Oral pill gastric retention and disassembly designs

Abstract

Aspects of the present disclosure relate to an article. In some embodiments, the article is a gastric retention device or a gastrointestinal device. In some embodiments, the article comprises one or more reservoirs comprising a therapeutic payload. In some embodiments, the article comprises one or more triggerable release mechanisms. In some embodiments, the triggerable release mechanism comprises a metal seal. In some embodiments, release of the therapeutic payload is accomplished via electrochemical dissolution of the metal seal. Other aspects of the disclosure relate to methods for delivering a drug using the drug delivery articles disclosed herein.

Description

[0001] ORAL PILL GASTRIC RETENTION AND DISASSEMBLY DESIGNS

[0002] RELATED APPLICATIONS

[0003] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 63 / 514,807, filed July 21, 2023, and entitled “DEVICES AND MATERIALS FOR LIVE CELL PROTECTION AND DELIVERY IN THE GASTROINTESTINAL TRACT,” to U.S. Provisional Patent Application No. 63 / 514,814, filed July 21, 2023, and entitled “ORAL PILL GASTRIC RETENTION AND DISASSEMBLY DESIGNS,” to U.S. Provisional Patent Application No. 63 / 514,818, filed July 21, 2023, and entitled “ORAL PILL WATER-TIGHT PAYLOAD CHAMBER DESIGN WITH TRIGGERABLE RELEASE,” and to U.S. Provisional Patent Application No. 63 / 514,822, filed July 21, 2023, and entitled “LOW POWER BATTERY AND SIGNALING SYSTEMS,” which are incorporated herein by reference in their entirety for all purposes.

[0004] GOVERNMENT SPONSORSHIP

[0005] This invention was made with government support under FA8650-21-2-7120 awarded by the Air Force Office of Scientific Research. The government has certain rights in the invention.

[0006] BACKGROUND

[0007] Recent advances in extended release pharmacologic systems are predominantly limited to subcutaneous, transdermal, intravaginal, and surgical implants. Conventional solutions include invasive modalities such as surgical implants (including, e.g., wireless, programmable structures available from MicroCHIPS, Inc. (Lexington, MA)) or modalities limited to specialized applications such as birth control (including, e.g., NuvaRing® and Implanon®, both available from Merck & Co., Inc. (Whitehouse Station, NJ)). Structures like those available from MicroCHIPS are also limited to delivering therapeutic agents with high potency because they can be administered in only microgram or smaller quantities.

[0008] Accordingly, improved systems and methods are needed. SUMMARY

[0009] The subject matter of the present disclosure involves, in some cases, interrelated products, alternative solutions to a particular problem, and / or a plurality of different uses of one or more systems and / or articles.

[0010] Some aspects are related to articles. In some embodiments, the article comprises one or more reservoirs, each reservoir comprising a therapeutic pay load, the one or more reservoirs having a total combined volume of greater than or equal to 10 microliters; one or more triggerable release mechanisms associated with each of the reservoirs such that, upon receipt of a signal, each triggerable release mechanism releases the therapeutic pay load from the one or more reservoirs; and an electrical system associated with the triggerable release mechanisms, the electrical system comprising a short-range wireless component; wherein each reservoir is adapted and designed to maintain therapeutic efficacy of the therapeutic payload for greater than or equal to 10 days under physiological conditions.

[0011] In some embodiments, the article comprises one or more reservoirs, each reservoir configured to contain a therapeutic payload, the one or more reservoirs having a total combined volume of greater than or equal to 10 microliters; one or more triggerable release mechanisms associated with each of the reservoirs such that, upon receipt of a signal, each triggerable release mechanism is configured to release the therapeutic pay load from the one or more reservoirs; and an electrical system associated with the triggerable release mechanisms, the electrical system comprising short-range wireless component; wherein each reservoir is adapted and designed to maintain therapeutic efficacy of the therapeutic payload for greater than or equal to 10 days under physiological conditions.

[0012] In some embodiments, the article is a drug delivery article. In some embodiments, the drug delivery article comprises a reservoir body at least partially disposed between a payload and a physiological medium, or other encompassing system; a sealing component adjacent the reservoir body such that the sealing component isolates the payload from the physiological medium, or other encompassing system; an actuator associated with the sealing component, wherein, upon application of energy from the actuator to the sealing component, at least a portion of the sealing component is removed and the payload is at least partially exposed to the physiological medium, or other encompassing system.

[0013] In some embodiments, the drug delivery article comprises a reservoir body at least partially disposed between a payload and a physiological medium, or other encompassing system; a sealing component adjacent the reservoir body such that the sealing component isolates the payload from the physiological medium, or other encompassing system; an energy delivery interface associated with the sealing component and one or more systems external to the drug delivery article, wherein, upon application of energy from the one or more systems to the energy delivery interface, the payload is at least partially exposed to the physiological medium, or other encompassing system.

[0014] In some embodiments, the reservoir body and / or the sealing component may advantageously have a low permeability to water vapor and / or permeance to water to facilitate isolating a payload contained within the interior volume at least partially defined by the reservoir body and / or sealing component from physiological media outside of the interior volume (e.g., at a location internal the subject). Accordingly, in some embodiments, the reservoir body and / or the sealing component may be configured to maintain a relative humidity therein at any of a variety of suitable levels. In some embodiments, the reservoir body and / or the sealing component is configured to maintain a relative humidity within an interior volume defined by the reservoir body and / or the sealing component of less than or equal to 80%, less than or equal to 70%, less than or equal to 60%, less than or equal to 50%, or less than or equal to 40% for at least 1 day, at least 5 days, at least 10 days, at least 30 days, at least 60 days, at least 90 days, at least 120 days, at least 150 days, at least 180 days, at least 210 days, at least 240 days, at least 264 days, at least 270 days, and / or up to 300 days when the reservoir body and / or the sealing component is at a location internal to the subject. In some embodiments, the ability of the reservoir body and / or the sealing component to maintain a relative humidity therein may be tested using a humidity sensor contained within the interior volume defined by the reservoir body and / or the sealing component.

[0015] According to some embodiments, the drug delivery article, comprises a reservoir body comprising a payload portion and an opening; a dissolvable metal layer adjacent the opening such that the dissolvable metal layer seals the payload portion; a working electrode in electrical communication with the metal layer; a power source in electrical communication with the working electrode; wherein, upon application of a voltage from the power source to the metal layer, the metal layer degrades such that the dissolvable metal layer at least partially dissolves.

[0016] Some aspects are related to methods. In some embodiments, the method is a method for delivering a drug. In some embodiments, the method for delivering a drug comprises administering to a subject a drug delivery article comprising a reservoir body, the reservoir body comprising a pay load portion, an opening, and a dissolvable metal layer adjacent the opening; applying a voltage to the dissolvable metal layer such that the dissolvable metal layer dissolves, releasing the contents of the payload portion to a location internal to the subject.

[0017] Still other aspects are related to articles configured for triggerable gastric exit. In some embodiments, the article configured for triggerable gastric exit comprises a capsule comprising a releasable cap, the releasable cap comprising one or more coupling components; one or more retention arms, each retention arm mechanically coupled to the capsule via the one or more coupling components; a spring disposed within the cap; and a degradable component associated with the spring, such that upon degradation of the degradable component, the spring ejects the cap from the capsule and the one or more retention arms disassociate from the capsule, wherein, prior to degradation of the degradable component, the article is configured to be retained at a location internal to a subject for at least 7 days.

[0018] In some embodiments, articles are disclosed. In some embodiments, the article comprises one or more reservoirs, each reservoir comprising a therapeutic payload, the one or more reservoirs having a total combined volume of greater than or equal to 10 microliters; and one or more triggerable release mechanisms associated with each reservoir such that, upon receipt of an external signal, each triggerable release mechanism releases the therapeutic payload from the one or more reservoirs; wherein each reservoir is adapted and designed to maintain therapeutic efficacy of the therapeutic payload for greater than or equal to 10 days under physiological conditions.

[0019] Other advantages and novel features of the present disclosure will become apparent from the following detailed description of various non-limiting embodiments of the disclosure when considered in conjunction with the accompanying figures. In cases where the present specification and a document incorporated by reference include conflicting and / or inconsistent disclosure, the present specification shall control.

[0020] BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Non-limiting embodiments of the present disclosure will be described by way of example with reference to the accompanying figures, which are schematic and are not intended to be drawn to scale unless otherwise indicated. In the figures, each identical or nearly identical component illustrated is typically represented by a single numeral. For purposes of clarity, not every component is labeled in every figure, nor is every component of each embodiment of the disclosure shown where illustration is not necessary to allow those of ordinary skill in the art to understand the disclosure. In the figures:

[0022] FIG. 1 illustrates the proposed energy -efficient ingestible drug delivery system and its operation scenario, according to some embodiments;

[0023] FIG. 2a shows a diagram of the drug reservoir and the gold membrane in cross- sectional view, according to some embodiments. FIG. 2b shows a microscopic picture of FIG. 2a, according to some embodiments;

[0024] FIG. 3a shows a schematic of the mechanism of electrochemical gold dissolution for the proposed drug delivery system, according to some embodiments. FIG. 3b shows a micrograph for the gold membrane anode and the cathode fabricated on a silicon wafer used for the in vitro characterization studies, according to some embodiments;

[0025] FIG. 4a shows a plot of the linear sweep voltammetry (LSV) (scan rate = 50 mV / s) of the gold membrane in SGF of pH 1 that indicates the driving voltage range of the gold dissolution, according to some embodiments. FIG. 4b shows a plot of the energy (mJ / mm) versus driving voltage (V) and illustrates the trade-off between the gold dissolution time and energy at each driving mode in SGF of pH 1, according to some embodiments. FIG. 4c shows a plot of time (sec) versus energy (mJ / mm) at each driving mode, according to some embodiments;

[0026] FIG. 5a illustrates a block diagram of an exemplary electronic subsystem of the present disclosure, according to some embodiments; FIG. 5b illustrates an exemplary assembly of the electronic subsystem of the present disclosure, according to some embodiments. FIG. 5c illustrates a timing diagram of the electronic system for the energy-efficient ingestible drug delivery system, according to some embodiments;

[0027] FIG. 6 is a photograph illustrating the ex vivo experimental setup used herein, according to some embodiments. A porcine stomach was fixed and accessed at the gastro-esophageal junction for the deployment of the device to the stomach, according to some embodiments;

[0028] FIG. 7a shows a plot of the measured dissolution energy of the drug reservoir prototype at each driving mode as determined in the ex vivo experiments disclosed herein, according to some embodiments. FIG. 7b shows the corresponding microscopic pictures of the gold membranes before and after gold dissolution, according to some embodiments;

[0029] FIG. 8 show a schematic illustrating the payload chamber fabrication process and key materials, according to some embodiments;

[0030] FIG. 9 shows that varying the thickness of the SU-8 support layer improves handling robustness during fabrication. SU-8 mesh layer thickness above 10 m was explored. A thickness of 25 pm proved optimal in terms of improved rigidity (better handling / chamber manufacturability) without suffering from delamination, according to some embodiments.

[0031] FIG. 10 shows the effect of varying the mesh size of the SU-8 support layer. The smallest mesh size (150 pm) showed the best performance in improving the mechanical robustness of the gold film, according to some embodiments;

[0032] FIG. 11 provides a detailed view of the SU-8 mesh, according to some embodiments;

[0033] FIG. 12 shows pictures illustrating the results following long-term soaking tests in SGF with Methylene Blue leak indicator dye, according to some embodiments;

[0034] FIG. 13 shows theoretical calculations of target moisture vapor transmission rates (MVTR), according to some embodiments;

[0035] FIG. 14 shows the dependence of long-term viability on material identity and water vapor permeability. Test A was used to select top performing materials without including the impact of the gold membrane. Test B was used to validate top performing materials in the context of a gold sealed chamber. Test B demonstrates that a properly optimized chamber sealed with a gold film just 300 nm thick can maintain the viability of the internal bacterial for at least 11 days at 37 °C in simulated gastric fluid (FEP 2), according to some embodiments;

[0036] FIG. 15 shows an illustration of the cross-section of version 1 and version 2 of the development flex PCB, according to some embodiments;

[0037] FIG. 16 shows the initial design of the pill-form factor printed circuit board that interfaces with the main electronics on one end (left panel) and the chamber exit port on the other (right panel). This single-chamber design is be used to de-risk electrical and mechanical attachment methods to the chamber gold layer, according to some embodiments;

[0038] FIG. 17a shows the development flex PCB ver.l, according to some embodiments. The board has a flexible substrate that allows conformal adhesion to the gold / SU-8 membrane. The center gold-plated copper ring is connected to the gold membrane via conductive epoxy. The gold cathode at the edge is be electroplated with platinum. The adhesive film at the backside helps to fix the flex PCB to the gold membrane during the electrical connection process, according to some embodiments. FIG. 17b shows an exemplary device after the electrical connection of the flex PCB and the gold membrane using silver epoxy. The gold membrane is attached to the 3D printed chamber as described elsewhere herein, according to some embodiments. FIG. 17c shows the device after the encapsulation process. The two layers of epoxy are manually applied with a needle under the microscope, according to some embodiments;

[0039] FIG. 18 shows the characterization of electrochemical parameters of gold dissolution and the gold film with SU-8 layer before / after dissolution by applying DC driving voltage, according to some embodiments;

[0040] FIG. 19 shows the characterization of electrochemical gold degradation at the driving voltage of 1.5 V under different physiological conditions, according to some embodiments. The total energy (left), average current during the gold dissolution (middle), and total time for the gold dissolution completion (right) was measured under pH 1-4 at 37C, according to some embodiments. The anode is a bare gold membrane of a diameter of 2mm and a thickness of 300nm, and the cathode is a platinum electrode, according to some embodiments. The data are normalized to the value at pH 1, according to some embodiments; FIG. 20 shows the electrochemical dissolution of gold membrane with SU-8 layer, according to some embodiments. The pictures are before (left), during (middle), and after (right) the dissolution. The diameter of the exposed area of the gold / SU-8 membrane was approximately 2.4mm, according to some embodiments. The characterization was performed under the condition of pH 2 simulated gastric fluid (SGF) at 37 °C with the optimal driving voltage of 1.5V respect to the platinum counter electrode, according to some embodiments;.

