5602b in place. When the capsule 5600 is ingested, it travels through the GI tract. As the capsule 5600 passes through the intestinal fluids, the enteric coating 5608b dissolves. Once the enteric coating 5608b dissolves, the spring 5608a pushes the slider 5602b back away from the capsule 5600 (open mode). As a result, the exit orifice 5607 becomes concentric with the nozzle 5611 and a jet of fluid is emitted.

[0370] FIG. 57 illustrates an ingestible device 5700 with another spring-activated slidable housing portion 5712, according to some embodiments described herein. The ingestible device 5700 uses a compression spring (spring 5703) as the drive mechanism and a compression spring 5708a (spring with a sliding top cap 5712) as the release mechanism. A piston 5704 separates the reservoir 5705 from the spring chamber, and an enteric coating 5708b is used to initiate the release mechanism. An O-ring 5710 is used to provide a seal between the piston 5704 and the cylinder. The compression spring 5703 applies a force to the piston 5704, which transfers this force in the form of pressure to the liquid dispensable substance. The same pressure is transferred to the top cap slider 5712 in the form of a radial force. However, this The pressure acts over a small area (the area of ​​the exit orifice 5714) resulting in a small lateral force on the upper slider 5712. When the capsule 5700 is assembled, the spring 5703 is left in a compressed mode (slider 5712 in closed position). When the capsule 5700 is ingested, it travels through the GI tract. As the capsule 5700 passes through the intestinal fluids, the enteric coating 5708b dissolves. Once the enteric coating 5708b has dissolved, the spring 5708a pushes the slider 5712 back away from the capsule 5700 (open mode). As a result, the exit orifice 5714 becomes concentric with the nozzle 5716 and a jet of fluid is emitted.

[0371] FIG. 58 illustrates an ingestible device 5800 including a dissolving-away closure component 5808a and a pressurized chamber 5803, according to some embodiments described herein. The ingestible device 5800 consists of two chambers, one filled with a dispensable substance and the other with compressed gas. A wax valve 5808a actuated by a positioning board 5822 is used as the closure component. A large portion of the pressure chamber 5803 is occupied by a release mechanism and a necessary battery 5821. A wax valve wire 5808b is connected to the wax valve 5808a and uses an electric current to melt the wax. The timing of this operation is controlled by the positioning board 5822. In this embodiment, a fully controlled release mechanism is used. When the capsule 5800 reaches the target area, the positioning kit is actuated to direct a predetermined electric current to the wax valve 5808a. A heating element receives this electric current and melts or weakens the wax valve 5808a. As the wax weakens or is removed from nozzle 5810, gas pressure from pressurized chamber 5803 pushes against bellows 5804, resulting in a pressurized jet of liquid dispensable substance emerging from nozzle 5810, thus delivering the dispensable substance.

[0372] FIG. 59 illustrates an ingestible device 5900 including a dissolvable pin closure component 5908 and a spring-activated sliding piston 5914, according to some embodiments described herein. One of the key challenges of effective capsule design is the seal between the two chambers since there is a significant pressure difference between the two chambers inside the capsule, and the dispenseable substance tends to enter the pressure or spring chamber from the dispenseable substance chamber. An embodiment addresses this by reducing the pressure difference between the two chambers during the shelf life and before jet delivery. For example, the ingestible device 5900 includes a compression spring 5903 that is held using the dissolvable pin 5908. Additionally, an O-ring 5912 is used to provide a seal between the piston 5914 and the housing. With this design, there is no force applied to the piston 5904 and the liquid in the chamber 5906 as long as the pin 5908 is in place. The force applied by the spring 5903 results in a shear stress on the pin 5908. When the capsule 5900 is ingested, the pin 5908 melts, resulting in the spring force being transformed into a pressurized jet of liquid. An enteric coating on the end of the pin 5908 may further enhance the specificity of the trigger location. During the shelf life of the capsule 5900 and prior to ingestion, there is no significant amount of pressure acting on the dispensable substance, and as a result, the sealing challenge is easy to address. At 200 psi design pressure, the pin is expected to withstand approximately 20 lbf, including design considerations for the shear strength of the dissolvable pin. As the capsule 5900 passes through the GI tract, the pin 5908 begins to melt. Once the pin 5908 melts, there is no support for the piston 5904 to keep it in place. The force of the spring 5903 becomes a significant pressure on the fluid. At some point, the pin 5908 fails and the piston 5904 moves to the left, releasing a high pressure jet of fluid through the nozzle 5910.

[0373] FIG. 60 illustrates an ingestible device 6000 including a shuttle slider closure component 6012 and a pressurized chamber 6010, according to some embodiments described herein. The ingestible device 6000 includes two chambers separated by a wall 6002 made of polycarbonate. The right chamber is a pressurized chamber 6010 pressurized with a glued seal 6028 and a bellows 6006 is attached within the left chamber. There is no opening connecting the two chambers 6006, 6010. An osmotic release mechanism is used to connect the two chambers 6006, 6010 through a sliding valve 6012. As shown in FIG. 60, a zymogen 6014 is contained inside a small container below the sliding valve 6012. The zymogen 6014 is separated from the GI fluids by a water permeable membrane 6016 covered with an enteric coating 6018. A shuttle slider 6012 is attached above the zymogen 6014. The slider 6012 has an opening 6020 in the middle. The slider shuttle 6012 is sandwiched between two slabs of polycarbonate with pressure through port 6022. When the slider shuttle 6012 is in closed mode, the holes on the polycarbonate slab are not concentric with the holes on the slider shuttle 6012. When the slider shuttle 6012 is in open mode, the holes in the slider and the polycarbonate slab surrounding it are all concentric, allowing gas and pressure to be exchanged between the two chambers 6006, 6010.

[0374] When the ingestible device 6000 reaches a target location in the small intestine, the enteric coating 6018 that separates the membrane 6016 from the GI fluids dissolves. Water begins to pass through the membrane 6016 and enter the zymogen 6014. Over time, the amount of water inside the zymogen 6014 increases, increasing the pressure on the sliding shuttle 6012. When the pressure reaches a certain value, the shuttle 6012 slides up and its port becomes concentric with the hole on the 2-polycarbonate slab adjacent to the slider. At this point, the high pressure gas moves into the left chamber. This results in an increase in pressure on the bellows 6006. When the pressure on the bellows 6006 reaches a certain value, the bioabsorbable plug 6024 is expelled from the nozzle 6026 and a jet of the dispenseable substance is delivered to the target site.

[0375] FIG. 61 illustrates an ingestible device 6100 including a hydrogen cell actuator 6112 and a burst disk closure component 6106 according to some embodiments described herein. The ingestible device 6100 employs a hydrogen cell 6103 as a dispenseable substance actuator. The selection of the dispense site is determined by an algorithm. A location confirmation algorithm is used to control the activation time of the hydrogen cell 6103. A bellows 6104 is used to isolate the dispenseable substance from the location confirmation device and the hydrogen cell 6103. A burst disk 6106 is used to ensure that the dispenseable substance does not erupt from the nozzle 6018 before the pressure of the dispenseable substance reaches the design pressure. The capsule 6100 may also include a retention disk 6114 in close proximity to the burst disk 6106. When the capsule 6100 reaches the target location in the GI tract, a location confirmation kit activates the hydrogen cell 6103. Upon activation, the battery begins to release hydrogen into a small closed volume 6105 inside the capsule 6100, and as more hydrogen is released, pressure builds. The hydrogen battery 6103 is powered using a battery 6110 and controlled and / or operated using a printed circuit board assembly 6112. As the hydrogen pressure within the capsule 6100 increases, the pressure on the bellows 6104 also increases, forcing the dispensable substance against the burst disk 6106. When the pressure of the dispensable substance reaches the burst pressure of the burst disk 6106, the disk 6106 bursts, directing the high pressure dispensable substance through the nozzle 6108 and into the target tissue.

[0376] FIG. 62 illustrates another ingestible device 6200 including a hydrogen cell actuator 6014 and a burst disk closure component 6206 according to some embodiments described herein. In these embodiments, the interior chamber of the ingestible device 6200 is divided into two sections. The left section 6202, surrounded by a bellows 6204, contains the liquid dispenseable substance. A burst disk 6206 is used to block the flow of the dispenseable substance through the nozzle 6218 until the dispenseable substance pressure reaches a design criterion. The left section 6202 further includes a retaining ring 6222. A drive mechanism is mounted within the right chamber 6208. The drive mechanism is actuated through a bioabsorbable coating mechanism, which is mounted on the outer surface 6210 of the capsule 6200. The main difference between FIG. 61 and FIG. 62 is that the bioabsorbable coating mechanism replaces the location confirmation kit. These are cost savings and increased volume available for the dispenseable substance bellows.

[0377] When capsule 6200 is ingested, it passes through the digestive system. As capsule 6200 enters the small intestine, bioabsorbable coating 6212 dissolves in intestinal fluids. Segmented conductor 6214 is exposed to intestinal fluids, which act as a liquid conductor to close hydrogen release circuit 6216. Capsule 6200 is actuated to begin releasing hydrogen inside right chamber 6208 of capsule 6200, which includes pressurizable chamber 6220. If capsule 6200 is completely sealed, the release of hydrogen results in an increase in pressure inside capsule 6200. As gas pressure increases, pressure on bellows 6204 increases, which results in an increase in dispensable substance pressure inside bellows 6204. When the dispensable substance pressure reaches a design threshold of burst disk 6206, disk 6206 bursts and the high pressure dispensable substance flows through nozzle 6218 toward the target area.

[0378] As an alternative to incorporating a compressed air chamber, a vacuum may be substituted for the purpose of attachment to the intestinal wall. Similar to the positive pressure concept, the suction concept incorporates an active release / location confirmation mechanism that is activated once the capsule reaches the target location. Once the release mechanism is activated, the suction mechanism provides the drive necessary to draw the tissue into the capsule (or attach the capsule to the tissue). Once attached, another drive mechanism (such as a needle and osmotic pressure) may be used to inject the agent into the tissue. One potential advantage of this concept may be the delivery of a relatively large payload of a dispenseable substance directly to a desired location, e.g., tissue in the GI tract of a subject.

[0379] 63 illustrates an ingestible device 6300 including a vacuum actuator chamber 6308 and an enteric coating closure component according to some embodiments described herein. Some embodiments include a vacuum actuator. The vacuum actuator 6308 can be used to adhere the ingestible device to the intestinal wall and / or to draw a dispenseable substance from a dispenseable substance reservoir, for example, during adherence to the intestinal wall. In some embodiments, the ingestible device provides a suction of approximately 7.5 psi vacuum (7.2 psi absolute pressure).

[0380] Similar to the positive pressure embodiment, the suction actuator includes an active release / location mechanism that is activated when the capsule reaches the target location in response to a detection signal, e.g., a coating configured to dissolve in response to chemical interaction with a chemical typically found in close proximity to the target location. Once the release mechanism is activated, the suction mechanism provides the drive necessary to draw tissue into the capsule 6300 (or attach the capsule to tissue). Once attached, another drive mechanism (such as a needle and osmotic pressure) can be used to inject the dispenseable substance into the tissue.

[0381] The ingestible device 6300 describes a dispenseable substance delivery mechanism based on such aspiration and direct needle injection. Unlike some of the previous concepts where a high pressure jet of fluid is used to inject the dispenseable substance into the tissue, in this concept the direct penetration of the needle 6306 into the tissue is the dispenseable substance delivery mechanism. The capsule 6300 contains several chambers inside the steel body. These chambers are the needle chamber 6310, the pre-vacuum chamber 6312 (on the left), and the dispenseable substance bellows 6314, the salt chamber 6316 (on the right). The needle chamber has an opening with a grip spear on top pointing towards the interior volume of the chamber. The pointed end of the needle 6306 fits into the center of the aspirator opening 6304. The other end of the needle 6306 sits within the bellows 6314. The needle chamber 6310 has a port 6318 at the bottom connecting it to the pre-vacuum chamber 6312. This port 6318 is sealed with a short time delay enteric coating. A pre-vacuum chamber 6312 is located at the bottom of the needle chamber 6310 and has two ports 6320, 6318. The port 6320 at the top left of the chamber is used to generate vacuum pressure and the other port connects it to the needle chamber. The vacuum port 6320 is sealed with an adhesive seal 6322 after the chamber 6312 is evacuated to the required pressure. The right section of the capsule consists of two chambers: a dispensable substance chamber 6314 and a salt chamber 6316. One chamber 6314 is surrounded by a bellows 6324 and holds a liquid dispensable substance. One end of the needle 3606 is located inside the chamber 6314 to provide a low resistance path for the dispenseable substance to flow through the needle 6306 towards the target. The bellows 6324 is surrounded by the salt chamber 6316. The chamber 6316 has an opening 6326 to the surroundings through a semi-permeable membrane 6328. The membrane is covered with a long-delay enteric coating.

[0382] When the capsule 6300 is ingested, it travels through the GI tract. GI tract fluids enter the needle chamber 6310 and dissolve the short-delay enteric coating. With proper design of the capsule 6300, it can be ensured that the coating is completely dissolved when the capsule 6300 reaches the target area. As the short-delay enteric coating dissolves, the port 6322 is exposed and the pre-vacuum chamber 6312 draws the target tissue into the needle chamber 6310. The needle 6306 penetrates the tissue and the spear 6330 continues to attach the capsule 6300 to the tissue. Eventually, the long-delay enteric coating also dissolves, exposing the port 6326 and the semi-permeable membrane 6328 to the GI fluid. Due to an osmotic effect, fluid is transported through the membrane 6328 to the salt chamber 6316, increasing pressure in the salt chamber 6316 and the bellows 6324. As pressure in the salt chamber 6316 increases, the dispenseable substance is forced out of the bellows 6324, through the needle 6306 and into the target tissue. Eventually, the body's natural defense mechanisms weaken the grip of the spear 6330 on the tissue and the tissue is released.

[0383] 64 illustrates a system 6400 including an ingestible device 6410 and an attachable reservoir 6420. The ingestible device 6410 can be designed as described elsewhere herein, except that it does not include a storage reservoir as an integral component. The attachable reservoir 6420 can be designed as described elsewhere herein, except that it is not an integral component of the ingestible device 6410.

[0384] In some embodiments, the storage reservoir 6420 is loaded with a dispensable substance (e.g., a therapeutic agent) prior to being disposed within and / or coupled to the ingestible device 6410. As shown in FIG. 64, the ingestible device housing 6410 includes one or more openings 6430 configured to receive the storage reservoir 6420. However, other embodiments can be implemented to attach an attachable storage reservoir to the ingestible device, some of which are described below. Optionally, the ingestible device housing 6410 includes one or more openings configured as vents.

[0385] Typically, the dispenseable substance is placed in the storage reservoir 6410, which is then affixed to the ingestible device 6410. For example, the reservoir 6420 may be manufactured, packaged, and / or shipped separately from the device 6410. Optionally, the reservoir 6420 and the device 6410 are combined relatively shortly before the subject ingests the device. Given that the safe life of an ingestible device without a dispenseable substance (e.g., therapeutic agent) is likely to be substantially longer than the safe life of the dispenseable substance (e.g., therapeutic agent), it may be desirable in some cases to use an affixable device, particularly when it is undesirable or inconvenient to load a dispenseable substance onto an ingestible device in which a storage reservoir is an integral component.

[0386] In general, the attachable storage reservoir and the ingestible device can be designed in any suitable manner so that the storage reservoir can be attached to the ingestible device as needed. Example designs include a storage reservoir that fits completely within the ingestible device (e.g., within the ingestible device such that the storage reservoir is sealed within the device when the device is ingested by the subject), a storage reservoir that fits partially within the ingestible device, and a storage reservoir that is carried by the housing of the device. In some embodiments, the storage reservoir is a snap fit with the ingestible device. In some embodiments, the storage reservoir is a friction fit with the ingestible device. Optionally, the storage reservoir is coupled to the ingestible device by a threaded connection. Such a threaded connection may include a seal, such as an O-ring seal. In some embodiments, the storage reservoir is coupled to the ingestible device using a biasing mechanism, such as one or more springs, one or more latches, one or more hooks, one or more magnets, and / or electromagnetic radiation. In some embodiments, the storage reservoir can be a pierceable member. In some embodiments, the ingestible device has a sleeve in which the storage reservoir fits securely. In some embodiments, the storage reservoir is disposed in / on a slidable track / groove so that it can be moved over the piercing needle when delivery of the dispenseable substance is desired. In some embodiments, a seal can be used in addition to the attachment mechanism to reduce or even prevent fluid intrusion and / or to trap internal pressure inside the capsule (e.g., for gas generation cell embodiments and / or pre-pressurized embodiments). In some embodiments, the storage reservoir is made of a soft plastic coating that contacts the needle in any orientation to deliver the dispenseable substance as needed. In general, the storage reservoir can be made of one or more suitable materials, such as, for example, one or more plastics and / or one or more metals or alloys. Exemplary materials include silicone, polyvinyl chloride, polycarbonate, and stainless steel. Optionally, the design can be such that the storage reservoir carries some or all of the electrical components used by the ingestible device.While the above description relates to one storage reservoir, it is understood that the ingestible device can be designed to hold any desired number of storage reservoirs (e.g., 2, 3, 4, 5). The different storage reservoirs can have the same or different designs. In some embodiments, the ingestible device (when fully assembled and packaged) meets the regulatory requirements for marketing a medical device in one or more jurisdictions selected from the United States, the European Union or any member state thereof, Japan, China, Brazil, Canada, Mexico, Colombia, Argentina, Chile, Peru, Russia, UK, Switzerland, Norway, Turkey, Israel, any member state of the Gulf Cooperation Council, South Africa, India, Australia, New Zealand, South Korea, Singapore, Thailand, Philippines, Malaysia, Vietnam, and Indonesia.

