Therapeutic Payload Delivery Mechanisms

Abstract

An embodiment includes an ingestible capsule comprising a housing including a therapeutic payload delivery section, a power source, a release mechanism, and a detection mechanism, the detection mechanism being sensitive to an environment outside the housing, the ingestible capsule being configured to pass through the GI tract of a subject mammal, during which the detection mechanism is configured to output a signal that varies according to the GI tract environment, the detection mechanism including one or more sensors from among a VOC gas sensor, a TCD gas sensor, a reflectometer formed by a transmitting antenna of the ingestible capsule connected in series with a directional coupler and configured to measure a reflected signal from the transmitting antenna, and an accelerometer, and the release mechanism is configured to release the therapeutic payload from the therapeutic payload delivery section into the GI tract at a release timing determined according to the output signal.

Description

[Technical field]

[0001] The present invention relates to ingestible capsules for delivering a therapeutic payload directly to a selected location within the gastrointestinal (GI) tract of a mammal, including a human. [Background technology]

[0002] Gas sensor capsules such as those disclosed in EP3497437A1 contain a gas sensor within an ingestible capsule so that readings can be obtained from within the gastrointestinal (GI) tract of a mammal and from which analyte gas concentration readings can be determined.

[0003] A process for determining the type and concentration of specific gases in a multi-gas mixture based on readings taken from within the GI tract by a gas sensor mounted in an ingestible capsule is disclosed in EP 3 619 526 A1.

[0004] Therapeutic substances such as drugs, prebiotics, and probiotics are used to treat a plethora of conditions and diseases. Drugs administered in clinics can be administered in several ways, including via intravenous drip, injected directly into the bloodstream, subcutaneous injection, orally, or as a rectal suppository. However, drugs given by clinics to be administered by patients at home cannot be administered via intravenous drip or directly into the bloodstream due to lack of specialist expertise and equipment. Of the remaining techniques, subcutaneous injections are unpopular due to the reluctance of non-medically trained personnel to administer injections. Such reluctance can lead to drugs being administered incorrectly or not at all.

[0005] Therefore, drugs (or other therapeutic substances) given by clinics to be administered at home tend to be for oral consumption or for suppositories. Suppositories may be unpopular due to the discomfort and hygiene concerns associated with rectal administration. Furthermore, rectal administration is inappropriate for some drug / treatment scenarios. Oral consumption of traditional drug tablets or capsules may be the optimal form of administration in some cases. However, there are scenarios where a therapeutic payload is necessary or most effective when it reaches various stages of the GI tract that may pass through the stomach, and where the therapeutic substance can be broken down by passing through the stomach.

[0006] There are also scenarios in which side effects caused by consumption of a particular therapeutic substance may be reduced or avoided if the therapeutic substance can be released at a stage in the GI tract past the stomach.

[0007] If a therapeutic substance could be delivered directly to a selected location within the GI tract, the amount of therapeutic substance consumed could be reduced.

[0008] Capsules for oral consumption can be configured to dissolve or otherwise degrade in the GI tract at a particular rate to deliver a therapeutic substance contained therein to the GI tract, at which point the capsule wall is breached. However, such capsules are not consistent in their rate of decomposition depending on the environmental conditions within the GI tract. Furthermore, because the rate of movement of substances through the GI tract is unpredictable, the location at which such capsules deliver their payload to the GI tract is highly probabilistic.

[0009] The efficacy of therapeutic agents is improved in some scenarios by localized release directly to specific regions of the GI tract, rather than via ingestible or rectal suppositories that release therapeutic agents to non-deterministic regions of the GI tract For example, the efficacy of prebiotics and probiotics is improved by release to the large intestine.

[0010] Systemic uptake of therapeutic substances can have undesirable effects (sometimes called side effects). Depending on the disease or condition being addressed by the treatment and the therapeutic problem, some side effects can be reduced in severity or avoided by locally releasing the therapeutic substance to a specific area of ​​the GI tract, thus reducing systemic uptake.

[0011] It is desirable to provide an ingestible capsule that delivers a therapeutic substance to a selected location within the GI tract. Summary of the Invention

[0012] Embodiments include an ingestible capsule comprising a biocompatible indigestible housing including a therapeutic payload delivery compartment, a power source, a release mechanism, and a VOC gas sensor, the VOC gas sensor being exposed to an environment external to the housing, the ingestible capsule being configured to pass through the gastrointestinal (GI) tract of a subject mammal, during which the VOC gas sensor is configured to output an output signal that varies according to a concentration of one or more components of a gas mixture to which the VOC gas sensor is exposed, and the release mechanism being configured to cause the therapeutic payload to be released from the therapeutic payload delivery compartment into the GI tract at a release timing determined according to the output signal.

[0013] Optionally, the release mechanism is configured to identify an ileocecal indicator in the output signal in real time and determine the release timing according to the identification of the ileocecal indicator.

[0014] Optionally, the ileocecal transition indicator is a characteristic or combination of characteristics of a reading, series of readings, pattern, geometric feature, and / or mathematical feature in the recording of the output signal as a function of time, which characteristic or combination of characteristics is predefined as being caused by a transition of the ingestible capsule across the ileocecal region.

[0015] Optionally, the release timing is immediate upon identification of the ileocecal indicator, or the release timing is a predetermined period after identification of the ileocecal indicator.

[0016] Optionally, the release timing is a period of time after the ileocecal transition of the capsule to allow for collection of sufficient sensor data to indicate or confirm presence within the large intestine. Note that embodiments may be configured to detect the ICJ transition itself (and thus conclude that the capsule is within the large intestine), or may be configured to directly detect presence within the large intestine.

[0017] Optionally, the release mechanism comprises a microcontroller and a release actuator, wherein the microcontroller is configured to record representations of the output signal over a recent duration period t on a rolling basis during the identification phase and process the recorded representations of the output signal over the recent duration period t to identify the presence or absence of an ileocecal transition indicator, and the microcontroller is configured to determine a release timing upon identification of the ileocecal indicator and cause the release actuator to release the therapy payload from the therapy payload delivery section.

[0018] Optionally, the release mechanism comprises a transceiver and an actuator, the antenna configured to transmit a transmission signal representative of the output signal to the remote processing device during the identification phase, and the transceiver configured to cause the therapy payload to be released from the therapy payload carrying section by the release actuator immediately or after a predetermined delay upon receiving a notification signal from the remote processing device.

[0019] Optionally, the VOC gas sensor includes a sensor side and a heater side, and the output signal includes only a sensor side output signal component generated by the sensor side when no power is provided to the heater side by the power supply.

[0020] Optionally, the VOC gas sensor includes a sensor side and a heater side, and the output signal includes a sensor side output signal component generated by the sensor side and a heater side output signal component generated by the heater side.

[0021] Optionally, the emission mechanism is configured to identify the ileocecal indicator in the representation of the output signal by identifying a predefined characteristic in the sensor-side output signal component contemporaneously with a predefined characteristic in the heater-side output signal component.

[0022] Optionally, the VOC gas sensor comprises a heating element and is configured to drive the heating element in a pulsed manner, and the VOC gas sensor output signal includes separate readings each taken at the same point in phase of a respective pulse of the heating element.

[0023] Optionally, the VOC gas sensor output signal is, or is proportional or directly proportional to, the resistance across a sensor side of the VOC gas sensor.

[0024] Optionally, the release mechanism is configured to identify the ileocecal indicator in a representation of the output signal by defining a maximum value of the output signal during a calibration phase and progressing the calibration phase during a live phase to identify a predefined characteristic in the output signal, wherein identifying the predefined characteristic includes identifying a reduction in the output signal to a level that is more than a predefined amount or percentage below the defined maximum value, identifying a subsequent increase in the output signal, and determining that the output signal does not decrease for a predefined duration period immediately following the identified increase, wherein the reduction is a negative slope over a predefined period or number of readings.

[0025] Optionally, the therapeutic payload is a drug, a prebiotic substance, a fecal transplant, a biological substance, and / or a probiotic substance.

[0026] An embodiment is a system comprising an ingestible capsule and a remote processing device, the ingestible capsule comprising a biocompatible indigestible housing including a therapeutic payload delivery compartment, a power source, a release mechanism, and a VOC gas sensor, the VOC gas sensor being exposed to gases external to the housing, the ingestible capsule being configured to pass through a gastrointestinal (GI) tract of a subject mammal, during which the VOC gas sensor is configured to output an output signal that varies according to a concentration of one or more components of a gas mixture to which the VOC gas sensor is exposed, the release mechanism being configured to cause the therapeutic payload to be released from the therapeutic payload delivery compartment into the GI tract at a release timing determined according to the output signal, the release mechanism being configured to control a release timing of the therapeutic payload from the therapeutic payload delivery compartment into the GI tract, the release mechanism being configured to control a release timing of the therapeutic payload from the therapeutic payload delivery compartment into the GI tract at a release timing determined according to the output signal ... the capsule transceiver is configured to transmit a transmission signal representative of the output signal to the remote processing device during the identification phase, and the capsule transceiver is configured to cause the therapy payload to be released from the therapy payload carrying section by the release actuator immediately or after a predetermined delay upon receiving a notification signal from the remote processing device, the remote processing device being configured to communicate with the capsule transceiver, including receiving the transmission signal representative of the output signal, and a processor configured to process the output signal to identify an ileocecal indicator in the output signal in real time and cause the remote processing device transceiver to transmit a notification signal to the capsule transceiver in accordance with the identification of the ileocecal indicator.

[0027] An embodiment includes a method, comprising providing an ingestible capsule according to an embodiment to a subject mammal for ingestion, processing an output signal of the VOC gas sensor to determine a release timing of a therapeutic payload, and causing the therapeutic payload to be released into the GI tract of the subject mammal at the determined release timing.

[0028] The embodiments provide a deterministic mechanism for releasing a therapeutic payload to a specific region of the GI tract. The embodiments actively sense the location of an ingestible capsule within the GI tract and determine the timing of release of the therapeutic payload according to the sensed location. The therapeutic payload is released locally to a specific region of the GI tract, e.g., the colon.

[0029] The effectiveness of the therapeutic payload is improved by accurate determination of the release location rather than relying on probabilistic methods.

[0030] It overcomes the inconvenience, reluctance, pain, and other problems associated with subcutaneous and rectal suppository methods of therapeutic payload delivery.

[0031] Side effects associated with release of a therapeutic payload to regions of the GI tract other than a particular region are reduced or avoided. For example, side effects associated with release to the stomach can be reduced or avoided by direct release to the large intestine. The ingestible capsules disclosed herein provide a mechanism for reducing the toxic effects of a therapeutic payload, such as a drug, by delivering the therapeutic payload directly to the site of action, as opposed to via the bloodstream to the liver. For example, to treat irritable bowel syndrome.

[0032] The embodiments utilize an accurate, reliable and robust mechanism for determining capsule location.

[0033] An embodiment includes an ingestible capsule comprising a housing, the housing being a biocompatible indigestible housing containing a therapeutic payload carrying compartment, a power source, a release mechanism, and a detection mechanism, the detection mechanism being sensitive to an environment outside the housing, the ingestible capsule being configured to pass through the gastrointestinal (GI) tract of a subject mammal, during which the detection mechanism is configured to output an output signal that varies according to the GI tract environment outside the housing, the detection mechanism including one or more sensors from among a VOC gas sensor, a TCD gas sensor, a reflectometer formed by a transmitting antenna of the ingestible capsule connected in series with a directional coupler and configured to measure a reflected signal from the transmitting antenna, and an accelerometer, and the release mechanism is configured to cause the therapeutic payload to be released from the therapeutic payload carrying compartment into the GI tract at a release timing determined according to the output signal.

[0034] Optionally, the ingestible capsule comprises processor hardware configured to identify in real time one or more ileocecal transition indicators in the output signal of the sensing mechanism, and to determine said release timing according to identification of the ileocecal indicators.

[0035] Optionally, the sensing mechanism is a direct gas sensing mechanism comprising a VOC gas sensor, the direct gas sensing mechanism is contained within the capsule in a direct gas sensing portion that is sealed from other components of the ingestible capsule by a gas impermeable membrane and is exposed to a gas mixture in an environment external to the ingestible capsule via a gas permeable membrane in the housing at the direct gas sensing portion, and an output signal output by the sensing mechanism includes a VOC concentration reading of the VOC gas sensor.

[0036] Optionally, the VOC gas sensor includes a sensor side and a heater side, and the output signal includes only a sensor side output signal component generated by the sensor side when no power is provided to the heater side by the power supply.

[0037] Optionally, the direct gas sensing mechanism further comprises a TCD gas sensor or the ingestible capsule is configured to take a TCD reading via the heater side of the VOC gas sensor, and the output signal output by the sensing mechanism further comprises a TCD reading of the VOC gas sensor and / or the TCD gas sensor.

[0038] Optionally, identifying the ileocecal transition indicator includes identifying an increase in a sensor-side VOC gas sensor reading accompanied by a concomitant increase in H2 concentration, the H2 concentration being derived from a TCD reading of the TCD gas sensor and / or a heater-side reading of the VOC gas sensor.

[0039] Optionally, identifying the ileocecal transition indicator includes identifying an increase in a sensor-side VOC gas sensor reading accompanied by a simultaneous increase in a CH4 concentration, the CH4 concentration being derived from a TCD reading of the TCD gas sensor and / or a heater-side reading of the VOC gas sensor.

[0040] Optionally, the sensing mechanism is a non-contact sensing mechanism contained within a portion of the ingestible capsule that is sealed from an environment outside the ingestible capsule by a housing, the non-contact sensing mechanism including at least one of an accelerometer and a reflectometer, the reflectometer comprising a transmitting antenna connected in series with a directional coupler and configured to measure a reflected signal from the transmitting antenna, and an output signal output by the sensing mechanism includes an accelerometer reading and / or a reflectometer reading.

[0041] Optionally, the non-contact sensing mechanism comprises a reflectometer and the ingestible capsule further comprises a diode detector, the diode detector forming part of the reflectometer, the diode detector configured to receive a reflected signal from the antenna and measure an amplitude of the reflected signal, and the reflectometer reading in the output signal comprises an amplitude measurement of the reflected signal.

[0042] Optionally, the ingestible capsule further comprises a quadrature demodulator, the quadrature demodulator forming part of a reflectometer, the quadrature demodulator configured to receive the reflected signal from the antenna via the directional coupler and extract phase information of the reflected signal relative to the carrier signal, and the reflectometer reading in the output signal includes the extracted phase information of the reflected signal.

[0043] Optionally, the ingestible capsule further comprises an antenna impedance control mechanism comprising a variable capacitor configured to vary the impedance of the transmitting antenna; and a controller, wherein the reflectometer and the antenna impedance control mechanism form a closed or feedback loop, and the controller is configured to receive measurements of the amplitude of the reflected signal from the diode detector and execute a control algorithm to use the amplitude measurements to generate an antenna impedance control signal that sets a capacitance of the variable capacitor to vary the impedance of the antenna to reduce the amplitude of the reflected signal, and wherein the reflectometer reading in the output signal comprises a reading of the antenna impedance control signal.

[0044] Optionally, the closed loop or feedback loop further comprises a quadrature demodulator, where phase information is extracted by the quadrature demodulator and output to a controller, where the controller is configured to use the amplitude and phase information to generate the antenna impedance control signal.

[0045] Optionally, the non-contact sensing mechanism comprises an accelerometer, which measures an orientation of the ingestible capsule relative to a reference system fixed with respect to a gravity vector, and the microcontroller processes the accelerometer measurements by determining whether the orientation of the ingestible capsule obtained by each accelerometer measurement is greater than a threshold angular displacement from a reference orientation, and if the threshold angular displacement is not met, proceeding to a next accelerometer measurement without changing the reference orientation, and if the threshold angular displacement is met, changing the reference orientation to match the orientation of the ingestible capsule obtained by the respective accelerometer measurement, and identifying the ileocecal transition indicator and / or gastroduodenal transition indicator includes detecting that a rate of change of the reference orientation meets a detection criterion.

[0046] Optionally, the non-contact sensing mechanism comprises an accelerometer, which measures an orientation of the ingestible capsule relative to a reference frame that is fixed relative to a gravity vector, and the microcontroller processes the accelerometer measurements by iterating chronologically for each successive accelerometer measurement for each of three orthogonal axes in a fixed spatial relationship relative to the ingestible capsule derivable from the orientation readings, calculating a change in the orthogonal axis relative to the gravity vector from the preceding accelerometer measurement as a scalar value, applying a low pass filter to the calculated change, and recording the cumulatively filtered calculated change, and identifying the ileocecal transition index and / or gastroduodenal transition index includes detecting a step change in the rate of increase of the cumulatively filtered calculated change that meets a detection criterion.

[0047] Optionally, the output signal output by the sensing mechanism includes an accelerometer reading and a reflectometer reading, and determining the release timing includes identifying that an ileocecal transition indicator is present in readings from the reflectometer and the accelerometer, processing the reflectometer readings and the accelerometer readings to identify the presence of a first ileocecal transition indicator in one of the reflectometer readings and the accelerometer readings, processing the other of the reflectometer readings and the accelerometer readings to identify a second ileocecal transition indicator within a predefined time window of timing of the first ileocecal transition indicator, and determining the release timing as either immediate or after a predefined delay in response to identifying the first ileocecal transition indicator and the second ileocecal transition indicator within the predefined time window.

[0048] Optionally, the or each ileocecal transition indicator and / or gastroduodenal transition indicator is a characteristic or combination of characteristics of a reading, series of readings, pattern, geometric feature, statistical feature, and / or mathematical feature in the recording of the output signal as a function of time, which characteristic or combination of characteristics is predefined as being caused by transition of the ingestible capsule across the ileocecal region or caused by transition from the stomach to the duodenum.

[0049] Optionally, the ingestible capsule comprises a microcontroller, and the release mechanism comprises a microcontroller and a release actuator, the microcontroller being configured to record, on a rolling basis during the identification phase, a representation of the output signal over a recent duration period t and process the recorded representation of the output signal over the recent duration period t to identify the presence of one or more ileocecal transition indicators, and the microcontroller being configured to determine a release timing upon identification of the presence of the one or more ileocecal transition indicators, and to cause the release actuator to release the therapeutic payload from the therapeutic payload delivery section based on the determined release timing.

[0050] Optionally, the ingestible capsule comprises a microcontroller, and the release mechanism comprises a microcontroller and a release actuator, wherein the microcontroller is configured to record, on a rolling basis during the identification phase, representations of the output signal over a recent duration period t and process the recorded representations of the output signal over the recent duration period t to identify the presence of the one or more gastroduodenal transition indicators, and the microcontroller is configured to determine a release timing upon identification of the presence of the one or more gastroduodenal transition indicators, and to cause the release actuator to release the therapeutic payload from the therapeutic payload delivery section based on the determined release timing.

[0051] Optionally, the ingestible capsule comprises a microcontroller, and the release mechanism comprises said microcontroller and a release actuator, wherein the microcontroller is configured to record, on a rolling basis during the identification phase, a representation of the output signal over a recent duration period t, identify a presence of one or more gastroduodenal transition indicators, and after identifying the presence of the one or more gastroduodenal transition indicators, process the recorded representation of the output signal over the recent duration period t to identify the presence of one or more ileocecal transition indicators, and the microcontroller is configured to determine a release timing upon identification of the presence of the one or more ileocecal transition indicators, and cause the release actuator to release the therapeutic payload from the therapeutic payload delivery section based on the determined release timing.

[0052] Optionally, the therapeutic payload is one or more of a drug, a pharmaceutical agent, a prebiotic substance, a fecal transplant, and / or a probiotic substance.