[0041] FIG. 21 shows the electronic release of bacteria from a chamber quantified by measuring the release of a constitutively luminescent bacterial strain into the external medium, according to some embodiments;

[0042] FIG. 22 shows the electrochemical power parameters confirming that the theoretical energy consumption matches experimental results and empirical quantification of power dependence on exposed gold area during electronic bacterial release in FIG. 21, according to some embodiments;

[0043] FIG. 23 shows a diagram of bacterial chambers with additional functions that can interface with on-board bacteria, according to some embodiments;

[0044] FIG. 24 shows the manufacturing and performance of bacterial chambers protected from low pH ingress, according to some embodiments. FIG. 24a shows bacterial chambers protected against low pH during stomach transit by inclusion of a film made of an enteric polymer (L100-55) attached via an adhesive layer (black), according to some embodiments. FIG. 24b shows that the enteric film hardens after exposure to simulated gastric fluid (SGF), but dissolves away after a brief exposure (< Ihr) to neutral pH (PBS) allowing the bacteria to be exposed to the chemical environment of the small intestine, according to some embodiments. FIG. 24c shows a close-up view (red, dashed square in panel FIG. 24b) of enteric protected pill casings showing no porous membrane fouling after exposure to neutral pH (PBS), according to some embodiments. FIG. 24d shows an analysis of internal pH of fluid inside casing chambers by spotting contents onto pH paper, according to some embodiments. First two rows are control spots of the indicated fluids. Last two rows are spots from three chambers each from a protected or un-protected pill casing exposed to simulated gastric fluid (SGF) for 18 hours. Bottom legend indicates corresponding pH of the resulting color change. FIG. 25 shows that enteric-protected bacterial chambers preserve viability and function of on-board bacteria through simulated exposure to the stomach, according to some embodiments. FIG. 25a shows unprotected or enteric -protected bacterial chambers loaded with constitutively luminescent bacterial cells and exposed to simulated intestinal fluid (SIF only, blue) or simulated ingestion with a 1-hour exposure to pH 1.2 simulated gastric fluid (SGF+SIF) at 37 °C, according to some embodiments. FIG. 25b shows a plot of the cell viability as a function of the protective film (or controls), according to some embodiments. Geometric mean and geometric 95% confidence intervals are plotted on top of individual replicate chambers. N = 8 (4 chambers x 2 pill casings), Multiple unpaired t-tests, (*) P < 0.0332, (ns) not significant. FIG. 25c shows a plot of the luminescence of the same chambers from the inner side of the casings through the optically clear backing film, according to some embodiments. Total chamber luminescence was quantified (FIJI, Image J) and divided by the total chamber colony forming units (CFU) from panel B. The limit of detection (LOD) was set at 2.5x the standard deviation of the background signal divided by the largest viability value observed. Values below the LOD were set equal to the LOD and all values were normalized to set the LOD = 1. Geometric mean and geometric 95% confidence intervals are plotted on top of individual replicate chambers. N = 8 (4 chambers x 2 pill casings). FIG. 25d shows images used for luminescence quantification in FIG. 25c, according to some embodiments.

[0045] FIG. 26 shows a schematic illustrating the workflow for use of an exemplary GL resident system as contemplated herein, including, but not limited to (i) fabrication & storage, (ii) administration, (iii) gastric retention and (iv) triggerable disassembly, according to some embodiments;

[0046] FIG. 27 shows a schematic illustrating the differences in location, safety, and pH on payload release between tethered GLresident systems and gastric-only GLresident systems as contemplated herein, according to some embodiments;

[0047] FIG. 28 shows a diagram of a percutaneous endoscopic gastrostomy model in swine that was developed to evaluate the viability of transpyloric tethered-based gastric devices. FIG. 28 also shows a computer automated drawing (CAD) of an exemplary tethered-based gastric device as well as photographs showing the percutaneous incision following placement in swine, according to some embodiments; FIG. 29 shows exemplary modes of observed failure for the tethered-based gastric devices, according to some embodiments;

[0048] FIG. 30 shows in vivo results of tether-based devices following placement into swine (e.g, 50-80 kg) over a period of 3 to 10 days, according to some embodiments;

[0049] FIG. 31 is a schematic illustrating that tether-based devices may be used to deliver small payloads and with smaller accessory subsystems, and that gastric-only systems allow delivery of higher payloads with larger accessory subsystems, according to some embodiments;

[0050] FIGs. 32a and 32b illustrates the gastric-only device design and various generations of fabricated prototypes with varying arm properties (e.g., length, angles between adjacent arms, etc). FIG. 32a also provides photographs and X-ray images demonstrating in vivo delivery of the gastric-only systems, according to some embodiments;

[0051] FIGs. 33a and 33b illustrates common failure modes and developed mitigation methods for the gastric-only systems, according to some embodiments;

[0052] FIG. 34a shows the results from modeling studies designed to identify the bend radius of the retaining arms that induced the least amount of fatigue, according to some embodiments;

[0053] FIGs. 34b-c show the results from cycling until failure of devices with nonpassivated and passivated arms, according to some embodiments;

[0054] FIG. 34d shows a PEEK arm holder where the NiTi arms are passivated with PEEK, according to some embodiments;

[0055] FIG. 35 shows x-ray images of gastric-only devices with a 1mm bend radius 36 days post implantation within the stomach of pigs, according to some embodiments. FIG. 35 also shows photographs of moisture indicators encapsulated within said devices after 36 days post transplantation, according to some embodiments;

[0056] FIG. 36 shows photographs of gastric-only devices with a bend radius of either 1.5 mm or 2.2 mm and repeated x-ray images of said devices over a 19 to 62 day period, according to some embodiments;

[0057] FIG. 37 shows an exemplary design iteration process for the gastric-only devices, according to some embodiments; FIG. 38 shows a series of CAD drawings illustrating an exemplary actuation of disassembly for the gastric-only devices contemplated herein, according to some embodiments;

[0058] FIG. 39 shows a series of CAD drawings illustrating an exemplary mechanism for the decoupling of the top port from the bottom port of the gastric-only devices as contemplated herein, according to some embodiments,

[0059] FIG. 40 shows a series of photographs and x-ray images demonstrating triggerable in vivo disassembly and passage of gastric-only devices after 2 days of residency in a pig stomach, according to some embodiments;

[0060] FIG. 41 also shows a series of photographs and x-ray images demonstrating triggerable in vivo disassembly and passage of additional gastric-only devices, as contemplated herein, after 2 days of residency in a pig stomach, according to some embodiments;

[0061] FIG. 42 shows a series of photographs and x-rays of evaluating device failures observed in exemplary gastric-only devices following in vivo delivery and subsequent retrieval, according to some embodiments;

[0062] FIG. 43 provides a summary of the number of in vivo retention studies and in vivo triggering studies included in the present disclosure;

[0063] FIG. 44 provides a plot of the study number as a function of the total number of days exemplary devices have been retained in pig stomachs, according to some embodiments;

[0064] FIG. 45a provides a table summarizing the arm coupling geometries tested, the number of arms employed, the arm lengths tested, whether or not the device passed through an animals stomach (or failed), and the number of days the intact device was retained in the gut of a test animal without failure, according to some embodiments;

[0065] FIG. 45b shows data of three independent in vivo studies of gastric residence; according to some embodiments;

[0066] FIG. 45c provides a table and plot summarizing the retention time of various article designs within a pig stomach, according to some embodiments; FIG. 46 provides CAD drawings, schematics, x-rays and endoscopic images demonstrating localization tracking from gastric retention to disassembly and passage, according to some embodiments;

[0067] FIG. 47 provides CAD drawings, schematics, and endoscopic images demonstrating the mechanical disassembly of the gastric-only devices, according to some embodiments;

[0068] FIG. 48a shows a series of photographs following (i) a sealed moisture test, (ii) a disassembly test, and (iii) a fatigue test, according to some embodiments;

[0069] FIGS. 48b shows results from a moisture ingress test of a sealed article, according to some embodiments;

[0070] FIGs. 49a and 49b show multiple plots of load versus time for various gastric devices, according to some embodiments;

[0071] FIG. 50 shows a decision tree used to evaluate the tethered system as well as exemplary x-ray images, endoscopic images, and photographs supporting decisions made at branch points, according to some embodiments.

[0072] FIG. 51 shows key design requirements for the payload chamber, according to some embodiments;

[0073] FIG. 52 illustrates the differences between tethered systems and gastric-only delivery systems, according to some embodiments;

[0074] FIG. 53a shows a cross-sectional diagram of the microwell within the payload chamber, according to some embodiments. FIG. 53b shows a gastric-only device sealed with a metal foil, according to some embodiments;

[0075] FIG. 54 shows key design requirements for maintaining payload stability within the pay load chamber, according to some embodiments;

[0076] FIG. 55a shows a plot of the percent cell viability of bacteria formulated with various species-specific materials, according to some embodiments; FIG. 55b shows the temporal dynamics of various formulations comprising bacteria over a 210-day period at 37°C, according to some embodiments;

[0077] FIG. 56a shows that enteric polymers can protect devices from acidic stimulated gastric fluid (SGF), according to some embodiments; FIG. 56b shows that bacterial- loaded capsules coated with enteric polymers have higher cell viability when exposed to SGF fluid for prolong times, according to some embodiments; FIG. 56c shows a representative setup used to test the permeability of chamber materials, according to some embodiments;

[0078] FIG. 57 shows the experimental validation progress of moisture vapor transmission rate (MVTR) on bacterial chamber performance, according to some embodiments;

[0079] FIG. 58a (top) shows a cross-section of an experimental set-up used to test the permeability of the chamber material, according to some embodiments; FIG. 58a (bottom) shows a plot of bacterial cell viability as a function of time for various chamber materials, according to some embodiments; FIG. 58b (let, top) shows a cross-section of an second experimental set-up used to test the permeability of the chamber material, according to some embodiments; FIG. 58b (left, bottom) shows a plot of bacterial cell viability as a function of time for polypropylene (PP) and fluorinated ethylene propylene (FEP), according to some embodiments; FIG. 58b (right) shows photographs of the metal seal at day 0 and day 10 for PP and FEP, according to some embodiments;

[0080] FIG. 59a shows a plot of the bacterial cell viability as a function of metal seal integrity at day 5 both in vitro and in vivo, according to some embodiments; FIG. 59b shows photographs of intact metal seals and exposed metal seals (e.g., broken), according to some embodiments; FIG. 59c shows devices at day 0 or day 5 after in vivo delivery, according to some embodiments;

[0081] FIG. 60a shows a series of photographs and CAD drawings for various stainless steal seal designs, according to some embodiments. FIG. 60b shows a plot of the percent bacterial viability as a function of the seal geometry at day 0 and day 11 at 37°C, according to some embodiments. FIG. 60c shows photographs illustrating placement of the devices in vivo, according to some embodiments;

[0082] FIG. 61 shows key design requirements for the release pay load, according to some embodiments;

[0083] FIG. 62a shows an illustration of the electrochemical reactions involved in the dissolution of gold when exposed to gastric fluid, according to some embodiments; FIG. 62b shows a computer automated drawing (CAD) illustrating an exemplary design integrating the gold membrane with MVP electronics via a PCB wrap-around to enable a current to be applied to the gold membrane, according to some embodiments. FIG. 62c shows the photographs of the final assembly of the exemplary device as described in FIG. 62b, according to some embodiments;

[0084] FIG. 63a shows a plot of current as a function of time for exemplary devices, according to some embodiments. FIG. 63b shows electrochemical dissolution of gold films sealed using a first sealing method, according to some embodiments. FIG. 63c shows electrochemical dissolution of gold films sealed using a second sealing method, according to some embodiments.

[0085] FIG. 64a shows a photograph of an exemplary device with a gold membrane anode and a platinum black cathode, according to some embodiments. FIG. 64b shows a plot of the total energy dissipated as a function of pH (left), a plot of the total dissolution time as a function of pH (middle), and the average dissolution current as a function of pH (right), according to some embodiments. FIG. 64c shows the DC driving voltages, measured energy, and dissolution time for gold membrane anodes and a gold chloride cathode, according to some embodiments.

[0086] FIG. 65a (top row) shows a series of graphics illustrating the experimental setup to test the release kinetics of bacteria following dissolution of the metal seal. FIG. 65b shows a plot of the release kinetics following dissolution of the metal seal versus a control sample over an 8 hour period, according to some embodiments.

[0087] FIG. 66 is a schematic diagram of an article, according to one set of embodiments.

[0088] FIG. 67 shows an exemplary implemented mutual authentication protocol, according to one set of embodiments.

[0089] FIG. 68 shows a comparison between wireless communication sources that are applicable to implantable electronics, according to one set of embodiments.

[0090] FIG. 69 shows a block diagram of an exemplary article, according to one set of embodiments.

[0091] FIG. 70 shows an exemplary BLE (Bluetooth Low Energy) timing diagram, according to one set of embodiments.

[0092] FIG. 71 shows an exemplary implemented mutual authentication process, according to one set of embodiments. FIG. 72 shows an exemplary arrangement of batteries inside a 000 capsule and corresponding battery capacity for ingestible electronics, according to one set of embodiments.

[0093] FIG. 73 shows an exemplary security-enhanced BLE communication using mobile BLE (mobile application) and capsule BLE (evaluation board), according to one set of embodiments.

[0094] FIG. 74 shows a flowchart of an exemplary Pseudo-Random Number Generator (PRNG), according to one set of embodiments.

[0095] FIG. 75 shows a BLE output measurement setup, according to one set of embodiments.

[0096] FIGs. 76A-76B shows measured BLE TX output signals, according to one set of embodiments: (a) detailed view of a single channel output (channel #37) and (b) the outputs of the entire BLE channels (channels #0 ~ #39) from 2.402 GHz to 2.48 GHz.