[0387] Although the foregoing description relates to a system 6400 including an ingestible device 6410 and an attachable reservoir 6420, the present disclosure is not limited in this sense. For example, in some embodiments, an ingestible device can include one or more storage reservoirs as an integral component and can also be designed for use with one or more attachable reservoirs. Optionally, the attachable reservoir 6420 can also include features to allow recognition of the reservoir for purposes of adjusting capsule dispensing parameters and / or to prevent reuse of the device. Typically, an ingestible device disclosed herein includes one or more processing devices and one or more machine-readable hardware storage devices. In some embodiments, the one or more machine-readable hardware storage devices store instructions executable by the one or more processing devices to determine the location of the ingestible device within a portion of the subject's GI tract. In certain embodiments, the one or more machine-readable hardware storage devices store instructions executable by the one or more processing devices to transmit data to an external device (e.g., a base station external to the subject, such as a base station carried on an item worn by the subject) that can implement the data to determine the location of the device within the subject's GI tract.

[0388] In some embodiments, the location of the ingestible device within the subject's GI tract can be determined with an accuracy of at least 85%, e.g., at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, 100%. In such embodiments, portions of the subject's GI tract can include, for example, the esophagus, stomach, duodenum, jejunum, and / or the terminal ileum, cecum, and colon.

[0389] In certain embodiments, the position of the ingestible device within the subject's esophagus can be determined with an accuracy of at least 85%, eg, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, 100%.

[0390] In some embodiments, the location of the ingestible device within the subject's stomach can be determined with an accuracy of at least 85%, e.g., at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, 100%.

[0391] In certain embodiments, the location of the ingestible device within the subject's duodenum can be determined with an accuracy of at least 85%, e.g., at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, 100%.

[0392] In some embodiments, the location of the ingestible device within the subject's jejunum can be determined with an accuracy of at least 85%, e.g., at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, 100%.

[0393] In certain embodiments, the location of the ingestible device within the subject's terminal ileum, cecum and colon can be determined with an accuracy of at least 85%, e.g., at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, 100%.

[0394] In some embodiments, the location of the ingestible device within the subject's cecum can be determined with an accuracy of at least 85%, e.g., at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, 100%.

[0395] As used herein, the term "reflectance" refers to a value derived from light emitted by a device, reflected back to the device, and received by a detector within or on the device. For example, in some embodiments, this refers to light emitted by a device, a portion of which is reflected by an exterior surface of the device, and the light is received by a detector located within or on the device.

[0396] As used herein, the term "illumination" refers to any electromagnetic radiation. In some embodiments, illumination may be within the infrared (IR) range, the visible spectrum, and ultraviolet (UV) light, and illumination may have the majority of its power centered at a particular wavelength within the range of 100 nm to 1000 nm. In some embodiments, it may be advantageous to use illumination that has the majority of its power limited to one of the infrared (750 nm to 1000 nm), red (600 nm to 750 nm), green (495 nm to 600 nm), blue (400 nm to 495 nm), or ultraviolet (100 nm to 400 nm) spectrums. In some embodiments, multiple illuminations with different wavelengths may be used. For illustrative purposes, the embodiments described herein may refer to the use of the green or blue spectrum of light. However, it will be understood that these embodiments may use any suitable light having wavelengths substantially or approximately within the green or blue spectrum defined above, and the localization systems and methods described herein may use any suitable spectrum of light.

[0397] 65, there is shown a diagram of an example embodiment of an ingestible device 65100 that may be used to identify locations within the gastrointestinal (GI) tract. It will be understood that certain details regarding the design of the ingestible device 65100 are not shown in FIG. 65 and the following figures, and that in general, various aspects of ingestible devices described elsewhere herein may be implemented in the ingestible device 65100 and the ingestible devices shown in the following figures.

[0398] In some embodiments, the ingestible device 65100 may autonomously determine whether it is located in the stomach, a particular portion of the small intestine, such as the duodenum, jejunum, or ileum, or the large intestine, by utilizing sensors that operate at different wavelengths of light. Additionally, the ingestible device 65100 may be configured to autonomously determine whether it is located within a portion of the small intestine or large intestine, such as the duodenum, jejunum, cecum, or colon.

[0399] The ingestible device 65100 may have a housing 65102 shaped similar to a pill or capsule. The housing 65102 of the ingestible device 65100 may have a first end 65104 and a second end 65106. The first end 65104 may include a first wall 65108 and the second end 65106 may include a second wall 65110. In some embodiments, the first end 65104 and the second end 65106 of the ingestible device 65100 may be manufactured separately and attached together by a connector 65112.

[0400] In some embodiments, the ingestible device 65100 may include an optically transparent window 65114. The optically transparent window 65114 may transmit various types of illumination in the visible, infrared, or ultraviolet light spectrum, and the ingestible device 65100 may have various sensors and illuminators disposed within the housing 65102 and behind the transparent window 65114. This may allow the ingestible device 65100 to be configured to transmit illumination at different wavelengths through the transparent window 65114 to an environment external to the housing 65102 of the ingestible device 65100 and detect reflectance from a portion of the illumination that reflects back through the transparent window 65114 from the environment external to the housing 65102. The ingestible device 65100 may then use the detected level of reflectance to determine the location of the ingestible device 65100 within the GI tract. In some embodiments, the optically transparent window 65114 may be of any shape and size and may surround the periphery of the ingestible device 65100. In this case, the ingestible device 65100 may have multiple sets of sensors and illuminators azimuthally positioned at different positions behind the window 65114.

[0401] In some embodiments, the ingestible device 65100 may optionally include an opening 65116 in the second wall 65110. In some embodiments, the second wall 65110 may be configured to rotate (e.g., by a suitable motor or other actuator housed within the ingestible device 65100) about a longitudinal axis of the ingestible device 65100. This may allow the ingestible device 65100 to obtain a fluid sample from the GI tract or release a substance into the GI tract through the opening 65116.

[0402] FIG. 66 shows an exploded view of the ingestible device 65100. In some embodiments, the ingestible device 65100 may optionally include a rotation assembly 65118. The optional rotation assembly 65118 may include a motor 65118-1 driven by a microcontroller (e.g., a microcontroller coupled to a printed circuit board 65120), a rotational position sensing ring 65118-2, and a storage subunit 65118-3 configured to fit inside the second end 65104. In some embodiments, the rotation assembly 65118 may rotate the second end 65104 and the opening 65116 relative to the storage subunit 65118-3. In some embodiments, there may be a cavity on the side of the storage subunit 65118-3 that functions as a storage chamber. When the opening 65116 aligns with a cavity on a side of the storage subunit 65118-3, the cavity on the side of the storage subunit 65118-3 may be exposed to the environment outside the housing 65102 of the ingestible device 65100. In some embodiments, the storage subunit 65118-3 may be loaded with a drug or other substance before the ingestible device 65100 is administered to a subject. In this case, the drug or other substance may be released from the ingestible device 65100 by the opening 65116 aligning with a cavity within the storage subunit 65118-3. In some embodiments, the storage subunit 65118-3 may be configured to hold a fluid sample obtained from the GI tract. For example, the ingestible device 65100 may be configured to align the opening 65116 with a cavity within the storage subunit 65118-3, thus allowing the fluid sample from the GI tract to enter the cavity within the storage subunit 65118-3. The ingestible device 65100 may then be configured to seal the fluid sample inside the storage subunit 65118-3 by further rotating the second end 65106 relative to the storage subunit 65118-3. In some embodiments, the storage subunit 118-3 may also include a hydrophilic sponge, which may enable the ingestible device 65100 to better draw certain types of fluid samples into the ingestible device 65100.In some embodiments, the ingestible device 65100 may be configured to obtain a sample from within the GI tract or release a substance into the GI tract in response to determining that the ingestible device 65100 has reached a predetermined location within the GI tract. For example, the ingestible device 65100 may be configured to obtain a liquid sample from the GI tract in response to determining that the ingestible device has entered the jejunum portion of the small intestine (e.g., as determined by process 65900 described in connection with FIG. 73). Other ingestible devices capable of obtaining a sample or releasing a substance are described in commonly assigned PCT Application No. PCT / CA2013 / 000133, filed Feb. 15, 2013, commonly assigned U.S. Provisional Application No. 62 / 385,553, and commonly assigned U.S. Provisional Application No. 62 / 376,688, each of which is incorporated herein by reference in its entirety. It is understood that any suitable method of obtaining a sample or releasing a substance may be incorporated into some of the embodiments of the ingestible devices disclosed herein, and that the systems and methods for determining the position of an ingestible device may be incorporated into any suitable type of ingestible device.

[0403] The ingestible device 65100 may include a printed circuit board (PCB) 65120 and a battery 65128 configured to power the PCB 65120. The PCB 65120 may include a programmable microcontroller, as well as control and memory circuitry for holding and executing firmware or software for coordinating the operation of the ingestible device 65100, and various components of the ingestible device 65100. For example, the PCB 65120 may include memory circuitry for storing data, such as a data set of measurements collected by the sensing subunit 65126, or instructions to be executed by the control circuitry to implement a localization process, such as one or more of the processes described herein, including, for example, those described below in connection with one or more of the associated flow charts. The PCB 65120 may include a detector 65122 and an illuminator 65124, which together form the sensing subunit 65126. In some embodiments, the control circuitry within the PCB 65120 may include a processor, communication circuitry, or any other suitable type of circuitry for operating the ingestible device 65100. For illustrative purposes, only a single detector 65122 and a single illuminator 65124 are shown forming a single sensing subunit 65126. However, it is understood that in some embodiments, there may be multiple sensing subunits within the ingestible device 65100, each with a separate illuminator and detector. For example, there may be several sensing subunits spaced azimuthally around the PCB 65120, which may enable the ingestible device 65100 to transmit illumination and detect reflectance or ambient light in all directions around the device. In some embodiments, the sensing subunit 65126 may be configured to generate illumination using the illuminator 65124, which is directed radially away from the ingestible device 65100 through the window 65114. This illumination may reflect into the environment external to the ingestible device 65100 and the reflected light returning to the ingestible device 65100 through the window 65114 may be detected as reflectance by the detector 65122.

[0404] In some embodiments, the window 65114 may be any suitable shape and size. For example, the window 65114 may extend around the entire perimeter of the ingestible device 65100. In some embodiments, there may be multiple sensing subunits (e.g., similar to sensing subunit 65126) positioned at different locations behind the window. For example, three sensing subunits may be positioned behind the window at the same vertical location, but spaced 120 degrees apart in azimuth. This may enable the ingestible device 65100 to transmit illumination radially in all directions around the ingestible device 65100 to measure each of the corresponding reflectances.

[0405] In some embodiments, the illuminator 65124 may be capable of generating illumination at a variety of different wavelengths within the ultraviolet, infrared, or visible spectrum. For example, the illuminator 65124 may be implemented by using red-green-blue light emitting diode packages (RGB-LEDs). These types of RGB-LED packages are capable of delivering red, blue, or green illumination, or a combination of red, blue, or green illumination. Similarly, the detector 65122 may be configured to sense reflected light of the same wavelength as the illumination generated by the illuminator 65124. For example, if the illuminator 65124 is configured to generate red, blue, or green illumination, the detector 65122 may be configured to detect (e.g., through the use of appropriately configured photodiodes) the different reflectances generated by the red, blue, or green illumination. These detected reflectances may be stored by the ingestible device 65100 (e.g., within the memory circuitry of the PCB 65120) and then used by the ingestible device 65100 in determining the position of the ingestible device 65100 within the GI tract (e.g., through the use of process 65500 (FIG. 69), process 65600 (FIG. 70), or process 65900 (FIG. 73)).

[0406] It is understood that the ingestible device 65100 is intended to be illustrative and not limiting. It will be understood that modifications to the general shape and structure of the various devices and mechanisms described in connection with FIGS. 65 and 66 may be made without significantly altering the function and operation of the devices and mechanisms. For example, the ingestible device 65100 may have a housing formed from a single piece of molded plastic, rather than being split into a first end 65104 and a second end 65106. As an alternative, the location of the window 65114 within the ingestible device 65100 may be moved to some other location, such as the center of the ingestible device 65100, or one of the ends of the ingestible device 65100. Additionally, the systems and methods described in connection with FIGS. 65-74 may be implemented on any suitable type of ingestible device, provided that the ingestible device is capable of detecting the reflectance or level of illumination in some capacity. For example, in some embodiments, the ingestible device 65100 may be modified to replace the detector 65122 with an image sensor, and the ingestible device may be configured to measure relative levels of red, blue, or green light by decomposing the recorded image into its individual spectral components. Other examples of ingestible devices with location verification capabilities that may be utilized to implement the systems and methods described in connection with FIGS. 65-75 are described in commonly owned PCT Application No. PCT / US2015 / 052500, filed September 25, 2015, which is incorporated herein by reference in its entirety. Additionally, it should be noted that features and limitations described in any one embodiment may apply to any other embodiment herein, and descriptions and examples relating to one embodiment may be combined in any appropriate manner with any other embodiment.

[0407] 67 is a schematic diagram of an ingestible device during an example transition through the gastrointestinal (GI) tract, according to some embodiments of the present disclosure. The ingestible device 65300 may include any portion of any other ingestible device described in this disclosure (e.g., ingestible device 65100 (FIG. 65)) and may be any suitable type of ingestible device with location verification capabilities. For example, the ingestible device 65300 may be an embodiment of the ingestible device 65100 without the optional opening 65116 (FIG. 65) or the optional rotating assembly 65118 (FIG. 66). In some embodiments, the ingestible device 65300 may be ingested by a subject, and the ingestible device 65300 may be configured to determine its location within the GI tract as the ingestible device 65300 travels through the GI tract. For example, movement of the ingestible device 65300 and the amount of light detected by the ingestible device 65300 (e.g., using detector 65122 (FIG. 66)) may vary substantially depending on the position of the ingestible device 65300 within the GI tract, and the ingestible device 65300 may be configured to use this information to determine the position of the ingestible device 65300 within the GI tract. For example, the ingestible device 65300 may detect reflectance based on ambient light from the surrounding environment or illumination generated by the ingestible device 65300 (e.g., generated by illuminator 65124 (FIG. 65)) and use this information to determine the position of the ingestible device 65300 through processes as described herein. The current position of the ingestible device 65300 and the time at which the ingestible device 65300 detects each transition between various portions of the GI tract may then be stored by the ingestible device 65300 (e.g., in a memory circuit of the PCB 65120 (FIG. 66)) and may be used for any suitable purpose.

[0408] Shortly after the ingestible device 65300 is ingested, it may pass through the esophagus 65302, which may connect the subject's mouth to the stomach 65306. In some embodiments, the ingestible device 65300 may be configured to determine that it has entered the esophageal portion of the GI tract by measuring (e.g., with detector 65122 (FIG. 66)) the amount and type of light in the environment surrounding the ingestible device 65300. For example, the ingestible device 65300 may detect higher levels of light in the visible spectrum while outside the subject's body compared to the levels of light detected while inside the GI tract (e.g., with detector 65122 (FIG. 66)). In some embodiments, the ingestible device 65300 may have previously stored data (e.g., on a memory circuit of PCB 65120 (FIG. 66)) indicating typical levels of light detected when outside the body, and the ingestible device 65300 may be configured to determine that an intrusion into the body has occurred when the detected level of light (e.g., detected using detector 65122 (FIG. 66)) has decreased beyond a threshold level (e.g., a decrease of at least 20-30%) for a sufficient period of time (e.g., 5.0 seconds).

[0409] In some embodiments, the ingestible device 65300 may be configured to detect a transition from the esophagus 65302 to the stomach 65306 by passing through the sphincter 65304. In some embodiments, the ingestible device 65300 may be configured to determine whether it has entered the stomach 65306 based at least in part on a number of parameters, such as, but not limited to, the use of light or temperature measurements (e.g., by the detector 65122 (FIG. 66) or by a thermometer internal to the ingestible device 65300), pH measurements (e.g., by a pH meter internal to the ingestible device 65300), time measurements (e.g., as detected through the use of a clock circuit contained within the PCB 65120 (FIG. 66)), or any other suitable information. For example, the ingestible device 65300 may be configured to determine that the ingestible device 65300 has entered the stomach 65306 after detecting that a measured temperature of the ingestible device 65300 exceeds 31 degrees Celsius. Additionally or alternatively, the ingestible device 65300 may be configured to automatically determine that it is in the stomach 65306 after one minute (or another pre-set time minute parameter, 80 seconds, 90 seconds, etc.) has elapsed from the time the ingestible device 65300 was ingested or one minute (or another pre-set time minute parameter, 80 seconds, 90 seconds, etc.) has elapsed from the time the ingestible device 65300 detects that it is in the GI tract.

[0410] The stomach 65306 is a relatively large, open, hollow organ, and therefore the ingestible device 65300 may have a relatively large range of movement. In contrast, within the tubular interiors of the duodenum 65310, jejunum 65314, and ileum (not shown), all of which collectively form the small intestine, movement of the ingestible device 65300 is relatively restricted. Additionally, the interior of the stomach 65306 has different optical properties than the duodenum 65310 and jejunum 65314, which may enable the ingestible device 65300 to detect a transition from the stomach 65306 to the duodenum 65310 through appropriate use of measured reflectance (e.g., through use of reflectance measured by detector 65122 (FIG. 66)) as used in conjunction with process 65600 (FIG. 70).

[0411] In some embodiments, the ingestible device 65300 may be configured to detect a pyloric transition from the stomach 65306 through the pylorus 65308 to the duodenum 65310. For example, in some embodiments, the ingestible device 65300 may be configured to periodically generate illumination (e.g., with illuminator 65124 (FIG. 66)) in green and blue wavelengths and measure the resulting reflectance (e.g., with detector 65122 (FIG. 66)). The ingestible device 65300 may then be configured to use a ratio of the detected green reflectance to the detected blue reflectance to determine (e.g., in process 65600 (FIG. 70)) whether the ingestible device 65300 is located within the stomach 65306, or the duodenum 65310. This may in turn enable the ingestible device 65300 to detect a pyloric transition from the stomach 65306 to the duodenum 65310, an example of which is described in connection with FIG. 70.