[0053] Optionally, the ingestible capsule comprises a wireless transceiver, the release mechanism comprises a wireless transceiver and a release actuator, the antenna configured to transmit a transmission signal representing the output signal to the remote processing device during the identification phase, and the transceiver configured to cause the therapeutic payload to be released from the therapeutic payload carrying section by the release actuator immediately or after a predetermined delay upon receiving a notification signal from the remote processing device.

[0054] Optionally, the release mechanism comprises a microcontroller and a release actuator, the therapeutic payload carrying section comprises a section of the ingestible capsule housing, a sealed chamber, and an elastic material membrane defining at least a portion of a wall of the sealed chamber, the therapeutic payload being sealed within the sealed chamber, and the release actuator comprises an elastic material membrane breaking mechanism configured to break the elastic material membrane at a determined release timing, thereby opening the sealed chamber and allowing the therapeutic payload to exit the ingestible capsule through one or more openings in the section of the ingestible capsule housing.

[0055] Optionally, the elastic material membrane rupturing mechanism includes a power source and a heating element, the heating element being at least partially positioned within or facing an inner surface of the treatment payload carrying section, and at least a portion of a wall of the sealed chamber defined by the elastic material membrane being positioned to contact the heating element, and the power source being configured to transfer energy to the heating element at a determined release timing and under the control of the microcontroller, increasing the temperature of the heating element, which in turn ruptures the elastic material membrane, thereby opening the sealed chamber.

[0056] Optionally, the power source of the elastic material membrane rupture mechanism is a supercapacitor configured to be trickle charged by the ingestible capsule power source over a period of time beginning with a triggering event of the ingestible capsule, and to release charge to the heating element at a release timing determined under the control of the microcontroller.

[0057] Optionally, the supercapacitor and the heating element are impedance matched, or impedance matched within a specified tolerance.

[0058] Optionally, the heating element is a resistive heating element including one or more of the following: SMT resistor, metal resistance wire, Nichrome, MEMS heater element.

[0059] Optionally, the elastic material membrane rupturing mechanism comprises a power source and a laser diode focused on the elastic material membrane, and the microcontroller of the ingestible capsule is configured to activate the laser diode at a determined release timing to rupture the elastic material membrane, thereby opening the sealed chamber.

[0060] Optionally, the elastic material membrane rupturing mechanism includes a front spring-loaded mechanical needle, and the microcontroller of the ingestible capsule is configured to release the front spring-loaded mechanical needle at a determined release timing, causing the front spring-loaded mechanical needle to bounce against the elastic material membrane and rupture the elastic material membrane, thereby opening the sealed chamber.

[0061] Optionally, the release mechanism comprises a microcontroller and a release actuator, the therapeutic payload carrying section comprises a section of the ingestible capsule housing, a sealed chamber, and an elastic material membrane defining at least a portion of a wall of the sealed chamber, the therapeutic payload being sealed within the sealed chamber, the chamber being sealed by a releasable valve, and the release actuator comprises a releasable valve release mechanism configured to release the releasable valve at a determined release timing, thereby unsealing the sealed chamber and allowing the therapeutic payload to exit the ingestible capsule through one or more openings in the section of the ingestible capsule housing.

[0062] Optionally, the releasable valve is a twisted hose and the releasable valve release mechanism is a shape memory alloy wire or a micromotor configured to untwist the hose under the control of a microcontroller of the ingestible capsule, thereby opening the chamber and allowing the contents of the chamber to exit the ingestible capsule through one or more openings in the housing of the ingestible capsule.

[0063] Optionally, the elastic material membrane rupturing mechanism comprises a power source, a shape memory alloy wire, and a breaking member, wherein the power source is configured to transmit energy to the shape memory alloy wire at a determined release timing and under the control of a microcontroller to initiate a phase change in the material level of the shape memory alloy wire, thereby applying a force to the breaking member to bring the breaking member into contact with the elastic material membrane and breaking the elastic material membrane, thereby opening the sealed chamber.

[0064] Optionally, the elastic material membrane breaking mechanism comprises a motor and a breaking member, and the microcontroller is configured to power the motor at the determined release timing, thereby applying a force to the breaking member to bring the breaking member into contact with the elastic material membrane and breaking the elastic material membrane, thereby opening the sealed chamber.

[0065] Optionally, the release mechanism comprises a microcontroller and a release actuator, the therapeutic payload carrying compartment comprises a section of an ingestible capsule housing, a sealed chamber, and an elastic material membrane defining at least a portion of a wall of the sealed chamber, within which a liquid diluent is sealed, the therapeutic payload is a lyophilized drug or other therapeutic substance in powder, dehydrated, or other solid form, within a space exterior to the sealed chamber and contained within the therapeutic substance carrying compartment defined at least in part by the elastic material membrane, the section of the ingestible capsule housing includes one or more openings enabling fluid communication between the therapeutic payload carrying compartment and an exterior of the capsule, the one or more openings being occluded by the elastic material membrane and being unoccluded following rupture of the elastic material membrane by the elastic material membrane rupture mechanism at a determined release timing, the rupture of the elastic material membrane allowing the liquid diluent to mix with the therapeutic payload in the therapeutic payload carrying compartment and with fluid from said environment exterior to the capsule via the one or more openings.

[0066] Optionally, the elastic material membrane is in tension on a rigid open frame, the rigid open frame defining one or more openings, the one or more openings being sealed by the elastic material membrane while the sealing chamber is sealed and at least partially open after rupture of the elastic material membrane by the release actuator.

[0067] Optionally, the rigid open frame defines, in addition to the one or more openings, one or more further openings, which are sealed by an outer cover that is separate from or part of the housing of the ingestible capsule.

[0068] Optionally, the elastic material membrane is a balloon filled with a therapeutic substance or liquid diluent and in an expanded state within the therapeutic substance delivery compartment, covering one or more openings in a section of the housing of the ingestible capsule.

[0069] Optionally, the ingestible capsule includes an environmental sensor, the readings include environmental sensor readings, the environmental sensor being an environmental temperature sensor, an environmental relative humidity sensor, or an environmental temperature sensor and an environmental humidity sensor, and processing the recorded measurements includes determining an excretion event timing by detecting an excretion indicator, the excretion indicator being a change in the environmental sensor reading between an internal environmental condition of the target mammal and an external environmental condition at the location of the target mammal, and the excretion event timing being a timing of excretion of the ingestible capsule by the target mammal.

[0070] Optionally, the ingestible capsule comprises a wireless transceiver configured to transmit a data transmission payload from the ingestible capsule via Bluetooth, Bluetooth Long Range, and / or 433 MHz wireless transmission techniques, the data transmission payload including one or more of: a record of release timing, a record of emptying timing, a record of one or more identified ileocecal transition indicators, a record of one or more identified gastroduodenal transition indicators, a record of an electrode signal indicative of rupture of an elastic material membrane opening a chamber containing a therapeutic payload or liquid diluent, an output signal output by the sensing mechanism, and one or more metrics representative of the output signal output by the sensing mechanism.

[0071] Optionally, transmission of the data transmission payload by the wireless transceiver is triggered by one or more of: a determination that an excretion event has occurred; a determination of an ejection timing; a determination that the ejection timing and a predefined delay after the ejection timing have elapsed; and receipt of an electrode signal at the ingestible capsule's microcontroller indicating the rupture of an elastic material membrane that opens a chamber containing a therapeutic payload or liquid diluent.

[0072] Optionally, the sensing mechanism includes a direct gas sensing mechanism and a non-contact sensing mechanism.

[0073] Embodiments include an ingestible capsule comprising a housing, the housing being a biocompatible indigestible housing containing a therapeutic payload carrying compartment, a power source, a release mechanism, and a detection mechanism, the detection mechanism being sensitive to an environment outside the housing, the ingestible capsule being configured to pass through the gastrointestinal (GI) tract of a subject mammal, during which the detection mechanism is configured to output an output signal that varies according to the GI tract environment outside the housing, and the release mechanism being configured to release the therapeutic payload from the therapeutic payload carrying compartment into the GI tract at a release timing determined according to the output signal.

[0074] It is noted that the sensing mechanism is sensitive to the environment outside the housing, and that the sensing mechanism is located within the housing, and thus the interaction between the external environment and the sensing mechanism occurs within the housing. Nevertheless, the sensing mechanism is sensitive to changes in the environment in which the capsule is located. Specifically, the sensing mechanism is sensitive to the composition of the environment in which the capsule is located and / or the interaction between the capsule and the environment in which the GI tract is located. The composition of the GI tract is a combination of fluid compositions including at least one of liquids and gases present in the GI tract at the location of the capsule, and may also include surrounding tissue. The exact composition changes as the capsule progresses along the GI tract, and the extent to which different components of the composition affect the sensing mechanism varies according to the identity of the components and their placement relative to the capsule (and relative to the antenna location within the capsule) and relative to other components of the GI tract. For example, antenna reflectivity is affected by interfaces between different transmission environments. In the accelerometer example, it can be seen that the sensing mechanism (including the accelerometer) is sensitive to changes in the capsule's motion caused by physical interactions between the capsule and the environment in which the capsule is located.

[0075] An embodiment includes an ingestible capsule comprising a housing including a therapeutic payload delivery section, a power source, a release mechanism, and a detection mechanism, the detection mechanism being sensitive to an environment outside the housing, the ingestible capsule being configured to pass through the GI tract of a subject mammal, during which the detection mechanism is configured to output a signal that varies according to the GI tract environment, the detection mechanism including one or more sensors from among a VOC gas sensor, a TCD gas sensor, a reflectometer formed by a transmitting antenna of the ingestible capsule connected in series with a directional coupler and configured to measure a reflected signal from the transmitting antenna, and an accelerometer, and the release mechanism is configured to release the therapeutic payload from the therapeutic payload delivery section into the GI tract at a release timing determined according to the output signal. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0076] Embodiments are illustrated below, by way of example, with reference to the accompanying drawings, in which: [Brief description of the drawings]

[0077] [Figure 1A] 1 illustrates the exterior of an ingestible capsule of one embodiment. [Figure 1B] 1 illustrates the exterior of an ingestible capsule of one embodiment. [Figure 1C] 1 illustrates the exterior of an ingestible capsule of one embodiment. [Figure 1D] 1 illustrates the exterior of an ingestible capsule of one embodiment. [Figure 1E] 1 illustrates the exterior of an ingestible capsule of one embodiment. [Diagram 2] FIG. 2 is a schematic diagram of electronic components inside an ingestible capsule in one embodiment. [Figure 3A] FIG. 2 is a schematic diagram of electronic components inside an ingestible capsule in a local processing embodiment. [Figure 3B] FIG. 2 is a schematic diagram of electronic components inside an ingestible capsule in a remote processing embodiment. [Figure 3C]FIG. 2 is a schematic diagram of electronic components inside an ingestible capsule in a combined local and remote processing embodiment. [Figure 3D] A reflectometer is shown. [Figure 3E] FIG. 2 is a schematic diagram of electronic components inside the ingestible capsule. [Figure 4] 1 illustrates a system according to one embodiment. [Figure 5A] 1 shows a VOC output signal obtained in a live implementation of one embodiment. [Figure 5B] 1 shows a VOC output signal and an ICJ index within the VOC output signal obtained in a live implementation of one embodiment. [Figure 6] 1 shows a VOC output signal and an ICJ index within the VOC output signal obtained in a live implementation of one embodiment. [Figure 7A] 1 is a schematic diagram of an ingestible capsule of one embodiment showing an ejection actuator before and after ejection. [Figure 7B] FIG. 1 is a schematic diagram of a release mechanism. [Figure 7C] FIG. 1 is a schematic diagram of a release mechanism. [Figure 7D] 1 is a sequence of diagrams illustrating the formation, filling, and rupture of a sealed chamber for a treatment substance. [Figure 7E] FIG. 2 is a cross-sectional view of an ingestible capsule. [Figure 7F] FIG. 2 is a cross-sectional view of an ingestible capsule. [Figure 8] 1 shows a CO2 concentration signal and ICJ index obtained in a live implementation of one embodiment. [Figure 9A] 13 shows a plot of the sensing mechanism output signal from a sample ingestible capsule. [Figure 9B] 13 shows a plot of the sensing mechanism output signal from a sample ingestible capsule. [Figure 9C] 13 shows a plot of the sensing mechanism output signal from a sample ingestible capsule. [Figure 10] A processing device is shown.

[0078] Capsule Structure 1A-1E are several different views of the appearance of ingestible capsule 10. As shown in FIGS. 1A-1E, ingestible capsule 10 consists of a housing, such as a gas-impermeable shell 11, having an opening covered by a gas-permeable membrane 12. Gas-impermeable shell 11 is formed from a biocompatible indigestible outer layer, such as a biocompatible indigestible polymer. A sensing mechanism is contained within the housing and may include a direct gas sensing mechanism that requires fluid communication with the environment outside capsule 10 and / or a non-contact sensing mechanism that does not require fluid communication with the environment outside capsule 10. In capsule 10 with a direct gas sensing mechanism that requires fluid communication with the environment surrounding the housing to sense the composition of the gas mixture in or surrounding capsule 10, the fluid communication is enabled through gas-permeable membrane 12, shown in FIG. 1B. Behind gas-permeable membrane 12 is a sensing headspace that contains the direct gas sensing mechanism and is sealed from other components within capsule 10. That is, any on-board gas sensors are contained within the housing and are in fluid communication with the environment surrounding the housing via the gas permeable membrane 12. The remaining components of the ingestible capsule 10 are not in fluid communication with the environment surrounding the housing until a determined release timing, when some fluid communication is permitted between the external environment and the therapeutic substance delivery section 22 via the opening 760. The opening 760 is sealed until the determined release timing. The gas permeable membrane 12 is optional, as the capsule 10 may determine the release timing via a signal output from a non-contact sensing mechanism.

[0079] FIG. 1A shows an end of the capsule 10 with an opening 731 that communicates with an opening in a chamber that contains a therapeutic payload, the chamber being sealed by a one-way valve or some other sealing member. In the example of a valve, the opening 731 allows access to the valve for inserting the therapeutic substance into the sealed chamber after the capsule 10 is manufactured, for example, via a needle, syringe, or some other mechanism adapted to cooperate with the valve to allow the therapeutic substance to flow through the valve and into the chamber. It is noted that alternative capsule configurations do not require the opening 731 for inserting the therapeutic substance into the chamber. In particular, the therapeutic substance may be inserted into the chamber prior to completion of the capsule 10, i.e., during manufacture, such that the therapeutic substance is inserted into the chamber and the sealed chamber is enclosed in the housing by joining two or more sections of the housing together. That is, the opening 731 allowing the insertion of a needle for inserting the therapeutic payload into the capsule 10 is optional.

[0080] FIG. 1C is a side view showing the placement of an opening 760 in the housing. The opening allows for fluid communication across the housing, but the opening 760 may be blocked by an elastic material membrane 722 in the therapeutic payload carrying compartment of the capsule 10, which forms at least a wall of a sealed container carrying the therapeutic payload. The therapeutic substance carrying compartment is a section of the housing and may include an inner wall dividing the capsule 10 to define the therapeutic payload carrying compartment 22 at an end (e.g., approximately coinciding with the circumference marked at 112) having an opening 760 defined by the inner wall, and a section of the capsule housing between the inner wall and the end. The inner wall may be configured to allow electronic connectors to pass through and to fluidly seal the therapeutic substance carrying compartment of the capsule 10 from a compartment of the capsule carrying electronic components, including one or more of, for example, a power source, a microcontroller, and a wireless transceiver. Thus, it is not necessary to block the opening 760. The therapeutic payload is sealed from fluids external to the sealed chamber in which it is delivered until the time of release, but fluids from the external environment may be allowed to enter the therapeutic substance delivery section 22 of the capsule (defined by the lateral inner wall and the capsule housing between the inner wall and the end of the capsule 10). Reference numeral 112 indicates the approximate location of the inner wall. The capsule may or may not have an external feature at the location indicated by 112. Optionally, the two parts of the capsule housing may be joined together at the circumferential line 112. Optionally, the inner wall may be formed partially or completely by a printed circuit board 740.

[0081] 1D and 1E are isometric views of the capsule shown in FIGS. 1A-1C.

[0082] The housing may be HDPE laser welded with optional PDMS membrane 12. Optionally, the housing includes one or more openings 760 leading from the exterior of the ingestible capsule to a therapeutic substance delivery compartment inside the ingestible capsule that is sealed from a portion of the ingestible capsule 10 that houses electronic components including power sources, sensing mechanisms, wireless transceivers, reflectometers, microcontrollers, and on-board processors, and the openings 760 are sealed prior to the determined release timing such that fluids outside the capsule 10 do not mix with the therapeutic payload until the determined release timing.

[0083] One or more of the electronic components may be arranged on a rigid flex printed circuit board. In particular, the antenna may be arranged on a flex printed circuit board due to spatial considerations. The flex printed circuit board on which the antenna is printed may be part of or connected to the rigid flex printed circuit board on which the other electronic components are mounted. The capsule may be constituted by a printed circuit board that has only rigidity, in particular in a configuration that does not include an antenna.

[0084] The capsule 10 includes memory hardware and processor hardware. The memory hardware stores processing instructions for processing output signals from the sensing mechanism to identify indicia of motility events, including one or more of ingestion, gastroduodenal transition, ileocecal transition, and elimination, to determine release timing and, optionally, to generate report data for transmission from the capsule. Alternatively, the processing instructions may be to coordinate transmission of the output signals from the capsule 10 for processing elsewhere and to receive signals that determine release timing. The memory hardware may also store processing instructions for processing signals from electrodes or conductive pads in the deployment sensing mechanism to determine that the therapeutic substance has been deployed, to determine whether to activate the release mechanism (i.e., at the second or third thought), and, alternatively or additionally, to include such determination in the report data for transmission from the capsule. The processing instructions stored by the memory hardware are executed by the processor hardware. Optionally, the memory hardware and the processor hardware are provided as part of a microcontroller. It should be noted, however, that capsule 10 may be configured with a microcontroller configured to distribute data and power among the various electronic components of capsule 10, and dedicated memory hardware and / or dedicated processor hardware provided independent of the microcontroller but coupled to it for exchanging power and data with the other components.

[0085] The data reported by the ingestible capsule 10 (i.e., the data transmission payload transmitted from the capsule 10 to the receiving device 30) may be used for one or more of: compliance monitoring, dose delivery confirmation, and treatment monitoring.

[0086] Alternatively, capsule 10 may be configured without a direct gas sensor (direct gas sensor is taken to mean a gas sensor that requires direct physical contact between the sensor and the gas sample). That is, capsule 10 may be configured with a reflectometer (described in more detail below) and / or an accelerometer instead of a VOC gas sensor, without a TCD gas sensor, so that no contact between the sensor and the gas mixture or gas sample is required, and therefore no gas permeable membrane is required. It is further noted that TCD gas sensing capability may be provided by the heater side of a VOC gas sensor.

[0087] If the capsule 10 is configured with an accelerometer and is configured to use the output signal generated by the accelerometer, the accelerometer may be a three-axis accelerometer configured to sense the direction and magnitude of the capsule rotation within the intestine by sensing the displacement of the gravity vector relative to an axis fixed to the capsule's reference frame. In addition, the accelerometer may be configured to directly measure the change in angular velocity of the capsule or to perform gyroscopic sensing as part of the accelerometer sensing. Combining three-axis acceleration with three-axis angular velocity is sometimes referred to as a six-axis accelerometer or six-axis inertial measurement.

[0088] The term "non-contact sensing mechanism" is used to refer to either or both of a reflectometer and an accelerometer.

[0089] The term "direct gas sensing mechanism" is used to refer to either or both of the VOC gas sensors and the TCD gas sensors.

[0090] The term "sensing mechanism" is used to collectively refer to non-contact sensing mechanisms and / or direct gas sensing mechanisms.