[0097] FIG. 77. shows a plot of draining current from the simulated BLE that was used for the characterization of battery lifetime, according to one set of embodiments.

[0098] FIG. 78 shows an exemplary wake-up receiver-based ingestible BLE system, according to one set of embodiments.

[0099] FIGs. 79A-79C show, (a) Die photo of the FBAR provided by Broadcom, (b) lumped circuit model, and (c) measured and model-based simulated impedance of the FBAR, according to one set of embodiments.

[0100] FIG. 80 shows an exemplary timing diagram of the wake-up data transmission with its duty-cycling scheme, according to one set of embodiments.

[0101] FIG. 81 shows an exemplary overall architecture of a wake-up Rx, according to one set of embodiments.

[0102] FIG. 82 shows time-domain simulation results of the wake-up Rx, according to one set of embodiments.

[0103] FIG. 83 shows the power breakdown of the wake-up Rx, according to one set of embodiments.

[0104] FIGs. 85-86 show images of a disassembled and assembled article, respectively, according to one set of embodiments.

[0105] FIGs. 87-89 show schematic illustrations and images of exemplary articles, according to some embodiments. FIGs. 90a-90b show an experimental setup and related results obtained from quantifying mechanical robustness of thin metal foils of an article, according to some embodiments.

[0106] FIG. 91 shows subcomponent testing for articles for in vivo evaluation, according to some embodiments.

[0107] FIG. 92a shows a test of in vivo robustness of a payload chamber device with integrated electronics according to some embodiments.

[0108] FIG. 92b shows a design of printed circuit board (PCB) integration into a 1- chamber device via a PCB “wrap-around” approach and results obtained with the device, according to some embodiments.

[0109] FIG. 93 shows results obtained from an article having a gold-SU8 sealing component, according to some embodiments.

[0110] FIG. 94 shows a device image for in vivo electrochemical gold dissolution of gold membrane (left) and a result summary (right).

[0111] FIG. 95 shows test conditions and result summary of testing two pre-treatment methods for the gold electrode.

[0112] FIG. 96 shows a summary of the characteristics of different metal membranes for ingestible therapeutic delivery.

[0113] Fig. 97 shows a first and second design for an electrical-integrated device for in vivo testing, according to some embodiments.

[0114] FIGs. 98-100 show results regarding the viability of bacterial tablets of the second design from Fig. 97 in the electronics bay after in vivo exposure for >10 days, according to some embodiments.

[0115] FIG. 101 shows a schematic diagram of the chamber of an article, according to some embodiments.

[0116] FIG. 102 shows the design of an article without a pogo pin holder, according to some embodiments.

[0117] FIG. 103 shows results related to device design to facilitate improved liquid resistance and module for gastric retention, according to some embodiments.

[0118] FIGs. 104a- 104b show results demonstrated wirelessly triggered release of a pay load from an article, according to some embodiments. FIGs. 105a- 105b show results demonstrated functioning of electronic components of articles at a location internal to the subject over a long time, according to some embodiments.

[0119] DETAILED DESCRIPTION

[0120] Aspects of the present disclosure relate to drug delivery articles and their methods of use. The drug delivery articles disclosed herein may be useful, for example, for delivering a therapeutic payload (e.g., a drug, a bacteria) to a location internal to a subject (e.g., stomach, an implant) in need thereof. In some embodiments, the drug delivery article comprises a reservoir body comprising a payload. In some embodiments, the payload is sealed within an interior volume at least partially defined by the reservoir body. In some such embodiments, the interior volume may further be defined by a sealing component, non-limiting examples of which include a metal layer, a ceramic layer (e.g., glass), a rubber gasket, and / or a propylene layer. In some embodiments, the payload is sealed within an opening of the reservoir body via a dissolvable metal layer. When the sealing component includes a metal layer, the metal layer may be triggered, in some embodiments, to dissolve, or at least partially dissolve, for example, by electrochemical dissolution. In some embodiments, dissolution or at least partial dissolution of the metal layer, permits delivery of the payload (e.g., a drug) to the location internal to the subject (e.g., stomach). Other aspects of the disclosure relate to methods for delivering a drug using the drug delivery articles disclosed herein.

[0121] The articles and methods described herein may be useful, for example, as a general platform for delivery of a wide variety of pharmaceutical agents that otherwise are generally delivered via injection directly into tissue due to degradation in the gastrointestinal (GI) tract. In some cases, the articles and methods may be configured to deliver therapeutic payloads at a desired location and / or at a desired time and / or over a desired duration to a subject.

[0122] Advantageously, in some embodiments, the articles and methods described herein may be useful as a general platform for delivery of a wide variety of therapeutic payloads (e.g., bacteria, therapeutic agents) that are typically delivered via injection directly into tissue due to degradation in the GI tract. For example, the article may be capable of localizing itself to a specified location (e.g., allowing loaded drugs to avoid long passages through the GI tract fluid before diffusing into the blood stream). This article, in some cases, may serve as a platform to allow therapeutic payloads and / or drugs that are currently degraded by the enzymes in the GI tract to be absorbed with higher bioavailability.

[0123] In some embodiments, a drug delivery article comprises a reservoir body. In some embodiments, a reservoir body can have any suitable shape known to the skilled artisan. Exemplary embodiments include, but are not limited to, circular, rectangular, triangular, or the like. In some embodiments, the drug delivery article may comprise any suitable number of reservoir bodies. For example in some embodiments the drug delivery article comprises two or more reservoir bodies. In some embodiments the drug delivery article comprises at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 20, at least 30, at least 40, at least 50, or at least 100 or more reservoir bodies.

[0124] In some embodiments, the reservoir body comprises a payload portion and an opening. According to some embodiments, the reservoir body may at least partially define an interior volume. The interior volume, in some embodiments, may comprise the payload portion. In some embodiments, a therapeutic payload (e.g., an active substance) is disposed within the payload portion. In some embodiments, the therapeutic payload may be any suitable therapeutic payload known to the skilled artisan. Exemplary therapeutic pay loads are described below.

[0125] According to some embodiments, the therapeutic payload comprises one or more therapeutics, diagnostics, and / or enhancement agents, such as drugs, nutrients, microorganisms, in vitro sensors, and tracers. In some embodiments, the active substance is a therapeutic, nutraceutical, prophylactic or diagnostic agent. In some embodiments, the therapeutic payload comprises one or more species of bacteria, virus, and / or fungi. In an exemplary set of embodiments, the therapeutic payload is a bacteria.

[0126] In some embodiments, each payload portion has a volume of greater than or equal to 1 pL, greater than or equal to 5 pL, greater than or equal to 10 pL, greater than or equal to 20 pL, greater than or equal to 30 pL, greater than or equal to 40 pL, and / or less than or equal to 50 pL, less than or equal to 60 pL, less than or equal to 70 pL, less than or equal to 80 pL, less than or equal to 90 pL, or less than or equal to 100 pL. Each reservoir of the plurality of sealable reservoirs may independently be sized and shaped with a particular dimension. In some embodiments, at least some of the reservoirs of the plurality of sealable reservoirs has a volume of greater than or equal to 1 pL, greater than or equal to 2 pL, greater than or equal to 3 pL, greater than or equal to 5 pL, greater than or equal to 10, pL, greater than or equal to 20 pL, greater than or equal to 30 pL, greater than or equal to 40 pL, greater than or equal to 50 pL, greater than or equal to 60 pL, greater than or equal to 70 pL, greater than or equal to 80 pL, greater than or equal to 90 pL, or greater than or equal to 100 pL, or greater than or equal to 250 pL. In some embodiments, at least some of the reservoirs of the plurality of sealable reservoirs has a volume of less than or equal to 250 pL, less than or equal to 100 pL, less than or equal to 90 pL, less than or equal to 80 pL, less than or equal to 70 pL, less than or equal to 60 pL, less than or equal to 50 pL, less than or equal to 40 pL, less than or equal to 30 pL, less than or equal to 20 pL, less than or equal to 10 pL, less than or equal to 5 pL, less than or equal to 3 pL, less than or equal to 2 pL, or less than or equal to 1 pL. Combinations of the above-referenced ranges are also possible (e.g., greater than or equal to 1 pL and less than or equal to 250 pL). Advantageously, a relatively small sized chamber (e.g., less than or equal to 5 pL may lower the power requirements of the system or device. Of course, other ranges are possible as this disclosure is not so limited. In some embodiments, some of the chambers of the plurality of chambers has a volume within the above-referenced ranges. In some embodiments, all of the chambers have a volume within the above-referenced ranges.

[0127] In some embodiments, each payload portion is adapted and designed to maintain therapeutic efficacy of the therapeutic payload for greater than or equal to 10 days under physiological conditions. In some embodiments, each payload portion is adapted and designed to maintain therapeutic efficacy of the therapeutic payload for greater than or equal to 60 days under physiological conditions. In some embodiments, each payload portion is adapted and designed to maintain therapeutic efficacy of the therapeutic payload for greater than or equal to 10 days, greater than or equal to 20 days, greater than or equal to 30 days, greater than or equal to 40 days, greater than or equal to 50 days, or greater than or equal to 60 days under physiological conditions. In some embodiments, each payload portion is adapted and designed to maintain therapeutic efficacy of the therapeutic payload for less than or equal to 60 days, less than or equal to 50 days, less than or equal to 40 days, less than or equal to 30 days, less than or equal to 20 days, or less than or equal to 10 days under physiological conditions.

[0128] In some embodiments, the payload portion comprises an opening. In some embodiments, the opening has a diameter of greater than or equal to 1 mm and less than or equal to 5 mm. In some embodiments, the opening has a diameter of greater than or equal to 1 greater than or equal to 2 mm, greater than or equal to 3 mm, greater than or equal to 4 mm, or greater than or equal to 5 mm. In some embodiments, the opening has a diameter of less than or equal to 5 mm, less than or equal to 4 mm, less than or equal to 3 mm, less than or equal to 2 mm, or less than or equal to 1 mm. Combinations of the foregoing ranges are possible. Other ranges are also possible.

[0129] According to some embodiments, the drug delivery article comprises a sealing component. In some embodiments, the sealing component is adjacent to the opening of the reservoir body such that the sealing component and the reservoir body fully define an interior volume therein, e.g., which may serve as a therapeutic payload. Non-limiting examples of suitable materials which the sealing component may comprise include a metal layer, a ceramic layer (e.g., glass), a rubber gasket, and / or a propylene layer. In some embodiments, the sealing component, or at least a portion thereof, may be electrically conductive (e.g., the sealing component comprises an electrically conductive materials). In some embodiments, the sealing component is configured and designed to be in electrical communication with one or more electrical components of the article. In an illustrative embodiment, the sealing component may comprise a metal layer (e.g., such as a dissolvable metal layer as described in more detail below) cut to a shape suitable for use as a seal (e.g., a chamber seal) as well as comprising a portion that extends (e.g., wraps around) at least a portion of the article (e.g., an internal surface) in electrical communication (e.g., electrical contact) with one or more internal electronics. In some such embodiments, the sealing component and / or metal layer advantageously acts as a power delivery interface.

[0130] In some embodiments, the sealing component comprises a metal seal, which in some cases may be a dissolvable metal seal. In some embodiments, the drug delivery article comprises a dissolvable metal layer. The dissolvable metal layer, according to some embodiments, is adjacent the opening of the reservoir body such that the dissolvable metal layer seals the payload portion loaded within the reservoir body. In some embodiments, the dissolvable metal layer is any suitable dissolvable metal layer known to the skilled artisan. In some embodiments, the dissolvable metal layer comprises a metal. The metal may be any suitable metal known to the skilled artisan. For example, in some embodiments, the dissolvable metal comprises a transition metal. In some embodiments the dissolvable metal comprises an alloy. As defined herein, an “alloy” refers to any metallic substance composed of two or more elements as either a compound or a solution. In some embodiments, the alloy comprises one or more of iron, manganese nickel, chromium, molybdenum, titanium, vanadium, tungsten, cobalt, and niobium. In some embodiments, the alloy may comprise additional elements, for example, including non-metallic elements.

[0131] In some embodiments, the dissolvable metal layer is selected from the group consisting of carbon steel, carbon steel coated in gold, and copper. In some embodiments, the dissolvable metal layer comprises gold. In some embodiments, the dissolvable metal layer comprises carbon steel. In some embodiments, the dissolvable metal layer comprises carbon steel coated in gold. In some embodiments, the dissolvable metal layer comprises copper.

[0132] In some embodiments, the dissolvable metal layer has a thickness of greater than or equal to 100 nm and less than or equal to 50 pm. In some embodiments the dissolvable metal layer has a thickness of greater than or equal to 100 nm, greater than or equal to 200 nm, greater than or equal to 300 nm, greater than or equal to 400 nm, greater than or equal to 500 nm, greater than or equal to 600 nm, greater than or equal to 700 nm, greater than or equal to 800 nm, greater than or equal to 900 nm, greater than or equal to 1 pm, greater than or equal to 10 pm, greater than or equal to 20 pm, greater than or equal to 30 pm, greater than or equal to 40 pm, or greater than or equal to 50 pm. In some embodiments, the dissolvable metal layer has a thickness of less than or equal to 50 pm, less than or equal to 40 pm, less than or equal to 30 pm, less than or equal to 20 pm, less than or equal to 10 pm, less than or equal to 1 pm, less than or equal to 900 nm, less than or equal to 800 nm, less than or equal to 700 nm, less than or equal to 600 nm, less than -500 nm, less than or equal to 400 nm, less than or equal to 300 nm, less than or equal to 200 nm, or less than or equal to 100 nm. According to some embodiments, the thickness of the metal layer may be selected such that the metal layer may be robust enough to maintain a mechanical separation between an interior volume of an article and an exterior of the volume. For instance, the metal layer may facilitate separation of a therapeutic payload within an article from a physiological medium external the article.

[0133] In some embodiments, the drug delivery articles, disclosed herein, further comprise a photoresist layer adjacent the metal layer. As used herein, when a component is referred to as being “on” or “adjacent” another component, it can be directly on or adjacent the component, or an intervening component also may be present. A component that is “directly on”, “directly adjacent” or “in contact with” another component means that no intervening component is present.