[0412] Similarly, in some embodiments, the ingestible device 65300 may be configured to detect a retropyloric transition from the duodenum 65310 to the stomach 65306. The ingestible device 65300 typically naturally transitions from the stomach 65306 to the duodenum 65310 and toward the jejunum 65314 and the remainder of the GI tract. However, similar to other ingested substances, as a result of the subject's movements or due to the organ's natural behavior with the GI tract, the ingestible device 6530 may occasionally transition in the reverse direction from the duodenum 65310 to the stomach 65306. To accommodate this possibility, the ingestible device 65300 may be configured to periodically generate illumination in green and blue wavelengths (e.g., with illuminator 65124 (FIG. 66)) and continue to measure the resulting reflectance (e.g., with detector 65122 (FIG. 66)) to detect whether the ingestible device 65300 has returned to the stomach 65306. An exemplary detection process is described in further detail in conjunction with FIG.

[0413] After entering the duodenum 65310, the ingestible device 65300 may be configured to detect transition through the duodenal jejunal flexure 65312 into the jejunum 65314. For example, the ingestible device 65300 may be configured to use reflectance to detect peristalsis within the jejunum 65314 caused by contraction of smooth muscle cells lining the walls of the jejunum 65314. Specifically, the ingestible device 65300 may be configured to begin periodically transmitting illumination (and measuring the resulting reflectance (e.g., with the detector 65122 and illuminator 65124 of the sensing subunit 65126 ( FIG. 66 ))) at a sufficiently high frequency to detect muscle contractions within the jejunum 65314. The ingestible device 65300 may then determine that it has entered the jejunum 65314 in response to detecting either a first muscle contraction, or a predetermined number of muscle contractions (e.g., after detecting three muscle contractions in sequence). The interaction of the ingestible device 65300 with the walls of the jejunum 65314 is also described in relation to FIG. 68, and an example of this detection process is described in further detail in relation to FIG.

[0414] 68 is a schematic diagram of an ingestible device during an example transition through the jejunum, according to some embodiments of the present disclosure. Diagrams 65410, 65420, 65430, and 65440 show the ingestible device 65400 as it travels through the jejunum (e.g., jejunum 65314) and how it interacts with the peristalsis created by the walls 65406A and 65406B (collectively, walls 65406) ​​of the jejunum. In some embodiments, the ingestible device 65400 may include any portion of any other ingestible device described in this disclosure (e.g., ingestible device 65100 ( FIG. 65 ) or ingestible device 65300 ( FIG. 67 )) and may be any suitable type of ingestible device with location verification capabilities. For example, the ingestible device 65400 may be substantially similar to the ingestible device 65300 (FIG. 67) or the ingestible device 65100 (FIG. 66), with the window 65404 being the same as the window 65114 (FIG. 65) and the sensing subunit 65402 being the same as the sensing subunit 65126 (FIG. 66).

[0415] The schematic diagram 65410 shows the ingestible device 400 inside the jejunum when the wall 65406 of the jejunum is relaxed. In some embodiments, the closed tubular structure of the jejunum naturally orients the ingestible device 65400 longitudinally along the length of the jejunum, with the window 65404 facing the wall 65406. In this orientation, the ingestible device 65400 may use the sensing subunit 65402 to generate illumination (e.g., with the illuminator 65124 (FIG. 66)) toward the wall 65406 and detect the resulting reflectance (e.g., with the detector 65122 (FIG. 66)) from the portion of the illumination that reflects off the wall 65406 and back through the window 65404. In some embodiments, the ingestible device 65400 may be configured to use the sensing subunit 65402 to generate illumination and measure the resulting reflectance at a frequency sufficient to detect peristalsis inside the jejunum. For example, in healthy human subjects, peristalsis may occur at a rate of approximately 0.05 Hz to 0.33 Hz. Thus, the ingestible device 65400 may be configured to generate illumination and measure the resulting reflectance at least once every 2.5 seconds (i.e., the minimum rate to potentially detect a 0.2 Hz signal), and preferably at a higher rate, such as once every 0.5 seconds, where the overall reliability of the detection process may be improved due to more available data points. It is understood that the ingestible device 65400 does not need to collect measurements at precise intervals, and in some embodiments, the ingestible device 65400 may be adapted to analyze data collected at more irregular intervals, provided there is still a sufficient number of appropriately spaced data points to detect a 0.05 Hz to 0.33 Hz signal.

[0416] Diagram 65420 shows ingestible device 65400 inside the jejunum as the wall 65406 of the jejunum begins to contract to form peristalsis. Diagram 65420 shows contracting portion 65408A of wall 65406A and contracting portion 65408B of wall 65406B (collectively, contracting portion 65408 of wall 65406) ​​forming peristalsis inside the jejunum. As different portions of wall 65406 contract and relax, peristalsis progresses along the length of the jejunum, making it appear as if the contracting portion 65408 of wall 65406 is progressing along the length of the jejunum (i.e., as shown by the contracting portion 65408 progressing from left to right in diagrams 65410-65430). While in this position, the ingestible device 65400 may detect (e.g., through the use of illuminator 65124 and detector 65122 of sensing subunit 65126 (FIG. 66)) a similar level of reflectance as is detected when no peristalsis is occurring (e.g., as is detected when the ingestible device 65400 is in the position shown in diagram 65410).

[0417] The schematic 65430 shows the ingestible device 65400 inside the jejunum as the wall 65406 of the jejunum continues to contract, clamping around the ingestible device 65400. As peristalsis progresses along the length of the jejunum, the contracted portion 65408 of the wall 65406 may clamp tightly around the ingestible device 65400, bringing the inner surface of the wall 65406 into contact with the window 65404. While in this position, the ingestible device 65400 may detect a change in reflectance detected as a result of the illumination generated by the sensing subunit 65402. The absolute value of the change in measured reflectance may depend on several factors, such as the optical properties of the window 65404, the spectral content of the illumination, and the optical properties of the wall 65406. However, the ingestible device 65400 may be configured to store data sets having reflectance values ​​over time and look for periodic changes in the data sets that coincide with the frequency of peristalsis (e.g., by analyzing the data sets in the frequency domain and looking for peaks between 0.05 Hz and 0.33 Hz). This may allow the ingestible device 65400 to detect muscle contractions due to peristalsis without foreseeing the exact changes in reflectance signal amplitude that may result from peristaltic muscle contraction detection. An example procedure for detecting muscle contractions is further described in connection with FIG. 73, and an example reflectance data set collected while the ingestible device 65400 is located inside the jejunum is described in connection with FIG. 74.

[0418] Diagram 440 shows the ingestible device 65400 inside the jejunum as peristalsis passes through the ingestible device 65400. Diagram 65440 shows contractions 65408 forming peristalsis inside the jejunum that have passed an end of the ingestible device 65400. As different portions of the wall 65406 contract and relax, peristalsis progresses along the length of the jejunum, making it appear as if the contractions 65408 of the wall 65406 are progressing along the length of the jejunum (i.e., as shown by the contractions 65408 progressing from left to right in diagrams 65410-65430). While in this position, the ingestible device 65400 may detect (e.g., through the use of illuminator 65124 and detector 65122 of sensing subunit 65126 (FIG. 66)) a similar level of reflectance as is detected when no peristalsis is occurring (e.g., as is detected when the ingestible device 65400 is in the position shown in diagram 65410, or diagram 65420).

[0419] Depending on the species of the subject, peristalsis may occur with a relatively predictable regularity. After peristalsis passes the ingestible device 65400 (e.g., as shown in diagram 65440), the wall 65406 of the jejunum may relax again (e.g., as shown in diagram 65410) until the next peristalsis begins to form. In some embodiments, the ingestible device 65400 may be configured to continue to collect reflectance value data while it is inside the GI tract and may store data sets with reflectance values ​​over time. This may allow the ingestible device 65400 to detect each muscle contraction as peristalsis passes the ingestible device 65400 (e.g., as shown in diagram 65430), and may allow the ingestible device 65400 to count the number of muscle contractions that have occurred and determine that the current location of the ingestible device 65400 is inside the jejunum. For example, the ingestible device 65400 may be configured to monitor possible muscle contractions while within either the stomach or duodenum, and in response to detecting muscle contractions consistent with peristalsis, may determine that the ingestible device 65400 is moving into the jejunum.

[0420] FIG. 69 is a flow diagram illustrating some aspects of a localization process used by an ingestible device. FIG. 69 may be described in relation to an ingestible device 65100 for illustrative purposes, but this is not intended to be limiting, and any part or all of the localization procedure 65500 described in FIG. 69 may be applied to any device described in this application (e.g., ingestible devices 65100, 65300, and 65400), and any of the ingestible devices may be used to perform one or more parts of the process described in FIG. 69. Additionally, features of FIG. 69 may be combined with any other system, method, or process described in this application. For example, portions of the process of FIG. 69 may be incorporated into or combined with the pylorus transition detection procedure described by FIG. 70, or the jejunum detection process described by FIG. 73.

[0421] At 65502, the ingestible device (e.g., ingestible device 65100, 65300, or 65400) collects a measurement of ambient light (e.g., via detector 65122 (FIG. 66)). For example, the ingestible device 65100 may be configured to periodically measure the level of ambient light (e.g., via detector 65122 (FIG. 66)) in an environment surrounding the ingestible device 65100. In some embodiments, the type of ambient light being measured may depend on the configuration of the detector 65122 within the ingestible device 65100. For example, if the detector 65122 is configured to measure red, green, and blue wavelengths of light, the ingestible device 65100 may be configured to measure the ambient amount of red, green, and blue light from the surrounding environment. In some embodiments, the amount of ambient light measured by the ingestible device 65100 is greater in areas outside the body (e.g., a brightly lit room in which the ingestible device 65100 is administered to the subject) and within the subject's oral cavity compared to the ambient levels of light measured by the ingestible device 65100 when within the esophagus, stomach, or other portions of the GI tract (e.g., the esophagus 65302, stomach 65306, duodenum 65310, or jejunum 65314 (FIG. 67)).

[0422] At 65504, the ingestible device (e.g., ingestible device 65100, 65300, or 65400) determines (e.g., using control circuitry within PCB 65120 (FIG. 66)) whether the ingestible device has detected entry into the GI tract. For example, the ingestible device 65100 may be configured to determine when a most recent measurement of ambient light (e.g., the measurement collected in 65502) indicates that the ingestible device has entered the GI tract. For example, at 65502, the first time the ingestible device 65100 collects a measurement of ambient light, the ingestible device 65100 may store that measurement (e.g., using memory circuitry within PCB 65120 (FIG. 66)) as a typical level of ambient light outside the body. The ingestible device 65100 may then be configured to compare the most recent measurement of the ambient light to a typical level of ambient light outside the body (e.g., using control circuitry within the PCB 65120 (FIG. 66)) and determine that the ingestible device 65100 is in the GI tract if the most recent measurement of the ambient light is substantially less than the typical level of ambient light outside the body. For example, the ingestible device 65100 may be configured to detect that it is in the GI tract in response to determining that the most recent measurement of the ambient light is less than or equal to 20% of the typical level of ambient light outside the body. If the ingestible device 65100 determines that it is in the GI tract (e.g., the ingestible device 65100 is in at least the esophagus 65302 (FIG. 67)), the process 65500 proceeds to 65506. Alternatively, if the ingestible device 65100 determines that it has not detected an intrusion into the GI tract (e.g., as a result of the most recent measurement being similar to a typical level of ambient light outside the body), the process 65500 proceeds to 65502, where the ingestible device 65100 collects further measurements. For example, the ingestible device 65100 may be configured to wait a predetermined amount of time (e.g., 5 seconds, 10 seconds, etc.) and then collect another measurement of the ambient light level from the environment surrounding the ingestible device 65100.

[0423] At 65506, the ingestible device (e.g., ingestible device 65100, 65300, or 65400) waits for a transition from the esophagus to the stomach (e.g., from the esophagus 65302 to the stomach 65306 (FIG. 67)). For example, the ingestible device 65100 may be configured to wait a predetermined period of time after entering the GI tract before determining that it has entered the stomach (e.g., the stomach 65306 (FIG. 67)). For example, a typical esophageal transition time in a human subject may be approximately 15-30 seconds. In this case, after detecting at 65504 that the ingestible device 65100 has entered the GI tract (i.e., after detecting that the ingestible device 65100 has reached at least the esophagus 65302 (FIG. 67)), the ingestible device 65100 may be configured to wait one minute, or a similar period of time (e.g., 90 seconds) that is longer than a typical esophageal transit time, before automatically determining that the ingestible device 65100 has entered at least the stomach (e.g., stomach 65306 (FIG. 67)).

[0424] In some embodiments, the ingestible device (e.g., ingestible device 65100, 65300, or 65400) may also determine that it is in the stomach based on pH or temperature measurements. For example, the ingestible device 65100 may be configured to determine that it is in the stomach if the temperature of the ingestible device is elevated to at least 31 degrees Celsius (i.e., consistent with the temperature inside the stomach) or if the measured pH of the environment surrounding the ingestible device 65100 is sufficiently acidic (i.e., consistent with the acidic nature of gastric juices that may be found inside the stomach).

[0425] At 65508, the ingestible device (e.g., ingestible device 65100, 65300, or 65400) stores data indicating that the ingestible device has entered the stomach (e.g., stomach 306 (FIG. 67)). For example, after waiting a sufficient amount of time at 65506, the ingestible device 65100 may store (e.g., within memory circuitry of the PCB 65120 (FIG. 66)) data indicating that the ingestible device 65100 has at least entered the stomach. Once the ingestible device 65100 has reached at least the stomach, the process 65500 proceeds to 65510, where the ingestible device 65100 may be configured to collect data to detect entry into the duodenum (e.g., duodenum 65310 (FIG. 67)).

[0426] In some embodiments, process 65500 may also proceed simultaneously from 65508 to 65520, where ingestible device 65100 may be configured to detect muscle contractions and gather data to detect entry into the jejunum (e.g., jejunum 65314 (FIG. 67)). In some embodiments, ingestible device 65100 may be configured to simultaneously monitor entry into the duodenum at 65516-65518 and detect entry into the jejunum at 65520-65524. This may allow ingestible device 65100 to determine when it is entering the jejunum (e.g., as a result of detecting muscle contractions) even if it is not initially able to detect entry into the duodenum (e.g., as a result of the ingestible device passing through the duodenum too quickly).

[0427] At 65510, the ingestible device (e.g., ingestible device 65100, 65300, or 65400) collects measurements of green and blue reflectance levels (e.g., through use of illuminator 65124 and detector 65122 of sensing subunit 65126 (FIG. 66)) while in the stomach (e.g., stomach 65306 (FIG. 67)). For example, ingestible device 100 may be configured to periodically collect measurements of green and blue reflectance levels while in the stomach. For example, ingestible device 65100 may be configured to transmit green illumination and blue illumination (e.g., using illuminator 65124 (FIG. 66)) every 5-15 seconds and measure the resulting reflectance (e.g., using detector 65122 (FIG. 66)). Each time the ingestible device 65100 collects a new set of measurements, the measurements may be added to a stored dataset (e.g., stored within the memory circuitry of the PCB 65120 (FIG. 66)). The ingestible device 65100 may then use this dataset to determine whether the ingestible device 65100 is still inside the stomach (e.g., stomach 65306 (FIG. 67)), or the duodenum (e.g., duodenum 65310 (FIG. 67)).

[0428] In some embodiments, an ingestible device (e.g., ingestible device 65100, 65300, or 65400) may be configured to detect a first reflectance based on generating illumination at a first wavelength approximately within the green spectrum of light (between 495-600 nm) and detect a second reflectance based on generating illumination at a second wavelength approximately within the blue spectrum of light (between 400-495 nm). In some embodiments, the ingestible device may ensure that the illumination within the green spectrum and the illumination within the blue spectrum have wavelengths separated by at least 50 nm. This may allow the ingestible device 65100 to sufficiently distinguish between the two wavelengths when detecting the reflectance (e.g., with detector 65122 (FIG. 66)). It is understood that a separation of 50 nm is intended to be exemplary and not limiting, and that it may be possible to use less separation depending on the accuracy of the detector within the ingestible device 65100.

[0429] At 65512, the ingestible device (e.g., ingestible device 65100, 65300, or 65400) determines (e.g., using control circuitry within PCB 65120 (FIG. 66)) whether the ingestible device has detected a transition from the stomach (e.g., stomach 65306 (FIG. 67)) to the duodenum (e.g., duodenum 65310 (FIG. 67)) based on the ratio of green and blue (G / B) reflectance levels. For example, the ingestible device 65100 may obtain (e.g., from a memory circuitry of PCB 65120 (FIG. 66)) a data set including historical data for each ratio of green reflectance to blue reflectance measured at each time. Generally speaking, the duodenum (e.g., duodenum 65310 (FIG. 67)) of a human subject reflects a higher ratio of green light to blue light compared to the ratio of green light to blue light reflected by the stomach (e.g., stomach 65306 (FIG. 67)). Based on this, the ingestible device 65100 may be configured to obtain a first set of ratios from a data set representing the results of recent measurements and compare them to a second set of ratios from a data set representing the results of past measurements. If the ingestible device 65100 determines that the average value of the first set of ratios is substantially greater than the average value of the second set of ratios (i.e., the ratio of reflected green light to reflected blue light is increasing), the ingestible device 65100 may determine that it is entering the duodenum (e.g., duodenum 65310 (FIG. 67)) from the stomach (e.g., stomach 65306 (FIG. 66)). If the ingestible device 65100 detects a transition from the stomach (e.g., stomach 65306 (FIG. 67)) to the duodenum (e.g., duodenum 65310 (FIG. 67)), the process 65500 proceeds to 65514, where the ingestible device 65100 stores data indicating that the ingestible device 65100 has entered the duodenum (e.g., duodenum 65310 (FIG. 67)). Alternatively, if the ingestible device determines that the ingestible device has not transitioned from the stomach (e.g., stomach 65306 (FIG. 67)) to the duodenum (e.g., duodenum 65310 (FIG. 67)), the process 65500 returns to 65510 to collect more measurements of green and blue reflectance levels while still in the stomach (e.g., stomach 65306 (FIG. 67)).An example procedure for using green and blue reflectance measurements to monitor the transition between the stomach and duodenum is described in further detail in connection with FIG.