[0091] Additionally, it should be noted that capsule 10 may include one or more direct gas sensors contained in a compartment defined by a gas-permeable membrane and sealed from the remainder of the ingestible capsule contents by a gas-impermeable membrane.

[0092] It should further be noted that the capsule 10 may include one or more direct gas sensors in addition to the reflectometer and / or accelerometer.

[0093] Capsule Components 2 is a schematic diagram of the components inside the housing, in which the sensing mechanism is a direct gas sensing mechanism provided by a VOC gas sensor 132.

[0094] The components include a power source 16, which may include, for example, one or more silver oxide batteries. Lithium or other battery chemistries may be used according to requirements and technical specifications. The power source 16 provides power to the other components via a bus or via a direct connection. Figure 2 is shown with a bus connection for illustrative purposes.

[0095] The VOC gas sensors 132 are each less than a few mm in size, with the sensor side 132a being sensitive to both O2 and H2 as well as other gases including CH4 and SCFAs. The VOC gas sensor 132 may be considered an aerobic sensor. The VOC gas sensor 132 may be configured to obtain a sensor side reading and a driver or heater side reading. The heater side 132b reading may be used to determine the thermal conductivity of the ambient gas, and thus the heater side reading of the VOC is a TCD reading. The sensor side 132a reading is used to determine the concentration of volatile organic compounds in the ambient gas, and is a VOC reading. The term reading is used as an example of an output signal, which represents separate readings at different times. Alternatively, the output signal may be a continuous signal that is processed as a continuous signal or sampled at separate times to obtain readings.

[0096] The readings from the VOC heater side 132b are used to provide a measurement or indication of the H2 concentration in the gas mixture to which the VOC gas sensor 132 is exposed. Optionally, the readings from the VOC heater side 132b are a component signal of the output signal of the VOC gas sensor 132. The output signal of the VOC sensor side 132a may be used only to identify the ileocecal indicator. Alternatively, the output signal of the VOC heater side 132b may be used in some cases to corroborate the ileocecal indicator identified in the output signal of the VOC sensor side 132a. For example, reliability may be improved by identifying contemporaneous indicators in the readings of the VOC heater side 132b.

[0097] The VOC sensor side 132a (i.e., the VOC sensing element) may form a resistor in a voltage divider network, the output of which is measured as the VOC sensor side live reading. A conversion may be applied in the capsule 10 and / or as part of the process to convert the output of the voltage divider network to a resistance measurement from the sensing element. The VOC sensor side may be driven by a consistent (i.e., repeating) voltage pulse profile. The VOC sensor side readings may be taken synchronously with the voltage pulse profile such that there is no phase shift between the timing of the voltage pulse and the reading.

[0098] The VOC gas sensor 132 is contained in a portion of the capsule 10 that is sealed from the power source 16 and other electronic components. The exterior surface of this portion of the capsule, or a portion thereof, is composed of a selectively permeable membrane. For example, the VOC gas sensor 132 may include a heater that is driven to heat the sensor portion 132a to a temperature at which a sensor reading is obtained (i.e., the measurement temperature). The heater may be driven in a pulsed manner, such that there is a time variation in the sensing portion temperature, such that the measurement temperature is obtained without consuming the power required to continuously maintain the measurement temperature for a period of time sufficient to obtain a reading. Alternatively, the VOC gas sensor sensing side 132a may be operated in a "cold" state, i.e., without any power being supplied to the heating side. Different implementation scenarios may require different confidence levels in the indicators to be identified and may therefore be configured to operate in different ways. Other factors may affect the way the VOC gas sensor 132 operates. For example, when additional payload capacity is needed, operating the VOC gas sensor side 132a at a lower temperature consumes less power and therefore requires fewer batteries in the power source 16. For example, the power source 16 may be a battery, such as a silver oxide or lithium cell battery, or a plurality of such batteries.

[0099] The ingestible capsule 10 includes a microcontroller that controls the distribution of data and power between the components of the capsule. The microcontroller may have its own data processing capabilities to identify motion event indicators in the signals output by the sensing mechanism, or there may be a dedicated on-board processor separate from the microcontroller that provides such functionality. Alternatively, the output signal may be transmitted to an off-board processor via Bluetooth or another data transmission technique.

[0100] The ingestible capsule 10 is configured to use the VOC gas sensor 132 as a direct gas sensing mechanism to collect data in which an ileocecal transition indicator and optionally also a gastroduodenal transition indicator are detectable to determine release timing of a release mechanism for releasing a therapeutic substance directly into the GI tract (particularly the small intestine or large intestine) of a subject. Alternatively or in addition to the one or more gas sensors, the ingestible capsule 10 may comprise a non-contact sensing mechanism comprising a reflectometer formed by a transmitting antenna 17 in series with a directional coupler 171, and optionally also a three-axis accelerometer 19, as illustrated in FIG. 3E.

[0101] The data transmission payload for transmission by the wireless transceiver 18 to the receiving device 30 may include one or more of: a record of the release timing, a record of one or more identified ileocecal transition indicators, a record of one or more identified gastroduodenal transition indicators, a record of electrode signals indicative of rupture of the balloon filled with therapeutic payload or liquid diluent, an output signal output by the sensing mechanism, and one or more metrics representative of the output signal output by the sensing mechanism. The therapeutic payload in the balloon may be in liquid or powder form.

[0102] Depending on the regulations and other considerations of the jurisdiction in which the ingestible capsule 10 is being used, there may be no data transmission payload to transmit from the capsule 10, such that a wireless transceiver 18 is not required (note that in some ingestible capsules, a wireless transceiver may be required even if there is no data transmission payload, inasmuch as it forms part of a reflectometer that measures an antenna reflectivity signal as part of a non-contact sensing mechanism).

[0103] Optionally, the ingestible capsule 10 may be provided with a colored dye carrying the therapeutic payload, such that identification of the colored dye in the stool provides evidence of release of the therapeutic payload into the target GI tract. The colored dye also indicates that the capsule has reached the colon, in which case it can be assumed with a high degree of certainty that the capsule 10 has safely exited the GI tract. This acts as a low-cost excretion detector. An alternative excretion detector is an on-board temperature sensor, monitoring the output signal therefrom to identify a drop in temperature, and transmitting a report of the drop in temperature from the capsule 10 to the receiving device 30 via the wireless transceiver 18 before the capsule 10 is flushed.

[0104] VOC Gas Sensor The VOC gas sensor 132 is a semiconductor sensor.

[0105] The VOC sensor 132 may be configured to obtain a sensor side reading and a driver or heater side reading. The heater side reading may be used to determine the thermal conductivity of the ambient gas, thus the heater side reading of the VOC is a TCD reading. The sensor side reading is used to determine the concentration of volatile organic compounds in the ambient gas, thus the VOC reading. Regardless of whether a heater side reading is being obtained, the heater may be driven to heat the sensor side of the VOC gas sensor and the ambient gas mixture. The heater may be driven in a pulsed manner.

[0106] The output signal of a VOC gas sensor may be continuous or may be a series of discrete signal pulses, with each signal pulse representing a sensor reading. In the case of a continuous output signal, a series of readings representing the output signal may be obtained by periodically sampling the output signal.

[0107] The VOC sensor side is sensitive to both O2 and H2 as well as other gases, and therefore these readings may be utilized in the second branch. Other gases include CH4 and SCFA. Optionally, the VOC sensor side readings are not used in the second branch, and the VOC sensor side readings are used only to detect the ileocecal indicator. Optionally, the VOC sensor side (i.e., the VOC sensing element) forms a resistor in a voltage divider network, the output of which is measured as the VOC sensor side live reading. A conversion may be applied in the capsule 10 and / or as part of the process of converting the output of the voltage divider network to a resistance measurement from the sensing element. The VOC sensor side may be driven by a consistent (i.e., repeated) voltage pulse profile. The VOC sensor side readings may be taken synchronously with the voltage pulse profile such that there is no phase shift between the timing of the voltage pulse and the readings.

[0108] Australian Patent Application No. 2021 / 903378 discloses methods, programs and apparatus for determining the location of an ingestible capsule within the GI tract.

[0109] release mechanism The components also include a release mechanism 20. There are three main functional forms of the release mechanism 20 disclosed herein. Regardless of the functional form, the release mechanism 20 includes a release actuator 21 in physical communication with a therapeutic payload carrying section 22. Different release mechanism 20 configurations are illustrated in Figures 3A-3E. The therapeutic payload may be a drug, prebiotic, probiotic, pharmaceutical, fecal implant material, or other therapeutic substance configured to be released into the GI tract for a therapeutic effect.

[0110] The release actuator 21 is physically coupled to the releasable therapeutic payload-carrying section, specifically to a portion of the capsule housing of the therapeutic payload-carrying section, such that actuation of the actuator creates an opening, aperture, or irregularity in the housing such that the therapeutic payload-carrying section, and by extension the therapeutic payload itself, is exposed to the environment outside the capsule 10 and thus released into the GI tract. The electronic components of the capsule 10 are sealed from the therapeutic payload-carrying section. Alternatively, the capsule housing may contain the therapeutic payload-carrying section within an open framework or via a portion having one or more apertures open to the environment outside the housing, and the therapeutic payload-carrying section is closed via a valve or some other sealing member configured to be opened by the release actuator. For example, a twisted hose is pulled by the release actuator to release the twist and deploy the therapeutic payload to the environment outside the capsule 10. The configuration of the release actuator and hose may be such that deployment of the therapeutic payload occurs over a period of time as the capsule 10 transitions through the colon. For example, the period may be between 30 minutes and 1 hour, between 1 hour and 2 hours, or more than 2 hours.

[0111] A particular release actuator is illustrated in Figures 7A and 7B and described in more detail below. Therapeutic payload carrying section 22 may include a balloon filled with a therapeutic substance, and optionally also additional fluids such as liquid or gas or a combination thereof. Release actuator 21 bursts the balloon and releases the therapeutic payload from the balloon through one or more openings in the capsule housing and into the target GI tract. Note that the portion of ingestible capsule 10 containing the balloon and having one or more openings is sealed from the portion of ingestible capsule 10 containing electronic components (unless a component is specifically described as being in therapeutic payload carrying section 22 if required, for example, as part of release actuator 21).

[0112] Because it is desirable to minimize power consumption (and therefore the size of the required power supply), the ejection actuator 21 may store potential energy in a spring or the like, which energy is released by the ejection actuator 21 to create an opening, aperture, perforation, or irregularity in the housing.

[0113] The housing is formed from a biocompatible indigestible polymer. Optionally, the polymer may be scored or otherwise formed to be thinner at the location of the portion physically coupled to the release actuator 21 so that the portion in question may be opened with a high degree of predictability. Additionally, the surrounding area may be formed thicker to be stronger and thus reduce the likelihood that openings, apertures, perforations, or irregularities in the housing will extend beyond the coupled portion.

[0114] In capsule 10 where the sensing mechanism is a direct gas sensing mechanism, a headspace is defined within capsule 10 that is fluidly isolated from the remainder of the capsule interior but in communication with the GI tract through an opening in the capsule housing. Within the headspace, a pierceable sealed (biocompatible, indigestible) film or foil contains the therapeutic payload, and a release actuator 21 is configured to pierce (i.e., break) the film or foil to release the payload into the GI tract through the opening in the capsule housing. Note that the film or foil may span or partially span the opening, or may otherwise be in spatial communication with the opening, such that piercing the foil causes release of the payload into the GI tract through the opening. Perforation of the foil or film may be by release of a spring that presses the foil or film against a piercing or piercing member, or may be by rotation of a rotating member, such as a motor, that causes the foil or film to be peeled, pierced, or pierced.

[0115] The release actuator 21 may be any actuation mechanism arranged to cause the release of the packaged therapeutic payload from the package into the GI tract, a particular example being shown in Figure 7A and described below.

[0116] Therapeutic Payload Delivery Section The therapeutic payload-carrying section 22 may include a single section that carries all of the therapeutic payload (i.e., the required dose). Optionally, the therapeutic payload-carrying section 22 may include multiple sub-sections, each sub-section carrying a portion (i.e., a fraction) of the required dose of the therapeutic payload. In the case of multiple sub-sections, the capsule 10 may be preset at the time of manufacture or may be configurable after manufacture by the clinician (e.g., via the microcontroller 15 or otherwise by sending a control signal from an external controller to the wireless transceiver 18 to switch between the two release modes). One mode is a simultaneous release mode in which multiple sub-sections are released by the release mechanism 21 in a single release timing (i.e., simultaneously or approximately simultaneously, such as one after the other with no delay between the release of subsequent sub-sections), and the other mode is an interval release mode in which the sub-sections are released by the release mechanism 21 in succession with a predefined interval between successive releases. The intervals may all be of predefined equal length (i.e., regular intervals) or may be of predefined unequal length (i.e., irregular intervals). Thus, the release mechanism 21 may be controllable via the microcontroller 15 or otherwise to release the therapeutic substance in a single release timing or multiple distributed release timings.

[0117] Specific Examples of Release Mechanisms The first functional form is shown in FIG. 3A. In FIG. 3A, the sensing mechanism is a direct gas sensing mechanism provided by the VOC gas sensor 132. In the first functional form, referred to as a local processing form of the release mechanism, the release mechanism 20 includes a microcontroller 15, and the release timing decision is made by processing the output signal of the VOC gas sensor 132 mounted on the ingestible capsule 10 by the microcontroller 15. The microcontroller 15 includes a memory 151 and a processor 152. The microcontroller 15 is configured with middleware or software for performing its functions with respect to identifying indicators in the output signal of the VOC gas sensor 132 and determining the release timing of the therapeutic payload. The lines around the release mechanism 20 are dashed to indicate that the components therein do not necessarily perform functions related only to the release mechanism 20, but may perform other functions. For example, the microcontroller 15 may perform functions including power and data distribution, data sampling, data processing, identifying motion event indicators, determining the release timing, etc.

[0118] A second functional form is shown in Figure 3B. In the second functional form, referred to as the remote processing form of the release mechanism, the release mechanism 20 includes a wireless transceiver 18, and the release timing decision is made by transmitting a representation of the VOC gas sensor output signal to the remote processing device and receiving a notification signal in response, which is an instruction from the remote processing device to trigger the actuator 21 to cause the therapeutic payload to be released. Figure 4 shows a configuration of a system implementing the second functional form (note that the target mammal 40 is for illustrative purposes and does not form part of the system), and note that in the particular example of Figure 4, the remote processing device 22 includes a dedicated remote transceiver 30 for communicating directly with the on-board transceiver 18, and a data processor 24 for processing the received data to identify indicators and therefore determine the release timing. The remote processing device 22 may be a single device functioning as the transceiver 30 and the data processor 24, or may be multiple devices cooperating via data communication to implement the functionality.

[0119] The wireless transceiver 18 comprises an antenna 17 and a directional coupler 171, which in combination function as a reflectometer configured to measure at least the amplitude and optionally the reflectivity and phase of the reflected signal. The reflectometer is one example of a non-contact sensing mechanism that may be used in combination with or instead of the direct gas sensing mechanism 132.

[0120] In addition, the ingestible capsule 10 may implement both local and remote processing functional forms. A third functional form is shown in Figure 3C. The third functional form combines local and remote processing to process the output signal of the VOC gas sensor 132 and determine the release timing.

[0121] Thus, a system implementing the third functional form may have the arrangement illustrated in FIG. 4 (note that the target mammal 40 is for illustrative purposes and does not form part of the system).

[0122] Non-contact detection mechanism FIG. 3E is a schematic diagram of components within ingestible capsule 10 where the sensing mechanism is a non-contact sensing mechanism provided by at least one of an accelerometer 19, such as a three-axis accelerometer, and a reflectometer formed by antenna 17 and directional coupler 171. Microcontroller 15 samples reflectance measurements from antenna 17 via directional coupler 171. The signal being transmitted may be a data signal with a data transmission payload to report information from ingestible capsule 10 (such as one or more of movement event timing, release timing, indication that release has occurred, excretion event timing, etc.), or may be a pilot or other signal without a data payload and transmitted by wireless transceiver 18 for the sole purpose of making reflectance measurements. The reflectometer may be configured to measure only the amplitude, or may be configured to measure the phase and amplitude of the reflected signal. The reflectometer may be configured to measure the reflectance from a signal transmitted at a particular carrier frequency or frequencies. The reflectometer may be configured to measure the reflectance from a signal transmitted at a carrier frequency that sweeps between two defined extremes with a predefined interval between them.

[0123] The readings from the reflectometer (amplitude measurements) are shown in Figure 9C and indicate the presence of gradient changes in the ileocecal transition timing and also the gastroduodenal transition timing. Thus, the release timing can be determined based on the reflectometer readings.

[0124] 9A-9C, and metrics calculated from the raw accelerometer readings, indicate the presence of indications in ileocecal transition timing, and also gastroduodenal transition timing. Thus, ejection timing can be determined based on the accelerometer readings.

[0125] Capsule 10 may include only one of the reflectometer and the accelerometer. Because the reflectometer has functionality beyond sensing, i.e., reporting and other communications, such as with receiving device 30, an ingestible capsule with a reflectometer as the only sensing mechanism is particularly cost effective.

[0126] Non-contact sensing mechanisms: reflectometers and accelerometers Optionally, the sensing mechanism may be a non-contact sensing mechanism that includes both an accelerometer and a reflectometer.

[0127] If the capsule 10 is configured to release a therapeutic payload into the small intestine, the release timing can be determined by identifying a gastroduodenal transition indicator in the reflectometer readings and a contemporaneous (up to within a predefined time window) gastroduodenal transition indicator in the accelerometer readings. The release timing can be immediate or after a predefined delay of the indicator timing.

[0128] If the capsule 10 is configured to release a therapeutic payload into the large intestine, the release timing can be determined by identifying an ileocecal transition indicator in the reflectometer readings and a contemporaneous (up to within a predefined time window) ileocecal transition indicator in the accelerometer readings. The release timing can be immediate or after a predefined delay in indicator timing. Optionally, a further condition can be that a gastroduodenal transition indicator is detected in either or both of the reflectometer readings and the accelerometer readings at a time preceding the ileocecal transition indicator. Optionally, the process of detecting the ileocecal transition indicator does not begin until the gastroduodenal transition indicator or a contemporaneous (up to within a predefined time window) indicator is detected.

[0129] System Architecture As shown in Figure 4, in addition to the capsule 10, the system further comprises a receiving device 30 that receives the data transmitted by the capsule from within the GI tract of the subject mammal during the live phase. Concurrently or subsequently, the receiving device 30 processes the received data and may also upload some or all of the received data to a remote processing device 24, such as a cloud-based service, for further processing. The remote computer may be a cloud resource, or a standalone computer at the premises of a clinician where the subject is a patient, or a server (whether cloud-based or not) at a service provider where the clinician is a subscriber / customer / service user.

[0130] The receiving device 30 may be a dedicated device (designed to store and optionally process data received from the capsule 10) or may be a general-purpose device such as a smartphone. The smartphone may be running an app (downloaded thereto prior to capsule ingestion) for storing and optionally processing data received from the capsule 10. In particular, the capsule 10 may be equipped with a Bluetooth transceiver 18 and the receiving device 30 may be a Bluetooth-enabled tablet, smartphone, or personal computer.

[0131] Optionally, the system may further comprise a remote processing device 24, such as a server forming part of a cloud computing environment or some other distributed processing environment. The remote processing device 24 may be a server provided by or on behalf of a clinical center where the subject 40 is a patient and which is responsible for interpreting the results (i.e., data transmission payload) generated by the capsule 10 and reporting them to the subject 40.

[0132] Because the processing may be performed by a smartphone application or a dedicated receiving device 30, the term remote processing device may also be used collectively to refer to either or both of the receiving device 30 (whether a smartphone or a dedicated device) and the computing device 24.