[0134] In some embodiments, articles comprising metal layers comprising carbon steel do not comprise said photoresist layer. In some embodiments, the photoresist layer comprises a photoresist mesh. In some embodiments, the photoresist layer has a thickness of greater than or equal to 10 pm and less than or equal to 100 pm. In some embodiments the photoresist layer has a thickness of greater than or equal to 10 pm, greater than or equal to 20 pm, greater than or equal to 30 pm, greater than or equal to 40 pm, greater than or equal to 50 pm, greater than or equal to 60 pm, greater than or equal to 70 pm, greater than or equal to 80 pm, greater than or equal to 90 pm, or greater than or equal to 100 pm. In some embodiments, the photoresist layer has a thickness of less than or equal to 100 pm, less than or equal to 90 pm, less than or equal to 80 pm, less than or equal to 70 pm, less than or equal to 60 pm, less than or equal to 50 pm, less than or equal to 40 pm, less than or equal to 30 pm, less than or equal to 20 pm, or less than or equal to 10 pm. Combinations are also possible in other embodiments. For example, in some embodiments the photoresist layer has a thickness of greater than or equal to 10 pm and less than or equal to 100 pm. Other combinations are also possible in other embodiments. In some embodiments, the photoresist layer may provide mechanical stability to the adjacent metal layer.

[0135] In some embodiments, the dissolvable metal layer and / or photoresist layer has a low permeability to water vapor and / or low pH fluids. In some embodiments, the dissolvable metal layer supports sealing of the reservoir body. In some embodiments, other components of the article may have a low permeability to water vapor. For instance, a reservoir, e.g., a pay load chamber, may have a low permeability to water vapor. In some instances, a low permeability to water may advantageously prevent exposure of components interior of an article to a fluid external to the article such as a physiological fluid.

[0136] In some embodiments, the drug delivery articles comprise one or more electronic components. In some embodiments, the one or more electronic component comprises a working electrode. The working electrode may be any suitable working electrode known to those of skill in the art. For example, in some embodiments, the working electrode comprises platinum black. In other embodiments, the working electrode comprises silver foil coated in silver / silver chloride.

[0137] In some embodiments, the one or more electronic component(s) comprises a power source. The power source may be any suitable power source known to one of skill in the art. In some embodiments, the one or more electronic component comprises a printed circuit board (PCB). The PCB may be any suitable PCB known to those of skill in the art. Other electronic components are also contemplated here, for example, receivers, ultrasonic sensors, and the like.

[0138] As will be apparent from the description throughout this disclosure, the articles and methods disclosed herein may include many variations of the above description, not limited to any particular type of electronic component (e.g., battery, power source, actuator such as an electrical actuation control system, microcontroller, PCB, wireless component, a central processor, a power management system, a system wakeup controller, electronic sensors such as temperature sensors and / or humidity sensors, etc.). In some embodiments, an electrical system may include one or more electronic components. In accordance with some embodiments, the articles described herein may be configured such that the electronic components (and / or electrical systems comprising one or more electronic components) thereof may remain electronically functional at a location internal to the subject. In some embodiments, electronic functionality comprises operating as intended while at the location internal to the subject, e.g., to monitor a parameter of the article, communicate to a location external to the subject, or the like. In some embodiments, the articles described herein may be configured to maintain electronic functionality for any of a variety of times for which the article may be located at a location internal to the subject. For instance, the article may be configured to be retained at a location internal to the subject (e.g., the stomach) for at least 30 days, at least 60 days, at least 90 days, at least 120 days, at least 150 days and / or up to 180 days, up to 210 days, up to 240 days, up to 264 days, up to 240 days, or up to 300 day while maintaining electronic functionality of an electrical system thereof.

[0139] In some embodiments, one or more of the electronic components described herein comprises a (micro)controller and / or (micro)processor. In some embodiments, the controller is configured (e.g., programmed) to receive and transmit data commands to / from one or more components of the component and / or the smartphone (or other consumer electronic device). In some embodiments, the data includes one or more signals from one or more sensors. In some embodiments, the controller may be configured to adjust various parameters based on external metrics e.g., in response to a signal from a sensor in electrical communication with the controller.

[0140] The embodiments described herein can be implemented in any of numerous ways. For example, the embodiments may be implemented by any suitable type of analog and / or digital circuitry. In some embodiments, the embodiments may be implemented using hardware or a combination of hardware and software. When implemented using software, suitable software code can be executed on processing circuitry including any suitable processor (e.g., a microprocessor) or collection of processors, whether provided in a single computer or distributed among multiple computers (or other consumer electronic devices). It should be appreciated that any component or collection of components that perform the functions described above can be generically considered as one or more controllers that control the above-discussed functions. The one or more controllers can be implemented in numerous ways, such as with dedicated hardware or with one or more processors programmed using microcode or software to perform the functions recited above. The one or more embodiments can be implemented in numerous ways, such as with dedicated hardware, or with general purpose hardware (e.g., one or more processors) that is programmed using microcode or software to perform the functions recited above.

[0141] In some embodiments, the embodiments described herein comprise wireless capabilities for enabling suitable communication with other devices / systems (e.g., for controlling aspects of the electronic component(s), controlling a source of electromagnetic radiation, controlling a sensor or other component). Wireless devices are generally known in the art and may include, in some cases, LTE, WiFi and / or Bluetooth systems. In some embodiments, the systems and / or devices described herein comprise such a wireless device (e.g., a short-range wireless component).

[0142] In some embodiments, the embodiments described herein may be configured to adjust various parameters in response to an input from a user and / or a signal from a sensor and / or an externally located consumer electronic device.

[0143] In some embodiments, the system is associated with and / or comprises a power source. The power source may include any appropriate material(s), such as one or more batteries, photovoltaic cells, etc. Non-limiting examples of suitable batteries include Li- polymer (e.g., with between 100 and 1000 mAh of battery life), Li-ion, nickel cadmium, nickel metal hydride, silver oxide, or the like. In some cases, the battery may apply a voltage (e.g., to a degradable material as described herein) in response to a physiological and / or external metric and / or signal (e.g., by a user). For example, the voltage may be used to trigger the dissolution of a layer by e.g., applying a voltage to a degradable component as described herein. For example, the average magnitude of the voltage applied to the degradable component(s) may be between 0.001 to 0.01 V, between 0.01 to 0.1 V, between 0.1 V and 10.0 V, between 1.0 V and 8.0 V, between 2.0 V and 5.0 V, between 0.1 V and 5.0 V, between 0.1 V and 1.5 V, between 0.1 V and 1.0 V, between 1.0 V and 3.0 V, between 3.0 V and 8.0 V, or any other appropriate range.

[0144] Any electronic component circuitry may be implemented by any suitable type of analog and / or digital circuitry. For example, the electronic component circuitry may be implemented using hardware or a combination of hardware and software. When implemented using software, suitable software code can be executed on any suitable processor (e.g., a microprocessor) or collection of processors. The one or more electronic components can be implemented in numerous ways, such as with dedicated hardware, or with general purpose hardware (e.g., one or more processors) that is programmed using microcode or software to perform the functions recited above.

[0145] In this respect, it should be appreciated that one implementation of the embodiments described herein comprises at least one computer-readable storage medium (e.g., RAM, ROM, EEPROM, flash memory or other memory technology, or other tangible, non-transitory computer-readable storage medium) encoded with a computer program (i.e., a plurality of executable instructions) that, when executed on one or more processors, performs the above-discussed functions of one or more embodiments. In addition, it should be appreciated that the reference to a computer program which, when executed, performs any of the above-discussed functions, is not limited to an application program running on a host computer. Rather, the terms computer program and software are used herein in a generic sense to reference any type of computer code (e.g., application software, firmware, microcode, or any other form of computer instruction) that can be employed to program one or more processors to implement aspects of the techniques discussed herein.

[0146] In some embodiments, the one or more electronic components are in electrical communication another component of the drug delivery article. For example, in some embodiments, the working electrode is in electrical communication with the metal layer. In some embodiments, the power source is in electrical communication with the metal layer. In some embodiments, the power source is electrical communication with the working electrode.

[0147] In some embodiments, the drug delivery articles disclosed herein further comprise a conductive epoxy. In some embodiments, the conductive epoxy is any suitable conductive epoxy to the skilled artisan. In some embodiments, the drug delivery articles comprise a conductive epoxy adjacent one or more electronic components. In some embodiments, the drug delivery articles disclosed herein further comprise an encapsulation epoxy. In some embodiments, the encapsulation epoxy is any suitable encapsulation epoxy to the skilled artisan. In some embodiments, the drug delivery articles comprise an encapsulation epoxy adjacent one or more electronic components.

[0148] In some embodiments, the drug delivery article further comprises an antenna associated with the one or more electronic components. In some embodiments, the antenna associated with the one or more electronic components is configured to receive a wireless signal. In some embodiments, upon receipt of the wireless signal, the electronic component triggers the dissolution of the metal layer such that the dissolvable metal layer at least partially dissolves. For example, in some embodiments, receipt of a wireless signal triggers the power supply to apply a voltage to the metal layer, thus triggering the electrochemical dissolution, or partial dissolution, of the dissolvable metal layer. In some embodiments, electronic component triggers the release of the therapeutic payload. In some embodiments, the electrical component triggers between 30% and 100% dissolution of the dissolvable metal layer. In some embodiments, the electrical component triggers greater than or equal to 30%, greater than or equal to 40%, greater than or equal to 50%, greater than or equal to 60%, greater than or equal to 70%, greater than or equal to 80%, greater than or equal to 90%, or greater than or equal to 100% dissolution of the dissolvable metal layer. In some embodiments, the electrical component triggers less than or equal to 100%, less than or equal to 90%, less than or equal to 80%, less than or equal to 70%, less than or equal to 60%, less than or equal to 50%, less than or equal to 40%, or less than or equal to 30% dissolution of the dissolvable metal layer.

[0149] In some embodiments, the one or more electronic components are connected to the drug delivery article using one or more techniques known to those skilled in the art. For example, in some embodiments the one or more electronic components are mechanically pressfit into the drug delivery article. In other embodiments, the one or more electronic components are connected to the drug delivery article using a bonding method. In some embodiments the bonding method is any suitable bonding method known to those of skill in the art. For example, in some embodiments the bonding method comprises chip bonding. In other embodiments, the bonding method comprises wire-tacking adhesives. In some embodiments, the bonding method comprises potting an encapsulation. Without wishing to be bound by any particular theory, potting is a method known in the art that comprises the filling small spaces or services with the material that will protect components from physical and environmental damage. Typical resins used for potting are epoxies, all your things, silicones, and accolades, the latter usually being UV-curing formulations. In some embodiments, encapsulation comprises casting and / or molding electronic component using similar resins as described above. In some embodiments, the bonding method uses an adhesive. In some embodiments, the adhesive comprises an electrically conductive adhesives, a thermally conductive adhesives, or an ultraviolet curing adhesives. Other adhesives are also contemplated in other embodiments, for example, cyanoacrylates, silicone resins, and polyimides.

[0150] In some embodiments, the one or more electronic components trigger dissolution of the dissolvable metal layer (e.g., that seals the payload portion). For example, in some embodiments, an actuator may be present to provide energy (e.g., thermal energy, radiation, electrical energy, etc.) to facilitate dissolution of the metal layer. In some embodiments, an actuator may be configured to directly provide energy internal of an article to a sealing component, e.g., to facilitate removal of at least a portion of the sealing component. A non-limiting example includes providing electrical energy from a power source to a working electrode to dissolve at least a portion of a sealing component comprising a metal layer. In some embodiments, an external system may be present external of the article and may provide energy to an interface, whereafter the energy is transferred to a sealing component, e.g., to facilitate removal of at least a portion of the sealing component. For instance, upon application of a voltage from the power source (e.g., electronic component) to the metal layer the metal layer degrades such that the dissolvable metal layer at least partially dissolves. In some embodiments, at least partial dissolution of the metal layer may expose an interior volume of the article to a fluid external of the article. In some such embodiments, a therapeutic agent contained within the article may be exposed to a fluid external the article. In some embodiments, at least partial dissolution of the metal layer may result in the metal layer being more fragile (e.g., due to a smaller thickness), which may facilitate mechanical breakdown and release of a therapeutic payload from the article. In some embodiments, the dissolution of the dissolvable metal comprises between 100 mJ and 10 J of power. In some embodiments, the dissolution of the dissolvable metal comprises greater than or equal to 100 mJ, greater than or equal to 500 mJ, greater than or equal to 1 J, greater than or equal to 2 J, greater than or equal to 5 J, greater than or equal to 4 J, greater than or equal to 5 J, greater than or equal to 6 J, greater than or equal to 7 J, greater than or equal to 8 J, greater than or equal to 9 J, or greater than or equal to 10 J of power. In some embodiments the dissolution of the dissolvable metal comprises less than or equal to 10 J, less than or equal to 9 J, less than or equal to 8 J, less than or equal to 7 J, less than or equal to 6 J, less than or equal to 5 J, less than or equal to 4 J, less than or equal to 3 J, less than or equal to 2 J, less than or equal to 1 J, less than or equal to 500 mJ, or less than or equal to 100 mJ of power.

[0151] In some embodiments, the dissolution of the dissolvable metal comprises less than or equal to 10 J of power. In other embodiments, the dissolution of the dissolvable metal comprises less than or equal to 1 J of power. In other embodiments still, the dissolution of the dissolvable metal comprises less than or equal to 100 mJ of power. In some embodiments, the voltage supplied from the power source (e.g., electronic component) is greater than or equal to 1 V and less than or equal to 2 V. In some embodiments, the supplied voltage is greater than or equal to 1 V, greater than or equal to 1.1 V, greater than or equal to 1.2 V, greater than or equal to 1.3 V, greater than or equal to 1.4 V, greater than or equal to 1.5 V, greater than or equal to 1.6 V, greater than or equal to 1.7 V, greater than or equal to 1.8 V, greater than or equal to 1.9 V, or greater than or equal to 2 V. In some embodiments, the supplied voltage is less than or equal to 2V, less than or equal to 1.9 V, less than or equal to 1.8 V, less than or equal to 1.7 V, less than or equal to 1.6 V, less than or equal to 1.5V, less than or equal to 1.4 V, less than or equal to 1.3 V, less than or equal to 1.2 V, less than or equal to 1.1 V, or less than or equal to 1 V.