[0430] In some embodiments, the first time the ingestible device 65100 detects a transition from the stomach (e.g., stomach 65306 (FIG. 67)) to the duodenum (e.g., duodenum 65310 (FIG. 67)), the ingestible device 65100 may be configured to take an average of a second set of data (e.g., a set of data previously recorded while in the stomach 65306 (FIG. 67)) and store this (e.g., within the memory circuitry of the PCB 65120 (FIG. 67)) as a typical ratio of green light to blue light detected within the stomach (e.g., stomach 65306 (FIG. 67)). This stored information may later be used by the ingestible device 65100 to determine when the ingestible device 65100 re-enters the stomach (e.g., stomach 65306 (FIG. 67)) from the duodenum (e.g., duodenum 65310 (FIG. 67)) as a result of a retropylorus transition.

[0431] At 65514, the ingestible device (e.g., ingestible device 65100, 65300, or 65400) stores data indicating that the ingestible device has entered the duodenum (e.g., duodenum 65310 (FIG. 67)). For example, the ingestible device 65100 may store a flag within local memory (e.g., memory circuitry of the PCB 65120) indicating that the ingestible device 65100 is currently within the duodenum. In some embodiments, the ingestible device 65100 may also store a timestamp indicating the time the ingestible device 65100 entered the duodenum. Once the ingestible device 65100 reaches the duodenum, the process 65500 proceeds to 65520, where the ingestible device 65100 may be configured to detect muscle contractions to gather data to detect entry into the jejunum (e.g., jejunum 65314 (FIG. 67)). The process 65500 also proceeds from 65514 to 65516, where the ingestible device 65100 can be configured to collect additional data to consider re-entry from the duodenum (e.g., duodenum 65310 (FIG. 67)) into the stomach (e.g., stomach 65306 (FIG. 67)).

[0432] At 65516, the ingestible device (e.g., ingestible device 65100, 65300, or 65400) collects measurements (e.g., using sensing subunit 65126 (FIG. 66)) of green and blue reflectance levels while in the duodenum (e.g., duodenum 65310 (FIG. 67)). For example, ingestible device 65100 may be configured to periodically collect measurements (e.g., using sensing subunit 65126 (FIG. 66)) of green and blue reflectance levels while in the duodenum, similar to the measurements taken while in the stomach at 65510. For example, ingestible device 65100 may be configured to transmit green and blue illumination (e.g., using illuminator 65124 (FIG. 66)) every 5-15 seconds and measure the resulting reflectance (e.g., using detector 65122 (FIG. 66)). Each time the ingestible device 65100 collects a new set of measurements, the measurements may be added to a stored dataset (e.g., stored within the memory circuitry of the PCB 65120 (FIG. 66)). The ingestible device 65100 may then use this dataset to determine whether the ingestible device 65100 is still inside the duodenum (e.g., duodenum 65310 (FIG. 67)) or whether the ingestible device 65100 has transitioned back into the stomach (e.g., stomach 65306 (FIG. 67)).

[0433] At 65518, the ingestible device (e.g., ingestible device 65100, 65300, or 65400) determines a transition from the duodenum (e.g., duodenum 65310 (FIG. 67)) to the stomach (e.g., stomach 65306 (FIG. 67)) based on the ratio of the measured green reflectance level to the measured blue reflectance level. In some embodiments, the ingestible device 65100 may compare the ratio of the measured green reflectance level to the measured blue reflectance level recently collected by the ingestible device 65100 (e.g., measurements collected at 65516) to determine whether the ratio of the measured green reflectance level to the measured blue reflectance level is similar to the average ratio of the measured green reflectance level to the measured blue reflectance level found in the stomach (e.g., stomach 65306 (FIG. 67)). For example, the ingestible device 65100 may obtain (e.g., from a memory circuit of the PCB 65120 (FIG. 66)) data indicative of an average ratio of measured green reflectance levels to measured blue reflectance levels found in the stomach, and if a recently measured ratio of measured green reflectance levels to measured blue reflectance levels is sufficiently similar to the average levels in the stomach (e.g., within 20% of the average ratio of measured green reflectance levels to measured blue reflectance levels found in the stomach), it may determine that the ingestible device 65100 has transitioned back to the stomach. If the ingestible device detects a transition from the duodenum (e.g., duodenum 65310 (FIG. 67)) to the stomach (e.g., stomach 65306 (FIG. 67)), the process 65500 proceeds to 65508 to store data indicating that the ingestible device has entered the stomach (e.g., stomach 65306 (FIG. 67)) and continues to monitor for further transitions. Alternatively, if the ingestible device does not detect transition from the duodenum (e.g., duodenum 65310 (FIG. 67)) to the stomach (e.g., stomach 65306 (FIG. 67)), the process 65500 proceeds to 65516 to collect additional measurements of green and blue reflectance levels while in the duodenum (e.g., duodenum 65310 (FIG. 67)), which can be used to continue to monitor for possible back transition into the stomach.An example procedure for using green and blue reflectance measurements to monitor the transition between the stomach and duodenum is described in further detail in connection with FIG.

[0434] At 65520, the ingestible device (e.g., ingestible device 65100, 65300, or 65400) periodically collects reflectance level measurements (e.g., using sensing subunit 65126 (FIG. 66)) while in the duodenum (e.g., duodenum 65310 (FIG. 67)). In some embodiments, the ingestible device (e.g., ingestible device 65100, 65300, or 65400) may collect similar periodic measurements while in the stomach as well. In some embodiments, these periodic measurements may enable the ingestible device 65100 to detect muscle contractions (e.g., muscle contractions due to peristalsis as described in connection with FIG. 68), which may indicate entry into the jejunum (e.g., jejunum 65314 (FIG. 67)). The ingestible device 65100 may be configured to collect periodic measurements using any suitable wavelength of illumination, or a combination of multiple wavelengths of illumination (e.g., by generating illumination using illuminator 65124 and detecting the resulting reflectance using detector 65122 (FIG. 66)). For example, in some embodiments, the ingestible device 65100 may be configured to generate red, green, and blue illumination, store separate data sets indicative of the red, green, and blue illumination, and analyze each of the data sets separately to look for frequency components indicative of detected muscle contractions within the recorded data. In some embodiments, the measurements collected by the ingestible device 65100 at 65520 may be fast enough to detect peristalsis within the subject. For example, in a healthy human subject, peristalsis may occur at a rate of approximately 0.05 Hz to 0.33 Hz. Thus, the ingestible device 65400 may be configured to generate illumination and measure the resulting reflectance at least once every 2.5 seconds (i.e., a minimum rate to potentially detect a 0.2 Hz signal), and preferably at a higher rate, such as once every 0.5 seconds or faster, and store a value indicative of the resulting reflectance in a dataset (e.g., within a memory circuit of the PCB 65120 (FIG. 66)). After collecting additional data (e.g., after collecting one new data point, or a predetermined number of new data points), the process 65500 proceeds to 65522, where the ingestible device 65100 determines whether a muscle contraction has been detected.

[0435] At 65522, the ingestible device (e.g., ingestible device 65100, 65300, or 65400) determines (e.g., using control circuitry within PCB 65120 (FIG. 66)) whether the ingestible device detects a muscle contraction based on the reflectance level measurements (e.g., as collected by sensing subunit 65126 (FIG. 66)). For example, the ingestible device 65100 may retrieve a quantity of data stored as a result of measurements made at 65520 (e.g., retrieve the past minute of data from memory circuitry within PCB 65120 (FIG. 66)). The ingestible device 65100 may then convert the retrieved data into the frequency domain and look for peaks in a frequency range that may correspond to peristalsis. For example, in a healthy human subject, peristalsis may occur at a rate of approximately 0.05 Hz to 0.33 Hz, and the ingestible device 65100 may be configured to look for peaks in the frequency domain representation of the data between 0.05 Hz and 0.33 Hz that are above a threshold. If the ingestible device 65100 detects contractions based on the reflectance levels (e.g., based on detecting peaks in the frequency domain representation of the data between 0.05 Hz and 0.33 Hz), the process 65500 proceeds to 65524 to store data indicating that the device is in the jejunum. Alternatively, if the ingestible device 65100 does not detect muscle contractions, the process 65500 proceeds to 65520 to collect periodic measurements of reflectance levels while in the duodenum (e.g., duodenum 65310 (FIG. 67)). In some embodiments, the ingestible device (e.g., ingestible device 65100, 65300, or 65400) may store data indicating that a muscle contraction has been detected (e.g., within the memory circuitry of PCB 65120 (FIG. 66)), and process 65500 will not begin 65522-65524 until a sufficient number of muscle contractions have been detected.

[0436] At 65524, the ingestible device (e.g., ingestible device 65100, 65300, or 65400) stores (e.g., within the memory circuitry of the PCB 65120 (FIG. 66)) data indicating that the device is in the jejunum (e.g., jejunum 65314 (FIG. 67)). For example, in response to detecting that muscle contractions are occurring at 65522, the ingestible device 65100 may determine that it has entered the jejunum 65314 and is no longer inside the duodenum (e.g., duodenum 65310 (FIG. 67)) or stomach (e.g., stomach 65306 (FIG. 67)). In some embodiments, the ingestible device 65100 may continue to measure muscle contractions while in the jejunum and may store data indicating the frequency, number, or intensity of the muscle contractions over time (e.g., within the memory circuitry of the PCB 65120 (FIG. 66)). In some embodiments, the ingestible device 65100 can also be configured to monitor one or more transitions, including the jejunum to ileum transition, the ileum to cecum ileocecal transition, and the cecum to colon transition, and can detect exit from the body (e.g., by measuring ambient light reflectance, temperature, or levels).

[0437] In some embodiments, the ingestible device (e.g., ingestible device 65100, 65300, or 65400) may also determine that it has entered the jejunum (e.g., jejunum 65314 (FIG. 67)) after a predefined time has elapsed after detecting entry into the duodenum (e.g., duodenum 65310 (FIG. 67)). For example, in the absence of a reverse pylorus transition from the duodenum (e.g., duodenum 65310 (FIG. 67)) back to the stomach (e.g., stomach 65306 (FIG. 67)), a typical transition time for an ingestible device to reach the jejunum from the duodenum in a healthy human subject is less than three minutes. In some embodiments, the ingestible device (e.g., ingestible device 65100, 65300, or 65400) may thus be configured to automatically determine that it has entered the jejunum after spending at least three minutes inside the duodenum. This determination may be made separately from a determination made based on measured muscle contractions (e.g., a determination made in 65522), and in some embodiments, the ingestible device 65100 may determine that it has entered the jejunum in response to detecting muscle contractions or after three minutes have elapsed since entering the duodenum (e.g., as determined by storing data in 65514 indicating the time the ingestible device entered the duodenum).

[0438] For illustrative purposes, 65512-65518 of process 65500 describe an ingestible device (e.g., ingestible device 65100, 65300, or 65400) that measures green reflectance and blue reflectance, calculates a ratio of the two reflectances, and uses this information to determine when the ingestible device has transitioned between the duodenum and the stomach. However, in some embodiments, other wavelengths of light besides green and blue may be used, provided that the light of the selected wavelengths has different reflective properties within the stomach and duodenum (e.g., as a result of different reflectance coefficients of stomach and duodenal tissue).

[0439] It will be understood that the steps and descriptions of the flow charts of the present disclosure, including FIG. 69, are merely illustrative. Any of the steps and descriptions of the flow charts, including FIG. 69, may be modified, omitted, rearranged, and performed in alternative orders or in parallel, two or more of the steps may be combined, or any additional steps may be added, without departing from the scope of the present disclosure. For example, the ingestible device 65100 may calculate the mean and standard deviation of multiple data sets in parallel to speed up the overall computation time. As another example, the ingestible device 65100 may collect data periodic measurements to detect possible muscle contractions (e.g., at 65520-65522) while simultaneously collecting green and blue reflectance levels (e.g., at 65510-65518) to determine transitions to and from the stomach and duodenum. Additionally, it should be noted that the steps and descriptions in FIG. 69 may be combined with any other systems, devices, or methods described in this application, including processes 65600 (FIG. 70) and 65900 (FIG. 73), and any ingestible device or system described in this application (e.g., ingestible device 65100, 65300, or 65400) may be used to perform one or more of the steps in FIG. 69.

[0440] 70 is a flow diagram illustrating some aspects of a process for detecting transitions from the stomach to the duodenum and from the duodenum back to the stomach according to some embodiments of the present disclosure, which may be used in determining the location of an ingestible device as it passes through the gastrointestinal (GI) tract. In some embodiments, the process 65600 may begin when the ingestible device first detects that it has entered the stomach and continues as long as the ingestible device determines that it is within the stomach or duodenum. In some embodiments, the process 65600 may end only when the ingestible device determines that it has entered the jejunum or has otherwise passed through the duodenum and stomach. FIG. 70 may be described in relation to an ingestible device 65100 for illustrative purposes, but this is not intended to be limiting, and any portion or all of the duodenum detection process 65600 described in FIG. 70 may be applied to any device described in this application (e.g., ingestible device 65100, 65300, or 65400), and any of the ingestible devices may be used to perform one or more portions of the process described in FIG. 70. Additionally, features of FIG. 70 may be combined with any other system, method, or process described in this application. For example, portions of the process described by the process of FIG. 70 may be incorporated into the process 65500 described in relation to FIG. 69.

[0441] At 65602, the ingestible device (e.g., ingestible device 65100, 65300, or 65400) retrieves (e.g., from a memory circuit within PCB 65120 (FIG. 66)) a data set having a ratio of measured green reflectance levels to measured blue reflectance levels over time. For example, ingestible device 65100 may retrieve a data set from PCB 65120 including a recently recorded (e.g., as recorded at 65510 or 65516 of process 65500 (FIG. 69)) ratio of measured green reflectance levels to measured blue reflectance levels. In some embodiments, the retrieved data may include a ratio of measured green reflectance levels to measured blue reflectance levels over time. Example plots of a data set of ratios of measured green reflectance levels to measured blue reflectance levels are further described in connection with FIGS. 71 and 72.

[0442] At 65604, the ingestible device (e.g., ingestible device 65100, 65300, or 65400) includes in the data set the new measurement (e.g., as performed by sensing subunit 65126 (FIG. 66)) of the ratio of the measured green reflectance level to the measured blue reflectance level. For example, the ingestible device 65100 may be configured to record new data from time to time by transmitting green and blue illumination (e.g., with illuminator 65124 (FIG. 66)), detecting an amount of reflectance received due to the green and blue illumination (e.g., with detector 65122 (FIG. 66)), and storing data indicative of the amount of reflectance received (e.g., in a memory circuit within PCB 65120 (FIG. 66)). The ingestible device 65100 may be configured to record new data every 5-15 seconds, or any other convenient time interval. For purposes of illustration, the ingestible device 65100 is described as storing and retrieving a ratio of a measured green reflectance level to a measured blue reflectance level (e.g., if at a given time the amount of green reflectance detected was the same as the amount of blue reflectance detected, then the ratio of green and blue reflectance at that given time would be "1.0"); however, it is understood that the green reflectance data and the blue reflectance data may be stored separately within the memory of the ingestible device 65100 (e.g., stored within the memory circuitry of the PCB 65120 (FIG. 66) as two separate data sets).

[0443] At 65606, the ingestible device (e.g., ingestible device 65100, 65300, or 65400) obtains a first subset of recent data by applying a first sliding window filter to the dataset. For example, the ingestible device 65100 may use a sliding window filter to obtain a predetermined amount of recent data in the dataset, where the dataset may include any new values ​​of the ratio of measured green reflectance levels to measured blue reflectance levels obtained at 65604. For example, the ingestible device may be configured to select 10-40 data points from the dataset, or the ingestible device 65100 may be configured to select a predetermined range of data values ​​between 15 seconds of data and 5 minutes of data. In some embodiments, other ranges of data may be selected depending on how often measurements are recorded and the particular application at hand. For example, any suitable amount of data may be selected within the sliding window, provided that it is sufficient to detect statistically significant differences between the data selected within the second sliding window (e.g., the second subset of data selected in 65614).

[0444] In some embodiments, the ingestible device (e.g., ingestible device 65100, 65300, or 65400) may also be configured to remove outliers from a dataset or to remove unnecessary noise in a dataset. For example, the ingestible device 65100 may select a first subset of data, or any other subset of data, by first obtaining a raw set of values, by applying a window filter to the dataset (e.g., selecting a particular range of data to include). The ingestible device 65100 may then be configured to identify outliers within the raw set of values, for example, by identifying data points that are more than three standard deviations away from the mean of the raw set of values, or any suitable threshold. The ingestible device 65100 may then determine the subset of data by removing the outliers from the raw set of values. This may enable the ingestible device 65100 to avoid false information when determining whether the ingestible device 65100 is located inside the stomach or duodenum.

[0445] At 65608, the ingestible device (e.g., ingestible device 65100, 65300, or 65400) determines whether the most recently detected location was the duodenum (e.g., duodenum 65310 (FIG. 67)). In some embodiments, the ingestible device 65100 may store (e.g., within the memory circuitry of the PCB 65120 (FIG. 66)) a data flag indicating the most recent portion of the GI tract that it was detected to be within. For example, each time the ingestible device 65100 detects entry into the stomach (e.g., detects entry into the stomach 65306 (FIG. 67) as a result of a determination made at 65610), a flag is stored in memory (e.g., as part of the data storage at 65612) indicating that the ingestible device 65100 is within the stomach. If the ingestible device 65100 subsequently detects entry into the duodenum (e.g., detects entry into the duodenum 65310 (FIG. 67) as a result of the determination made in 65624), then another, different flag is stored in memory (e.g., as part of the data storage in 65624) indicating that the ingestible device 65100 is within the duodenum. In this case, the ingestible device 65100 may retrieve the most recently stored flag at 65608 to determine whether the flag indicates that the ingestible device 65100 was most recently inside the duodenum. If the ingestible device 65100 detects that it was recently in the duodenum, process 65600 proceeds to 65610, where the ingestible device compares recent measurements (e.g., including recent measurements made at 65606) of the ratio of the measured green reflectance level to the measured blue reflectance level to a typical ratio measured within the stomach and uses this information to determine whether a reverse pyloric transition from the duodenum back to the stomach is occurring. Alternatively, if the ingestible device 65100 detects that it was not recently in the duodenum (e.g., because it was instead in the stomach), process 65600 proceeds to 65614, where the ingestible device compares recent measurements (e.g., including recent measurements made at 65606) of the ratio of the measured green reflectance level to the measured blue reflectance level to a past measurement and uses this information to determine whether a pyloric transition from the stomach to the duodenum is occurring.