[0133] power supply The power source 16 is a battery or supercapacitor capable of powering the sensors and electronic circuitry including the processor hardware 151 and memory hardware 152. A lifespan of at least 48 hours can be set as a minimum requirement for the GI capsule. The number of silver oxide batteries in the power source 16 is configurable depending on the required lifespan and other specifications of the capsule. For example, long-range Bluetooth may consume more power than standard Bluetooth. The capsule may be configured to switch from long-range Bluetooth transmission to standard Bluetooth transmission when the energy stored in the battery falls below a predefined threshold, and the on-board processor is configured to monitor the stored energy level. The capsule 10 requires sufficient stored energy to activate the release mechanism.

[0134] In a particular example, capsule 10 contains a supercapacitor that is trickle charged from a silver oxide battery or another type of battery and then releases its stored energy to a wire in contact with a balloon containing the therapeutic substance, thus heating the wire and rupturing the balloon, releasing the therapeutic substance into the GI tract through an opening in the capsule housing.

[0135] Communication between the capsule and the receiving device During the live phase of the capsule 10 (i.e. after start-up or other power-on event), the connection between the capsule 10 and the receiving device 30 is via a data transmitter on the capsule, which may be part of a wireless transceiver 18, e.g. a Bluetooth transceiver, which may operate according to the standard Bluetooth transmission protocol or according to the Bluetooth low energy transmission protocol. Other operable communication technologies include LoRa, wifi, and 433 MHz radio. Other radio frequencies may be used in addition to or instead of 433 MHz.

[0136] Optionally, there may be multiple wireless transceivers on the capsule 10, such as a Bluetooth or primary transceiver and an NFC or secondary transceiver. A single integrated chip may provide both so that certain circuits do not need to be duplicated. However, the single integrated chip includes two separate antennas, one for Bluetooth communication (e.g., at 2.4 Ghz) and one for NFC communication (e.g., at 13.6 MHz). The capsule 10 may be equipped with two separate wireless communication mechanisms, each configured to at least one of transmit and receive data with a smartphone or tablet within communication range. The wireless communication mechanism may be a primary or Bluetooth wireless communication mechanism, or a secondary or NFC wireless communication mechanism.

[0137] For example, the smartphone or tablet 30 may be running an application that manages data communication with the capsule 10, and in particular may be configured to store, process, and / or transmit data from the capsule 10. The same application may facilitate communication with a communication mechanism on the capsule 10, for example, by encoding one or more signals transmitted from the smartphone or tablet with a code that the capsule 10 is preconfigured to accept as a key to unlock functionality. That is, the capsule 10 is preconfigured to only respond to received signals that are encoded with a code. The code is unique to a particular capsule instance.

[0138] Pairing or coupling The primary wireless data transmitter may be a Bluetooth transmitter, a wifi transmitter, a radio transmitter, or another form of wireless data transmitter. The primary radio transmitter may be configured to transmit within the 433 MHz band. In either case, the primary wireless data transmitter may be provided as part of the primary wireless data transceiver. For example, the primary wireless data transceiver may receive signals when performing pairing or any other form of coupling to at least the receiving device 30. The capsule 10 may be configured to enter a wireless pairing or coupling mode immediately upon the start of the live phase (i.e., first full power-up), and the subject or another user is instructed (via written instructions or via an application running on the receiving device itself) to pair or couple the capsule 10, specifically its primary wireless transceiver, to the receiving device 30 prior to ingestion of the capsule 10. However, embodiments may be configured such that pairing or coupling is not required, for example, the capsule 10 may be configured to broadcast data to the receiving device in a data transmission technique that is not dependent on pairing or coupling status. The pairing or coupling establishes a data communication connection or path for the transmission of a data transmission payload from capsule 10 to receiving device 30 by the primary data transceiver.

[0139] The data transmission payload is data transmitted from capsule 10 to receiver device 30 during a pre-excretion transmission routine, a post-excretion transmission routine, or both. The data transmission payload may comprise one or more of raw readings from sensors or quasi-sensors aboard capsule 10, one or more metrics calculated by on-board processing of the raw readings, kinetic event indicators identified by on-board processing of the raw readings, and report data including indications of therapeutic substance release and timing thereof.

[0140] Activation via NFC In a particular example, capsule 10 may include a Bluetooth transceiver for transmitting readings, event reports, and / or other payload data to the Bluetooth transceiver of receiving device 30, and an NFC transceiver for performing a handshake, etc. with the NFC transceiver of receiving device 30 to provide power to capsule 10.

[0141] NFC can be used for activation independent of having a Bluetooth transceiver: BT operates at 2.4 GHz while NFC operates at 13.56 MHz, so they may utilize separate antennas.

[0142] Optionally, the secondary transceiver may be configured to receive an encoded activation control signal from a smartphone or tablet (tablet in this context meaning a tablet computer) running an application configured to manage the interaction between the smartphone or tablet and the capsule 10, which initiates a live phase of the capsule 10 during which the capsule sensors take readings and the readings themselves or metrics and / or reports based on the readings are transmitted from the capsule 10 to the smartphone or table via the primary wireless data transceiver. The secondary wireless data transceiver is therefore active in a listen phase preceding the live phase of the capsule. The primary wireless data transceiver is inactive (i.e. does not consume any power) during the listen phase. Once the encoded activation control signal is received (and the capsule 10 powers up in response), the listen phase ends and the secondary wireless data transceiver becomes inactive. The primary wireless data transceiver is active during the live phase.

[0143] To conserve battery power, the capsule 10 operates in a standby or listen mode during the time between release from manufacture and the start of the live phase during which readings are recorded by the on-board sensors and transmitted from the capsule. The standby or listen mode is an extremely low power mode. The live phase of the capsule is initiated prior to ingestion by the subject mammal. The mechanism for exiting the standby or listen mode and entering the live phase includes a reed switch coupled to a magnet on the packaging, which is triggered by the release of the capsule from the packaging and powers up the processor, the sensor, and the primary transceiver when triggered (i.e., initiating the live phase). An alternative mechanism is based on near field communication NFC. In the alternative mechanism, the capsule 10 is maintained in a standby or listen mode (in the specific example of NFC, this is the sense mode) before being given to the subject. In the listen mode, the on-board microcontroller (i.e., the processor) enters the live phase when an electromagnetic field is detected along with an appropriately coded activation control message. A tablet computer or mobile phone with NFC capabilities running an application configured to manage interaction with and processing of data received from the capsule 10 can generate an appropriately encoded activation control message. In particular, a back-end server can link a user account to a particular capsule instance, so that when the user logs into the application and selects to activate the capsule, the application performs a lookup to the back-end server to determine how to encode the activation control message. In other words, optionally, the encoding is unique for each capsule. Alternatively, the encoding may be uniform across a batch of capsules or across all capsules.

[0144] The NFC transceiver may be on the same integrated chip as the primary transceiver. The NFC transceiver may be located at an end of the capsule and near the housing to facilitate communication with a tablet computer or mobile phone.

[0145] Primary Transceiver: Post-excretion Data Transmission Routine There are two main data transmission routines, and the ingestible capsule may be configured to use either or both depending on implementation details (i.e., use case). In the post-excretion data transmission model, signals from the sensors are received in the processor hardware 151 (also utilizing the storage capabilities of the memory hardware 152) and processed on-board the capsule 10 to determine the timing of the release of the release mechanism. The on-board processor 151 may also be configured to compile and store a report of the therapeutic payload release as a data transmission payload pending transmission to the receiver device 30, which may include one or more of the following: a record of the indicator, reading, or metric that triggered the release mechanism; a record of the release mechanism trigger and its timing; and an indicator of successful operation of the release mechanism. Other characteristics and readings, or groups of readings of interest, may include, for example, a maximum or minimum reading from a particular sensor or from a metric calculated by combining the sensors. The maximum or minimum may be a local maximum or local minimum reading, where local is defined, for example, by a predefined timing or motion event determined to have occurred by the capsule 10 itself. A specific example is maximum or minimum H2 concentration, which is a metric calculated from gas sensor readings by appropriately calibrated processor hardware.

[0146] For example, the data transmission payload may include one or more of the following: an indication to trigger the release mechanism, a record of the reading or metric, a record of the release mechanism trigger and its timing, and an indication of successful operation of the release mechanism.

[0147] Capsule 10 may be configured without a data transmission mechanism or with only an NFC transceiver for activation purposes, and transmission of a data transmission payload from capsule 10 is optional. For example, an on-board processor may process sensor readings to determine when to release a release mechanism and actuate the release mechanism accordingly, resulting in capsule 10 releasing its therapeutic payload. Further processing and data transmission steps are optional. Reporting data may be stored and transmitted from capsule 10 in embodiments configured accordingly, or such storage and transmission is not performed.

[0148] Capsules 10 that do not store data or transmit from the capsule 10 may still be equipped with a transmit antenna, since the transmit antenna may act as a sensor to sense the dielectric properties of the environment surrounding the capsule 10 and thus form part of a reflectometer indicating the location of the capsule 10 within the GI tract. In such cases, the transmit antenna may be configured to frequency sweep or transmit at a fixed frequency, for example using a pilot signal with no data payload.

[0149] In a post-void data transmission routine, once the expulsion of the capsule 10 from the GI tract is detected (e.g., by the temperature sensor 14a signal and / or by the accelerometer 19 signal), a data transmission payload is transmitted by the wireless transceiver. Metrics further include peak H2 level or value, timing of peak H2, and total H2 (area under the curve). Such metrics may be calculated by the on-board processor hardware 151 during transit through the subject's GI tract and may be transmitted from the capsule 10 to a receiving device during a post-void transmission as part of a report or otherwise.

[0150] In the post-excretion data transmission routine, transmission may occur via a Bluetooth transmission mode that is independent of pairing status. That is, for example, if the Bluetooth transceiver is paired to the receiving device 30, it transmits the data transmission payload to the paired receiving device, and if the Bluetooth transceiver is not paired, it broadcasts the data transmission payload to the receiving device 30 in an inquiry mode (sometimes called discovery mode or beacon mode) without pairing. The Bluetooth protocol has an inquiry mode in which the device broadcasts a unique identifier, name, and other information. The data transmission payload, or portions thereof, may include or be included with such other information. In particular, the data transmission payload may be prioritized or otherwise filtered by the processor hardware 151, so that information deemed particularly important, such as an indication that an excretion has occurred (important for clinical reasons to know that the capsule 10 has been excreted), and possibly information such as the timing of the release of the payload therefrom via the release mechanism, is transferred from the capsule 10 in priority to other information.

[0151] Following the inquiry mode transmission, the transceiver may again attempt to pair, connect, or otherwise couple with the receiving device and, if successful, may attempt to transmit the remainder of the data transmission payload. Of course, such pairing, connecting, or coupling may have been performed prior to initial ingestion, such that the Bluetooth transceiver is attempting to re-pair, re-connect, or re-couple with the receiving device 30. Note that while this discussion uses Bluetooth as an example transmission protocol, the same techniques may be applied to different transmission protocols.

[0152] If there is a data transmission payload pending transmission from capsule 10 after the broadcast of its unique identifier, name, and other information during the Bluetooth inquiry mode, capsule 10 may be configured to initiate or resume a data communication connection (i.e., pairing or re-pairing) with receiving device 30. If the communication connection is successfully initiated or resumed, then transmission of that data transmission payload that was pending transmission from capsule 10 occurs while the data communication connection remains active.

[0153] The Bluetooth primary transceiver 18, or any other primary wireless data transceiver 18, may be configured to automatically reconnect following an initial (i.e., pre-ingestion) connection to the receiver device 30. The receiver device 30 may run an app or web app to guide the subject on how to ingest the capsule 10, to inform the subject that an excretion event has been determined, and optionally also inform the subject that the data transmission payload has been successfully transmitted to the receiver device 30 and therefore that the capsule 10 can be flushed. It should be noted that the terms pairing, connecting, and coupling are interchangeable herein and each refers to the establishment of a wireless connection between two devices for wireless data transfer.

[0154] It should be noted that the data transmission payload may be transmitted throughout the capsule 10's passage through the GI tract, depending on the pairing, coupling, or connection to the receiver device 30. However, confirmation that the therapeutic payload has been released and that an excretion event has been determined by the capsule is particularly important information since the safety of the capsule 10 depends on the capsule 10 being expelled and efficacy depends on the release of the therapeutic payload. Thus, once a connection is established between the wireless data transmitter 18 and the receiver device 30, the remaining data transmission payloads (if any) are transmitted, whereas information representative of the release and timing of the therapeutic substance and the determination of the occurrence of an excretion event (i.e., a report thereof) takes priority and may be transmitted in a broadcast or query mode.

[0155] In Bluetooth inquiry mode, data may be transmitted to the receiving device 30, or any Bluetooth receiving device within range of the capsule 10, without pairing. The primary transceiver 18 is operable in Bluetooth inquiry mode or Bluetooth low energy mode. The capsule 10 may store and transmit data transmission payload readings from one or more sensors representing a predefined period on either side of an identified motion indicator. For example, this may be of only gas sensor signals, or of all sensors. Such readings may be used to add reliability to the identified motion indicator with respect to determining whether a motion event has occurred and / or may provide other information useful in a health or clinical context.

[0156] More generally, the data transmitted according to the post-excretion data transmission routine may be any data transmission payload that has not yet been transmitted. For example, the primary transceiver 18 may be configured to transmit a data transmission payload to a paired receiving device while still in the GI tract (this element of the transmission is referred to herein as the pre-excretion data transmission routine). However, some or all of the data transmission payload may be pending transmission at the time of excretion due to issues such as signal attenuation, noise, power issues, temporary pairing failure, or if pairing was never performed initially, or for other reasons. In that case, the remaining data transmission payload is transmitted according to the post-excretion data transmission routine once excretion is detected. Note that downsampling of the data transmission payload may be performed before being transmitted via the post-excretion data transmission routine. Note further that some elements of the data transmission payload may be prevented from being transmitted via the post-excretion data transmission routine. For example, the bandwidth and also the time for transmission may be limited such that sensor readings may be excluded from the data transmitted pursuant to the post-excretion data transmission routine, although the report data itself, including the determined timing of release of the therapeutic substance, confirmation of release of the therapeutic substance, and an indication of the occurrence of an excretion event, may be included.

[0157] Primary Transceiver: Post-excretion Data Transmission Routine In a pre-elimination data transmission technique, signals may be transmitted continuously (despite errors, failures, and other unintended interruptions) by the primary transceiver 18, such as sensor readings or metrics representative of sensor readings. Alternatively, event reports may be transmitted in real time, such as movement events (passage between sections of the GI tract, ingestion, excretion) and / or therapeutic substance release events and their timing. In a pre-elimination data transmission routine, the processor hardware 151 coordinates the receipt of signals from the sensors and storage in the memory hardware 152 for transmission by the wireless transceiver 18.

[0158] In the example of Bluetooth primary transceiver 18, in a pre-elimination transmission routine, the transceiver may operate according to a long-range or coded-phy Bluetooth transmission procedure, such as BTLE Coded PHY. Compared to conventional Bluetooth transmission protocols, a signal power increase of approximately 10 dB is achievable via the BTLE Coded PHY Bluetooth transmission procedure.

[0159] During the data transmission phase of the ingestible capsule 10 (i.e., a short burst after excretion in a post-excretion data transmission routine, and during the pre-excretion data transmission routine while the ingestible capsule 10 is in use, i.e., during transit through the GI tract while in the GI tract of the subject mammal 40 and taking and transmitting reading and / or report data), the wireless transmitter 18 transmits the readings to the receiving device 30, which may be a dedicated device for receiving and storing the readings (and optionally having a user interface) or may be a multi-function device such as a mobile phone (such as a smartphone) with a Bluetooth transceiver or another wireless transceiver. The mobile phone may be running an application that processes some or all of the data transmission payload to generate an exercise report or a diagnosis of a medical condition based on either the exercise metrics, or a report of therapeutic payload delivery and / or excretion, and / or diagnostic metrics contained in or derivable from the data transmission payload. Alternatively, the application may be configured to transmit the data transmission payload to a server or another processing device to generate a report or diagnosis based on the data transmission payload. The subject mammal 40 does not need to remain within any particular range of the remote computer 20 during the live phase.

[0160] The capsule 10 with Bluetooth transceiver 18 may communicate directly with the user's smartphone, which eliminates any need for a dedicated receiving device (a smartphone taking on the role of receiving device 30). The receiving device 30 (whether a dedicated device or a mobile phone or tablet computer) may process the readings or other received data itself, or may upload the received data to a remote computer 20 for processing (i.e., identifying exercise indicators, determining exercise event timing, reporting therapeutic substance excretion and elimination, resolving gas analytes). The uploading may be continuous during the live phase of the capsule, or the uploading may be after the live phase of the capsule has ended. The receiving device 30 may also store the readings so that loss of connectivity between the receiving device 30 and the remote processing device is not significant.

[0161] Pretreatment The on-board processor 151 may apply one or more processing or pre-processing steps, as described in more detail below. Digitization of the readings is performed by the sensor itself, by the processor 151, or by the wireless transceiver 18. The digitized readings are transmitted via the antenna 17. Readings of the capsule 10 are made instantaneously and are associated with the moment they are made. For example, a timestamp may be associated with the readings by the microcontroller 15, the wireless transmitter 18, or at the receiver device 30 or remote computer 20. For example, if the readings are made and transmitted approximately instantaneously (i.e., within a second or a few seconds) by the wireless transmitter 18, the time of receipt by the receiver device may be associated with the reading as a timestamp. Processing of the readings, discussed further below, depends somewhat on the relative timing of the readings (i.e., so that contemporaneous readings from different sensors can be distinguished as being contemporaneous), but accuracy down to the level of a second, a few seconds, or tens of seconds may be sufficient.

[0162] Primary transceiver configuration and antenna reflectivity related readings Commercial bands (such as 433 MHz and Bluetooth 2.4 GHz) are used by the primary transceiver antenna 17 so that electromagnetic waves in this frequency range can safely penetrate mammalian tissue 40. Other commercial bands may be used. Coding may be applied at the digitization stage to ensure that the data transmitted by the capsule 10 is distinguishable from data transmitted by other similar capsules 10. The transmitting antenna 17 may be, for example, a pseudo-patch type for transmitting data outside the body data acquisition system. The power source 16 is a battery or a supercapacitor capable of powering the sensors and electronic circuitry. The power source is selected to have sufficient stored energy to power the capsule 10 from ingestion to excretion, taking into account the power required to operate the therapeutic substance release mechanism, obtain the readings required to determine release timing, transmit signals if the capsule 10 is configured to transmit those signals, as well as power a processor and / or microcontroller. The number and capacity of silver oxide batteries in the power source 16 are configurable according to the required life and other specifications of the capsule.

[0163] Reflectance readings from the antenna can be used in combination with readings from other sensors or alone as an indication of GI tract location. Such readings may be obtained as reflectance from a signal transmitted from the antenna and including a data transmission payload, or from a signal that does not have a data transmission payload and is transmitted solely for the purpose of obtaining reflectance readings. In the case of a signal including a data transmission payload, the frequency may be determined according to a transmission protocol, and in the absence of a data transmission payload, the frequency may be a fixed pilot signal frequency or the antenna may be configured to periodically sweep the frequency.

[0164] The antenna 17 may be in series with a directional coupler 171. The directional coupler 171 and the antenna 17 are configured as a reflectometer. The reflectometer measures the amplitude of the reflected signal by a diode detector. The reflectometer amplitude measurement is a reading that represents the electromagnetic properties of the material near the capsule (specifically, at the interface between the capsule housing and the GI tube). For example, a good impedance match between the antenna and the environment surrounding the capsule 10 results in a low amplitude reflected signal and therefore a low amplitude measurement. A poor impedance match between the antenna and the environment surrounding the capsule 10 results in a high amplitude reflected signal and therefore a high amplitude measurement.