[0152] As described below and elsewhere herein, application of a voltage by the power supply to the dissolvable metal layer triggers dissolution of the dissolvable metal layer such that the therapeutic payload within the reservoir body is free to diffuse out of the reservoir body. In some embodiments, release of the therapeutic payload occurs within less than or equal to 6 hours after application of the voltage from the power source. In some embodiments, release of the therapeutic payload occurs within less than or equal to 6 hours, less than or equal to 5 hours, less than or equal to 4 hours, less than or equal to 3 hours, less than or equal to 2 hours, less than or equal to 1 hour, less than or equal to 45 minutes, less than or equal to 30 minutes, less than or equal to 15 minutes or less than or equal to 10 minutes after application of the voltage from the power supply.

[0153] Other aspects of the present disclosure generally relate to methods using any one of the drug delivery articles disclosed herein. In some embodiments, the methods relate to delivery of a drug to a subject in need thereof, using any one of the drug delivery articles disclosed herein. Accordingly, in some embodiments, the methods comprise administering to a subject a drug delivery article. As described below and elsewhere herein, the drug delivery articles, according to some embodiments, comprise a reservoir body. In some embodiments the reservoir body comprises a pay load portion, an opening, and a dissolvable metal layer adjacent the opening.

[0154] In some embodiments, the methods comprise administering the drug delivery article to a subject (e.g., orally). In certain embodiments, the drug delivery article may be administered surgically (e.g., implanted), orally, rectally, vaginally, nasally, or uretherally. In certain embodiments, the drug delivery article is administered such that at least a portion of the system resides at a location internal to the subject (e.g., the gastrointestinal tract). In some embodiments, the location internally of the subject is the colon, the duodenum, the ileum, the jejunum, the stomach, or the esophagus.

[0155] In some embodiments, the methods comprise applying a voltage to the dissolvable metal layer. In some embodiments, the voltage applied (e.g., by an electronic component such as a power supply) is greater than or equal to 1 V and less than or equal to 2 V. In some embodiments, the supplied voltage is greater than or equal to 1 V, greater than or equal to 1.1 V, greater than or equal to 1.2 V, greater than or equal to 1.3 V, greater than or equal to 1.4 V, greater than or equal to 1.5 V, greater than or equal to 1.6 V, greater than or equal to 1.7 V, greater than or equal to 1.8 V, greater than or equal to 1.9 V, or greater than or equal to 2 V. In some embodiments, the voltage applied is less than or equal to 2V, less than or equal to 1.9 V, less than or equal to 1.8 V, less than or equal to 1.7 V, less than or equal to 1.6 V, less than or equal to 1.5V, less than or equal to 1.4 V, less than or equal to 1.3 V, less than or equal to 1.2 V, less than or equal to 1.1 V, or less than or equal to 1 V.

[0156] In some embodiments, applying a voltage to the dissolvable metal layer results in dissolution, or at least partial dissolution, of the dissolvable metal layer. In some embodiments, between 30% and 100% of the dissolvable metal layer is dissolved. In some embodiments, greater than or equal to 30%, greater than or equal to 40%, greater than or equal to 50%, greater than or equal to 60%, greater than or equal to 70%, greater than or equal to 80%, greater than or equal to 90%, or greater than or equal to 100% of the dissolvable metal layer is dissolved following application of said voltage. In some embodiments, less than or equal to 100%, less than or equal to 90%, less than or equal to 80%, less than or equal to 70%, less than or equal to 60%, less than or equal to 50%, less than or equal to 40%, or less than or equal to 30% of the dissolvable metal layer is dissolved following application of said voltage.

[0157] In some embodiments, dissolving the dissolvable metal layer releases the contents of the payload portion to location internal to the subject (e.g., colon, the duodenum, the ileum, the jejunum, the stomach, or the esophagus). The payload portion, according to some embodiments, comprises a therapeutic payload (e.g., an active substance). Accordingly, in some embodiments, the articles and methods described herein are compatible with one or more therapeutic, diagnostic, and / or enhancement agents, such as drugs, nutrients, microorganisms, in vitro sensors, and tracers. In some embodiments, the active substance, is a therapeutic, nutraceutical, prophylactic or diagnostic agent.

[0158] Agents can include, but are not limited to, any synthetic or naturally-occurring biologically active compound or composition of matter which, when administered to a subject (e.g., a human or nonhuman animal), induces a desired pharmacologic, immunogenic, and / or physiologic effect by local and / or systemic action. For example, useful or potentially useful within the context of certain embodiments are compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals, Certain such agents may include molecules such as proteins, peptides, hormones, nucleic acids, gene constructs, etc., for use in therapeutic, diagnostic, and / or enhancement areas, including, but not limited to medical or veterinary treatment, prevention, diagnosis, and / or mitigation of disease or illness.

[0159] In some embodiments, the therapeutic payload comprises a microorganism such as bacteria (e.g., engineered bacteria).

[0160] In certain embodiments, the active substance is one or more specific therapeutic agents. As used herein, the term “therapeutic agent” or also referred to as a “drug” refers to an agent that is administered to a subject to treat a disease, disorder, or other clinically recognized condition, or for prophylactic purposes, and has a clinically significant effect on the body of the subject to treat and / or prevent the disease, disorder, or condition. Listings of examples of known therapeutic agents can be found, for example, in the United States Pharmacopeia (USP), Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10th Ed., McGraw Hill, 2001; Katzung, B. (ed.) Basic and Clinical Pharmacology, McGraw-Hill / Appleton & Lange; 8th edition (September 21, 2000); Physician’s Desk Reference (Thomson Publishing), and / or The Merck Manual of Diagnosis and Therapy, 17th ed. (1999), or the 18th ed (2006) following its publication, Mark H. Beers and Robert Berkow (eds.), Merck Publishing Group, or, in the case of animals, The Merck Veterinary Manual, 9th ed., Kahn, C.A. (ed.), Merck Publishing Group, 2005; and “Approved Drug Products with Therapeutic Equivalence and Evaluations," published by the United States Food and Drug Administration (F.D.A.) (the “Orange Book"). Examples of drugs approved for human use are listed by the FDA under 21 C.F.R. §§ 330.5, 331 through 361, and 440 through 460, incorporated herein by reference; drugs for veterinary use are listed by the FDA under 21 C.F.R. §§ 500 through 589, incorporated herein by reference. In certain embodiments, the therapeutic agent is a small molecule. Exemplary classes of therapeutic agents include, but are not limited to, analgesics, anti-analgesics, anti-inflammatory drugs, antipyretics, antidepressants, antiepileptics, antipsychotic agents, neuroprotective agents, anti-proliferatives, such as anti-cancer agents, antihistamines, antimigraine drugs, hormones, prostaglandins, antimicrobials (including antibiotics, antifungals, antivirals, antiparasitics), antimuscarinics, anxioltyics, bacteriostatics, immunosuppressant agents, sedatives, hypnotics, antipsychotics, bronchodilators, anti-asthma drugs, cardiovascular drugs, anesthetics, anti-coagulants, inhibitors of an enzyme, steroidal agents, steroidal or nonsteroidal anti-inflammatory agents, corticosteroids, dopaminergics, electrolytes, gastrointestinal drugs, muscle relaxants, nutritional agents, vitamins, parasympathomimetics, stimulants, anorectics and anti-narcoleptics. Nutraceuticals can also be incorporated into the drug delivery device. These may be vitamins, supplements such as calcium or biotin, or natural ingredients such as plant extracts or phytohormones.

[0161] In other embodiments, the active substance is a protein or other biological macromolecule.

[0162] In some embodiments, the therapeutic agent is a small molecule drug having molecular weight less than about 2500 Daltons, less than about 2000 Daltons, less than about 1500 Daltons, less than about 1000 Daltons, less than about 750 Daltons, less than about 500 Daltons, less or than about 400 Daltons. In some cases, the therapeutic agent is a small molecule drug having molecular weight between 200 Daltons and 400 Daltons, between 400 Daltons and 1000 Daltons, or between 500 Daltons and 2500 Daltons.

[0163] In some embodiments, the therapeutic agent is selected from the group consisting of active pharmaceutical agents such as insulin, nucleic acids, peptides, bacteriophage, DNA, mRNA, human growth hormone, monoclonal antibodies, adalimumab, epinephrine, GLP-1 Receptor agoinists, semaglutide, liraglutide, dulaglitide, exenatide, factor VIII, small molecule drugs, progrstin, vaccines

[0164] In certain embodiments, the therapeutic pay load may be released with a pulse release profile. For example, in some embodiments, the therapeutic payload may be released on the first day after administration and during another 24 hour period such as starting during the third day, the fourth day, or the fifth day, but is not substantially released on other days. Those skilled in the art would understand that other days and / or combinations of pulsing and continuous release are also possible.

[0165] The therapeutic payload may be released at a relatively constant average rate (e.g., a substantially zero-order average release rate) over a time period of at least about 24 hours. In certain embodiments, the therapeutic payload is released at a first-order release rate (e.g., the rate of release of the therapeutic payload is generally proportional to the concentration of the therapeutic payload) of a time period of at least about 24 hours.

[0166] In some embodiments, at least a portion of the therapeutic payload loaded into the structure is released continuously (e.g., at varying rates) over the residence time period of the structure. Residence time periods are described in more detail, below.

[0167] The bacteria, whether naturally occurring or genetically modified, may undergo one or more chemical and / or biological reactions when exposed to a particular biomarker (or if the particular is removed or is not present), which may subsequently result in additional chemical and / or biological reactions.

[0168] In various embodiments, the therapeutic payload comprises Escherichia coli (e.g., E. coli, E. coli Nissle 1917 (EcN)). In some embodiments, the bacteria may be suitable as a bacterial biosensor as described in International Patent Application No. PCT / US2022 / 026406 filed on April 26, 2022, which is herein incorporated by reference in its entirety. For example, various embodiments comprise a biosensor for detecting the presence (or absence) of a chemical and / or biological species, such a biomolecule or a biomarker. In some embodiments, the biosensor is a bacterial biosensor comprising one or more bacteria, wherein the bacteria can detect the presence (or absence) of one or more chemical and / or biological species (e.g., biomarkers). In some embodiments, the bacteria comprise bioengineered bacteria, wherein the bacteria has been genetically modified (e.g., plasmid insertion) to detect the presence (or absence) of one or more chemical and / or biological species. The bacteria, whether naturally occurring or genetically modified, may undergo one or more chemical and / or biological reactions when exposed to a particular biomarker (or if the particular is removed or is not present), which may subsequently result in additional chemical and / or biological reactions. In some embodiments, the presence of a biomarker (e.g., nitric oxide, NO) may cause a first chemical and / or biological reaction. In some embodiments, the presence of the biomarker may cause the first chemical and / or biological reaction to produce a species involved in a second chemical and / or biological reaction. In some such embodiments, the second chemical and / or biological reaction includes a regulatory molecule (e.g., a protein / peptide) involved in the regulation of DNA and / or RNA, such as a promotor. In some such embodiments, the regulatory molecule may be produced from the first and / or second chemical and / or biological reaction and may then bind to a promotor to initiate transcription. This may result in the production of a specific enzyme, which may, in some cases, facilitate the generation of a signal within the bacteria.

[0169] By way of example, the first chemical and / or biological reaction can be a first biological reaction (e.g., provided to the bacteria by a plasmid) in which NO is the biomarker. The NO may bind or react with a species characteristic of the first biological reaction to produce a regulatory molecule, such as a promoter. The promoter may activate a second chemical and / or biological reaction, such as a second biological reaction, which may subsequently generate a signal, for example by activating (or deactivating) a biolumine scent molecule (e.g., green fluorescent protein, GFP). Of course, other biomarkers and chemical and / or biological reactions are possible and are described elsewhere herein.

[0170] The bacterial biosensors may be configured, in some cases, to detect a variety of biomolecules or biomarkers. In some embodiments, the bacterial biosensors are configured to detect NO. In some embodiments, the bacterial biosensors are configured to detect reactive oxygen species (ROS), such as peroxides, hydroxyl radicals, and / or superoxide. In some embodiments, the bacterial biosensors are configured to detect thiosulfate and / or tetrathionate. Other species the bacterial biosensors may be configured to detect include, but are not limited to, inflammatory markers, proteins, DNA, RNA, hormones, chemical analytes, or the like.

[0171] In some embodiments, a plurality of bacterial and / or enzymatic biosensors are configured for non-blood-based detection of a gastrointestinal inflammatory process and / or disease state of the subject. However, in some embodiments, one or more biosensors may be configured to detect one or more components or blood and / or serum.

[0172] Advantageously, the devices described herein may be configured to detect two or more different biomolecules and / or biomarkers. For example, in an illustrative set of embodiments, the detection of a single biomolecule by a first biosensor may indicate a first disease state of the subject. In some embodiments, the detection of two different biomolecules by two different biosensors may indicate a second disease state, different than the first disease state, of the subject. In some embodiments, the plurality of sealable chambers, biosensors, and photodetectors advantageously provide a combinatorial approach to disease detection and monitoring in a subject. For example, different combinations of positive results (e.g., a detectable signal produced by a biosensor) by different biosensors may be correlated with different diseases and / or disease states.

[0173] In an exemplary illustration of the above noted detection, in some embodiments, a first detectable signal produced by a first biosensor corresponds to a first disease state. In some embodiments, a second detectable signal produced by a second biosensor (different than the first biosensor) corresponds to a second disease state, different than the first disease state. In some embodiments, the presence of the first detectable signal and the second detectable signal corresponds to a third disease state, different than the first disease state and the second disease state. In some embodiments, the presence of a third detectable signal produced by a third biosensor corresponds for a fourth disease state. In some embodiments, the presence of the first detectable signal and / or the second detectable signal and the third detectable signal corresponds to a fifth disease state. Other combinations and diseases / disease states are also possible.