[0446] The process 65600 proceeds from 65608 to 65610 if the ingestible device determines that it was most recently in the duodenum. At 65610, the ingestible device (e.g., ingestible device 65100, 65300, or 65400) determines (e.g., using control circuitry within PCB 65120 (FIG. 66)) whether the current G / B signal is similar to an average G / B signal recorded within the stomach. For example, the ingestible device 65100 may be configured to have previously stored data (e.g., within memory circuitry of PCB 65120 (FIG. 66)) indicating an average ratio of measured green reflectance levels to measured blue reflectance levels measured within the stomach. The ingestible device 65100 may then retrieve this stored data indicating the average ratio of the measured green reflectance level to the measured blue reflectance level in the stomach and compare it to recent measurements to determine if the ingestible device 65100 has returned from the duodenum to the stomach. For example, the ingestible device 65100 may determine whether the average value of a first subset of recent data (i.e., the average value of the recently measured ratios of the measured green reflectance level to the measured blue reflectance level) is less than the average ratio measured within the stomach to the measured blue reflectance level, or less than the average ratio measured within the stomach plus a predetermined number times the standard deviation of the ratio measured within the stomach. For example, if the average ratio of measured green reflectance levels to measured blue reflectance levels within the stomach was "1" with a standard deviation of "0.2", then the ingestible device 100 may determine whether the average value of the first subset of data is less than "1.0+k*0.2", where "k" is a number between 0 and 5. It is understood that in some embodiments, the ingestible device 65100 may be configured to use different threshold levels to determine whether the average value of the first subset of recent data is sufficiently similar to the average ratio of measured green reflectance levels to measured blue reflectance levels within the stomach.In response to determining that the recent ratio of the measured green reflectance levels to the measured blue reflectance levels is similar to the average ratio of the measured green and blue reflectance levels found in the stomach, the process 65600 proceeds to 65612, where the ingestible device 65100 stores data indicating that it has re-entered the stomach from the duodenum. Alternatively, in response to determining that the recent ratio of the measured green and blue reflectance levels is sufficiently different from the average ratio of the measured green and blue reflectance levels found in the stomach, the ingestible device 65100 proceeds directly to 65604 to continue acquiring new data on an ongoing basis.

[0447] At 65612, the ingestible device (e.g., ingestible device 65100, 65300, or 65400) stores data indicating that a retropyloric transition from the duodenum to the stomach was detected. For example, the ingestible device 65100 may store (e.g., within the memory circuitry of the PCB 65120 (FIG. 66)) a data flag indicating that it was most recently detected to be within the stomach portion of the GI tract (e.g., stomach 65306 (FIG. 67)). In some embodiments, the ingestible device 65100 may also store (e.g., within the memory circuitry of the PCB 65120 (FIG. 66)) data indicating the time that the ingestible device 65100 detected a retropyloric transition from the duodenum to the stomach. This information may be used by the ingestible device 65100 at 65608, and as a result, the process 65600 may proceed from 65608 to 65614 rather than from 65618 to 65610. After the ingestible device 65100 stores data indicating that a retropyloric transition from the duodenum to the stomach has been detected, the process 65600 proceeds to 65604, where the ingestible device 65100 continues to collect additional measurements and monitors for further transitions between the stomach and the duodenum.

[0448] The process 65600 proceeds from 65608 to 65614 if the ingestible device determines that it was not recently in the duodenum (e.g., as a result of instead being recently in the stomach). At 65614, the ingestible device (e.g., ingestible device 65100, 65300, or 65400) obtains a second subset of previous data by applying a second sliding window filter to the data set. For example, the ingestible device 65100 may use a sliding window filter to obtain a predetermined amount of older data from a past time range, which may be separated from the recent time range used to select the first subset of data collected in 65606 by a predetermined time period. In some embodiments, any suitable amount of data may be selected by the first and second window filters, and the first and second window filters may be separated by any suitable predetermined time. For example, in some embodiments, the first window filter and the second window filter may each be configured to select a predetermined range of data values ​​from the data set, the predetermined range being between 15 seconds and 5 minutes of data. In some embodiments, the recent measurements and the past measurements may then be separated by a predetermined time period that is between 1 and 5 times the data values ​​of the predetermined range. For example, the ingestible device 65100 may select the first subset of data and the second subset of data to each be one minute of data selected from the data set (i.e., selected to have one minute in the predetermined range), where the first subset of data and the second subset of data are selected from recorded measurements that are at least two minutes apart (i.e., the predetermined time period is two minutes, which is twice the range used to select the subset of data using the window filter).As another example, the ingestible device 100 may select the first subset of data and the second subset of data to each be 5 minutes of data selected from the data set (i.e., selected to have a predetermined range of 5 minutes), and the first subset of data and the second subset of data are selected from recorded measurements that are at least 10 minutes apart (i.e., the predetermined period is 2 minutes, which is twice the range used to select the subset of data using the window filter).

[0449] In some embodiments, if the ingestible device 65100 has recently transitioned from the duodenum to the stomach (e.g., as determined by checking recent data stored within the ingestible device 65100 at 65612), the ingestible device 65100 may select at 65614 a second subset of data from a time frame in which the ingestible device 65100 is known to be within the stomach. In some embodiments, the ingestible device 65100 may alternatively select a previously recorded mean and standard deviation for the ratio of green reflectance and blue reflectance within the stomach (e.g., the mean and standard deviation of data recorded within the stomach, as previously recorded within the memory circuitry of the PCB 65120 at 65620) instead of the second subset of data. In this case, the ingestible device 65100 may simply use the previously recorded mean and previously recorded standard deviation when making its determination at 65616, rather than expending resources to calculate the mean and standard deviation of the second subset.

[0450] At 65616, the ingestible device (e.g., ingestible device 65100, 65300, or 65400) determines whether the difference between the mean of the second subset and the mean of the first subset is greater than a predetermined multiple of the standard deviation of the first subset. For example, the ingestible device 65100 may calculate the difference between the mean of the first subset of recent data and the mean of the second subset of historical data to determine whether the difference is greater than three times the standard deviation of the second subset of historical data. It is understood that in some embodiments, any convenient threshold level other than three times the standard deviation may be used, such as any value between 1-5 times the standard deviation. Also, in some embodiments, the ingestible device may instead set the threshold level based on the standard deviation of the second subset instead of the first subset. In response to a determination that the difference between the mean of the first subset and the mean of the second subset is greater than a predetermined multiple of the standard deviation of the second subset, the process 65600 proceeds to 65618. If not, the process 65600 returns to 65604, where the ingestible device 65604 continues to collect new data for use in monitoring the transition between the stomach (e.g., stomach 65306 (FIG. 67)) and the duodenum (e.g., duodenum 65310 (FIG. 67)).

[0451] At 65618, the ingestible device (e.g., ingestible device 65100, 65300, or 65400) determines whether the determination made at 65616 is the first time that the difference between the mean of the first subset of recent data and the mean of the second subset of historical data is calculated to be greater than the standard deviation of the second subset. If the ingestible device determines that this is the first time that the difference between the mean of the first subset and the mean of the second subset is calculated to be greater than the standard deviation of the second subset, process 65600 proceeds to 65620 to store the average of the second subset of historical data as the average G / B signal in the stomach. Alternatively, if the ingestible device determines that the most recent determination made at 65616 is not the first time that the difference between the mean of the first subset of recent data and the mean of the second subset of historical data is calculated to be greater than the standard deviation of the second subset, process 65600 proceeds directly to 65622.

[0452] At 65620, the ingestible device (e.g., ingestible device 65100, 65300, or 65400) stores the average of the second subset as the average G / B signal in the stomach. For example, the ingestible device 65100 stores the average of the second subset of historical data as the average ratio of the measured green reflectance level to the measured blue reflectance level measured in the stomach (e.g., stored within the memory circuitry of the PCB 65120 (FIG. 66)). In some embodiments, the ingestible device 65100 also stores the standard deviation of the second subset of historical data as the typical standard deviation of the ratio of the measured green reflectance level to the measured blue reflectance level detected in the stomach. This stored information may be used at a later time (e.g., at 65610) by the ingestible device for comparison against future data, which may enable the ingestible device to detect a retropyloric transition from the duodenum (e.g., duodenum 65310 (FIG. 67)) back to the stomach (e.g., stomach 65306 (FIG. 67)), and may generally be used in place of other experimental data collected from the stomach (e.g., in place of the second subset of data at 65616). After storing the average of the second subset as the average G / B signal in the stomach, process 65600 proceeds to 65622.

[0453] At 65622, the ingestible device (e.g., ingestible device 65100, 65300, or 65400) determines whether the difference between the mean of the first subset of recent data and the mean of the second subset of historical data is greater than a predetermined threshold "M". In some embodiments, the predetermined threshold "M" may be large enough to ensure that the mean of the first subset is substantially greater than the mean of the second subset, allowing the ingestible device 65100 to be certain that it has detected actual transition into the duodenum. This may be particularly advantageous if the determination made at 65616 is potentially unreliable due to an unusually small standard deviation of the second subset of historical data. For example, a typical value for the predetermined threshold "M" may be about 0.1 to 0.5. If the ingestible device 65100 determines that the difference between the average of the first subset of recent data and the second subset of historical data is greater than a predetermined threshold, the process 65600 proceeds to 65624 to store data indicating that a pylorus transition from the stomach to the duodenum (e.g., from stomach 65306 to duodenum 65310 (FIG. 67)) was detected. Alternatively, if the ingestible device determines that the ratio of the average of the first subset to the second subset is less than or equal to the predetermined threshold "M" (i.e., determining that a transition to the duodenum has not occurred), the process 65600 proceeds directly to 65604 where the ingestible device 65100 continues to take new measurements to monitor possible transitions between the stomach and the duodenum.

[0454] In some embodiments, instead of using the difference between the average of the first subset of recent data and the average of the second subset of historical data, the ingestible device (e.g., ingestible device 65100, 65300, or 65400) determines whether the ratio of the average of the first subset of recent data to the average of the second subset of historical data is greater than a predetermined threshold "M". In some embodiments, the predetermined threshold "M" may be large enough to ensure that the average of the first subset is substantially greater than the average of the second subset, allowing the ingestible device 65100 to be certain that it has detected actual transition into the duodenum. This may be particularly advantageous if the determination made in 65616 is potentially unreliable due to an unusually small standard deviation of the second subset of historical data. For example, a typical value for the predetermined threshold "M" may be about 1.2 to 2.0. It will be appreciated that any convenient type of threshold or calculation may be used to determine whether the first subset of data and the second subset of data are statistically different from one another and also substantially different from one another with respect to an overall average value.

[0455] At 65624, the ingestible device (e.g., ingestible device 65100, 65300, or 65400) stores data indicating that a pyloric transition from the stomach to the duodenum was detected. For example, the ingestible device 65100 may store (e.g., within the memory circuitry of the PCB 65120 (FIG. 66)) a data flag indicating that the ingestible device 65100 most recently detected itself within the duodenal portion of the GI tract (e.g., the duodenum 65310 (FIG. 67)). In some embodiments, the ingestible device 65100 may also store (e.g., within the memory circuitry of the PCB 65120 (FIG. 66)) data indicating the time that the ingestible device 65100 detected a pyloric transition from the stomach to the duodenum. This information may be used by the ingestible device 65100 at 65608, and as a result, the process 65600 may proceed from 65608 to 65610 rather than proceeding from 65618 to 65614. After the ingestible device 65100 stores data indicating that a pyloric transition from the stomach to the duodenum has been detected, the process 65600 proceeds to 65604, where the ingestible device 65100 continues to collect additional measurements and monitors for further transitions between the stomach and the duodenum.

[0456] It will be understood that the steps and descriptions of the flow charts of the present disclosure, including FIG. 70, are merely illustrative. Any of the steps and descriptions of the flow charts, including FIG. 70, may be modified, omitted, rearranged, and performed in alternative orders or in parallel, two or more of the steps may be combined, or any additional steps may be added, without departing from the scope of the present disclosure. For example, the ingestible device 65100 may calculate the mean and standard deviation of multiple data sets in parallel to speed up the overall computation time. Additionally, it should be noted that the steps and descriptions of FIG. 70 may be combined with any other system, device, or method described in this application, and any of the ingestible devices or systems described in this application may be used to perform one or more of the steps of FIG. 70. For example, portions of process 65600 may be incorporated into 65508-65516 of process 65500 (FIG. 69) and may be part of a more general process for determining the location of an ingestible device. As another example, the ratio of detected blue to green light (e.g., as measured by 65604 and added to the dataset) may continue even outside of the stomach or duodenum, and similar information may be recorded by the ingestible device throughout its transition through the GI tract. Example plots of datasets of ratios of measured green to blue reflectance levels that may be collected throughout the GI tract are further described in connection with Figures 71 and 72 below.

[0457] FIG. 71 is a plot illustrating data collected during an example operation of an ingestible device (e.g., ingestible device 65100, 65300, or 65400) that may be used in determining the position of the ingestible device as it passes through the gastrointestinal (GI) tract, according to some embodiments of the present disclosure. FIG. 71 may be described in relation to ingestible device 65100 for illustrative purposes, but this is not intended to be limiting, and plot 65700 and data set 65702 may be representative of data collected by any device described in this application. Plot 65700 shows the ratio of measured green reflectance levels to measured blue reflectance levels over time. For example, the ingestible device 65100 may calculate a value for each point in the dataset 65702 by transmitting green and blue illumination at a given time (e.g., using illuminator 65124 (FIG. 66)), measuring the resulting green and blue reflectances (e.g., using detector 65122 (FIG. 66)), calculating the ratio of the resulting reflectances, and storing the ratio in the dataset along with a timestamp indicating the time the reflectances were collected.

[0458] At 65704, shortly after the ingestible device 65100 begins operation, the ingestible device 65100 determines that it has at least reached the stomach (e.g., as a result of making a determination similar to that described in connection with 65506 in process 65500 (FIG. 69)). The ingestible device 65100 continues to collect additional measurements of green and blue reflectance levels, and at 65706, the ingestible device 65100 determines that the pyloric transition from the stomach to the duodenum is occurring (e.g., as a result of making a determination similar to that described in connection with 65616-65624 in process 65600 (FIG. 70)). Notably, the values ​​in dataset 65702 jump sharply around 65706, indicating a higher ratio of measured green reflectance levels to measured blue reflectance levels typical of the duodenum.

[0459] The remainder of the dataset 65702 shows the ratio of measured green reflectance levels to measured blue reflectance levels across the remainder of the GI tract. At 65708, the ingestible device 65100 has reached the jejunum (e.g., as determined through measurements of muscle contractions, as described in connection with FIG. 73), and by 65710, the ingestible device 65100 has reached the cecum. It is understood that in some embodiments, the overall characteristics and appearance of the dataset 65702 varies within the small intestine (i.e., the duodenum, jejunum, and ileum) relative to the cecum. Within the jejunum and ileum, there may typically be a wide variation in the ratio of measured green reflectance levels to measured blue reflectance levels, resulting in relatively noisy data with a high standard deviation. In contrast, within the cecum, the ingestible device 65100 may measure a relatively stable ratio of measured green reflectance levels to measured blue reflectance levels. In some embodiments, the ingestible device 65100 may be configured to determine a transition from the small intestine to the cecum based on these differences. For example, the ingestible device 65100 may compare a recent window of data to a previous window of data and detect a transition to the cecum in response to determining that the standard deviation of the ratios in the recent window of data is substantially less than the standard deviation of the ratios in the previous window of data.

[0460] FIG. 72 is another plot illustrating data collected during an example operation of an ingestible device that may be used in determining the location of the ingestible device as it passes through the gastrointestinal (GI) tract, according to some embodiments of the present disclosure. As with FIG. 71, FIG. 72 may be described in relation to an ingestible device 65100 for illustrative purposes. However, this is not intended to be limiting, and plot 65800 and dataset 65802 may be representative of data collected by any device described in this application.

[0461] At 65804, shortly after the ingestible device 65100 begins operation, the ingestible device 65100 determines that it has at least reached the stomach (e.g., as a result of making a determination similar to that described in connection with 65506 in process 500 (FIG. 69)). The ingestible device 65100 continues to collect additional measurements of green and blue reflectance levels (e.g., using sensing subunit 65126 (FIG. 66)), and at 65806 the ingestible device 65100 determines that the pyloric transition from the stomach to the duodenum is occurring (e.g., as a result of making a determination similar to that described in connection with 65616-65624 in process 65600 (FIG. 70)). Notably, the values ​​in dataset 65802 show a sharp jump around 65806, which indicates a higher ratio of measured green reflectance levels to measured blue reflectance levels typical of the duodenum, followed immediately by a drop. As a result of the decrease in values ​​in dataset 65802, the ingestible device 65100 determines at 65808 that a reverse pyloric transition from the duodenum back to the stomach is occurring (e.g., as a result of making determinations similar to those described in connection with 65610-65612 of process 65600 (FIG. 70)). As a result of another increase in values ​​in dataset 65802, at 65810, the ingestible device 65100 determines that another pyloric transition from the stomach to the duodenum is occurring, whereupon the ingestible device 65100 proceeds forward into the jejunum, ileum, and cecum.

[0462] The remainder of the dataset 65802 indicates the ratio of measured green reflectance levels to measured blue reflectance levels across the remainder of the GI tract. In particular, at 65812 the ingestible device reaches the transition point between the ileum and the cecum. As described in connection with FIG. 71, the transition to the cecum is signaled by a decrease in the standard deviation in the ratio of measured green reflectance to measured blue reflectance over time, and the ingestible device 65100 may be configured to detect the transition to the cecum based on a determination that the standard deviation of a recent set of measurements taken from the jejunum or ileum is substantially less than the standard deviation of past measurements.