[0165] The reflectometer formed by antenna 17 and directional coupler 171 measures the amplitude of the reflected signal at the primary transceiver antenna 17. The reflected signal changes based on the impedance matching between antenna 17 and the environment in which capsule 10 is located, therefore, given that the impedance of antenna 17 is consistent throughout the capsule's passage through the GI tract, changes in the reflected signal are caused by changes in the impedance of the environment in which the capsule is located and therefore indicate the location of the capsule within the GI tract. The readings can indicate location by step changes or spikes indicating transitions between sections of the GI tract, or by absolute values ​​being associated with different GI tract sections as determined in a calibration process.

[0166] Optionally, in addition to the amplitude of the reflected signal, the reflectometer may be configured to measure the phase of the reflected signal. For example, the capsule 10 may include a quadrature demodulator to extract phase information from the reflected signal. The phase information provides a dimension in addition to the amplitude information that represents the reflected signal. In a first example, the phase information from the reflected signal may indicate a step change in the change in the environment surrounding the capsule such that analysis of the phase information provides a motion event indication that may trigger actuation of the release mechanism. In a second example, discussed in more detail below, the phase information allows a decision to be made on how to modify the antenna control signal to better match the antenna impedance to the impedance of the environment.

[0167] Quadrature demodulation converts the modulation of the reflectivity signal into imaginary and real baseband signals. The quadrature demodulator is driven by a carrier frequency (the carrier frequency is the frequency of transmission by the primary transceiver) sine wave with a 90 degree phase difference to generate two baseband signals that can be compared to generate the phase information. Low-pass filtering can be applied (to each of the imaginary and baseband signals) to filter out high frequency components at approximately twice the original baseband frequency.

[0168] The reflectometer readings (either amplitude and / or phase readings) provide the basis for distinguishing between gas, liquid, and solid materials at the location of the capsule within the GI tract and for distinguishing between different sections of the GI tract, so that release timing can be determined. The reflectometer readings (either amplitude and / or phase readings) provide the basis for distinguishing between different physical environments surrounding the capsule 10. The reflectometer readings enable the antenna 17 and directional coupler 171 to cooperate as an environmental dielectric and impedance sensor.

[0169] In certain examples, capsule 10 may be configured to release a therapeutic payload directly into the large intestine of subject mammal 40. An on-board processor may take readings from the reflectometer and process the readings to identify step changes or spikes identifiable as indicative of the stomach to small intestine transition (gastroduodenal transition) and the small intestine to large intestine transition (ileocecal transition). Alternatively, the readings themselves, and particularly the value ranges of the readings, may be associated with look-up table values ​​to indicate the section of the GI tract in which capsule 10 is located.

[0170] Reflectometer: Tunable Antenna Figure 3D shows a specific example of a reflectometer. Any embodiment having a reflectometer may have a reflectometer as shown in Figure 3D. Capsule 10 is configured to transmit a signal from antenna 17, which is either a data transmission payload or a pilot or other signal that does not contain data and is configured to allow a reflectometer reading to be obtained.

[0171] Because available energy is limited within capsule 10, capsule 10 can be configured to transmit signals in an energy efficient manner. The constrained volume and shape of capsule 10, combined with the changing electromagnetic properties of the surrounding environment during transitions in the GI tract of a subject mammal, means that impedance matching between antenna 17 and the surrounding environment is difficult to achieve. Better impedance matching improves transmission efficiency. Transmitter 18 may be, for example, a transceiver control circuit including a buffer to buffer data for transmission.

[0172] The transceiver illustrated in Figure 3B includes a tunable antenna 17. A reflected signal from the antenna 17 is generated during transmission, received at a directional coupler 171, and processed in a controller 181 to extract one or both of amplitude and phase information from the reflected signal.

[0173] The amplitude provides a measure of the amount of reflected energy. The phase information provides information about how the phase shifts between the transmitted and reflected signals. A step change in either or both can be caused by a change in the electromagnetic properties of the transmit environment, i.e., the environment in which the capsule 10 is located. Thus, reflectometer measurements (which is a collective term that applies to either or both of the amplitude and phase information) provide an indication of the environment surrounding the capsule or changes in the environment surrounding the capsule by their absolute value (and by reference to calibration information such as a look-up table) and / or by the presence of a step change in their values ​​(in which case calibration information is not necessary).

[0174] The antenna 17, directional coupler 171, controller 181, and variable capacitor 172 form a closed loop mechanism for measuring the efficiency of the antenna (the amplitude of the reflected signal measures the efficiency, with low amplitude indicating efficient and high amplitude indicating inefficient) and for generating, by controller 181, a control signal for variable capacitor 172 to minimize antenna reflectivity. Depending on how the reflectometer is configured, controller 181 may be configured to incrementally change the control signal for variable capacitor 172, compare the amplitude reading to the amplitude reading before the incremental change, and based on the comparison, decide whether to reverse the direction of the incremental change. In other aspects, in reflectometers that extract phase information, the phase information itself can inform controller 181 in which direction the control signal should be changed to reduce the amplitude reading.

[0175] The controller 181 is configured to generate a control signal to vary the capacitance of the variable capacitor 172, which varies the impedance of the antenna 17, based on the antenna reflectivity related readings. A control algorithm is responsible for determining the control signal output by the controller 181 to vary the capacitance of the variable capacitor 172, which varies the impedance of the antenna 17, to reduce the amplitude of the reflected signal from the antenna 17. The controller 181 may empirically generate the control signal by periodically adjusting the control signal in a given direction, comparing the reflectometer amplitude readings before and after the adjustment, and changing the direction of adjustment for the next periodic adjustment if the reflectometer amplitude readings increase from before the adjustment to after the adjustment, and maintaining the direction of adjustment for the next periodic adjustment if the antenna reflectivity related readings decrease from before the adjustment to after the adjustment. The controller may deterministically generate the control signal based on the reflectometer phase information, where a particular phase reading range indicates that the controller should increase the control signal, a particular phase reading range indicates that the controller should decrease the control signal, and optionally a particular phase reading range indicates that the controller should maintain the control signal. The level of the control signal generated by the controller 181 is proportional or directly proportional to the capacitance of the variable capacitor 172 and, therefore, the impedance of the antenna 17. As described above, since the antenna 17, the controller 181 and the variable capacitor 172 form a closed loop or feedback loop mechanism for impedance matching the antenna 17 to the surrounding environment (i.e., reducing the reflected signal amplitude), it logically follows that the control signal generated by the controller 181 to set the capacitance of the variable capacitor is proportional to the impedance of the environment surrounding the capsule 10. Thus, the control signal itself can be recorded as an antenna reflectivity related reading that is representative or indicative of the environment surrounding the capsule 10.

[0176] The reflectometer, comprised of directional coupler 171, controller 181, variable capacitor 172 and antenna 17, forming a closed loop (i.e., feedback loop), provides automatic tuning of antenna 17 to increase transmission efficiency. Furthermore, as described above, the control signal from controller 181 to variable capacitor 172 is indicative of the impedance of antenna 17 and therefore also of the environment surrounding capsule 10, and therefore the control signal itself may be sampled as an antenna reflectivity related reading for use in determining release timing. Changes in the control signal, or even the absolute value of the control signal itself (in combination with a calibrated look-up table), provide an indication of the location of capsule 10 within the GI tract of the subject mammal.

[0177] The capsule 10 may be configured to determine the timing of release when an indicator or indicators indicate the presence of the capsule 10 in a particular section of the GI tract, such as the small intestine or large intestine.

[0178] Transmitter 18, in the context of Figure 3D, is a circuit that provides a transmission signal (i.e., a carrier wave, optionally having an encoded data transmission payload, and any metadata required by the transmission protocol, etc.). Transmitter 18 may be a Bluetooth transmitter.

[0179] The readings of the ingestible capsule 10, including one or more of the readings from the environmental sensor 14, the heater side 132b of the VOC gas sensor 132, the sensor side 132a of the VOC gas sensor 132, and the TCD gas sensor 131, may also include a reflectometer reading. Thus, a change in capsule location within the GI tract causes a change in the antenna reflectivity related reading, thus providing an indication that a transition event between two sections of the GI tract has occurred. The reflectometer readings may be used in combination with or instead of the gas sensor readings. That is, a capsule 10 that includes a reflectometer, is configured to obtain reflectometer readings, and process the reflectometer readings to determine release timing does not require a gas sensor, and thus the gas sensor is optional. However, it should be noted that the gas sensor readings and the reflectometer readings may be combined to obtain an indication of the GI tract location. By combining the indications from different sensor types, a higher degree of confidence may be obtained than from readings from any single sensor type.

[0180] Ingestible capsule: Accelerometer As shown in FIG. 3E, the ingestible capsule 10 may further comprise an accelerometer 19. The accelerometer 19 is an example of a non-contact sensing mechanism. The accelerometer 19 may be a three-axis accelerometer. The rate of change of the angular position or orientation of the capsule 10 depends somewhat on the location within the GI tract, and thus the accelerometer readings provide an indication that a transition event between two sections of the GI tract has occurred. The accelerometer readings may measure angular acceleration about three axes of rotation, which may be mutually orthogonal.

[0181] Accelerometer readings may be used in combination with or instead of gas sensor readings, or accelerometer readings may be used in combination with reflectometer readings. That is, capsule 10, which includes accelerometer 19 and is configured to obtain and process accelerometer readings to determine release timing, does not require a gas sensor, and thus the gas sensor is optional. However, it should be noted that gas sensor readings and accelerometer readings, or accelerometer and reflectometer readings, may be combined to obtain an indication of GI tract location. By combining indications from different sensor types, a higher degree of confidence may be obtained than readings from any single sensor type.

[0182] Accelerometer and Accelerometer Data Processing The exemplary accelerometer 19 measures roll about three mutually orthogonal axes. Readings from the accelerometer 19 may be a vector with a component for each axis, with each component indicating either the instantaneous angular acceleration about the corresponding axis, or the average acceleration about the corresponding axis over a period of time since the preceding live reading. Alternatively, the readings may yield a three-dimensional orientation of the capsule. Processing of the readings from the accelerometer may be performed in the on-board processor 151, in the receiving device 30, or in the remote computer 20 to generate a representation (such as a plot versus time) of aggregated (i.e., all three axes) accelerometer readings from which markers (i.e., ileocecal transition indicators) are identifiable. Such plots or representations may also be used to identify indicators of movement events and thus determine ejection timing and / or the occurrence of ejection events. In FIG. 9C, a "normalized pitch angle" plot is generated. This is a metric representing the cumulative angular displacement of the capsule over time as measured by the three-axis accelerometer.

[0183] The first technique for processing the accelerometer data may be called displacement angle (see FIG. 9A). Displacement angle uses vector mathematics to calculate the angle between the gravity vector and the temporal vector. The temporal vector is pulled in the direction of the angle change only if this angle exceeds a given threshold (currently 90 degrees). It is then the accumulation of the change in the temporal vector that is visualized in the representation from which the markers are identifiable. It is generally found that the angle between the gravity vector and the temporal vector rarely exceeds the threshold in any one direction (small anterior-posterior changes in the stomach are effectively ignored by the inherent hysteresis of this algorithm), and that once into the tortuous lumen of the small intestine, the larger and more continuous orientation changes of the capsule cause this measure to accumulate significantly. Thus, the step change in the accumulated displacement angle measurement is the gastroduodenal transition index.

[0184] In an exemplary implementation of the movement angle, the accelerometer readings may provide a reading of the orientation of the ingestible capsule relative to a frame of reference that is fixed relative to the gravity vector. Processing the readings from the accelerometer may include recording the orientation of the ingestible capsule provided by the first accelerometer reading as a reference orientation, iterating over time with each successive accelerometer reading to determine whether the orientation of the ingestible capsule provided by each accelerometer reading is greater than a threshold angular displacement from the reference orientation, proceeding to the next accelerometer reading without changing the reference orientation if the threshold angular displacement is not met, and changing the reference orientation to match the orientation of the ingestible capsule provided by each accelerometer reading if the threshold angular displacement is met. An index such as a gastroduodenal transition index may be a step change in the rate of change of the reference orientation.

[0185] 9A shows that a step change in the plot of the shifted angle is discernible within a threshold period of a detected spike in the TCD gas sensor reading. Thus, the step change in the plot of the shifted angle increases the confidence of the hypothesis that the detected spike in the TCD gas sensor reading is caused by the gastroduodenal transition. There are two gastroduodenal transition indicators that are approximately contemporaneous, which allows the timing of one of the indicators (whereas, for example, the TCD gas sensor reading may be preselected) to be determined as the timing of the transition event.

[0186] The second technique for processing accelerometer data may be called total roll. Total roll calculates the angle between the gravity vector and each of the capsule X, Y, and Z axes, and expresses this as a continuous measure that can accumulate beyond 360 degrees. For example, if the capsule x-axis is at an angle of 350 degrees and rotates an additional 20 degrees, the resulting angle will be expressed as 370 degrees instead of 10 degrees. This is useful when representing the readings as a plot from which markers are identified, as it avoids the sudden angle changes associated with crossing the zero line. In this example, an actual change of 20Deg is visualized instead of an artificial change of 340Deg. In addition to this basic technique, low pass filtering may be applied to filter the raw data to remove sensor noise. Furthermore, angles are only calculated if the raw accelerometer data provides enough data to calculate a meaningful angle. An example of when this is not the case is when the two accelerometer axis values ​​used to calculate the azimuth angle about the third axis both approach zero. In this case, a meaningful angle cannot be determined because the calculation is dominated by the sensor noise.

[0187] The accelerometer readings provide a reading of the orientation of the ingestible capsule relative to a frame of reference that is fixed relative to the gravity vector. Exemplary processing of the accelerometer readings may include: iterating over time for each successive accelerometer reading for each of three orthogonal axes in a fixed spatial relationship relative to the ingestible capsule that can be derived from the orientation readings, calculating the change of the orthogonal axis relative to the gravity vector from the preceding accelerometer reading as a scalar value, applying a low pass filter to the calculated change, and recording the cumulatively filtered calculated change. A marker that serves as a gastroduodenal transition indicator or an ileocecal transition indicator may be, for example, an increase in the rate of increase of the cumulatively filtered calculated change (such as a spike or step change).

[0188] Plots of sensor readings for test capsules: Figures 9A-9C Figure 9A shows a step change in the angle of movement nearly simultaneous with an abrupt drop in the corrected TCD reading. The corrected (i.e., corrected for changes in environmental temperature) abrupt drop is known to be caused by the transition of the capsule 10 over the ileocecal area, and thus Figure 9A is evidence that an indication of the ileocecal transition is present in the accelerometer readings.

[0189] FIG. 9A also shows that gastroduodenal transition (gastric emptying) indicators are present in the corrected (corrected for environmental temperature variations) TCD gas sensor readings (in the form of spikes) with contemporaneous changes in the angular displacement plots (although due to the scale of FIG. 9A the changes appear small on the graph). Note further that the reflectometer readings, not shown in FIG. 9A, exhibit changes in gastroduodenal transition timing and ileocecal transition timing, which changes are indicative of corresponding motility events. FIG. 9C shows the reflectometer readings and motility event indicators.

[0190] FIG. 9A shows roll in each of the three mutually orthogonal dimensions, marked by gastric emptying events, from which it can be seen that changes in accelerometer readings correlate in time with spikes in the corrected TCD readings (i.e., can be used to add confidence to the detection of gastroduodenal transition indicators in temperature corrected TCD readings). FIG. 9A shows that the raw measurements from each axis of the triaxial accelerometer by themselves encompass indicators of both the gastroduodenal transition and the ileocecal transition, but a movement angle metric combining measurements from all three axes provides a clearer indication. FIG. 9A is further marked by the timing of the ileocecal transition event, from which it can be seen that a step change in movement angle is detectable, thus providing an indication that the ileocecal transition has occurred. Capsule orientation is measured using the triaxial accelerometer, which tracks the gravity vector with respect to the capsule's frame of reference. As the capsule leaves the stomach, it tends to experience rapid changes in its orientation as it transitions through the duodenum and small intestine. "Angle Travelled" simply accumulates orientation changes over a hysteresis angle of 90 degrees. This algorithm tends to be robust to the small changes in orientation experienced by the stomach and avoids some of the complexities of other approaches. The 90 degree threshold is exemplary and other threshold angles may be used.

[0191] The increase in VOC concentration indicated by the abrupt decrease in the kinetic hot plot in FIG. 9C provides the ileocecal transition timing. Although the VOC gas sensor readings are not shown in FIG. 9A, the ileocecal transition timing can be derived from the abrupt increase in the TCD gas sensor readings (and accelerometer data). FIG. 9B shows the VOC gas sensor readings referred to as kinetic (hot) in the legend. The abrupt decrease in the VOC gas sensor readings is the ileocecal junction transition indicator, and actually represents an increase in VOC concentration at the crossing from the small intestine to the large intestine (i.e., the Y-axis is inverted relative to the VOC concentration). FIG. 9B further shows the gastroduodenal transition timing and the associated increase in the corrected TCD reading, which is the gastroduodenal transition indicator. FIG. 9B shows the raw accelerometer readings from which it can be seen that there is a step change in the timing of the gastroduodenal transition and the ileocecal transition. The capsule 10 is configured to process the accelerometer readings by combining the three individual axis plots into a combined metric, such as the angle of movement as shown in Figure 9A or the total roll as shown in Figure 9C. Movement event metrics are more easily identified in the combined metrics.

[0192] The trace marked as movement (hot) in the capsule plot is the VOC gas sensor reading. As shown in FIG. 9C, the VOC gas sensor reading exhibits an increase in value (representing an increase in concentration of VOC) at the timing due to the passage of the capsule across the ileocecal area. In FIG. 9C, the increase in concentration of VOC is indicated by an increase in the reading from the VOC gas sensor (i.e., the axis is positive as far as the VOC gas sensor reading is concerned).

[0193] Figure 9A shows an ileocecal indicator in the form of a step change in a movement angle metric at the timing of the ileocecal transition. This step change is an example of a motion event indicator, specifically an ileocecal transition indicator. Figure 9C shows total roll in the same but different accelerometer data metric.

[0194] FIG. 9A shows that there is a gastroduodenal transition (gastric emptying, GET is gastric emptying timing) index during correction (correction for environmental temperature variation).

[0195] It should be noted that in general, the capsule 10 may determine the release timing based on the ileocecal transition timing, specifically when the therapeutic substance is intended to be delivered directly to the large intestine. Nevertheless, the capsule 10 may still be configured to determine the gastroduodenal transition timing. Specifically, the capsule 10 may determine the gastroduodenal transition timing to set a lower limit for the ileocecal transition timing. That is, logically, if the capsule 10 detects an ileocecal transition indicator, but has not yet determined that a gastroduodenal transition has occurred, the capsule 10 (specifically the on-board processor) may determine that the detected ileocecal transition indicator is not caused by an ileocecal transition event. For example, the on-board processor may be configured to process one or more of the reflectometer readings, the gas sensor readings, and the accelerometer readings to determine the timing of the gastroduodenal transition. Once the gastroduodenal transition timing is determined, readings obtained after the gastroduodenal transition are processed to detect the ileocecal transition indicator, determine the ileocecal transition timing, and therefore determine the release timing of the therapeutic substance.