[0174] A variety of suitable bacteria may be suitable for bacterial biosensors. In various embodiments, the bacterial biosensor comprises Escherichia coli (e.g., E. coli, E. coli Nissle 1917 (EcN)). However, other bacteria may be suitable for the bacterial biosensors. Non-limiting examples of other suitable bacteria include Bacteroidetes, Firmicutes, Actinobacteria, Proteobacteria. Other bacteria are possible as this disclosure is not so limited.

[0175] In some embodiments, the biosensor may comprise yeast, such as Saccharomyces cerevisiae (such as S. cerevisiae boulardii ) and / or other endogenous fungi, (e.g Candida albicans), without limitation. Other yeast are possible.

[0176] In some embodiments, one or more biosensors comprises an enzymatic biosensor or a non-enzymatic biosensor. An enzymatic biosensor may comprise an enzyme that recognizes a biomarker to produce an output that can be sensed by the electronic component of the device. In some embodiments, output comprises a signal generated through: 1) the enzymatic conversion of the biomarker into a new product; 2) biomarker- mediated inhibition or activation of the enzyme; or 3) biomarker-mediated modification of enzyme properties. By contrast, a non-enzymatic biosensor does not require interaction between an enzyme and a biomarker. For example, in some embodiments, a non-enzymatic biosensor may comprise a protein channel that facilitates signal flow (or output) when in the presence of an particular biomarker. In some embodiments, a non- enzymatic biosensor comprises an antibody or a binding protein that recognizes the presence of a biomarker. In some embodiments, the non-enzymatic biosensor comprises a nucleic acid that hybridizes to an analyte or otherwise binds to it (e.g., as an aptamer). In some embodiments, the non-enzymatic biosensor comprises of a transcription factor that alters gene expression upon binding to an analyte.

[0177] In some embodiments, the biosensors (e.g., bacterial biosensors) are configured to generate a luminescent signal, such a bioluminescent signal. Advantageously, a bioluminescent signal may be encoded into the biosensor so that light (or the absence thereof) may indicate the presence (or absence) of a biomarker detected by the biosensor.

[0178] In some embodiments, the bacteria is thetherapeutic payload.

[0179] In some embodiments, the therapeutic payload may comprise yeast, such as Saccharomyces cerevisiae (such as S. cerevisiae boulardii ) and / or other endogenous fungi, (e.g Candida albicans), without limitation. Other yeast are possible.

[0180] The term “subject," as used herein, refers to an individual organism such as a human or an animal. In some embodiments, the subject is a mammal ( e.g., , a human, a non-human primate, or a non-human mammal), a vertebrate, a laboratory animal, a domesticated animal, an agricultural animal, or a companion animal. In some embodiments, the subject is a human. In some embodiments, the subject is a rodent, a mouse, a rat, a hamster, a rabbit, a dog, a cat, a cow, a goat, a sheep, or a pig.

[0181] As used herein, a “fluid” is given its ordinary meaning, i.e., a liquid or a gas. A fluid cannot maintain a defined shape and will flow during an observable time frame to fill the container in which it is put. Thus, the fluid may have any suitable viscosity that permits flow. If two or more fluids are present, each fluid may be independently selected among essentially any fluids (liquids, gases, and the like) by those of ordinary skill in the art. Aspects of the present disclosure relate to articles configured for triggerable gastric release. In some embodiments, the articles comprise a capsule and one or more retention arms configured to retain the capsule at a location internal to a subject for a period of time. In some embodiments, the capsule further comprises a therapeutic payload that may be delivered after retention at the desired location. Dissociation of the one or more retention arms, via a triggered release mechanism, from the capsule body permits disassembly of the articles and permits removal of the articles from the subject through the gastrointestinal tract, according to some embodiments.

[0182] The articles described herein may be useful, for example, as a general platform for delivery of a wide variety of pharmaceutical agents that otherwise are generally delivered via injection directly into tissue due to degradation in the GI tract. In some cases, the article may be configured to deliver therapeutic pay loads at a desired location and / or at a desired time and / or over a desired duration to a subject.

[0183] Advantageously, in some embodiments, the articles described herein may be useful as a general platform for delivery of a wide variety of therapeutic payloads (e.g., bacteria, therapeutic agents) that are typically delivered via injection directly into tissue due to degradation in the GI tract. For example, the article may be capable of localizing itself to a specified location (e.g., allowing loaded drugs to avoid long passages through the GI tract fluid before diffusing into the blood stream). This article, in some cases, may serve as a platform to allow therapeutic payloads and / or drugs that are currently degraded by the enzymes in the GI tract to be absorbed with higher bioavailability.

[0184] The articles described herein can be useful, for example, in achieving gastric residence and / or slowed transit via oral administration for extended in vivo residence and administration of therapeutic, diagnostic, and / or enhancement agents. Certain embodiments of the articles described herein may offer certain advantages as compared to traditional articles configured for internal retention and / or drug release, for example, in their ability to adopt a shape and / or size small enough to be ingested by a subject; adopt a shape and / or size internally that slows or prevents further transit in a body cavity (e.g., the gastric cavity) (e.g., passage from the body of the stomach through the pylorus;) be loaded at high levels (e.g., high mass fraction) with therapeutic, diagnostic, and / or enhancement agents; facilitate controlled release of such therapeutic, diagnostic, and / or enhancement agents with low to no potential for burst release; maintain activity / stability of such therapeutic, diagnostic, and / or enhancement agents in a hostile environment such as the gastric environment for an extended duration; maintain safety with low to no potential for gastric or intestinal obstruction and / or perforation; and / or degrade / dissolve / disassociate into one or more forms configured for passing through a gastrointestinal tract. In certain embodiments, the articles described herein can be configured with durable residence times greater than at least twenty-four hours and lasting up to about one year, or more. In some embodiments, the articles described herein are compatible with subjects, including, but not limited to, humans and nonhuman animals. In further embodiments, articles can be configured to deliver a wide variety of therapeutic, diagnostic, and / or enhancement agents, thus potentially increasing and even maximizing patient treatment therapy adherence rates.

[0185] Aspects of the present disclosure generally relate to an article configured for triggerable gastric exit. In some embodiments the article comprises a capsule. In some embodiments, the capsule comprises a releasable cap. In some embodiments, the releasable cap comprises one or more coupling components.

[0186] In some embodiments, the article comprises one or more retention arms. In some embodiments, each retention arm is mechanically coupled to the capsule via the one or more coupling components.

[0187] In one set of embodiments, a shape of at least one of the one or more retention arms comprises a three-dimensional ring structure (i.e., an elliptical outline when projected onto a flat surface). In some embodiments, the ring structure is circular. In some embodiments, the ring structure is elliptical. In some such embodiments, the elliptical ring structure has a minor axis diameter comparable to the major axis of a capsule. In some embodiments, the ring structure comprises an elastic polymeric component and one or more linkers capable of controlled degradation attached to and / or incorporated into the ring structure. In some embodiments, one or more linkers are incorporated into the elliptical ring structure at one or more points along the minor axis. In some embodiments, one or more controlled degradation linkers are incorporated into the ring structure at one or more points along the major axis. According to some embodiments, the elliptical ring structure may be twisted into a form similar to a double helix for packing into a soluble container and / or binding with a retention element of the article. In some embodiments, the elliptical ring structure is twisted such that the axis of the helix is along the minor axis of the elliptical ring structure to avoid bending the helix to pack it into a soluble container. In accordance with some embodiments, following ingestion of an article comprising a twisted ring structure by a subject, the ring structure may expand such that at least one dimension is of similar size and / or is larger than the pylorus of the subject. Such expansion of the ring structure, in some embodiments, may facilitate retention of the article by the subject. According to some embodiments, portions of the ring structure may be degradable, which may facilitate eventual release of the article from the location internal to the subject. Further details regarding certain ring structures for retention of articles internal to a subject can be found in U.S. Patent No. 10,182,985, which is herein incorporated by reference in its entirety for all purposes.

[0188] In some embodiments, the article comprises a spring disposed within the cap (e.g., a coil spring, wave springs, Belleville washers, a beam, a membrane, a material having particular mechanical recovery characteristics). Those of ordinary skill in the art would understand that the term spring is not intended to be limited to coil springs, but generally encompass any reversibly compressive material and / or component which, after releasing an applied force on the material / component, the material / component substantially returns to an uncompressed length of the material / component under ambient conditions (e.g., within 40%, within 50%, within 60%, within 70%, within 80%, within 90%, within 95%, or any percentage in between, of the length of the material / component prior to compression). For example, as would be understood by those of ordinary skill in the art based upon the teachings of this specification, a spring as described herein may be a component that comprises a material and / or structure that has a particular shape and / or configuration, such that the component bends, twists, compresses, and / or expands in response to an applied force and, upon removal of said applied force, substantially returns to the former shape and / or configuration. In some embodiments, the spring is configured to be compressed and, upon dissolution of a degradable component, eject the cap. In some embodiments, the spring is configured to compress in response to an external force applied to the spring. In some embodiments, the spring is maintained in an at least partially compressed state (e.g., by the cap).

[0189] In certain embodiments, the term spring may be provided as, or further comprise, an expanding component. Those of ordinary skill in the art would understand the term extending component comprises reversibly and irreversibly compressive materials and are components which, upon stimulating and / or releasing a restraint on the expanding component, the expanding component extends in at least one direction (e.g., along its length). In some embodiments, the expanding component comprises a gaseous composition(s) for expanding the gaseous volume expanding component (e.g., a mixture of baking soda and vinegar).

[0190] In some embodiments, the spring and / or expanding component may extend in at least one direction via thermal expansion, swelling (e.g., due to fluid absorption), a gas driven process, a pneumatic process, a hydraulic process, an electrical motor, a magnetic mechanism, a torsional spring mechanism, a chemical gas generator, and / or an selfcatalyzing reaction. In an exemplary set of embodiments, the spring and / or expanding component may extend in at least one direction upon exposure of the spring and / or expanding component to a fluid (e.g., gastrointestinal fluid).

[0191] In some cases, the spring and / or the expanding component may be activated (e.g., extended in at least one direction, returns to an uncompressed length of the component) by any suitable activation mechanism. Non-limiting examples of suitable activation mechanisms include release of a pressure difference, electrical timer, light sensor, color sensor, enzymatic sensor, capacitance, magnetism, activation by applied stress (e.g., shape memory materials), external activation (e.g., applied magnetic field, applied light, reaction with gastrointestinal fluid such as stomach acid), and combinations thereof. In an exemplary set of embodiments, the spring and / or expanding component are activated by interaction (e.g., reaction) with a gastrointestinal fluid.

[0192] In some embodiments, the article comprises a degradable component associated with the spring, such that upon degradation of the degradable component, the spring ejects the from the capsule and the one or more retention arms dissociate from the capsule.

[0193] In some embodiments, the degradable component comprises a degradable material. Any suitable degradable material may be used. In some embodiments the degradable material is selected from the group consisting of sugar, gelatin, and isomalt. In some embodiments, the degradable material comprises sugar. In some embodiments, the degradable material comprises gelatin. In some embodiments, the degradable material comprises isomalt. Non-limiting examples of suitable materials for degradable materials include sugars and derivatives thereof (e.g., sugar alcohols such as isomalt, sugar mixtures such as toffee), starch, calcium carbonate, zinc, sodium chloride, and / or polymers (e.g., polyethylene glycol, polyvinylpyrrolidinone, polyvinylalcohol, polyethylene oxide, diethyl pyrocarbonate, hydrogels). Other materials are also possible. Without wishing to be bound by theory, the degradable material may be selected to be relatively brittle (e.g., such that the spring is released upon dissolution of the degradable material). In some embodiments, the degradable material may comprise a metal and / or a metal allow. Suitable metals for the degradable material include copper, gold, steel, In some embodiments, where the degradable material comprises a metal, the degradable material may be triggered to degrade by applying an electrical force to induce electrochemical reactions (e.g., the electrodissolution of the metal). Electrochemical degradation of the degradable material, in some embodiments, may facilitate release of spring and / or expanding component coupled therewith.

[0194] In certain embodiments, the degradable material may be configured to have a particular architecture which provides desirable dissolution profiles. For example, in some embodiments, the degradable material may be configured to enhance dissolution profiles, have controlled failure modes (e.g., breakage into small pieces at relatively predictable locations) and / or provide structural integrity of the degradable material.

[0195] In some embodiments, the degradable component degrades upon exposure to a gastric fluid. In some embodiments, the degradable component degrades in response to an external wireless signal received by the article.

[0196] In some embodiments, the article is configured to be retained at a location internal to a subject for at least seven days prior to degradation of the degradable component. In some embodiments, the article is configured to be retained at a location internal to the subject for at least 30 days, at least 60 days, at least 90 days, at least 120 days, at least 150 days and / or up to 180 days, up to 210 days, up to 240 days, up to 264 days, up to 240 days, or up to 300 days prior to degradation of the degradable component. In some embodiments, the location internal to the subject is the stomach of the subject. In some embodiments, as described elsewhere herein in more detail, one or more retention arms of the article may be configured to disassociate from the article to facilitate release (e.g., gastric release). In some embodiments, the dissociation of the one or more retention arms may be wirelessly initiated (e.g., a wireless triggered disassembly of the device, controlling disassembly of the device). It will be appreciated that, in some embodiments, the initiation of the disassociation may facilitate release of the article at any point in time from a location internal to the subject. For instance, the article may be contained within a stomach of a subject, and the article may be released following triggered disassociation of one or more retention arms from the article after at least 60 days and before 150 days of retaining of the article within the stomach.

[0197] In some embodiments, the capsule comprises a therapeutic payload (e.g., an active substance). In some embodiments, the therapeutic payload may be any suitable therapeutic payload known to the skilled artisan.