[0463] FIG. 73 is a flow diagram of example steps for detecting a duodenum-to-jejunum transition that may be used in determining the location of an ingestible device as it passes through the gastrointestinal (GI) tract, according to some embodiments of the present disclosure. FIG. 73 may be described in relation to an ingestible device 65100 for illustrative purposes, but this is not intended to be limiting, and any portion or entirety of the process 65900 described in FIG. 73 may be applied to any device described in this application (e.g., ingestible device 65100, 65300, or 65400), any of which may be used to perform one or more portions of the process described in FIG. 73. Additionally, features of FIG. 73 may be combined with any other system, method, or process described in this application. For example, portions of the process described by the process of FIG. 73 may be incorporated into the location verification process described by FIG. 69 (e.g., as portions of 65520-65524 of process 65500 (FIG. 69)). In some embodiments, the ingestible device 65100 may perform the process 65900 while in the duodenum or in response to detecting entry into the duodenum. In other embodiments, the ingestible device 65100 may perform the process 65900 while in the stomach or in response to detecting entry into the GI tract. It should also be understood that the process 65900 may be performed in parallel with any other process described in this disclosure (e.g., process 65600 (FIG. 70)), which may enable the ingestible device 65100 to detect entry into various portions of the GI tract without necessarily detecting entry into a prior portion of the GI tract.

[0464] For illustrative purposes, FIG. 73 may be described with respect to the ingestible device 65100 generating and determining based on a single set of reflectance levels generated at a single wavelength by a single sensing subunit (e.g., sensing subunit 65126 ( FIG. 66 )). However, it will be understood that the ingestible device 65100 may generate illumination at multiple wavelengths from multiple different sensing subunits positioned about the ingestible device (e.g., multiple sensing subunits positioned at different locations behind the window 65114 of the ingestible device 65100 ( FIG. 65 )), and each of the resulting reflectances may be stored as a separate data set. Moreover, each of these sets of reflectance levels may be used to detect muscle contractions by performing multiple versions of the process 65900, each one of the multiple versions of the process 65900 processing data for a different set of reflectances in response to data sets obtained from measurements at different wavelengths or measurements made by different sensing subunits.

[0465] At 65902, the ingestible device (e.g., ingestible device 65100, 65300, or 65400) obtains a set of reflectance levels. For example, the ingestible device 65100 may obtain a data set of previously recorded reflectance levels from memory (e.g., from a memory circuit of the PCB 65120 (FIG. 66)). Each of the reflectance levels may correspond to a reflectance previously detected by the ingestible device 65100 (e.g., using the detector 65122 (FIG. 66)) from illumination generated by the ingestible device 65100 (e.g., using the illuminator 65124 (FIG. 66)) and may represent a value indicative of the amount of light detected at a given reflectance. However, it is understood that any suitable frequency of light may be used, such as light in the infrared, visible, or ultraviolet spectrum. In so...

Claims

1. a housing defined by a first end, a second end substantially opposite the first end, and a wall extending longitudinally from the first end to the second end; an electronic component disposed within the housing; a gas generation cell disposed within the housing adjacent to the electronic component, a gas generating cell, the electronic component configured to operate the gas generating cell to generate gas; a storage reservoir disposed within the housing, a storage reservoir for storing a dispenseable substance, a first end of the storage reservoir being coupled to the first end of the housing; an outlet valve disposed at the first end of the housing, an outlet valve configured to allow the dispenseable substance to be released from the storage reservoir out the first end of the housing; a safety device disposed within or attached to said housing, a safety device configured to release internal pressure within the housing when the internal pressure exceeds a threshold level; 1. An ingestible device comprising:

2. 10. The ingestible device of claim 1, wherein the housing has a polycarbonate wall substantially thick enough to withstand an internal explosion without rupturing.

3. 2. The ingestible device of claim 1, wherein the safety device comprises an oxygen absorbing material that absorbs oxygen inside the housing to avoid an internal explosion.

4. The ingestible device of claim 1 , wherein the safety device comprises an inert, non-conductive dielectric that separates the gas generating cell from other components within the housing.

5. the safety device includes a relief valve disposed at the first end of the housing; The ingestible device of claim 1 , wherein the relief valve is configured to open when the internal pressure within the housing reaches the threshold level.

6. 2. The ingestible device of claim 1, wherein the safety device includes a rupture disk disposed at the first end of the housing, the rupture disk configured to rupture when the internal pressure within the housing reaches the threshold level.

7. 7. The ingestible device of claim 6, wherein the housing is configured to rupture in a controlled manner when the internal pressure within the housing reaches the threshold level.

8. The ingestible device of claim 1 , wherein the gas generation cell is a hydrogen generation cell mounted on and sealed from the electronic components.

9. 2. The ingestible device of claim 1, further comprising a piston adjacent to the gas-generating cell, the piston being urged to move toward the first end of the housing by pressure from the gas-generating cell.

10. 10. The ingestible device of claim 9, wherein the piston is integral with the gas generating cell in the form of a silicone seal that wraps around the gas generating cell, the gas generating cell being movable with the piston.

11. 2. The ingestible device of claim 1, wherein the storage reservoir is in the form of a bellows configured to be compressed by pressure from the gas generating cell.

12. The ingestible device of claim 1 , wherein the storage reservoir includes a plurality of chambers, each of the plurality of chambers storing a different dispensable substance.

13. 13. The ingestible device of claim 12, wherein the different dispensable substances are released simultaneously through the outlet valves.

14. 13. The ingestible device of claim 12, wherein the different dispensable substances from each of the plurality of the chambers are delivered through the outlet valve in sequence.

15. 13. The ingestible device of claim 12, wherein the different dispenseable substances from each of the plurality of chambers are controlled by different membranes, and the electronics control the gas generating cells to release gas that propels the membranes to deliver the respective dispenseable substances.

16. 2. The ingestible device of claim 1, further comprising a flexible diaphragm adjacent to the gas generating cell, the flexible diaphragm configured to deform toward the first end of the housing due to pressure from the gas generating cell.

17. a capillary plate positioned between the gas generating cell and the first end of the housing; a wax seal between the gas generating cell and the storage reservoir, the wax seal configured to melt and the dispenseable substance is forced through the capillary plate by pressure from the gas generating cell; The ingestible device of claim 1 , further comprising:

18. 15. The ingestible device of claim 14, wherein the capillary plate is comprised of concentric microchannels.

19. 15. The ingestible device of claim 14, wherein the gas-generating cell is encased in a folded foil configured to deform under the pressure from the gas-generating cell.

20. The wall is configured to separate into two clamshell halves along a longitudinal axis, and the ingestible device comprises: a diaphragm disposed within one clamshell half along the longitudinal axis and encasing the electronic components, the diaphragm configured to be deflected toward the other clamshell half by pressure from the gas generating cell.

2. The ingestible device of claim 1.

21. 2. The ingestible device of claim 1, wherein the outlet valve has an umbrella shape and the first end of the housing has a plurality of ports below the outlet valve for directing the dispensable substance radially out of the housing.

22. 2. The ingestible device of claim 1, wherein the outlet valve has a ring around the first end of the housing and a plurality of ports evenly distributed on the ring for directing the dispenseable substance out of the housing.

23. 2. The ingestible device of claim 1, wherein the outlet valve includes a dome slit extending out of the first end of the housing, the dispensable substance being delivered through the dome slit.

24. 2. The ingestible device of claim 1, wherein the outlet valve includes a hole in the first end of the housing, the hole being sealed with a wax or silicone material configured to be breached by the internal pressure from inside the housing.

25. 2. The ingestible device of claim 1, wherein the outlet valve is positioned at a center of gravity at the first end of the housing to reduce unbalanced forces and rotation of the capsule when the dispenseable substance is delivered through the outlet valve.

26. a light sensing unit disposed proximate the first end or the second end of the housing, the light sensing unit configured to transmit illumination to an environment external to the housing and detect reflections from the environment caused by the illumination; The electronic component includes: identifying a location of the ingestible device based on the reflection; activating the gas generating cell to generate gas if the identified location matches a predefined location; configured to:

2. The ingestible device of claim 1.

27. The electronic component includes: Controlling the gas generating cell to generate an internal pressure to deliver a metered dose of the dispensable substance outside the housing based on the characteristic of the reflection.

27. The ingestible device of claim 26, further configured to:

28. 28. The ingestible device of claim 27, wherein the electronic components include a variable resistor for controlling an amount of gas generated by the gas generating cell to meter the dose of the dispensable substance.

29. 28. The ingestible device of claim 27, wherein the metered dose of the dispensable substance is a one-time dose or multiple doses for systematic delivery.

30. 10. The ingestible device of claim 1, wherein the storage reservoir stores between 10 μL and 1500 μL of the dispensable substance.

31. The ingestible device of claim 1 , wherein the housing includes a loading port for loading the dispensable substance into the storage reservoir.

32. The ingestible device of claim 1 , wherein the dispensable substance comprises a therapeutic agent in the form of a powder, granules, liquid, or semi-liquid gel.

33. a housing defined by a first end, a second end substantially opposite the first end, and a wall extending longitudinally from the first end to the second end; an electronic component disposed within the housing; a gas generation cell disposed within the housing adjacent to the electronic component, a gas generating cell, the electronic component configured to operate the gas generating cell to generate gas; a storage reservoir disposed within the housing, a storage reservoir for storing a dispenseable substance, a first end of the storage reservoir being coupled to the first end of the housing; an injection device disposed at the first end of the housing, an injection device configured to inject the dispenseable substance from the storage reservoir outside the housing; a safety device disposed within or attached to said housing, a safety device configured to release internal pressure within the housing; 1. An ingestible device comprising:

34. 34. The ingestible device of claim 33, wherein the dispensable substance is expelled through the injection device with a force substantially sufficient to penetrate a mucous membrane.

35. 34. The ingestible device of claim 33, further comprising a component attached to an exterior of the housing, the component configured to position the injection device against an epithelial layer and spread the epithelial layer prior to delivery of the dispenseable substance.

36. 34. The ingestible device of claim 33, wherein the injection device is a syringe coupled to or disposed within the housing and having an injection portion extending outside the housing.

37. 34. The ingestible device of claim 33, wherein the injection device includes an injection port configured to penetrate an epithelial layer to inject the dispenseable substance.

38. 34. The ingestible device of claim 33, wherein the housing has a polycarbonate wall substantially thick enough to withstand an internal explosion without rupturing.

39. 34. The ingestible device of claim 33, wherein the safety device comprises an oxygen absorbing material that absorbs oxygen inside the housing to avoid an internal explosion.

40. 34. The ingestible device of claim 33, wherein the safety feature includes an inert, non-conductive dielectric that separates the gas generating cell from other components within the housing.

41. the safety device includes a relief valve disposed at the first end of the housing; the relief valve is configured to open when the internal pressure within the housing reaches the threshold level.

34. The ingestible device of claim 33.

42. 34. The ingestible device of claim 33, wherein the safety device includes a rupture disc disposed at the first end of the housing, the rupture disc configured to rupture when the internal pressure within the housing reaches the threshold level.

43. 43. The ingestible device of claim 42, wherein the housing is configured to rupture in a controlled manner when the internal pressure within the housing reaches the threshold level.

44. 34. The ingestible device of claim 33, wherein the gas generation cell is a hydrogen generation cell mounted on and sealed from the electronic components.

45. 34. The ingestible device of claim 33, further comprising a piston adjacent to the gas-generating cell, the piston being urged to move toward the first end of the housing by pressure from the gas-generating cell.

46. 46. ​​The ingestible device of claim 45, wherein the piston is integrated with the gas generating cell in the form of a silicone seal that wraps around the gas generating cell, the gas generating cell being movable with the piston.

47. 34. The ingestible device of claim 33, wherein the storage reservoir is in the form of a bellows configured to be compressed by pressure from the gas generating cell.

48. 34. The ingestible device of claim 33, wherein the storage reservoir comprises a plurality of chambers, each of the plurality of chambers storing a different dispensable substance.

49. 34. The ingestible device of claim 33, further comprising a flexible diaphragm adjacent to the gas generating cell, the flexible diaphragm configured to deform toward the first end of the housing due to pressure from the gas generating cell.

50. a capillary plate positioned between the gas generating cell and the first end of the housing; a wax seal between the gas generating cell and the storage reservoir, the wax seal configured to melt and the dispenseable substance is forced through the capillary plate by pressure from the gas generating cell; 34. The ingestible device of claim 33, further comprising:

51. 51. The ingestible device of claim 50, wherein the capillary plate is comprised of concentric microchannels.

52. 51. The ingestible device of claim 50, wherein the gas-generating cell is encased in a folded foil configured to deform under the pressure from the gas-generating cell.

53. The wall is configured to separate into two clamshell halves along a longitudinal axis, and the ingestible device comprises: a diaphragm disposed within one clamshell half along the longitudinal axis and encasing the electronic components, the diaphragm configured to be deflected toward the other clamshell half by pressure from the gas generating cell.

34. The ingestible device of claim 33.

54. a light sensing unit disposed proximate the first end or the second end of the housing, the light sensing unit configured to transmit illumination to an environment external to the housing and detect reflections from the environment caused by the illumination; The electronic component includes: identifying a location of the ingestible device based on the reflection; activating the gas generating cell to generate gas if the identified location matches a predefined location; configured to:

34. The ingestible device of claim 33.

55. The electronic component includes: Controlling the gas generating cell to generate an internal pressure to deliver a metered dose of the dispensable substance outside the housing based on the characteristic of the reflection.

55. The ingestible device of claim 54, further configured to:

56. 56. The ingestible device of claim 55, wherein the electronic components include a variable resistor for controlling an amount of gas generated by the gas generating cell to meter the dose of the dispensable substance.

57. 56. The ingestible device of claim 55, wherein the metered dose of the dispensable substance is a one-time dose or multiple doses for systematic delivery.

58. 34. The ingestible device of claim 33, wherein the storage reservoir stores between 10 μL and 1500 μL of the dispensable substance.

59. 34. The ingestible device of claim 33, wherein the housing includes a loading port for loading the dispensable substance into the storage reservoir.

60. 34. The ingestible device of claim 33, wherein the dispensable substance comprises a therapeutic agent in the form of a powder, granules, liquid, or semi-liquid gel.

61. a housing defined by a first end, a second end substantially opposite the first end, and a wall extending longitudinally from the first end to the second end; a light-sensing unit disposed on one side of the housing, a light sensing unit configured to detect reflections from an environment external to the housing; an electronic component disposed within the housing; a gas generation cell disposed within the housing adjacent to the electronic component, a gas generating cell, the electronic component configured to activate the gas generating cell to generate gas in response to identifying a location of the ingestible device based on the reflectance; a storage reservoir disposed within the housing, a storage reservoir for storing a dispenseable substance, a first end of the storage reservoir being coupled to the first end of the housing; a membrane in contact with the gas generating cell and configured to move or deform within the storage reservoir due to pressure generated by the gas generating cell; a dispensing spout disposed at the first end of the housing, a dispensing spout configured to deliver the dispenseable substance from the storage reservoir out of the housing; 1. An ingestible device comprising:

62. the dispensing port includes an outlet valve disposed at the second end of the storage reservoir; the outlet valve is configured to allow the dispenseable substance to be expelled from the storage reservoir out the first end of the housing.

62. The ingestible device of claim 61.

63. 62. The ingestible device of claim 61, wherein the dispensing spout has an umbrella shape and the second end of the housing has a plurality of ports below the outlet valve for directing the dispensable substance radially out of the housing.

64. 62. The ingestible device of claim 61, wherein the dispensing port has a ring around the second end of the housing and has a plurality of ports evenly distributed on the ring for directing the dispenseable substance out of the housing.

65. 62. The ingestible device of claim 61, wherein the dispensing spout includes a dome slit extending out of the second end of the housing, the dispensable substance being delivered through the dome slit.

66. 62. The ingestible device of claim 61 , wherein the dispensing spout includes a hole at the second end of the housing, the hole being sealed with a wax or silicone material configured to be broken by a burst of internal pressure from inside the housing.

67. 62. The ingestible device of claim 61 , wherein the dispensing port is positioned at a center of gravity at the second end of the housing to reduce unbalanced forces and rotation of the capsule when the dispensable substance is delivered through the dispensing port.

68. 62. The ingestible device of claim 61, wherein the dispensing port includes an injection nozzle disposed at the first end of the storage reservoir and an injection port configured to inject the dispensable substance from the storage reservoir outside the housing.

69. 62. The ingestible device of claim 61, wherein the dispensable substance is expelled through the dispensing spout with a force substantially sufficient to penetrate a mucous membrane.

70. 62. The ingestible device of claim 61, further comprising a component attached to the exterior of the housing, the component configured to position the dispensing spout against an epithelial layer and spread the epithelial layer prior to delivery of the dispensable substance.

71. a syringe coupled to or disposed within the housing and having an injection portion extending outside the housing; A gas actuator disposed within the housing, a gas actuator that electronically controls the syringe to inject the dispenseable substance into the location that the injection portion contacts; 62. The ingestible device of claim 61, further comprising:

72. 62. The ingestible device of claim 61, wherein the injection portion is configured to penetrate an epithelial layer to inject the dispenseable substance.

73. 62. The ingestible device of claim 61, wherein the housing has a polycarbonate wall substantially thick enough to withstand an internal explosion without rupturing.

74. 62. The ingestible device of claim 61, wherein the housing includes an oxygen absorbing material that absorbs oxygen inside the housing to avoid internal explosion.

75. 62. The ingestible device of claim 61, wherein the gas generating cell is isolated from other components within the housing by a coating of an inert, non-conductive liquid dielectric.

76. 62. The ingestible device of claim 61, wherein the first end of the housing includes a relief valve configured to open when internal pressure within the housing reaches a threshold level.

77. 62. The ingestible device of claim 61, further comprising a pressure release device disposed within the housing, the pressure release device releasing gas within the housing toward the gas generating cell to prevent upstream contamination of the substance in the storage reservoir when internal pressure within the housing reaches a threshold level.