[0196] The plots shown in Figures 9A and 9C are marked by kinetic events and kinetic information that can be derived from the plots, from which release timing can be determined. Additionally, when plot readings, kinetic markers, or other information are generated by the capsule 10 in cooperation with the receiving device 30 and the processing device 20, or operating independently, kinetic event indicators can be reported from the capsule 10 and utilized by a clinician or other operator to gain an understanding of, and potentially diagnose, the gut health condition. It should be appreciated that key indicators as an ingestible capsule transits through the GI tract include Gastric Emptying Time (GET), Small Bowel Transit Time (SBTT), Large Bowel Transit Time (LBTT), and Whole Bowel Transit Time (WGTT). Any one or combination of a number of these metrics can be beneficial to a physician in assessing the subject's human health condition and / or diagnosing a disease or condition. These metrics can be monitored with each capsule ingestion. There may be other biomarkers associated with the condition being treated that can also be monitored. In some cases, the location for dose deployment can be tailored for each patient based on this diagnostic information or other information known about the patient, e.g., if the distal colon is particularly problematic, dose deployment can be timed some time after the ICJ. The system can also learn how transition times for a particular patient vary, for example, to attempt and achieve delivery of the dose to the distal small intestine (this can assume somewhat consistent transition times through each patient's small intestine or allow for variations seen over time).

[0197] 9C provides further illustration of the presence of a gastroduodenal transition indicator in the accelerometer readings (step change in normalized pitch angle) and reflectometer readings 91 (referenced as direct coupler in FIG. 9C), where the reflectometer readings show a slope change from approximately flat (expected while capsule 10 is in the stomach, so the dielectric properties of the environment surrounding capsule 10 are consistent) to a negative slope at the timing of the transition. The slope change, or the negative slope itself, may be detected by capsule 10 as a gastroduodenal transition indicator.

[0198] 9C provides further illustration of the presence of the ileocecal transition indicator in the accelerometer readings (step change in normalized pitch angle) and reflectometer readings 91 (referenced as direct coupler in FIG. 9C), where the reflectometer readings show a slope change from approximately flat towards the distal end of the small intestine to an increase at the timing of the ileocecal transition. The slope change in the reflectometer readings, or the positive slope itself, may be detected by capsule 10 as the ileocecal transition indicator.

[0199] Additionally, Figure 9C shows the presence of a gastroduodenal transition indicator in the TCD gas sensor reading (shown as Hybrid CO2 in Figure 9C) in the form of a spike. Figure 9C also shows the presence of a slope change in the VOC gas sensor reading at the ileocecal transition, which slope change is an ileocecal transition indicator.

[0200] It should be noted that the capsule 10 may be configured with one, two, three or more sensors operable to generate a gastroduodenal indicator, and the on-board processor may be configured to process readings from those sensors to identify the gastroduodenal indicator, which may require only one indicator or may require two or more contemporaneous indicators from different sensors, for example, this may be the case when release timing is determined based on gastroduodenal transition timing or based on a determination that a gastroduodenal transition has been detected.

[0201] Similarly, it should be noted that the capsule 10 may be configured to have one, two, three or more sensors operable to generate an ileocecal transition indicator, and the on-board processor may be configured to process readings from those sensors to identify the ileocecal indicator, which may require only one indicator or may require two or more contemporaneous indicators from different sensors.

[0202] The contemporaneity is within a predefined time length of each other, e.g., 5 minutes, 10 minutes, 20 minutes, or 30 minutes. Optionally, the requirement for one or two or more indicators may be determined on the fly based on characteristics of the first detected indicator, e.g., spike height, magnitude of slope change, magnitude of variance change, etc., such that if the first detected indicator has characteristics that meet a predefined threshold, no further indicators are required and a motion event is determined to have occurred, or if the characteristics do not meet the predefined threshold, one or more further indicators within a predefined time window are required for a motion event to be determined to have occurred.

[0203] Data Processing A representation of the output signal of the VOC gas sensor 132 is transmitted to the remote processing device 20 for processing. The remote receiver 30 may be a smartphone connected to the capsule 10 via Bluetooth, or may be a transceiver that communicates directly with the (transceiver 18 of) the ingestible capsule 10 wirelessly via Bluetooth or a frequency such as 433 MHz. For example, the remote transceiver 30 may include a memory readable by the data processor 24. The receiver device 30 may provide a data connection, such as a wired connection, a wireless connection, a network connection, or a plug socket connection, to the data processor 24 (which may be a computer, a server computer, a cloud computing environment, a smartphone, a tablet). In this way, the capsule 10 only needs to be configured to establish a data connection with the remote transceiver 30, which may be a dedicated device for receiving and storing readings (optionally with a user interface) and for sending notification signals, or may be a multi-function device such as a mobile phone (such as a smartphone), so that the target mammal 40 does not need to remain within a certain range of the data processor 24 during the live phase. The remote transceiver 30 uploads a representation of the output signal of the VOC gas sensor to the data processor 24. The uploading may be continuous during the live phase of the capsule 10, where the live phase is while the ingestible capsule 10, and in particular the VOC gas sensor 132, is actively taking readings. Alternatively, rather than separate data processor and receiver devices, there may be a single device that receives and processes data from the capsule 10. The capsule 10 may include an on-board processor that processes signals, readings, etc. from the on-board sensors and triggers the release mechanism 20 based on that on-board processing (i.e., without any off-board processing).

[0204] The data processor 24 may be a cloud resource, or may be a standalone computer at the premises of a clinician whose subject is a patient, or may be a server (whether cloud-based or not) at a service provider to which the clinician is a subscriber / customer / service user.

[0205] For completeness, it is noted that an ingestible capsule configured according to a remote processing functionality configuration may still include a microcontroller 15 for controlling on-board functions such as power allocation, sampling of output signals, responding to received notifications, etc. However, the distinction between the two functionality configurations is that in the local processing functionality configuration, the microcontroller 15 itself processes the output signal of the VOC gas sensor 132, whereas in the remote processing functionality configuration, the microcontroller 15 coordinates the transmission of the output signal to the remote processing device, as well as the receipt and response of returned notification signals. It is noted that in the latter case, the microcontroller 15 may even be considered an element or component of the transceiver 18.

[0206] Moreover, the reverse is also true. That is, an ingestible capsule 10 configured according to a local processing functionality configuration may still include a wireless transceiver 17, for example, to realize a reflectometer function in a non-contact sensing mechanism. For example, depending on the implementation scenario, the ingestible capsule may combine a therapeutic payload delivery function with a diagnostic function, so that either the VOC gas sensor 132 itself and / or one or more additional on-board sensors (TCD gas sensor, accelerometer, directional coupler, temperature sensor, humidity sensor, etc.) generate readings that are transmitted by the wireless transceiver 17 to a receiving device for recording and further processing. Such additional (i.e., diagnostic) functionality is balanced against power consumption and volumetric capacity considerations depending on the embodiment. Volumetric capacity is important, since maximizing payload (i.e., therapeutic payload) capacity while keeping overall capsule size down is advantageous in certain scenarios. Furthermore, it is observed that the more power consuming components included in the capsule, the more energy is required and therefore the greater the capacity required for the power source.

[0207] In addition, the ingestible capsule may implement both local and remote processing functional forms. A third functional form is shown in FIG. 3C. The third functional form combines local and remote processing to process the output signal of the VOC gas sensor 132 and determine release timing. Thus, a system implementing the third functional form may have the arrangement illustrated in FIG. 4 (note that the target mammal 40 is for illustrative purposes and does not form part of the system).

[0208] Identifying the indicators The term processing device is used generally to refer to the local processing device (i.e., microcontroller 15) and the remote processing device 22, and optionally, the receiving device 30 insofar as the receiving device 30 processes the received data from capsule 10.

[0209] For example, the microcontroller 15 may be configured to determine the release timing by processing the output signal of the VOC gas sensor to identify a release indicator, such as an ileocecal indicator. In parallel, the microcontroller is transmitting a representation of the output signal of the VOC gas sensor to the remote processing device via the wireless transceiver 18. The microcontroller 15 is configured to identify a particular indicator (which may be referred to as a marker) in the output signal and, upon identifying the particular indicator (such as the ileocecal indicator), cause the actuator to release the therapeutic payload from the therapeutic payload delivery compartment at the release timing. The microcontroller 15 may be configured to identify indicators that are causally linked to the ileocecal transition of the ingestible capsule (i.e., indicators to a very high confidence level, such as 95% or more, or 99% or more). In parallel, the remote processing device may be processing the representation of the output signal transmitted via the wireless transceiver 18 to identify indicators. The enhanced processing capabilities of the remote processing device may mean that it is configured to identify indicators that are not identifiable by the microcontroller 15 (i.e., the microcontroller is configured to identify a subset of the indicators that the remote processing device is configured to identify). Thus, in some instances, the remote processing device identifies an indicium that was not identified by the microcontroller 15. The remote processing device transmits a notification signal to the wireless transceiver 18 to cause the ingestible capsule 10 to notify the identification of that indicium, and the transceiver is configured to cause the therapeutic payload to be released from the therapeutic payload-carrying compartment by the release actuator upon receiving the notification signal.

[0210] It should be noted that when referring to an index identified within the output signal (or a representation thereof) of a VOC gas sensor, the index may actually be an aggregation of multiple component indexes. For example, there may be a predefined set of component indexes that the processing device is configured to identify, with the cumulative effect of identifying, for example, two, three, or more, from the set representing the identification of the index. Examples of indexes include baseline shifts, spikes, step changes, slope changes, and thresholds or other conditions are applied to qualify when an index (an index in this sense incorporating component indexes) is considered to be identified.

[0211] Depending on the embodiment, multiple component indicators may be considered to identify an aggregate indicator when they are applied in a predefined order, or the order may be irrelevant. It should be further noted that the output signal of a VOC gas sensor may include multiple components, and thus, if a component indicator is identified in any one, a particular combination, a threshold ratio, or all of the component signals, the identified indicator may be considered to be identified.

[0212] The indicator identified by the processing device may be an ileocecal indicator, which is an indicator that the capsule 10 has transitioned through the ileocecal region at the interface of the small intestine and the large intestine. The ileocecal indicator in the output signal of the VOC gas sensor 132 is a characteristic such as a spike, a step change, or an inflection point in the output signal.

[0213] The size, range, height, or other parameters of the characteristic are indicative of reliability and therefore the parameters may be used to assess reliability to determine whether the characteristic is an indicator and therefore needs to determine release timing or whether further supporting indicators are needed such as may be provided by the heater side 132b of the VOC gas sensor.

[0214] The change in gas environment between the small and large intestine is significant because the bacterial population in the large intestine occurs at a significantly higher prevalence, promoting the production or increase of volatile substances and the decrease of O2 due to the fermentation of carbohydrates and proteins by the microbiota.

[0215] The VOC gas sensor output 132 from the sensor side 132a is sensitive to many different volatile analytes with the largest response being due to H2 and O2. A significant drop in the output signal of the VOC gas sensor sensing side 132a is observed upon transition through the ileocecal valve. As the capsule 10 transitions through the GI tract, the environment becomes increasingly anaerobic as O2 is consumed by bacteria.

[0216] FIG. 5A shows an indication of ICJ on a plot of the VOC sensor side output signal. The indication is a characteristic of the output signal. The sensor side output signal of the VOC gas sensor in FIG. 5B is represented by a plot showing a clearly distinguishable reduction in the highlighted area (within the ellipse). The remaining plots are from any additional on-board sensors including a TCD gas sensor that provides a measure of H2 concentration (if properly calibrated) and a temperature sensor that measures the temperature of the medium surrounding the capsule.

[0217] For example, the output signals may be processed by the processing device on a rolling basis, with the most recent period t of output signals being processed at a time.

[0218] 5B shows two plots of the output signal versus time, with the ICJ index highlighted within an ellipse on each plot. The ICJ index may be defined as a decrease in the VOC gas sensor output signal and a subsequent increase in the VOC gas sensor output signal that does not decrease within a predefined period of time after the onset of the increase. Here, the VOC gas sensor output signal may be the magnitude of a resistance reading from the sensor side 132a of the VOC gas sensor 132.

[0219] To determine that a first reduction has occurred, the calibration phase may be initiated by ingestion for a predefined period such as 2 hours (which may be determined by a marker from an on-board sensor such as a temperature sensor, or by user interaction with an application or interface on a remote computing device), during which the VOC gas sensor operates as if in a live phase, but the processing device (whether on-board or remote) is not actively processing the VOC gas sensor output signal to identify ICJ indications. During the calibration phase, the processing device records the maximum value of the output signal from the VOC gas sensor (e.g., the output signal may be a resistance reading of the sensor side 132a of the VOC gas sensor 132). The live phase follows the calibration phase. The output signal reduction threshold is predefined. The output signal reduction threshold may be predefined as a predefined amount or a predefined percentage of the maximum output signal recorded during the calibration phase. The first criterion is an output signal reduction exceeding the output signal reduction threshold below the maximum recorded value (from the calibration phase). During the live phase, the processing device is monitoring the output signal of the VOC gas sensor for a reduction above the output signal reduction threshold below the recorded maximum. Optionally, if the output signal is composed of discrete readings, the first criterion may be considered to be met when n or more consecutive readings exceed the output signal reduction threshold below the recorded maximum, where n may be 1, 2, 3, 5, or 10. If the output signal is a continuous signal, the first criterion may be considered to be met when the level of the output signal exceeds the output signal reduction threshold below the recorded maximum for more than a pre-set continuous period, the duration of which may be 0.1, 0.5, 1, 2, 3, 5, or 10 seconds. The second criterion may be that the output signal increases without a reduction within a time window immediately following the first criterion with a pre-defined duration (e.g., 10, 15, 20, 30 minutes).A reduction in the context of the second criterion may be a negative slope (over 1, 2, 3, 5, or more than 10 consecutive readings, or continuously over 0.1, 0.5, 1, 2, 3, 5, or 10 seconds), or a drop below a minimum value defined at the beginning of the increase. The indicator is identified by the first and second criteria being met. That is, the satisfaction of the first and second criteria is the identification of a predefined characteristic of the sensor side output signal. Once the indicator is identified, the release actuator is activated (immediately or following a predefined delay).

[0220] Alternatively, the indicator may be identified by plotting the difference in the VOC sensor side output signal versus time while the sensor is heated and finding a negative peak of a threshold size or greater. This difference locates a change point associated with the transition across the ileocecal area, but does not occur at the onset of the transition event. The onset of the transition event may be found by an initial inflection point from the baseline in the first derivative. However, embodiments do not necessarily require a specific event timing, but rather determine with a predefined confidence level that the transition across the ileocecal area occurred within a short (i.e., less than one minute) time of its occurrence. The onset of a transition event may be useful information for health and diagnostic purposes in assessing the movement of the capsule 10 through the GI tract.

[0221] As shown in FIG. 6, the ICJ transition indicator is also present in the determined H2 concentration percentage as a sudden increase in H2 when the capsule reaches the colon. H2 produced in the GI tract is a by-product of fermentation. Bacterial colonies are orders of magnitude greater in the large intestine than in the small intestine. Thus, the determined H2 concentration can be used to add confidence to the ileocecal indicator in the VOC sensor output. The H2 concentration can be measured by the output signal of the VOC gas sensor heater side 132b, which indicates the thermal conductivity of the gas surrounding the heater. For example, if a negative peak identified in the difference of the VOC sensor side output signal pair versus time does not exceed a threshold value but does exceed a second lower threshold value, a corroborating indicator may be found in the output signal of the VOC gas sensor heater side 132b, which may be linked to the H2 concentration by calibration and / or by further processing in the processing device.

[0222] A commercial band (such as 433 MHz) is used by the antenna 17 so that electromagnetic waves in this frequency range can safely penetrate mammalian tissue 40. Other commercial bands, such as Bluetooth, may be used for various applications. Coding may be applied at the digitization stage to ensure that the data transmitted by the capsule 10 is distinguishable from data transmitted by other similar capsules 10. The transmitting antenna 17 may be, for example, a pseudo-patch type for transmitting data outside the body data acquisition system. The power source 16 is a battery capable of powering the sensors and electronic circuits. A life of at least 48 hours is required for the gastrointestinal capsule. The number of silver oxide batteries in the power source 16 is configurable depending on the required life of the capsule and other specifications.

[0223] Power on The capsule 10 can be powered up by removal from the packaging which breaks the seal isolating the power source from the electronic components, thus initiating the live phase of the capsule, which continues, for example, until the power source is depleted or the therapeutic payload is released.

[0224] Power-on may be via an NFC handshake between an NFC transceiver on board the capsule 10 and an NFC transceiver of a smartphone running an application specifically configured to manage power-on, processing and storage of data received from the capsule 10.

[0225] Other powering options include a switch located under the flexible portion of the housing, and receiving a high intensity light with data encoded into the light, for example from a smartphone screen running an application for managing the interaction between the smartphone 30 and the capsule 10.

[0226] A reed switch that is held in a closed position by a magnet within the capsule packaging and that is opened by separating the capsule from the capsule packaging is a further example of a power-on or initiation mechanism.

[0227] Ejection actuator: Figure 7A 7A illustrates an ingestible capsule 10 with a biocompatible indigestible housing. In particular, FIG. 7A illustrates an exemplary release actuator 21 including a compression spring 211, a fuse wire 212, and a piercing member 213.

[0228] The biocompatible indigestible polymer capsule 10 has an opening 224 at one end, at which a headspace is defined by a flexible membrane 222. The headspace is isolated from the remainder of the capsule interior by the flexible membrane 222. The therapeutic payload carrying section 22 is glued or otherwise attached to the flexible membrane 222. The therapeutic payload 221 payload is contained within the therapeutic payload carrying section 22. The pierceable wall of the therapeutic payload carrying section 22 faces the opening 224 and faces the piercing member 213. The pierceable wall is made of a biocompatible material that is pierceable by the piercing member 213 under application of a compressive force. Examples include biocompatible indigestible polymers and biocompatible indigestible foils. A compressed helical spring 211 is pre-coiled and held in a coiled state by a fuse wire 212. The spring 211 abuts a rigid / inflexible surface 225 at the distal end of the opening 224 and abuts a flexible membrane 222 at the proximal end of the opening. At a time determined by the release mechanism 20, the fuse wire 212 is released, causing the spring to stretch against the rigid / inflexible surface 225, thus pushing against the flexible membrane 222 and thus the pierceable wall 223 towards the puncture member 213, causing the therapeutic payload 221 to be released into the GI tract via the opening 224. A shape memory alloy wire can also be used to release the spring loaded mechanism.

[0229] For example, reed switch 23 cooperates with the microcontroller to control power to VOC sensor 132. Gas permeable membrane 12 defines a headspace at the end of capsule 10 distal to opening 224. VOC sensor 132 is contained within the defined headspace, which may be fluidly isolated from the remainder of the capsule interior, but there are connections between battery power source 16, reed switch 23, microcontroller 15, and VOC sensor 132 for exchanging power and output signals.

[0230] Ejection actuator: Figures 7B, 7C, 7D, 7E, 7F Figure 7B illustrates a further exemplary ejection actuator, which is illustrative of a particular ejection actuator configuration and is not intended to illustrate all capsule components.

[0231] 7B is a heating element 743 mounted on a PCB 740 and configured to rupture a resilient material membrane 722. The therapeutic payload delivery section 22 comprises a section of an ingestible capsule housing and a sealed chamber, the resilient material membrane 722 defining at least a portion of a wall of the sealed chamber, within which the therapeutic payload is sealed.

[0232] The sealed chamber may be a balloon, as shown in Figure 7D, or may be an elastic material membrane 722 stretched over a rigid open frame component 770. The sealed chamber may carry the therapeutic substance itself, or it may carry a liquid diluent for mixing with the therapeutic substance (see Figure 7C).

[0233] FIG. 7D illustrates a rigid open frame component 770 and the arrangement of the rigid open frame component 770 and the elastic material membrane 722 to form a sealed chamber that fits within the therapeutic agent delivery section 22 of the ingestible capsule 10.