[0198] According to some embodiments, the articles described herein are compatible with one or more therapeutic, diagnostic, and / or enhancement agents, such as drugs, nutrients, microorganisms, in vivo sensors, and tracers. In some embodiments, the active substance, is a therapeutic, nutraceutical, prophylactic or diagnostic agent.

[0199] Agents can include, but are not limited to, any synthetic or naturally-occurring biologically active compound or composition of matter which, when administered to a subject (e.g., a human or nonhuman animal), induces a desired pharmacologic, immunogenic, and / or physiologic effect by local and / or systemic action. For example, useful or potentially useful within the context of certain embodiments are compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals, Certain such agents may include molecules such as proteins, peptides, hormones, nucleic acids, gene constructs, etc., for use in therapeutic, diagnostic, and / or enhancement areas, including, but not limited to medical or veterinary treatment, prevention, diagnosis, and / or mitigation of disease or illness.

[0200] In certain embodiments, the active substance is one or more specific therapeutic agents. As used herein, the term “therapeutic agent” or also referred to as a “drug” refers to an agent that is administered to a subject to treat a disease, disorder, or other clinically recognized condition, or for prophylactic purposes, and has a clinically significant effect on the body of the subject to treat and / or prevent the disease, disorder, or condition. Listings of examples of known therapeutic agents can be found, for example, in the United States Pharmacopeia (USP), Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10th Ed., McGraw Hill, 2001; Katzung, B. (ed.) Basic and Clinical Pharmacology, McGraw-Hill / Appleton & Lange; 8th edition (September 21, 2000); Physician’s Desk Reference (Thomson Publishing), and / or The Merck Manual of Diagnosis and Therapy, 17th ed. (1999), or the 18th ed (2006) following its publication, Mark H. Beers and Robert Berkow (eds.), Merck Publishing Group, or, in the case of animals, The Merck Veterinary Manual, 9th ed., Kahn, C.A. (ed.), Merck Publishing Group, 2005; and “Approved Drug Products with Therapeutic Equivalence and Evaluations," published by the United States Food and Drug Administration (F.D.A.) (the “Orange Book"). Examples of drugs approved for human use are listed by the FDA under 21 C.F.R. §§ 330.5, 331 through 361, and 440 through 460, incorporated herein by reference; drugs for veterinary use are listed by the FDA under 21 C.F.R. §§ 500 through 589, incorporated herein by reference. In certain embodiments, the therapeutic agent is a small molecule. Exemplary classes of therapeutic agents include, but are not limited to, analgesics, anti-analgesics, anti-inflammatory drugs, antipyretics, antidepressants, antiepileptics, antipsychotic agents, neuroprotective agents, anti-proliferatives, such as anti-cancer agents, antihistamines, antimigraine drugs, hormones, prostaglandins, antimicrobials (including antibiotics, antifungals, antivirals, antiparasitics), antimuscarinics, anxioltyics, bacteriostatics, immunosuppressant agents, sedatives, hypnotics, antipsychotics, bronchodilators, anti-asthma drugs, cardiovascular drugs, anesthetics, anti-coagulants, inhibitors of an enzyme, steroidal agents, steroidal or nonsteroidal anti-inflammatory agents, corticosteroids, dopaminergics, electrolytes, gastrointestinal drugs, muscle relaxants, nutritional agents, vitamins, parasympathomimetics, stimulants, anorectics and anti-narcoleptics. Nutraceuticals can also be incorporated into the drug delivery device. These may be vitamins, supplements such as calcium or biotin, or natural ingredients such as plant extracts or phytohormones.

[0201] In other embodiments, the active substance is a protein or other biological macromolecule.

[0202] In some embodiments, the therapeutic agent is a small molecule drug having molecular weight less than about 2500 Daltons, less than about 2000 Daltons, less than about 1500 Daltons, less than about 1000 Daltons, less than about 750 Daltons, less than about 500 Daltons, less or than about 400 Daltons. In some cases, the therapeutic agent is a small molecule drug having molecular weight between 200 Daltons and 400 Daltons, between 400 Daltons and 1000 Daltons, or between 500 Daltons and 2500 Daltons.

[0203] In some embodiments, the therapeutic agent is selected from the group consisting of active pharmaceutical agents such as insulin, nucleic acids, peptides, bacteriophage, DNA, mRNA, human growth hormone, monoclonal antibodies, adalimumab, epinephrine, GLP-1 Receptor agoinists, semaglutide, liraglutide, dulaglitide, exenatide, factor VIII, small molecule drugs, progrstin, vaccines.

[0204] In certain embodiments, the therapeutic pay load may be released with a pulse release profile. For example, in some embodiments, the therapeutic payload may be released on the first day after administration and during another 24 hour period such as starting during the third day, the fourth day, or the fifth day, but is not substantially released on other days. Those skilled in the art would understand that other days and / or combinations of pulsing and continuous release are also possible.

[0205] The therapeutic payload may be released at a relatively constant average rate (e.g., a substantially zero-order average release rate) over a time period of at least about 24 hours. In certain embodiments, the therapeutic payload is released at a first-order release rate (e.g., the rate of release of the therapeutic payload is generally proportional to the concentration of the therapeutic payload) of a time period of at least about 24 hours.

[0206] In some embodiments, at least a portion of the therapeutic payload loaded into the article is released continuously (e.g., at varying rates) over the residence time period of the article. Residence time periods are described in more detail, below.

[0207] In some embodiments, the therapeutic payload comprises one or more types of bacteria. The bacteria, whether naturally occurring or genetically modified, may undergo one or more chemical and / or biological reactions when exposed to a particular biomarker (or if the particular is removed or is not present), which may subsequently result in additional chemical and / or biological reactions.

[0208] In various embodiments, the therapeutic payload comprises Escherichia coli (e.g., E. coli, E. coli Nissle 1917 (EcN)). In some embodiments, the bacteria may be suitable as a bacterial biosensor, bacterial biosensors as described in International Patent Application No. PCT / US2022 / 026406 filed on April 26, 2022, which is herein incorporated by reference in its entirety. For example, various embodiments comprise a biosensor for detecting the presence (or absence) of a chemical and / or biological species, such a biomolecule or a biomarker. In some embodiments, the biosensor is a bacterial biosensor comprising one or more bacteria, wherein the bacteria can detect the presence (or absence) of one or more chemical and / or biological species (e.g., biomarkers). In some embodiments, the bacteria comprise bioengineered bacteria, wherein the bacteria has been genetically modified (e.g., plasmid insertion) to detect the presence (or absence) of one or more chemical and / or biological species. The bacteria, whether naturally occurring or genetically modified, may undergo one or more chemical and / or biological reactions when exposed to a particular biomarker (or if the particular is removed or is not present), which may subsequently result in additional chemical and / or biological reactions. In some embodiments, the presence of a biomarker (e.g., nitric oxide, NO) may cause a first chemical and / or biological reaction. In some embodiments, the presence of the biomarker may cause the first chemical and / or biological reaction to produce a species involved in a second chemical and / or biological reaction. In some such embodiments, the second chemical and / or biological reaction includes a regulatory molecule (e.g., a protein / peptide) involved in the regulation of DNA and / or RNA, such as a promotor. In some such embodiments, the regulatory molecule may be produced from the first and / or second chemical and / or biological reaction and may then bind to a promotor to initiate transcription. This may result in the production of a specific enzyme, which may, in some cases, facilitate the generation of a signal within the bacteria.

[0209] By way of example, the first chemical and / or biological reaction can be a first biological reaction (e.g., provided to the bacteria by a plasmid) in which NO is the biomarker. The NO may bind or react with a species characteristic of the first biological reaction to produce a regulatory molecule, such as a promoter. The promoter may activate a second chemical and / or biological reaction, such as a second biological reaction, which may subsequently generate a signal, for example by activating (or deactivating) a bioluminescent molecule (e.g., green fluorescent protein, GFP). Of course, other biomarkers and chemical and / or biological reactions are possible and are described elsewhere herein.

[0210] The bacterial biosensors may be configured, in some cases, to detect a variety of biomolecules or biomarkers. In some embodiments, the bacterial biosensors are configured to detect NO. In some embodiments, the bacterial biosensors are configured to detect reactive oxygen species (ROS), such as peroxides, hydroxyl radicals, and / or superoxide. In some embodiments, the bacterial biosensors are configured to detect thiosulfate and / or tetrathionate. Other species the bacterial biosensors may be configured to detect include, but are not limited to, inflammatory markers, proteins, DNA, RNA, hormones, chemical analytes, or the like.

[0211] In some embodiments, a plurality of bacterial and / or enzymatic biosensors are configured for non-blood-based detection of a gastrointestinal inflammatory process and / or disease state of the subject. However, in some embodiments, one or more biosensors may be configured to detect one or more components or blood and / or serum.

[0212] Advantageously, the devices described herein may be configured to detect two or more different biomolecules and / or biomarkers. For example, in an illustrative set of embodiments, the detection of a single biomolecule by a first biosensor may indicate a first disease state of the subject. In some embodiments, the detection of two different biomolecules by two different biosensors may indicate a second disease state, different than the first disease state, of the subject. In some embodiments, the plurality of sealable chambers, biosensors, and photodetectors advantageously provide a combinatorial approach to disease detection and monitoring in a subject. For example, different combinations of positive results (e.g., a detectable signal produced by a biosensor) by different biosensors may be correlated with different diseases and / or disease states.

[0213] In an exemplary illustration of the above noted detection, in some embodiments, a first detectable signal produced by a first biosensor corresponds to a first disease state. In some embodiments, a second detectable signal produced by a second biosensor (different than the first biosensor) corresponds to a second disease state, different than the first disease state. In some embodiments, the presence of the first detectable signal and the second detectable signal corresponds to a third disease state, different than the first disease state and the second disease state. In some embodiments, the presence of a third detectable signal produced by a third biosensor corresponds for a fourth disease state. In some embodiments, the presence of the first detectable signal and / or the second detectable signal and the third detectable signal corresponds to a fifth disease state. Other combinations and diseases / disease states are also possible.

[0214] A variety of suitable bacteria may be suitable for bacterial biosensors. In various embodiments, the bacterial biosensor comprises Escherichia coli (e.g., E. coli, E. coli Nissle 1917 (EcN)). However, other bacteria may be suitable for the bacterial biosensors. Non-limiting examples of other suitable bacteria include Bacteroidetes, Firmicutes, Actinobacteria, Proteobacteria. Other bacteria are possible as this disclosure is not so limited.

[0215] In some embodiments, the biosensor may comprise yeast, such as Saccharomyces cerevisiae (such as S. cerevisiae boulardii) and / or other endogenous fungi, (e.g., Candida albicans), without limitation. Other yeast are possible.

[0216] In some embodiments, one or more biosensors comprises an enzymatic biosensor or a non-enzymatic biosensor. An enzymatic biosensor may comprise an enzyme that recognizes a biomarker to produce an output that can be sensed by the electronic component of the device. In some embodiments, output comprises a signal generated through: 1) the enzymatic conversion of the biomarker into a new product; 2) biomarker- mediated inhibition or activation of the enzyme; or 3) biomarker-mediated modification of enzyme properties. By contrast, a non-enzymatic biosensor does not require interaction between an enzyme and a biomarker. For example, in some embodiments, a non-enzymatic biosensor may comprise a protein channel that facilitates signal flow (or output) when in the presence of an particular biomarker. In some embodiments, a non- enzymatic biosensor comprises an antibody or a binding protein that recognizes the presence of a biomarker. In some embodiments, the non-enzymatic biosensor comprises a nucleic acid that hybridizes to an analyte or otherwise binds to it (e.g., as an aptamer). In some embodiments, the non-enzymatic biosensor comprises of a transcription factor that alters gene expression upon binding to an analyte.

[0217] In some embodiments, the biosensors (e.g., bacterial biosensors) are configured to generate a luminescent signal, such a bioluminescent signal. Advantageously, a bioluminescent signal may be encoded into the biosensor so that light (or the absence thereof) may indicate the presence (or absence) of a biomarker detected by the biosensor.

[0218] In some embodiments, the therapeutic payload may comprise yeast, such as Saccharomyces cerevisiae (such as S. cerevisiae boulardii) and / or other endogenous fungi, (e.g., Candida albicans), without limitation. Other yeast are possible.

[0219] In some embodiments the article has a retention configuration. In some embodiments the retention configuration is such that the article is unable to pass through the pylorus of the subject until release of the From the capsule. In some embodiments, the degradable component is fluidically isolated from the gastric fluid at the location internal to the subject until the external wireless signal is received by the article.

[0220] In some embodiments, the article further comprises an electronic component. Electronic component may be any suitable electronic component known to the skilled artisan. In some embodiments, the article may comprise an electrical system. In some such embodiments, an electrical system may include two or more electronic components. For instance, in some embodiments, the electrical system comprises a power source (e.g., a battery), an actuator such as an electrical actuation control system, a microcontroller, a PCB, a wireless component, a central processor, a power management system, a system wakeup controller, and / or one or more electronic sensors such as temperature sensors and / or humidity sensors. In some embodiments, the electrical system may be contained within a container. In some embodiments, a container may have a low permeability to water vapor and / or permeance to water. Accordingly, in some embodiments, the container may be configured to maintain a relative humidity therein at any of a variety of suitable levels, e.g., to facilitate functioning of the electrical system contained therein and / or avoid degradation of the electrical system. In some embodiments, the container is configured to maintain a relative humidity within an interior volume defined by the container of less than or equal to 80%, less than or equal to 70%, less than or equal to 60%, less than or equal to 50%, or less than or equal to 40% for at least 1 day, at least 5 days, at least 10 days, at least 30 days, at least 60 days, at least 90 days, at least 120 days, at least 150 days, at least 180 days, at least 210 days, at least 240 days, at least 264 days, at least 270 days, and / or up to 300 days when the container is at a location internal to the subject. According to some embodiments, the container may be configured to maintain the relative humidity therein at less than or equal to 60% for at least 264 days when the container is at a location internal to the subject. In some embodiments, the ability of the container to maintain a relative humidity therein may be tested using a humidity sensor contained within the container. In some instances, the container may further comprise one or more reservoirs, triggerable release mechanisms, sealing components, retention arms and / or expanding components, and / or actuators.