78. 7. The ingestible device of claim 6, wherein the pressure relief device comprises a pressure relief burst disc.

79. 62. The ingestible device of claim 61, wherein the gas generation cell is a hydrogen generation cell mounted on and sealed from the electronic components.

80. 62. The ingestible device of claim 61, comprising a piston adjacent to the gas generating cell, the piston being urged to move toward the first end of the housing by pressure from the gas generating cell.

81. 81. The ingestible device of claim 80, wherein the piston is integrated with the gas generating cell in the form of a silicone seal that wraps around the gas generating cell, the gas generating cell being movable with the piston.

82. 62. The ingestible device of claim 61, wherein the storage reservoir is in the form of a bellows configured to be compressed by pressure from the gas generating cell.

83. 62. The ingestible device of claim 61, wherein the storage reservoir comprises a plurality of chambers, each of the plurality of chambers storing a different dispensable substance.

84. 62. The ingestible device of claim 61, further comprising a flexible diaphragm adjacent to the gas generating cell, the flexible diaphragm configured to deform toward the first end of the housing due to pressure from the gas generating cell.

85. a capillary plate positioned between the gas generating cell and the first end of the housing; a wax seal between the gas generating cell and the storage reservoir, the wax seal configured to melt and the dispenseable substance is forced through the capillary plate by pressure from the gas generating cell; 62. The ingestible device of claim 61, further comprising:

86. 86. The ingestible device of claim 85, wherein the capillary plate is comprised of concentric microchannels.

87. 62. The ingestible device of claim 61, wherein the gas-generating cell is encased in a folded foil configured to deform under the pressure from the gas-generating cell.

88. the wall is configured to separate into two clamshell halves along a longitudinal axis, the ingestible device further comprising: a diaphragm disposed within one clamshell half along the longitudinal axis and encasing the electronic components, the diaphragm being configured to deflect toward the other clamshell half due to pressure from the gas generating cell; 62. The ingestible device of claim 61.

89. the light-sensing unit is configured to transmit illumination to an environment external to the housing and detect reflections from the environment caused by the illumination; The electronic component includes: identifying a location of the ingestible device based on the reflection; activating the gas generating cell to generate gas if the identified location matches a predefined location; configured to:

62. The ingestible device of claim 61.

90. The electronic component includes: Controlling the gas generating cell to generate an internal pressure to deliver a metered dose of the dispensable substance outside the housing based on the characteristic of the reflection. further comprising:

90. The ingestible device of claim 89.

91. 91. The ingestible device of claim 90, wherein the electronic components include a variable resistor for controlling an amount of gas generated by the gas generating cell to meter the dose of the dispensable substance.

92. 91. The ingestible device of claim 90, wherein the metered dose of the dispensable substance is a one-time dose or multiple doses for systematic delivery.

93. 62. The ingestible device of claim 61, wherein the storage reservoir stores between 10 μL and 1500 μL of the dispensable substance.

94. 62. The ingestible device of claim 61, wherein the housing includes a loading port for loading the dispensable substance into the storage reservoir.

95. 62. The ingestible device of claim 61, wherein the dispensable substance comprises a therapeutic agent in the form of a powder, granules, liquid, or semi-liquid gel.

96. The ingestible device of claim 61 , wherein the electronic component is configured to automatically activate the gas generating cell in response to identifying the location of the ingestible device without any trigger mechanism or pre-programmed activation conditions external to the ingestible device.

97. 62. The ingestible device of claim 61, wherein the location of the ingestible device is identified based on the reflection indicative of an optical characteristic of the location without evaluating a pH level of the external environment.

98. 98. The ingestible device of claim 97, wherein the location includes either a first portion immediately behind the pyloric sphincter or a second portion immediately before the ileocecal valve.

99. a housing defined by a first end, a second end substantially opposite the first end, and a wall extending longitudinally from the first end to the second end; an electronic component disposed within the housing; a motion component disposed substantially within the storage reservoir and configured to be driven by the electronic component; a storage reservoir disposed within the housing, a storage reservoir for storing a dispenseable substance, a first end of the storage reservoir being coupled to the first end of the housing; a dispensing spout disposed at the first end of the housing, a dispensing spout configured to deliver the dispenseable substance from the storage reservoir out of the housing; 1. An ingestible device comprising:

100. the motion component is a gear motor; one or more suction ports disposed on the housing of the ingestible device and configured to draw luminal fluid into the storage reservoir; 100. The ingestible device of claim 99, further comprising:

101. 101. The ingestible device of claim 100, further comprising an auger device disposed around a portion of the gear motor inside the storage reservoir, the auger device being driven by the gear motor to rotate and mix the dispenseable substance with luminal fluid drawn into the storage reservoir.

102. 101. The ingestible device of claim 100, further comprising a wiper device longitudinally coupled to a portion of the gear motor internal to the storage reservoir, the wiper device being driven by the gear motor to rotate and mix the dispenseable substance with luminal fluid drawn into the storage reservoir.

103. a helical component disposed about a portion of the gear motor that is internal to the storage reservoir; a piston disposed at one end of the helical component, the helical component being driven to rotate by the gear motor such that the piston moves longitudinally along a pitch of the helical component toward the outlet valve; 101. The ingestible device of claim 100, further comprising:

104. further comprising one or more ports disposed on the housing, the one or more ports being temporarily sealed by a wax seal or an enteric coating; the wax seal or enteric coating dissolves after a period of time to allow luminal fluid to flow through the one or more ports into the storage reservoir; 100. The ingestible device of claim 99.

105. 100. The ingestible device of claim 99, wherein the housing includes a first half and a second half connected by a latch mechanism disposed within the ingestible device.

106. the latch mechanism is held closed by an enteric coating disposed on a surface of the housing; 106. The ingestible device of claim 105, wherein the enteric coating dissolves after a period of time to release the latching mechanism and allow the first half to separate from the second half.

107. 100. The ingestible device of claim 99, wherein the motion component is configured to create a motion that delivers the dispenseable substance to a first layer of cells of an inner wall of the GI tract.

108. 100. The ingestible device of claim 99, wherein the motion component is configured to produce a motion with sufficient force to deliver the dispenseable substance to a submucosal layer of an inner wall of the GI tract.

109. the motion component is configured to produce a first motion at a first time and a second motion at a second time; the dispensing port is configured to deliver a first amount of the dispenseable substance from the storage reservoir at the first time due to a first pressure generated by the first movement, and to deliver a second amount of the dispenseable substance from the storage reservoir at the second time due to a second pressure generated by the second movement.

100. The ingestible device of claim 99.

110. a housing defined by a first end, a second end substantially opposite the first end, and a wall extending longitudinally from the first end to the second end; an electronic component disposed within the housing; an enteric coating applied to and covering at least a portion of the exterior wall of the housing; a storage reservoir disposed within the housing, a storage reservoir for storing a dispenseable substance, a first end of the storage reservoir being coupled to the first end of the housing; a dispensing spout disposed at the first end of the housing, a dispensing spout configured to deliver the dispenseable substance from the storage reservoir out of the housing; 1. An ingestible device comprising:

111. further comprising one or more ports disposed on the exterior wall of the housing, the one or more ports being temporarily sealed by a wax seal or the enteric coating; the wax seal or the enteric coating dissolves after a period of time to: a) allow luminal fluid to flow through the one or more ports into the storage reservoir, and / or b) dispense a dispensable substance from the ingestible device through the one or more ports.

111. The ingestible device of claim 110.

112. 111. The ingestible device of claim 110, wherein the housing includes a first half and a second half connected by a latch mechanism disposed within the ingestible device.

113. the latch mechanism is held closed by the enteric coating; 113. The ingestible device of claim 112, wherein the enteric coating dissolves after a period of time to release the latching mechanism and allow the first half to separate from the second half.

114. a housing defined by a first end, a second end substantially opposite the first end, and a wall extending longitudinally from the first end to the second end; an actuating component disposed within the housing; a storage reservoir disposed within the housing, a storage reservoir for storing a dispenseable substance, a first end of the storage reservoir being coupled to the first end of the housing; A dispensing spout disposed on the housing, a dispensing spout configured to deliver the dispenseable substance from the storage reservoir out of the housing; a safety device disposed within or attached to said housing, a safety device configured to release internal pressure within the housing when the internal pressure exceeds a threshold level; 1. An ingestible device comprising:

115. 115. The ingestible device of claim 114, wherein the actuating components include a pump, a first reagent chamber for storing a first reagent, a second reagent chamber for storing a second reagent, and a septum sealing both the first reagent chamber and the second reagent chamber.

116. 116. The ingestible device of claim 115, wherein the pump is an osmotic pump or a peristaltic driven pump.

117. a semipermeable membrane disposed adjacent to the diaphragm; a pressure chamber disposed adjacent to the semipermeable membrane; 116. The ingestible device of claim 115, further comprising:

118. 116. The ingestible device of claim 115, wherein the diaphragm is configured to rupture due to a first pressure generated by the pump, such that the first reagent from the first reagent chamber passes through the semi-permeable membrane and enters the pressure chamber, the second reagent from the second reagent chamber passes through the semi-permeable membrane and enters the pressure chamber, and the first reagent contacts the second reagent to create a second pressure.

119. 119. The ingestible device of claim 118, further comprising a piston adjacent the pressure chamber, the piston being urged to move toward the first end of the housing by the second pressure.

120. 119. The ingestible device of claim 118, wherein the storage reservoir is in the form of a bellows configured to be compressed by the second pressure.

121. The actuation component comprises: a separable portion disposed at the second end of the housing; an osmotic pump disposed adjacent to the separable portion; Including, the detachable portion is attached to the osmotic pump with a dissolvable material and configured to detach from the osmotic pump when the dissolvable material dissolves.

115. The ingestible device of claim 114.

122. 122. The ingestible device of claim 121, further comprising a suction device positioned proximate to the first end of the housing and configured to suck a portion of the intestinal wall into the housing through the dispensing port when the first end of the housing is pressed against the intestinal wall.

123. 123. The ingestible device of claim 122, wherein the suction device includes a barbed disk disposed inwardly within the storage device.

124. a piston disposed proximate to the actuating component and configured to move toward the first end of the housing; a needle guide disposed longitudinally within the storage reservoir and having one end attached to the piston; a spring disposed adjacent the first end of the housing; and an injection needle disposed through the needle guide and the center of the spring; 115. The ingestible device of claim 114, further comprising:

125. a first enteric coating configured to dissolve upon exposure to luminal fluid within a first period of time; a second enteric coating configured to dissolve upon exposure to luminal fluid within a second period of time that is longer than the first period of time; and 115. The ingestible device of claim 114, further comprising:

126. The actuation component includes a first osmotic mechanism, the first osmotic mechanism comprising: a first semipermeable membrane disposed adjacent to the first enteric coating; a first chamber disposed adjacent to the first semipermeable membrane for storing soluble particles; a mesh disposed at an outlet of the first chamber and configured to prevent the soluble particles from exiting the first chamber; 115. The ingestible device of claim 114, comprising:

127. 115. The ingestible device of claim 114, wherein the first osmotic mechanism is configured to create a suction force on the ingestible device when the first enteric coating dissolves.

128. a second semipermeable membrane disposed adjacent to the second enteric coating; a second chamber disposed adjacent to the second semipermeable membrane for storing soluble particles; a piston disposed between the second chamber and the storage reservoir; and a second osmotic mechanism comprising: the second osmotic mechanism is configured to urge the piston toward the dispensing orifice of the ingestible device upon dissolution of the second enteric coating.

115. The ingestible device of claim 114.

129. 115. The ingestible device of claim 114, wherein the actuation component is configured to generate pressure to deliver the dispenseable substance to a first layer of cells of an inner wall of the GI tract.

130. 115. The ingestible device of claim 114, wherein the actuation component is configured to generate sufficient pressure to deliver the dispenseable substance to a submucosal layer of an inner wall of the GI tract.

131. the actuation component is configured to generate a first pressure at a first time and a second pressure at a second time; the dispensing port is configured to deliver a first amount of the dispenseable substance from the storage reservoir due to the first pressure at the first time, and to deliver a second amount of the dispenseable substance from the storage reservoir due to the second pressure at the second time.

115. The ingestible device of claim 114.

132. a housing defined by a first end, a second end substantially opposite the first end, and a wall extending longitudinally from the first end to the second end; a first actuating component and a second actuating component, both disposed within the housing; a first enteric coating attached to the first working component; and a second enteric coating attached to the second working component; and a storage reservoir disposed within the housing, a storage reservoir for storing a dispenseable substance, a first end of the storage reservoir being coupled to the first end of the housing; A dispensing spout disposed on the housing, a dispensing spout configured to deliver the dispenseable substance from the storage reservoir out of the housing; 1. An ingestible device comprising:

133. 133. The ingestible device of claim 132, wherein the first enteric coating is configured to dissolve when exposed to luminal fluids within a first period of time, and the second enteric coating is configured to dissolve when exposed to luminal fluids within a second period of time that is longer than the first period of time.

134. The first actuating component is an osmotic mechanism, a first semipermeable membrane disposed adjacent to the first enteric coating; a first chamber disposed adjacent to the first semipermeable membrane for storing soluble particles; a mesh disposed at an outlet of the first chamber and configured to prevent the soluble particles from exiting the first chamber; 133. The ingestible device of claim 132, comprising an osmotic mechanism comprising:

135. A suction device disposed adjacent to the dispensing port In addition, the first actuating component is configured to generate a suction force on the ingestible device when the first enteric coating dissolves.

133. The ingestible device of claim 132.

136. The second actuating component is an osmotic mechanism, a second semipermeable membrane disposed adjacent to the second enteric coating; a second chamber disposed adjacent to the second semipermeable membrane for storing soluble particles; a piston disposed between the second chamber and the storage reservoir; The osmotic mechanism includes the second osmotic mechanism is configured to urge the piston toward the dispensing orifice of the ingestible device upon dissolution of the second enteric coating.

133. The ingestible device of claim 132.

137. a dispenser having one end adjacent the dispensing port and another end connected to the storage reservoir; the injection device is configured to deliver the dispenseable substance when the piston is urged towards the dispensing orifice; 137. The ingestible device of claim 136.

138. 1. A method for delivering a dispensable substance into a gastrointestinal tract from an ingestible device, comprising: entering the GI tract with the ingestible device; generating a first pressure by a first osmotic mechanism upon dissolution of the first enteric coating; drawing a portion of the intestinal wall of the GI tract into the ingestible device with the first pressure; generating a second pressure by a second osmotic mechanism upon dissolution of the second enteric coating; moving a displacement member with the second pressure to deliver a pre-loaded dispensable substance from the ingestible device; A method comprising:

139. a storage reservoir configured to store a dispensable substance; a force generator component configured to cause the dispensable substance to exit the ingestible device through an opening in the ingestible device when a force generator generates a force; 1. An ingestible device comprising:

140. 140. The ingestible device of claim 139, wherein the ingestible device includes a housing.

141. 141. The ingestible device of claim 140, wherein the force generator is disposed at least partially within the housing.

142. 141. The ingestible device of claim 140, wherein the force generator is disposed entirely within the housing.

143. 143. The ingestible device of any of claims 140-142, wherein the storage reservoir is disposed at least partially within the housing.

144. 143. The ingestible device of any of claims 140-142, wherein the storage reservoir is disposed entirely within the housing.

145. the housing includes a first end, a second end, and a wall extending between the first end and the second end; the storage reservoir is adjacent the first end; 145. The ingestible device of claims 140-144.

146. 146. The ingestible device of any of claims 139-145, wherein the storage reservoir is attachable to the ingestible device.

147. 146. An ingestible device according to any of claims 139 to 145, wherein the storage reservoir is an integral component of the ingestible device.

148. The ingestible device of any of claims 139-147, further comprising an injection device configured such that when the force generator generates the force, the force moves the injection device to force the dispenseable substance out of the ingestible device through the opening.

149. 149. The ingestible device of claim 148, wherein the injection device comprises a syringe.

150. 150. The ingestible device of claim 148 or claim 149, further comprising a component configured to position the injection device against an epithelial layer to spread the epithelial layer prior to delivery of the dispenseable substance.

151. 151. The ingestible device of any of claims 148-150, wherein the injection device is configured such that the force it generates is sufficient to penetrate a mucous membrane.

152. The injection device comprises: The piston and a needle guide disposed within the storage reservoir and having an end attached to the piston; a spring coupled to the needle guide; an injection needle passing through the needle guide and a portion of the spring; 152. The ingestible device of any of claims 148-151, comprising:

153. 153. The ingestible device of claim 152, wherein the spring is configured to be compressed and the needle is configured to extend out of the ingestible device as the piston moves.

154. The injection device comprises: a truss mechanism for supporting the injection needle; a balloon configured to inflate to cause the truss mechanism along with the injection needle to extend out of the storage reservoir; 152. The ingestible device of any of claims 148-151, comprising:

155. The ingestible device of any of claims 139-154, further comprising a membrane configured such that when the force generator generates the force, the force moves the membrane to force the dispenseable substance out of the ingestible device and through the opening.

156. 156. The ingestible device of claim 155, wherein the membrane includes a piston configured to move the membrane with the force to force the dispenseable substance out of the ingestible device through the opening when the force generator generates the force.

157. The ingestible device of any of claims 139-156, further comprising a light sensing unit configured to detect reflections from an environment external to the ingestible device.

158. 158. The ingestible device of claim 157, comprising a housing and the light sensing unit configured to detect reflections from an environment external to the housing.

159. 159. The ingestible device of claim 158, wherein the ingestible device is configured to determine a position of the ingestible device based on the reflection detected by the light sensing unit.

160. 160. An ingestible device as described in claims 157-159, wherein the force generator generates the force based on the reflection detected by the optical sensing unit.

161. 161. The ingestible device of any of claims 139-160, further comprising electronic components within the housing, the electronic components configured to actuate the force generator.

162. 162. The ingestible device of claim 161, wherein the force generator is adjacent to the electronic component.

163. 163. The ingestible device of any of claims 139-162, further comprising a safety device configured to relieve internal pressure within the housing.