[0234] 7D is comprised of a series of images (i)-(vi) showing a sealed chamber being formed, assembled into a capsule, and opened at a determined release timing. In image (i), a rigid open frame component 770 is shown. The rigid open frame component 770 is sized to fit within the therapeutic substance delivery section 22 of the ingestible capsule 10 and defines an interior volume for delivering a dose of a therapeutic substance or liquid diluent, as required. The rigid open frame structure 770 defines a number of openings that will be sealed to form the sealed chamber.

[0235] In image (ii), the elastic material membrane 722 is stretched over the rigid open frame component 770. The elastic material membrane 722 is stretched, i.e. exerts tension across the membrane. In other words, a sealing chamber may be defined by the stretched elastic material membrane 722. A bond may be applied between the elastic material membrane 722 and the rigid open frame component 770 to ensure a seal between the two entities.

[0236] The elastic material membrane 722 may be formed from an elastomer, which may be rubber, latex, nitrile, or another elastomer, or a combination of one or more thereof.

[0237] In image (iii), a therapeutic substance or liquid diluent is inserted through the further opening (i.e., the further opening is not sealed by the elastic material membrane 722) into the unsealed or open chamber defined by the rigid open frame component 770 and the elastic material membrane 722.

[0238] In image (iv) the sealing of the chamber by closing the further opening is shown. In particular, the further opening is closed by an outer cover 723. The outer cover 723 may be joined to the frame at the end of the further opening as shown in image (iv). The outer cover may form part of the housing of the ingestible capsule 10 or may be separate from the housing and dimensioned to fit within the housing of the ingestible capsule 10.

[0239] In image (v) the sealed chamber or sealed container or sealed pod is shown bonded to other components of the ingestible capsule 10. The elastic material membrane 722 is in contact with the heating element 743 on the printed circuit board 740 and defines the inner surface of the therapeutic payload carrying section 22. An opening 760 in the housing of the capsule 10 is closed by the elastic material membrane 722 on the inside of the housing (i.e., fluid communication between the interior and exterior of the capsule 10 at the opening 760 is prevented). The heating element 743 may be mounted on the printed circuit board 740 or may be integrally formed with the printed circuit board 740.

[0240] In image (vi), the arrow indicates that the heating element 743 has caused the elastic material membrane 722 to rupture, such that the defined sealed chamber is no longer sealed and the therapeutic payload is permitted to exit the capsule 10 via the opening 760. In the particular example of Figure 7D, the elastic material membrane 722 is in a stretched state forming part of the wall of the sealed chamber, and thus, when the elastic material membrane 722 ruptures, it is pulled apart by tension, thereby facilitating the opening of the sealed chamber and the passage of the therapeutic payload from the capsule 10 and into the GI tract.

[0241] Returning to Fig. 7C, the sealed chamber is filled via a one-way valve 730 that seals an opening 731. Specifically, note that opening 731 is an opening in the housing 11 that allows the sealed chamber to be filled after manufacture of the capsule 10. Such opening 731 is optional, as the sealed chamber may be filled and sealed during manufacture of the capsule 10, as illustrated in Fig. 7D, in which case the placement of such opening 731 and valve 730 is not required.

[0242] The supercapacitor 716 is trickle charged by the power supply 16 when the capsule 10 is powered up. At the determined release timing, the microcontroller 15 causes the supercapacitor to discharge into the heating element 743, causing the heating element 743 to increase in temperature at a rate sufficient to rupture a portion of the wall of the sealed chamber formed by the elastic material membrane 722. The sealed chamber is opened, thus releasing the therapeutic substance through one or more openings in the capsule housing (openings not shown) and into the GI tract of the subject mammal 40. It should be noted that the sealed chamber may be a balloon that is expanded into the therapeutic substance delivery section 22 such that the fluid therein exerts an outward pressure on the walls of the balloon. In the balloon example, the rupture causes the balloon to burst and the therapeutic payload to be forced outwardly through the opening 760 upon bursting.

[0243] The capsule 10 includes a further rigid printed circuit board 741 on which the electronic components are mounted. The supercapacitor 716 is connected to the rigid circuit board 740 on which the heating element 743 is mounted via a section of a flexible circuit board 742 that provides a low resistance connection between the supercapacitor 716 and the heating element 743 to ensure, so far as is practicable, that the energy stored by the supercapacitor is dissipated by the heating element 743 and not by the electrical connection between the supercapacitor and the heating element 743.

[0244] 7E and 7F show cross-sectional and isometric cross-sectional views of an ingestible capsule 10. FIG. 7E shows a gas-permeable membrane (specifically permeable by GI tract gases) 12, which is omitted in FIG. 7F. The omission of the membrane in FIG. 7F is for illustrative purposes, and the capsule 10 has either a gas-permeable membrane 12 covering an opening (in the case of a direct gas sensing mechanism) or a covered end (in the case of a non-contact sensing mechanism). Note that the capsule 10 may have both a direct gas sensing mechanism and a non-contact sensing mechanism, in which case the gas-permeable membrane 12 is required. The rigid circuit board 740 provides a substrate on which, for example, the wireless transceiver 18, the microcontroller 15, and optionally the accelerometer 19 and / or other electronic components are mounted. The supercapacitor 716 is trickle-charged by the power source 16 and transfers charge to the heating element 743 at a determined release timing. The elastic material membrane 722 is stretched over the rigid open frame 770 to form a sealed chamber for carrying the therapeutic payload. At the determined release timing, the transfer of energy from the supercapacitor 716 to the heating element 743 increases the temperature of the elastic material membrane 722 to a temperature sufficient to rupture. The tension in the elastic material membrane 722 pulls it away from the rigid open frame 770, thereby allowing fluid from the GI tract to mix with the therapeutic payload through the opening 760. Specifically, Figures 7E and 7F show a space defined between the printed circuit board 740 on which the heating element 743 is mounted and the rigid open frame of 771, thereby allowing the heating element 743 to contact the elastic material membrane 722 in a space with reduced or no fluid communication with the remainder of the therapeutic payload carrying section 22. Thus, heat dissipation from the heating element 743 to the surrounding fluid is inhibited and heat dissipation from the heating element 743 to the elastic material membrane 722 is promoted.

[0245] A sealed chamber for delivering a therapeutic payload (therapeutic substance) can be formed by stretching the elastic material membrane 722 over the rigid open frame 770 or by inflating the elastic material membrane 722 that defines a balloon.

[0246] A balloon is a bag or receptacle with a sealable opening through which the balloon is configured to receive contents and expand into the space around the balloon in response to pressure exerted by the received contents. Specifically, the contents are forced into the balloon at a pressure that exceeds the pressure of the environment surrounding the balloon, thereby expanding the balloon into the surrounding space. The opening can be sealed, for example, via a one-way valve or some other mechanism, thereby preventing the contents from leaving the balloon and locking the balloon in an expanded state, assuming that the environmental pressure does not change or specifically does not increase beyond the pressure inside the balloon. A balloon with a valve is an example of a sealed chamber formed by a membrane of elastic material for containing or carrying a therapeutic payload.

[0247] Because the contents are held at a pressure above the environmental pressure, the balloon is prone to bursting upon penetration or rupture of the bag, releasing the contents stored within the balloon into the surrounding environment, the pressure differential prior to the bursting event causing the contents to project outwardly upon balloon rupture.

[0248] Optionally, the balloon is expandable, for example, including a bladder formed from an elastomer, which may be rubber, latex, nitrile, or another elastomer, or a combination of one or more thereof.

[0249] Alternatively, the balloon may be non-stretchable, for example formed from a foil.

[0250] The capsule 10 may comprise a balloon contained within a section of the housing that is configured to retain the balloon within the housing, but is not sealed against the surrounding environment, such that upon rupture of the balloon, the contents of the balloon are no longer retained within the capsule, either by ejection from the balloon rupture or by mixing with environmental fluids that are permitted to enter the housing and then exit the housing. For example, the housing may include one or more openings 760, windows, or perforations that allow for exchange of fluids and / or solid materials between the interior of the capsule and the surrounding environment.

[0251] The section of the housing configured to hold the balloon may be separate from the sealed section of the housing configured to hold the electronic components of the capsule 10.

[0252] In the case of a balloon within capsule 10, the contents include a therapeutic substance and a fluid, which may be a gas, such as air, and / or a liquid, such as a liquid diluent.

[0253] As shown in FIG. 7D, capsule 10 may include a rubber encapsulated open frame that can be filled and assembled into capsule 10, such that failure of the rubber causes it to peel away from the frame and release the contents into the surrounding environment.

[0254] The sealed chamber, which may be at least partially formed by the elastic material membrane 722 or by the balloon, may be filled at the time of manufacture and provided to the clinician loaded with a therapeutic substance and sealed. Alternatively, the sealed chamber may be filled at the clinician or pharmacy via a mechanism such as a syringe configured to insert contents into the balloon through a one-way valve in the balloon opening.

[0255] The valve may be, for example, an umbrella valve, a Belleville valve, a ball valve, or a dome valve, as examples of one-way valves that allow the sealed chamber to be filled with fluid while forming a seal between the interior of the balloon and the environment outside the balloon.

[0256] As an alternative to a valve, the sealing chamber may comprise a septum seal through which the balloon filling contents can be injected by a syringe needle, in this example the balloon material at the septum seal forms a seal when the filling needle is retracted.

[0257] As a further alternative to a valve, filling of the sealed chamber may be accomplished via an extruded tube that protrudes from the ingestible capsule 10 through an opening, which is subsequently heat staked down after filling of the chamber to seal the chamber and provide a smooth exterior shape for ingestion. Optionally, a one-way valve may be included on the outside of the tube to hold back pressurized fluid during the period when the chamber is filled with the therapeutic payload but the tube has not yet been heat staked. A further variation is to fill the chamber through an opening and then seal the chamber by welding a lid or cover over the opening.

[0258] 7B, the therapeutic substance is contained within a sealed chamber, a portion of the walls of which are formed by an elastic material membrane 722. The sealed chamber is fillable with contents including a therapeutic payload. The elastic material membrane 722 may be stretched over a rigid open frame or may be a balloon, the therapeutic payload delivery compartment positioned to allow the balloon to expand and fill the therapeutic delivery compartment 22 of the ingestible capsule 10 when the balloon is filled.

[0259] The release actuator comprises an elastic material membrane rupturing mechanism configured to rupture the elastic material membrane 722 at the determined release timing, thereby allowing the contents of the sealed chamber defined by the elastic material membrane 722, including the therapeutic payload, to exit the ingestible capsule through one or more openings in the section of the ingestible capsule housing that contains the sealed chamber. In Figure 7B, the elastic material membrane rupturing mechanism is a heating element 743, such as a wire and power supply 716, configured to provide power to the heating element 743 to cause the heating element 743 to heat at a sufficient rate to rupture the elastic material membrane 722.

[0260] The heating element 740 is at least partially disposed within or against an inner surface of the therapeutic payload delivery section 22, and the elastic material membrane 722 is positioned to expand to fill the therapeutic delivery section thereby contacting the heating element 743. An inner wall formed at least in part by the printed circuit board 740 may define a surface or wall of the therapeutic substance delivery section 22.

[0261] The power source 716 of the balloon bursting mechanism may be a battery or supercapacitor configured to be trickle charged by the ingestible capsule power source following an ingestible capsule triggering event and to release charge to the heating element 743 at a release timing under the control of the microcontroller. The battery or supercapacitor 716 may be impedance matched to the heating element 743 to improve power transfer to the heating element and optimize the heating rate of the elastic material film 722. Impedance matching is taken in this context to mean matching within a specified tolerance. The specified tolerance may be, for example, 1% or less, 5% or less, 10% or less, 15% or less, 20% or less, 25% or less. The impedance matching may include a connector between the supercapacitor 716 and the heating element 743 as part of the heating element 743.

[0262] It should be noted that for the heating element 743 to rupture the elastic material film 722, the energy must be received at a rate sufficient to exceed the energy loss via heat transfer from the heating element 743, which increases as the thermal differential between the heating element 743 and the surroundings increases. To improve power transfer between the power source and the heating element 743, the supercapacitor and the heating element 743 may be impedance matched.

[0263] Optionally, the rigid open frame around which the elastic material membrane 722 is stretched, and / or the inner wall of the capsule 10, and / or the printed circuit board 740 around the heating element 743 are configured to impede fluid flow around the heating element 743 to reduce heat loss to the surroundings and promote heat dissipation to the elastic material membrane 722.

[0264] Optionally, the therapeutic substance delivery chamber may include a deployment detection mechanism for detecting that the therapeutic payload has been deployed in the GI tract. For example, a pair of electrodes on the surface of the compartment may be covered by the elastic material membrane 722 while the sealed chamber is in a sealed state, and become uncovered when the elastic material membrane 722 breaks, resulting in a change in impedance of the electrodes, actively detecting the release. The electrodes may be connected to a microcontroller such that reports sent from the capsule 10, for example via the wireless transceiver 18, may include information representative of the positive detection and timing of the therapeutic payload release.

[0265] The report may be sent immediately upon detection, or upon capsule expulsion being detected, or at some other time. Alternatively or additionally, the report may include information representative of the determined release timing, and optionally also the ileocecal transition index or gastroduodenal transition index based on which the release timing is determined.

[0266] The deployment detection mechanism may include a conductive pad on a printed circuit board assembly next to the heating element 743 (i.e., providing one or more of processor hardware, memory hardware, wireless transceiver, and other reflectometer components, a microcontroller, power management, etc.), and the impedance across the conductive pad is periodically measured by a microcontroller or the like to identify a change in impedance when the elastic material membrane 722 transitions from a stretched state (which spans the conductive pad and forms part of the wall of the sealed chamber) to a ruptured state where fluid from the GI tract and / or the sealed chamber is present inside the capsule at the location of the conductive pad.

[0267] Alternative deployment detection mechanisms include optical presence detection, capacitive sensing, or mechanical switches.

[0268] As an alternative to the arrangement shown in Fig. 7B, the elastic material membrane rupture mechanism may include a power source, a shape memory alloy wire, and a rupture member, and the power source is configured to transmit energy to the shape memory alloy wire at a determined release timing and under the control of a microcontroller to initiate a phase change in the material level of the shape memory alloy wire, thereby applying a force to the rupture member to bring the rupture member into contact with the elastic material membrane and rupture the elastic material membrane 722. For example, the shape memory alloy wire undergoes a 5-10% shortening during the phase change, and this shortening exerts a tensile force that can directly or indirectly rupture the elastic material membrane 722.

[0269] As a further alternative, the elastic material membrane breaking mechanism comprises a motor and a breaking member, and the microcontroller is configured to power the motor at the determined release timing, thereby applying a force to the breaking member to bring the breaking member into contact with the elastic material membrane and break the elastic material membrane 722.

[0270] 7C shows an alternative form of therapeutic payload (therapeutic substance) contained within a sealed chamber. In the capsule 10 of FIG. 7C, the therapeutic substance 750 is in the therapeutic substance delivery chamber 22 but not within the sealed chamber. Specifically, the therapeutic substance 750 is in a powder, dehydrated, or otherwise solid form and is disposed within the therapeutic substance delivery chamber 22 such that it is sealed from the environment outside the capsule 10 by the elastic material membrane 722. Specifically, it is noted that there is at least one opening 760 (not shown, but also present in FIG. 7B) that allows for the exchange of fluid between the therapeutic substance delivery section 22 of the capsule 10 and the external environment, while the elastic material membrane 722 prevents fluid communication between the external environment and the portion of the therapeutic substance delivery chamber 22 that contains the therapeutic substance 750.

[0271] 7C, the sealed chamber is filled with a liquid diluent such that when the elastic material membrane 722 ruptures, the liquid diluent mixes with the therapeutic substance and the mixture is mixed with fluid from the environment external to the capsule 10 via one or more openings 760. Note that the openings are sized to allow sufficient time for the liquid diluent to mix with the therapeutic substance before exiting the capsule 10.

[0272] Heating element 743 may be a resistive heating element including one or more of the following: SMT resistors, metal resistance wire, Nichrome, MEMS heater elements.

[0273] In an alternative balloon rupture mechanism, the mechanism includes a power source and a laser diode focused on the elastic material membrane 722, and the microcontroller of the ingestible capsule is configured to activate the laser diode to rupture the elastic material membrane 722 at a determined release timing.

[0274] In a further alternative embodiment, the breaking mechanism includes a front spring-loaded mechanical needle, and the microcontroller of the ingestible capsule is configured to release the front spring-loaded mechanical needle at a determined release timing, causing the front spring-loaded mechanical needle to bounce into the elastic material membrane 722 and break the elastic material membrane 722.

[0275] In a further alternative, the release mechanism comprises a microcontroller and a release actuator, the therapeutic payload delivery compartment comprises a portion of the ingestible capsule housing including a balloon, the balloon being fillable with balloon contents including the therapeutic payload, the therapeutic payload delivery compartment arranged to allow the balloon to expand to fill the therapeutic delivery compartment when the balloon is filled, the balloon including a releasable valve, and the release actuator comprises a releasable valve actuation mechanism configured to actuate the releasable valve at said determined release timing, thereby allowing the balloon contents including the therapeutic payload to exit the ingestible capsule via one or more openings in the portion of the ingestible capsule housing including the balloon.

[0276] For example, the releasable valve may be a twisted hose and the releasable valve release mechanism is a shape memory alloy wire or a micromotor configured to untwist the hose under the control of a microcontroller of the ingestible capsule, thereby opening the chamber and allowing the contents of the chamber to exit the ingestible capsule through one or more openings in the housing of the ingestible capsule.

[0277] In a further alternative balloon rupture mechanism, the elastic material membrane rupture mechanism comprises a power source, a shape memory alloy wire, and a rupture member, wherein the power source is configured to transmit energy to the shape memory alloy wire at a determined release timing and under the control of a microcontroller to initiate a phase change in the material level of the shape memory alloy wire, thereby applying a force to the rupture member to bring the rupture member into contact with the elastic material membrane and rupture the elastic material membrane, thereby opening the sealed chamber.

[0278] Index Identification and Sensor Configuration In addition to the VOC gas sensor output (i.e., as an additional sensor output where an ICJ indicator is identifiable to add reliability to the VOC gas sensor output identified by the indicator) or as an alternative to the VOC gas sensor output (i.e., in embodiments that do not have a VOC gas sensor, where the VOC gas sensor is faulty, or where the indicator is not identifiable within the VOC gas sensor output signal for any reason), one or a combination of the following sensor outputs and indicators may be processed and identified: -TCD gas sensor from which a plot of H2 concentration against time can be derived by appropriate calibration (further information is given below), the ICJ indication is a sharp increase in H2 concentration (i.e. a positive slope above a predefined threshold). -TCD gas sensor from which a plot of CO2 concentration versus time can be derived by appropriate calibration, the ICJ indicator is the sharp increase in CO2 concentration (i.e., a positive slope above a predefined threshold). Figure 8 shows the ICJ indicator in a plot of CO2 concentration versus time. - A reflectometer formed by antenna 17 and directional coupler 171 (Figures 3B, 3D, 3E), the ICJ indication is a step change or spike in the reflectometer output (see below). -Accelerometer (see Figure 3E).

[0279] Optionally, the ingestible capsule further comprises a directional coupler in series with the antenna to form a reflectometer, the output signal of which is processed in a remote processing device to identify ICJ indices therein. The antenna 17 may be in series with the directional coupler 171. The directional coupler 171 and the antenna 17 are configured as a reflectometer. The reflectometer measures the amplitude of the reflected signal with a diode detector. The reflectometer measurement is a reading representative of the electromagnetic properties of materials in the vicinity of the capsule. The reflectometer reading provides the basis for distinguishing between gas, liquid, and solid substances at the location of the capsule in the GI tract. The reflectometer reading allows the antenna 17 and the directional coupler 171 to cooperate as an environmental dielectric sensor.

[0280] The capsule may generate an output signal from the reflectometer reading for transmission via the capsule transceiver to a remote processing device to identify the ICJ index. Thus, a change in capsule location within the GI tract causes a change in the reflectometer reading, thus providing an indication that a transition event between two sections of the GI tract has occurred.

[0281] The capsule may include a TCD gas sensor disposed alongside the VOC gas sensor in a headspace at an end of the capsule that is sealed from the outside environment by a gas permeable membrane and sealed from the remainder of the capsule interior. Embodiments also include the possibility of a TCD gas sensor function provided by the output of the heater side of the VOC gas sensor.

[0282] The heater side of the VOC sensor (operating as a TCD sensor) and the sensor side of the TCD sensor have different operating ranges, so that the TCD readings from the two sensors collectively span a wider operating temperature range than either of the sensors individually. Both sensors have heating elements. The TCD sensor has a lower operating temperature but higher accuracy. The heater side of the VOC increases the operating range but results in a less accurate TCD reading than the TCD sensor. The greater collective thermal range that the two gas sensors achieve in concert allows for better resolution of analytes in the processing of the output signal. The thermal conductivity of the constituent gases in the gas mixture of the GI tract varies with temperature, so by taking TCD readings at different operating temperatures, different gases can be resolved from one another. This is exploited in processing the output signal to identify ICJ indicators, which is through determining the identity and concentration of the constituent gases in the gas mixture surrounding the capsule 10.

[0283] The gas sensors are contained in a portion of the capsule 10 that is sealed from the power source 16 and other electronic components. At least a portion of the exterior surface of this portion of the capsule is constructed from a selectively permeable membrane. For example, the gas sensors include respective heaters that are driven to heat the sensing portion of each gas sensor to a temperature at which a sensor reading is to be taken (i.e., the measurement temperature). The heaters may be driven in a pulsed manner such that there is a time variation in the sensing portion temperature such that the measurement temperature is obtained without consuming the power required to continuously maintain the measurement temperature for a period of time sufficient to take a reading.

[0284] The gas sensor may be calibrated such that the gas sensor readings can be used to identify the composition of the gas mixture in the environment in which the capsule is located, and optionally also the concentration of a particular gas (i.e., a particular component of the gas mixture). The capsule 10 may also be configured to operate in the absence of such calibration, for example, when changes in the gas sensor signal are utilized to identify motility events such as gastroduodenal transition or ileocecal transition (note that the capsule may also be configured without a gas sensor). The calibration factor is collected during manufacture and applied to the recorded readings at the processing stage (i.e., by the remote processing device). In other aspects, this calibration may be performed on the capsule 10, the remote processing device, or any device that can access the calibration factor and the recorded readings from the gas sensor. Such calibration relates to a process related to measuring the concentrations of the constituent gases in the gas mixture in the capsule to identify an ICJ indicator in addition to or alternative to the ICJ indicator in the VOC gas sensor side output signal. Since the TCD readings are effectively measuring the rate of heat loss to the surroundings, measuring the temperature of the surroundings rather than relying on assumptions (i.e., prior knowledge of the internal temperature of the target mammal) improves accuracy. However, processing may rely on assumptions, for example, if the capsule 10 does not include an environmental temperature sensor, or if there is some problem with the environmental temperature sensor readings, or, for example, if the level of accuracy provided by the assumptions is acceptable in a particular implementation. Environmental temperature is a term used herein to refer to the temperature of the environment in which the capsule 10 is located, which is different from the operating temperature of the gas sensor. The sensitivity of the gas sensor 13 to different constituent gases varies according to the operating temperature of the sensor, and processing of the readings includes calibrating (also called adjusting or correcting) the readings from the gas sensor according to the contemporaneous operating temperature, and optionally also according to the contemporaneous environmental temperature.

[0285] 10 is a schematic diagram of a hardware configuration of a remote processing device 24. The remote processing device 24 may be implemented by one or more devices having the configuration shown in FIG.

[0286] The remote processing device 24 comprises multiple components interconnected by a bus connection. The bus connection is an exemplary form of data and / or power connection. Direct connections between components for the transfer of power and / or data may be provided in addition to or as an alternative to a bus connection.

[0287] The remote processing device 24 comprises memory hardware 991 and processing hardware 993; these components are essential regardless of the implementation. Further components are context dependent, including a network interface 995, input devices 997, and a display unit 999.

[0288] The memory hardware 991 stores processing instructions for execution by the processing hardware 993. The memory hardware 991 may include volatile and / or non-volatile memory. The memory hardware 991 may store data pending processing by the processing hardware 993 and may store data resulting from processing by the processing hardware 993.

[0289] The processing hardware 993 includes one or more interconnected cooperating CPUs for processing data according to the processing instructions stored by the memory hardware 991 .

[0290] The system may include one remote processing device according to the hardware configuration of FIG. 10, or multiple such devices operating in coordination with each other.

[0291] The network interface 995 provides an interface for transmitting and receiving data over a network. Connections to one or more networks are provided. The networks may be, for example, a local area network and / or the Internet. The connections may be wired and / or wireless.

[0292] The input devices 997 provide a mechanism for receiving input from a user. For example, such devices may include one or more of a mouse, a touchpad, a keyboard, an eye gaze detection system, and a touch screen touch interface. The input may be received over a network connection. For example, in the case of a server computer, a user may connect to the server through a connection to another computing device and provide input to the server using an input device of the other computing device.

[0293] The display unit 999 provides a mechanism for visually displaying data to a user. The display unit 999 may display a user interface where certain locations on the display unit act as buttons or other means allowing interaction with the data via an input mechanism such as a mouse. The server may be connected to the display unit 999 over a network.

[0294] The network interface may include or communicate with a remote processing device transceiver in data communication with capsule 10 .

[0295] Ulcerative colitis (UC) The therapeutic agent delivered by the therapeutic agent delivery compartment and released into the GI tract by UC may be a pharmaceutical formulation for the treatment of UC. In particular, the pharmaceutical formulation may be a corticosteroid, such as budesonide, or a 5-aminosalicylate, such as a preparation. The embodiments allow for precise release of the pharmaceutical formulation into the colon, such that the dose has high efficacy, as compared to conventional methods for administering pharmaceutical formulations intended to treat colonic conditions. Furthermore, the embodiments may be configurable to release the dose as a single discrete dose, with a release timing that may be, for example, immediately upon detection of the ICJ transition, or as a series of partial doses, with a series of partial release timings separated by predefined intervals. The capsule 10 may be configurable by the clinician at the time of manufacture or after manufacture (e.g., having a signal received by the microcontroller to change the configuration). Specifically, the inflamed tissue associated with UC may be all in the first part of the colon (best treated by a single dose), all in the distal end of the colon (best treated by a series of partial doses), or distributed along the entire colon (best treated by a series of partial doses). The clinician may be able to determine the distribution of inflamed tissue associated with UC in the subject and thus select a single individual dose or a series of partial doses. The selection may include selecting an appropriate pre-loaded capsule, or may include configuring the microcontroller 15 of the capsule 10 to behave in a particular manner by transmitting a signal from the controller device that is received at the microcontroller 15. There are toxic effects associated with the ingestion of pharmaceutical formulations, which are balanced against efficacy. The embodiments may improve the balance somewhat in favor of efficacy by delivering therapeutic substances to the site of inflammation associated with UC in a personalized manner (i.e., in a single discrete dose or a series of spaced doses). While UC is used as an example, it will be understood that other inflammatory GI conditions may be treated in a similar manner using capsule 10 of the embodiments, with similar advantages in improving the balance between efficacy and toxicity.

Claims

1. 1. An ingestible capsule comprising: a housing, the housing being a biocompatible, indigestible housing containing a therapeutic payload carrying compartment; Power supply and an ejection mechanism comprising a microcontroller and an ejection actuator; a sensing mechanism, the sensing mechanism being sensitive to an environment external to the housing; the ingestible capsule is configured to pass through the gastrointestinal (GI) tract of a mammalian subject, and during passage: the sensing mechanism is configured to provide an output signal that varies according to the GI tract environment external to the housing; A) the sensing mechanism includes one or more of a VOC gas sensor, a reflectometer formed by a transmitting antenna of the ingestible capsule connected in series with a directional coupler and configured to measure a reflected signal from the transmitting antenna, and an accelerometer; The microcontroller during the identification phase, on a rolling basis, recording a representation of the output signal over a recent duration period t, and processing the recorded representation of the output signal over the recent duration period t to identify the presence of one or more ileocecal transition indicators; configured to determine the release timing in response to identifying the presence of the one or more ileocecal transition indicators, and cause the release actuator to release the therapy payload from the therapy payload delivery section based on the determined release timing; and / or B) the sensing mechanism includes one or more of an accelerometer, a TCD gas sensor, and a reflectometer formed by a transmitting antenna of the ingestible capsule connected in series with a directional coupler, the reflectometer configured to measure a reflected signal from the transmitting antenna; The microcontroller during the identification phase, on a rolling basis, recording a representation of said output signal over a recent duration period t and processing said recorded representation of said output signal over said recent duration period t to identify the presence of one or more gastroduodenal transition indicators; determining the release timing in response to identifying the presence of the one or more gastroduodenal transition indicators, and causing the release actuator to release the therapeutic payload from the therapeutic payload delivery section based on the determined release timing. Ingestible capsule.

2. 2. The ingestible capsule of claim 1, wherein the sensing mechanism is a non-contact sensing mechanism contained within a portion of the ingestible capsule that is sealed from the environment outside the ingestible capsule by the housing, the non-contact sensing mechanism including at least one of an accelerometer and a reflectometer, the reflectometer having a transmitting antenna connected in series with a directional coupler and configured to measure a reflected signal from the transmitting antenna, and the output signal output by the sensing mechanism includes an accelerometer reading and / or a reflectometer reading.

3. the non-contact sensing mechanism comprises the reflectometer; 3. The ingestible capsule of claim 2, further comprising a diode detector, the diode detector forming part of the reflectometer, the diode detector configured to receive the reflected signal from the antenna and measure an amplitude of the reflected signal, and the reflectometer reading in the output signal comprises an amplitude measurement of the reflected signal.

4. 3. The ingestible capsule of claim 2, further comprising: an antenna impedance control mechanism comprising a variable capacitor configured to vary the impedance of the transmitting antenna; and a controller, wherein the reflectometer and the antenna impedance control mechanism form a closed or feedback loop, and the controller is configured to receive a measurement of the amplitude of the reflected signal from a diode detector and execute a control algorithm to use the amplitude measurement to generate an antenna impedance control signal that sets a capacitance of the variable capacitor to vary the impedance of the antenna so as to reduce the amplitude of the reflected signal, and wherein the reflectometer reading in the output signal comprises a reading of the antenna impedance control signal.

5. the output signal output by the sensing mechanism includes an accelerometer reading and a reflectometer reading, and determining the release timing includes identifying an ileocecal transition indicator being present in readings from the reflectometer and the accelerometer; processing the reflectometer readings and the accelerometer readings to identify the presence of a first ileocecal transition indicator in one of the reflectometer readings and the accelerometer readings; processing the other of the reflectometer readings and the accelerometer readings to identify a second ileocecal transition indicator within a predefined time window of timing of the first ileocecal transition indicator; and determining the release timing as either immediate or after a predefined delay in response to identifying the first ileocecal transition indicator and the second ileocecal transition indicator within the predefined time window.

6. 6. The ingestible capsule of any one of claims 1 to 5, wherein the therapeutic payload is one or more of a drug, a pharmaceutical agent, a prebiotic substance, a fecal transplant, and / or a probiotic substance.

7. the ingestible capsule comprises a wireless transceiver, the release mechanism comprises the wireless transceiver and a release actuator, and the antenna is configured to transmit a transmission signal representative of the output signal to a remote processing device during an identification phase; The ingestible capsule of any one of claims 1 to 5, wherein the transceiver is configured to cause the therapeutic payload to be released from the therapeutic payload carrying section by the release actuator immediately or after a predetermined delay when the transceiver receives a notification signal from the remote processing device.

8. the ejection mechanism comprises a microcontroller and an ejection actuator; the therapeutic payload delivery compartment comprising a section of the ingestible capsule housing, a sealed chamber, and a membrane of elastic material defining at least a portion of a wall of the sealed chamber, the therapeutic payload being sealed within the sealed chamber; 6. The ingestible capsule of claim 1, wherein the release actuator comprises an elastic material membrane rupturing mechanism configured to rupture the elastic material membrane at the determined release timing, thereby opening the sealed chamber and allowing the therapeutic payload to exit the ingestible capsule through one or more openings in the section of the ingestible capsule housing.

9. the elastic material membrane rupturing mechanism includes a power source and a heating element, the heating element being at least partially disposed within the therapy payload carrying compartment or facing an inner surface of the therapy payload carrying compartment, and the at least a portion of the wall of the sealed chamber defined by the elastic material membrane being disposed in contact with the heating element; 9. The ingestible capsule of claim 8, wherein the power source is configured to transfer energy to the heating element at the determined release timing and under the control of the microcontroller to increase the temperature of the heating element, causing the temperature increase to rupture the elastic material membrane, thereby opening the sealed chamber.

10. The elastic material membrane rupture mechanism includes: a power source and a laser diode focused on the elastic material membrane, wherein a microcontroller of the ingestible capsule is configured to activate the laser diode at the determined release timing to rupture the elastic material membrane and thereby open the sealed chamber; or a front spring-loaded mechanical needle, and a microcontroller of the ingestible capsule configured to release the front spring-loaded mechanical needle at the determined release timing, causing the front spring-loaded mechanical needle to bounce against the elastic material membrane and rupture the elastic material membrane, thereby opening the sealed chamber.

9. The ingestible capsule of claim 8.

11. the ejection mechanism comprises a microcontroller and an ejection actuator; the therapeutic payload delivery compartment comprising a section of the ingestible capsule housing, a sealed chamber, and a membrane of elastic material defining at least a portion of a wall of the sealed chamber, the therapeutic payload being sealed within the sealed chamber; the chamber is sealed by a releasable valve; a releasable valve release mechanism configured such that the release actuator releases the releasable valve at a determined release timing, thereby unsealing the sealed chamber and allowing the therapeutic payload to exit the ingestible capsule through one or more openings in the section of the ingestible capsule housing; the releasable valve is a twisted hose, and the releasable valve release mechanism is a shape memory alloy wire or a micromotor configured to untwist the hose under control of a microcontroller of the ingestible capsule, thereby opening the chamber and allowing the contents of the chamber to exit the ingestible capsule through one or more openings in the housing of the ingestible capsule. The ingestible capsule of any one of claims 1 to 5.

12. the ejection mechanism comprises a microcontroller and an ejection actuator; the therapeutic payload-carrying compartment comprises a section of the ingestible capsule housing, a sealed chamber, and a membrane of elastic material defining at least a portion of a wall of the sealed chamber, wherein a liquid diluent is sealed within the sealed chamber; the therapeutic payload is a lyophilized drug or other therapeutic substance in powder, dehydrated, or other solid form, contained within a therapeutic substance delivery compartment within the space exterior to the sealed chamber and defined at least in part by the elastic material membrane; 6. The ingestible capsule of claim 1, wherein the section of the ingestible capsule housing includes one or more openings that allow fluid communication between the therapeutic payload carrying compartment and the exterior of the capsule, the one or more openings being blocked by the elastic material membrane and being unblocked after rupture of the elastic material membrane by an elastic material membrane rupture mechanism at the determined release timing, the rupture of the elastic material membrane allowing the liquid diluent to mix with the therapeutic payload in the therapeutic payload carrying compartment and mix with fluid from the environment outside the capsule through the one or more openings.

13. the timing of release is immediate upon identification of the ileocecal index; or the release timing is a predetermined period after identification of the ileocecal indicator; or 2. The ingestible capsule of claim 1, wherein the release timings include a series of regularly or irregularly spaced partial release timings, a fraction of the therapeutic payload is released at each of the partial release timings, and the earliest partial release timing in the series is immediately after the identification of the ileocecal indicator or a predetermined period after the identification of the ileocecal indicator.

14. Providing an ingestible capsule to a mammalian subject for ingestion; processing an output signal of the sensing mechanism to determine the timing of release of the therapeutic payload; causing the therapeutic payload to be released into the GI tract of the subject mammal at a determined release timing; A method comprising: the ingestible capsule comprising: a housing, the housing being a biocompatible, indigestible housing containing a therapeutic payload carrying compartment; Power supply and an ejection mechanism comprising a microcontroller and an ejection actuator; a detection mechanism; the sensing mechanism is sensitive to an environment external to the housing; the ingestible capsule is configured to pass through the gastrointestinal (GI) tract of the mammalian subject, and during passage: the sensing mechanism is configured to provide an output signal that varies according to the GI tract environment external to the housing; A) the sensing mechanism includes one or more of a VOC gas sensor, a reflectometer formed by a transmitting antenna of the ingestible capsule connected in series with a directional coupler and configured to measure a reflected signal from the transmitting antenna, and an accelerometer; The microcontroller during the identification phase, on a rolling basis, recording a representation of the output signal over a recent duration period t, and processing the recorded representation of the output signal over the recent duration period t to identify the presence of one or more ileocecal transition indicators; configured to determine the release timing in response to identifying the presence of the one or more ileocecal transition indicators, and cause the release actuator to release the therapy payload from the therapy payload delivery section based on the determined release timing; and / or B) the sensing mechanism includes one or more of an accelerometer, a TCD gas sensor, and a reflectometer formed by a transmitting antenna of the ingestible capsule connected in series with a directional coupler, the reflectometer configured to measure a reflected signal from the transmitting antenna; The microcontroller during the identification phase, on a rolling basis, recording a representation of said output signal over a recent duration period t and processing said recorded representation of said output signal over said recent duration period t to identify the presence of one or more gastroduodenal transition indicators; determining the release timing in response to identifying the presence of the one or more gastroduodenal transition indicators, and causing the release actuator to release the therapeutic payload from the therapeutic payload delivery section based on the determined release timing. method.

15. 1. A system comprising an ingestible capsule and a remote processing device, the ingestible capsule comprising: a housing, the housing being a biocompatible, indigestible housing containing a therapeutic payload carrying compartment; Power supply and A release mechanism; a sensing mechanism, the sensing mechanism being sensitive to an environment external to the housing; the ingestible capsule is configured to pass through the gastrointestinal (GI) tract of a mammalian subject, and during said passage: the sensing mechanism is configured to provide an output signal that varies according to the GI tract environment external to the housing; the ejection mechanism comprises a capsule transceiver and an actuator, the capsule transceiver being configured to transmit a transmission signal representative of the output signal to a remote processing device during an identification phase; the capsule transceiver is configured to cause the therapeutic payload to be released from the therapeutic payload-carrying section by the release actuator immediately or after a predetermined delay upon receiving a notification signal from the remote processing device; the remote processing device comprising: a remote processing device transceiver configured to communicate with the capsule transceiver, including receiving the transmitted signal representing the output signal; and a processor, the processor processing the output signal to: A) one or more ileocecal transition indicators, wherein the sensing mechanism includes one or more sensors from among a VOC gas sensor, a reflectometer formed by a transmitting antenna of the ingestible capsule connected in series with a directional coupler and configured to measure a reflected signal from the transmitting antenna, and an accelerometer; and / or B) one or more gastroduodenal transition indicators in the output signal, wherein the sensing mechanism includes one or more from among an accelerometer, a TCD gas sensor, and a reflectometer formed by a transmitting antenna of the ingestible capsule connected in series with a directional coupler, the reflectometer configured to measure a reflected signal from the transmitting antenna. and configured to identify in real time either The processor further comprises: and configured to cause the remote processing device transceiver to transmit the notification signal to the capsule transceiver in accordance with the identification of the one or more ileocecal transition indicators and / or the one or more gastroduodenal transition indicators.

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