164. 164. The ingestible device of any of claims 139-163, wherein the storage reservoir stores the dispensable substance.

165. Equipped with an occluder, the occluder has a first state configured to prevent the dispensable substance from exiting the ingestible device through the opening in the ingestible device; and the occluder has a second state configured to permit the dispensable substance to exit the ingestible device through the opening in the ingestible device.

165. The ingestible device of any of claims 139-164.

166. 166. The ingestible device of claim 165, wherein the occluder comprises a magnet.

167. 166. The ingestible device of claim 165, wherein the occluder comprises a sliding pin.

168. 166. The ingestible device of claim 165, wherein the occluder comprises a burst disc.

169. 166. The ingestible device of claim 165, wherein the occluder comprises an enteric coating.

170. 166. The ingestible device of claim 165, wherein the occluder comprises an enteric coating and a sliding pin.

171. 166. The ingestible device of claim 165, wherein the occluder comprises an enteric coating and a magnet.

172. 166. The ingestible device of claim 165, wherein the occluder comprises a dissolvable pin.

173. 166. The ingestible device of claim 165, wherein the occluder comprises a dissolvable pin and an enteric coating.

174. 166. The ingestible device of claim 165, wherein the occluder comprises wax.

175. 175. The ingestible device of claim 174, wherein the wax is in the form of a plug.

176. 176. The ingestible device of claim 174 or claim 175, wherein the occluder further comprises a lead configured to melt the wax.

177. 177. The ingestible device of claim 176, wherein the lead is configured to be activated by a power source in response to commands from at least one computer processor.

178. 178. An ingestible device according to any of claims 165-177, wherein the occluder is disposed within a housing of the ingestible device.

179. 179. The ingestible device of any of claims 139-178, further comprising a bellows between the force generator and the storage reservoir.

180. 180. The ingestible device of claim 179, wherein the force generator is configured to apply the force to the bellows to force the dispensable substance out of the opening in the ingestible device.

181. The ingestible device of any of claims 139-180, further comprising a member within the opening of the ingestible device.

182. 182. The ingestible device of claim 181, wherein the member is in the form of a plug.

183. The ingestible device of claim 181 or claim 182, wherein the member comprises a bioabsorbable material.

184. 184. The ingestible device of any of claims 139-183, wherein the force generator includes a gas generating cell configured to generate gas to provide the force.

185. 185. The ingestible device of any of claims 139-184, wherein the force generator comprises a pressurized gas chamber.

186. 185. The ingestible device of any of claims 139-184, wherein the force generator comprises a vacuum chamber.

187. 185. The ingestible device of any of claims 139-184, wherein the force generator comprises a spring.

188. 185. The ingestible device of any of claims 139-184, wherein the force generator includes a compression spring and an extension spring.

189. The ingestible device of any of claims 139-184, wherein the force generator comprises a gear motor.

190. 190. The ingestible device of claim 189, wherein the ingestible device comprises an inlet configured to draw fluid into the storage reservoir.

191. 191. The ingestible device of claim 190, further comprising an auger device disposed around a portion of the gear motor inside the storage reservoir, the auger device configured to be driven by the gear motor to rotate and mix the dispenseable substance with the fluid drawn into the storage reservoir.

192. 191. The ingestible device of claim 190, further comprising a wiper device longitudinally coupled to a portion of the gear motor inside the storage reservoir, the wiper device configured to be driven by the gear motor to rotate and mix the dispenseable substance with the fluid drawn into the storage reservoir.

193. a helical component disposed about a portion of the gear motor that is internal to the storage reservoir; a piston disposed at one end of the helical element; Further equipped with the helical component is configured to rotate driven by the gear motor so that the piston moves longitudinally along the pitch of the helical component towards the outlet valve; 191. The ingestible device of claim 190.

194. 194. An ingestible device according to any of claims 139 to 193, wherein the ingestible device includes a housing configured to maintain the mechanical integrity of the ingestible device during use.

195. An ingestible device as described in any of claims 139 to 194, comprising a housing configured to maintain its mechanical integrity when pressure inside the housing increases during use of the ingestible device.

196. 196. The ingestible device of any of claims 139-195, further comprising a mechanism configured to reduce gas pressure inside the ingestible device.

197. 200. The ingestible device of claim 196, wherein the mechanism includes a gas absorbing material.

198. 200. The ingestible device of claim 196, wherein the mechanism includes an oxygen absorbing material.

199. 200. The ingestible device of claim 196, wherein the mechanism includes a relief valve configured to open when pressure within at least one region of the ingestible device reaches a threshold level.

200. 200. The ingestible device of any of claims 139-199, wherein the storage reservoir comprises multiple chambers.

201. 201. The ingestible device of claim 200, wherein each of the plurality of chambers is configured to store a different dispensable substance.

202. 202. The ingestible device of claim 200 or claim 201, wherein the ingestible device is configured to release the different dispensable substances from the ingestible device simultaneously.

203. 202. The ingestible device of claim 200 or claim 201, wherein the ingestible device is configured to release the different dispensable substances from the ingestible device in sequence.

204. An ingestible device according to any of claims 139 to 203, comprising electronic components configured to control the generation of force by the force generator to deliver a metered dose of the dispenseable substance out of the opening in the ingestible device.

205. The ingestible device of any of claims 139-204, wherein the dispenseable substance comprises a therapeutic agent.

206. 206. The ingestible device of claim 205, wherein the therapeutic agent is in at least one form selected from the group consisting of a powder, a granule, a liquid, and a semi-liquid gel.

207. The ingestible device of any of claims 139-206, further comprising a mechanism for attaching the ingestible device to a wall of the GI tract of a subject.

208. 208. The ingestible device of claim 207, wherein the mechanism includes an expandable hook.

209. The ingestible device of claim 208, wherein the hook is retractable.

210. The ingestible device of claim 208 or claim 209, wherein the hook comprises a needle configured to pierce the wall of the GI tract.

211. 211. The ingestible device of any of claims 208-210, wherein the hook is hollow and configured to deliver the dispenseable substance to the wall of the GI tract.

212. The ingestible device of any of claims 208-211, wherein the hook comprises a bioabsorbable material.

213. The ingestible device of any of claims 139-212, further comprising an enteric coating supported by at least a portion of a housing of the ingestible device.

214. The ingestible device of any of claims 139-213, further comprising an actuator.

215. 215. The ingestible device of claim 214, wherein the actuator comprises a pump.

216. The ingestible device of claim 214 or claim 215, wherein the actuator comprises an osmotic pump.

217. The ingestible device of any of claims 139-216, further comprising at least two different enteric coatings.

218. Housing and an enteric coating supported by at least a portion of the housing; a storage reservoir within said housing; Equipped with the storage reservoir is configured to store a dispenseable substance; Ingestible device.

219. The housing has an opening. In a first state of the ingestible device, the enteric coating covers the opening such that the enteric coating completely prevents the dispensable substance from exiting the ingestible device through the opening; and In a second state of the ingestible device, the enteric coating at least partially dissolves such that the enteric coating at least partially permits the dispensable substance to exit the ingestible device through the opening.

219. The ingestible device of claim 218.

220. the housing includes first and second portions; in a first state of the ingestible device, the enteric coating holds the first and second portions together; and and in the second state of the ingestible device, the enteric coating at least partially dissolves such that the enteric coating at least partially releases the first and second portions from one another.

220. The ingestible device of claim 218 or claim 219.

221. Housing and an actuator disposed within the housing; a storage reservoir disposed within the housing; Equipped with the storage reservoir is configured to store a dispenseable substance; Ingestible device.

222. 222. The ingestible device of claim 221, wherein the actuator comprises a pump.

223. 223. The ingestible device of claim 222, wherein the pump comprises an osmotic pump and / or a peristaltic driven pump.

224. A semipermeable membrane; a pressure chamber disposed adjacent to the semipermeable membrane; The ingestible device of any of claims 221-223, further comprising:

225. The ingestible device comprises: a first reagent chamber configured to store a first reagent; a second reagent chamber configured to store a second reagent; a septum sealing both the first reagent chamber from the second reagent chamber; Equipped with The ingestible device of any of claims 222-224.

226. The diaphragm is ruptured by a first pressure generated by the pump, so that: the first reagent passes through the semi-permeable membrane into the pressure chamber; the second reagent passes through the semi-permeable membrane into the pressure chamber; and The first reagent interacts with the second reagent to produce a second pressure. The ingestible device of claim 225 configured as follows.

227. 227. The ingestible device of claim 226, further comprising a piston adjacent the pressure chamber, the piston configured to move under the influence of the second pressure.

228. 227. The ingestible device of claim 225 or claim 226, wherein the storage reservoir includes a bellows configured to be compressed under the influence of the second pressure.

229. The actuator comprises: A separable part; an osmotic pump disposed adjacent to the separable portion; a dissolvable material that attaches the separable portion to the osmotic pump; Including, the detachable portion is configured to separate from the osmotic pump upon dissolution of the dissolvable material.

222. The ingestible device of claim 221.

230. The ingestible device of any of claims 221-229, further comprising a suction device configured to suck a portion of the intestinal wall through the dispensing port and into the housing when a portion of the ingestible device contacts a wall of the GI tract of a subject.

231. 231. The ingestible device of claim 230, wherein the suction device includes a barbed disk positioned inwardly within the storage device.

232. 222. The ingestible device of claim 221, further comprising first and second enteric coatings.

233. The actuator comprises: a first semipermeable membrane adjacent to the first enteric coating; a first chamber adjacent to the first semipermeable membrane for storing soluble particles; a mesh at an outlet of the first chamber configured to prevent the soluble particles from exiting the first chamber; 233. The ingestible device of claim 232, comprising:

234. 234. The ingestible device of claim 233, wherein the actuator is configured to generate a suction force on the ingestible device when the first enteric coating dissolves.

235. The actuator comprises: a second semipermeable membrane adjacent to the second enteric coating; a second chamber adjacent to the second semipermeable membrane for storing soluble particles; a piston between the second chamber and the storage reservoir; Further comprising: The actuator is configured to move the piston when the second enteric coating dissolves.

235. The ingestible device of claim 234.

236. Housing and a first actuating component within the housing; and a second actuating component, both disposed within said housing; and a first enteric coating attached to the first working component; a second enteric coating attached to the second working component; and a storage reservoir disposed within the housing; Equipped with the storage reservoir is configured to store a dispenseable substance, and the housing has an opening in fluid communication with the storage reservoir. Ingestible device.

237. 237. The ingestible device of claim 236, wherein the first enteric coating is configured to dissolve when exposed to luminal fluids within a first period of time, and the second enteric coating is configured to dissolve when exposed to luminal fluids within a second period of time that is longer than the first period of time.

238. The actuator comprises: a first semipermeable membrane adjacent to the first enteric coating; a first chamber adjacent to the first semipermeable membrane for storing soluble particles; a mesh at an outlet of the first chamber configured to prevent the soluble particles from exiting the first chamber; Including, 237. The ingestible device of claim 236.

239. 239. The ingestible device of claim 238, further comprising a suction device adjacent the opening, the actuator configured to generate a suction force on the ingestible device when the first enteric coating dissolves.

240. The actuator comprises: a second semipermeable membrane adjacent to the second enteric coating; a second chamber adjacent to the second semipermeable membrane for storing soluble particles; a piston between the second chamber and the storage reservoir; Further comprising: the actuator is configured to move the piston toward the opening when the second enteric coating dissolves.

240. The ingestible device of claim 238 or claim 239.

241. 241. The ingestible device of claim 240, further comprising an injection device having a first end proximate the dispensing port and a second end connected to the storage reservoir, the injection device configured to deliver the dispensable substance when the piston is propelled toward the dispensing port.

242. The ingestible device of any preceding claim, wherein the ingestible device comprises a plurality of outlet valves.

243. 33. The ingestible device of any of the preceding claims, wherein the outlet valve has a tapered sidewall.

244. 33. The ingestible device of any of the preceding claims, wherein the outlet valve has a straight sidewall.

245. 138. The ingestible device of any of claims 33-137, wherein the ingestible device comprises a plurality of dispensing ports configured to deliver the dispensable substance from the storage reservoir out of the housing.

246. 138. An ingestible device according to any of claims 33 to 137, wherein the dispensing spout has a tapered sidewall.

247. 138. The ingestible device of any of claims 33-137, wherein the dispensing spout has straight side walls.

248. 139. The method of claim 138, comprising moving the moving member with the second pressure to deliver the pre-loaded dispensable substance out of the ingestible device via a plurality of dispensing ports.

249. 139. The method of claim 138, wherein the dispensing spout has a tapered sidewall.

250. 139. The method of claim 138, wherein the dispensing port has straight side walls.

251. The ingestible device of any of claims 139 to 217, comprising a plurality of openings configured such that when the force generator generates a force, the dispenseable substance exits the ingestible device through the plurality of openings.

252. The ingestible device of any of claims 139-217, wherein the opening has tapered sidewalls.

253. The ingestible device of any of claims 139-217, wherein the opening has straight sidewalls.

254. 236. An ingestible device according to any of claims 218 to 235, wherein the housing has a plurality of openings configured to allow the dispenseable substance to exit the ingestible device via the plurality of openings.

255. The ingestible device of any of claims 218-235, wherein the opening has tapered sidewalls.

256. The ingestible device of any of claims 218-235, wherein the opening has straight sidewalls.

257. one or more processing devices; one or more machine-readable hardware storage devices storing instructions executable by one or more processing devices to determine the location of the ingestible device within a portion of the subject's GI tract with at least 85% accuracy; 20. The ingestible device of any preceding claim, further comprising:

258. one or more processing devices; one or more machine-readable hardware storage devices storing instructions executable by the one or more processing devices to determine with at least 70% accuracy that the ingestible device is in the cecum of a subject; The ingestible device of any of claims 1-256, further comprising:

259. one or more processing devices; one or more machine-readable hardware storage devices storing instructions executable by the one or more processing devices to transmit the data to an implementable device to determine the location of the medical device within a portion of the GI tract of a subject with at least 85% accuracy; The ingestible device of any of claims 1-256, further comprising:

260. one or more processing devices; one or more machine-readable hardware storage devices storing instructions executable by the one or more processing devices to transmit the data to an external device capable of implementing the data to determine with at least 70% accuracy that the ingestible device is in the cecum of a subject; Further comprising: The ingestible device of any of claims 1-256.

261. The ingestible device of any of claims 247-260, further comprising first and second light sources, the first light source configured to emit light at a first wavelength and the second light source configured to emit light at a second wavelength different from the first wavelength.

262. 262. The ingestible device of claim 261, further comprising first and second detectors, the first detector configured to detect light at the first wavelength and the second detector configured to detect light at the second wavelength.

263. A reservoir configured for use within an ingestible device, the reservoir containing a dispenseable substance.

264. 264. The reservoir of claim 263, wherein the reservoir is configured to fit partially within the interior of the housing of the ingestible device.

265. 264. The reservoir of claim 263, wherein the reservoir is configured to fit completely within the housing of the ingestible device.

266. A reservoir according to any one of claims 263 to 265, wherein the reservoir comprises a housing, the housing comprising plastic.

267. 267. The reservoir of claim 266, wherein the plastic comprises at least one material selected from the group consisting of PVC, silicone and polycarbonate.

268. A reservoir as described in any one of claims 263 to 265, wherein the reservoir includes a housing, the housing comprising a metal-based material.

269. The reservoir of claim 268, wherein the metal-based material comprises an alloy.

270. The reservoir of claim 268, wherein the metallic material comprises stainless steel.

271. A reservoir as described in any of claims 263 to 270, wherein the reservoir is configured to attach to the housing of the ingestible device.

272. A reservoir according to any of claims 263 to 271, wherein the reservoir is configured to be a friction fit with the ingestible device.

273. A reservoir according to any of claims 263 to 272, wherein the reservoir is configured to be secured to the ingestible device using a biasing mechanism.

274. 274. The reservoir of claim 273, wherein the biasing mechanism includes at least one member selected from the group consisting of a spring, a latch, a hook, a magnet, and electromagnetic radiation.

275. A reservoir according to any of claims 263 to 274, wherein the reservoir is configured to fit into a groove or track in the housing of the ingestible device.

276. A reservoir as described in any of claims 263 to 275, wherein the reservoir is configured to snap-fit ​​onto the ingestible device.

277. A reservoir according to any one of claims 263 to 276, wherein the reservoir is configured to be pierced.

278. A reservoir as described in any one of claims 263 to 277, wherein the reservoir is configured to carry an electronic component.

279. A reservoir as described in any one of claims 263 to 278, wherein the ingestible device meets FDA requirements.

280. A reservoir according to any of claims 263 to 279, wherein the reservoir is configured for use with an ingestible device according to any of claims 1 to 262.

281. an ingestible device; a reservoir configured for use within the ingestible device, the reservoir configured to hold a dispenseable substance; Including the kit.

282. The kit of claim 281, further comprising the dispenseable substance in the reservoir.

283. A kit according to claim 281 or claim 282, wherein the reservoir comprises a reservoir according to any of claims 263 to 280.

284. Delivering a therapeutic agent to a subject using an ingestible device according to any one of claims 1 to 262; A method comprising:

285. The method of claim 284, wherein the therapeutic agent is delivered to a location within the GI tract of the subject.

286. Attaching a reservoir according to any one of claims 263 to 280 to an ingestible device; A method comprising:

287. 287. The method of claim 286, further comprising disposing the therapeutic agent in a reservoir prior to attaching the reservoir to the ingestible device.

288. The method of claim 286 or claim 287, further comprising using the ingestible device to deliver the therapeutic agent to a subject after attaching the reservoir to the ingestible device.

289. The method of claim 288, wherein the therapeutic agent is delivered to a location within the GI tract of a subject.

290. The method of any of claims 286-289, further comprising determining the location of the ingestible medical device within a portion of the subject's GI tract with at least 85% accuracy.

291. 291. The method of claim 290, wherein determining the position of the ingestible device within the GI tract of a subject includes determining a light signal reflected within the GI tract, the reflected signal comprising at least two different wavelengths of light.

292. 300. The method of claim 291, wherein the reflected signal comprises light of at least three different wavelengths.

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