[0221] In some embodiments, the article further comprises a tether. In some embodiments the tether is configured to extend from the capsule into a second location intemal to the subject, different than the first location internal to the subject (e.g., the capsule may be configured to reside in the stomach of the subject and at least a portion may be configured to reside in a small intestine of the subject”). In some embodiments, the tether is configured to extend from the capsule into an intestine of the subject. In some embodiments, the tether comprises one or more therapeutic pay loads. The therapeutic payload may be any therapeutic payload known to the skilled artisan.

[0222] In some embodiments, the one or more retention arms comprises a super elastic material. The super elastic material may be any suitable super elastic material known to the skilled artisan.

[0223] In some embodiments, the one or more retention arms comprises a corrosion resistant material. The corrosion resistant material may be any suitable corrosion resistant material known to the skilled artisan. In some embodiments, the one or more retention arms comprises a fatigue resistant material. The fatigue resistant material may be any suitable fatigue resistant material known to the skilled artisan. In accordance with some embodiments, the fatigue resistant material may facilitate retention of the article comprising the one or more retention arms at a location internal to the subject.

[0224] In some embodiments, the capsule and / or the one or more coupling components mechanically coupling each of the one or more retention arms to the capsule of the article may be configured to facilitate fatigue resistance of the one or more retention arms. For instance, in some embodiments, the capsule and / or the one or more coupling components may be designed to bending of the one or more retention arms to reduce fatigue of the one or more bending arms over time.

[0225] In some embodiments, the article is a gastric retention device. In some embodiments, the article is a gastrointestinal retention device.

[0226] In some embodiments, the article is administered to a subject (e.g., orally). In certain embodiments, the system may be administered surgically (e.g., implanted), orally, rectally, vaginally, nasally, or uretherally. In certain embodiments, the system is administered such that at least a portion of the system resides at a location internal to the subject (e.g., the gastrointestinal tract). In some embodiments, the location internally of the subject is the colon, the duodenum, the ileum, the jejunum, the stomach, or the esophagus. As described above and herein, in some embodiments, a therapeutic pay load may be released at the location internal to the subject.

[0227] As described above and herein, the article is configured to reside within a subject for at least a period of time. The term residence time period generally refers to the length of time during which the article (or a component of the article) described herein is resided at a location internally of a subject as measured from the time initially present in the location internally of the subject to the time at which the article (or such component of the article being referenced) no longer resides at the location internally of the subject due to, for example, degradation, dissolution, and / or exit of the article or such component(s) of the article being referenced from the location internally of the subject. In an illustrative embodiment, the article may be orally administered such that the article resides at a location internally of the subject such as the stomach above the pylorus and exits through the pylorus into the intestine (e.g., after degradation of at least a portion of the article), where the residence time period is measured as the length of time between when the article initially resides in the stomach and when the article (or a component of the article being referenced) exits through the pylorus.

[0228] In some embodiments, the residence time period of at least a portion of the article is at least about 24 hours, at least about 48 hours, at least about 3 days, at 7 days, at least about 10 days, at least about 1 month, at least about 6 months, or at least about 1 year. In certain embodiments, the residence time period is less than or equal to about 2 years, less than or equal to about 1 year, less than or equal to about 6 months, less than or equal to about 1 month, less than or equal to about 10 days, less than or equal to about 7 days, less than or equal to about 3 days, or less than or equal to about 48 hours. Any and all closed ranges that have endpoints within any of the above-referenced ranges are also possible (e.g., between about 24 hours and about 2 years, between about 24 hours and about 1 year, between about 48 hours and about 7 days, between about 3 days and about 1 month, between about 7 days and about 6 months, between about 1 month and about 1 year). Other ranges are also possible.

[0229] In an exemplary embodiment, the one or more components are selected to mediate disassembly of the article after, for example, delivery of a therapeutic payload for over a desired residence time period (e.g., within 24 hours, within 48 hours, within one week, within one month), and facilitate safe passage through the lower intestinal tract of the subject. Exit from an orifice such as the gastric cavity may be achieved through disengagement of the one or more retention arms such that the ability to resist passage through an orifice (e.g., through the pylorus) is compromised, through breakage in the article through designed failure, etc.

[0230] In certain embodiments, the article in a first configuration has an uncompressed cross-sectional dimension. The uncompressed cross-sectional dimension is generally selected such that the article is retained at a location internally to a subject for a relatively long period of time (e.g., at least about 24 hours) even under physiological compressive forces (e.g., such as those in the digestive tract).

[0231] In some embodiments, the uncompressed cross-sectional dimension of the first configuration is at least about 2 cm, at least about 4 cm, at least about 5 cm, or at least about 10 cm. In certain embodiments, the uncompressed cross-sectional dimension of the first configuration is less than or equal to about 15 cm, less than or equal to about 10 cm, less than or equal to about 5 cm, or less than or equal to about 4 cm. Any and all closed ranges that have endpoints within any of the above-referenced ranges are also possible (e.g., between about 2 cm and about 15 cm). Those skilled in the art would be capable of selecting suitable uncompressed cross-sectional dimensions for articles based upon the teachings of this specification for specific orifices of a subject such that the article is retained.

[0232] In some embodiments, an article configured for residence (e.g., being retained in an orifice at a particular location internal to a subject) such as gastric residence comprises a three-dimensional structure having a plurality of projections (i.e. arms). In some embodiments, the structure with projections comprises a flexible material configured for elastic (non-plastic) deformation. The projections themselves may be flexible or rigid with flexible connections to a core. In some embodiments, one or more controlled degradation linkers (e.g., enteric elastomers) are attached to and / or incorporated into the structure, for example, along one or more projections, such as near or at the connection to a core. In some embodiments, each projection has a length equal to just less than the length of a soluble container such that the unencapsulated final form has a diameter equal to nearly twice the soluble container length. In some embodiments, the projections each may have a length of about 0.5 cm to about 2.5 cm (e.g., such that the structure has an uncompressed cross-sectional dimension of at least about 2 cm). Aspects of the present disclosure relate to an article. In some embodiments, the article is configured for gastrointestinal delivery of a therapeutic payload. In some embodiments, the article comprises one or more reservoirs comprising a therapeutic payload. In some embodiments, the article comprises one or more triggerable release mechanisms. In some embodiments, the triggerable release mechanism comprises a metal seal. In some embodiments, release of the therapeutic payload is accomplished via electrochemical dissolution of the metal seal.

[0233] In some embodiments, the reservoir may advantageously have a low permeability to water vapor and / or permeance to water to facilitate isolating a therapeutic payload contained within the interior volume at least partially defined by the reservoir body and / or sealing component from physiological media outside of the interior volume (e.g., at a location internal the subject). Accordingly, in some embodiments, the reservoir may be configured to maintain a relative humidity therein at any of a variety of suitable levels. In some embodiments, the reservoir is configured to maintain a relative humidity within an interior volume defined by the reservoir of less than or equal to 80%, less than or equal to 70%, less than or equal to 60%, less than or equal to 50%, or less than or equal to 40% for at least 1 day, at least 5 days, at least 10 days, at least 30 days, at least 60 days, at least 90 days, at least 120 days, at least 150 days, at least 180 days, at least 210 days, at least 240 days, at least 264 days, at least 270 days, and / or up to 300 days when the reservoir is at a location internal to the subject. In some embodiments, the ability of the reservoir to maintain a relative humidity therein may be tested using a humidity sensor contained within the interior volume defined by the reservoir.

[0234] The articles described herein may be useful, for example, as a general platform for delivery of a wide variety of pharmaceutical agents that otherwise are generally delivered via injection directly into tissue due to degradation in the GI tract. In some cases, the article may be configured to deliver therapeutic pay loads at a desired location and / or at a desired time and / or over a desired duration to a subject.

[0235] Advantageously, in some embodiments, the articles described herein may be useful as a general platform for delivery of a wide variety of therapeutic payloads (e.g., bacteria, therapeutic agents) that are typically delivered via injection directly into tissue due to degradation in the GI tract. For example, the article may be capable of localizing itself to a specified location (e.g., allowing loaded drugs to avoid long passages through the GI tract fluid before diffusing into the blood stream). This article, in some cases, may serve as a platform to allow therapeutic payloads and / or drugs that are currently degraded by the enzymes in the GI tract to be absorbed with higher bioavailability.

[0236] Aspects of the present disclosure generally relate to an article. In some embodiments the article comprises one or more reservoirs. In some embodiments, each reservoir comprises a therapeutic payload. In some embodiments, the plurality of reservoirs have a total combined volume of greater than or equal to 50 pL. In some embodiments, the article comprises one or more triggerable release mechanisms associated with each reservoir. In some embodiments, the triggerable release mechanism receives an external signal that triggers each triggerable release mechanism to release the therapeutic pay load from the one or more reservoirs. In some embodiments, each reservoir is adapted and designed to maintain therapeutic efficacy of the therapeutic payload for greater than or equal to 10 days under physiological conditions. It will be understood that, in some instances within the present disclosure, the reservoir may comprise a reservoir body and, optionally, other components such as a sealing component, or the like, as described elsewhere herein.

[0237] In some embodiments the article further comprises a semi-permeable membrane associated with each reservoir. In some embodiments, each semi-permeable membrane has a low permeability to water vapor and / or low pH fluids. In some embodiments, the semipermeable membrane has a thickness of greater than or equal to 1 pm.

[0238] In some embodiments the article further comprises a triggerable seal associated with each reservoir.

[0239] In some embodiments, the reservoir comprises a therapeutic payload (e.g., an active substance). In some embodiments, the therapeutic payload may be any suitable therapeutic payload known to the skilled artisan.

[0240] According to some embodiments, the articles described herein are compatible with one or more therapeutic, diagnostic, and / or enhancement agents, such as drugs, nutrients, microorganisms, in vivo sensors, and tracers. In some embodiments, the active substance, is a therapeutic, nutraceutical, prophylactic or diagnostic agent.

[0241] Agents can include, but are not limited to, any synthetic or naturally-occurring biologically active compound or composition of matter which, when administered to a subject (e.g., a human or nonhuman animal), induces a desired pharmacologic, immunogenic, and / or physiologic effect by local and / or systemic action. For example, useful or potentially useful within the context of certain embodiments are compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals, Certain such agents may include molecules such as proteins, peptides, hormones, nucleic acids, gene constructs, etc., for use in therapeutic, diagnostic, and / or enhancement areas, including, but not limited to medical or veterinary treatment, prevention, diagnosis, and / or mitigation of disease or illness.

[0242] In certain embodiments, the active substance is one or more specific therapeutic agents. As used herein, the term “therapeutic agent” or also referred to as a “drug” refers to an agent that is administered to a subject to treat a disease, disorder, or other clinically recognized condition, or for prophylactic purposes, and has a clinically significant effect on the body of the subject to treat and / or prevent the disease, disorder, or condition. Listings of examples of known therapeutic agents can be found, for example, in the United States Pharmacopeia (USP), Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10th Ed., McGraw Hill, 2001; Katzung, B. (ed.) Basic and Clinical Pharmacology, McGraw-Hill / Appleton & Lange; 8th edition (September 21, 2000); Physician’s Desk Reference (Thomson Publishing), and / or The Merck Manual of Diagnosis and Therapy, 17th ed. (1999), or the 18th ed (2006) following its publication, Mark H. Beers and Robert Berkow (eds.), Merck Publishing Group, or, in the case of animals, The Merck Veterinary Manual, 9th ed., Kahn, C.A. (ed.), Merck Publishing Group, 2005; and “Approved Drug Products with Therapeutic Equivalence and Evaluations," published by the United States Food and Drug Administration (F.D.A.) (the “Orange Book"). Examples of drugs approved for human use are listed by the FDA under 21 C.F.R. §§ 330.5, 331 through 361, and 440 through 460, incorporated herein by reference; drugs for veterinary use are listed by the FDA under 21 C.F.R. §§ 500 through 589, incorporated herein by reference. In certain embodiments, the therapeutic agent is a small molecule. Exemplary classes of therapeutic agents include, but are not limited to, analgesics, anti-analgesics, anti-inflammatory drugs, antipyretics, antidepressants, antiepileptics, antipsychotic agents, neuroprotective agents, anti-proliferatives, such as anti-cancer agents, antihistamines, antimigraine drugs, hormones, prostaglandins, antimicrobials (including antibiotics, antifungals, antivirals, antiparasitics), antimuscarinics, anxioltyics, bacteriostatics, immunosuppressant agents, sedatives, hypnotics, antipsychotics, bronchodilators, anti-asthma drugs, cardiovascular drugs, anesthetics, anti-coagulants, inhibitors of an enzyme, steroidal agents, steroidal or nonsteroidal anti-inflammatory agents, corticosteroids, dopaminergics, electrolytes, gastrointestinal drugs, muscle relaxants, nutritional agents, vitamins, parasympathomimetics, stimulants, anorectics and anti-narcoleptics. Nutraceuticals can also be incorporated into the drug delivery device. These may be vitamins, supplements such as calcium or biotin, or natural ingredients such as plant extracts or phytohormones.

[0243] In other embodiments, the active substance is a protein or other biological macromolecule.

[0244] In some embodiments, the therapeutic agent is a small molecule drug having molecular weight less than about 2500 Daltons, less than about 2000 Daltons, less than about 1500 Daltons, less than about 1000 Daltons, less than about 750 Daltons, less than about 500 Daltons, less or than about 400 Daltons. In some cases, the therapeutic agent is a small molecule drug having molecular weight between 200 Daltons and 400 Daltons, between 400 Daltons and 1000 Daltons, or between 500 Daltons and 2500 Daltons.

[0245] In some embodiments, the therapeutic agent is selected from the group consisting of active pharmaceutical agents such as insulin, nucleic acids, peptides, bacteriophage, DNA, mRNA, human growth hormone, monoclonal antibodies, adalimumab, epinephrine, GLP-1 Receptor agoinists, semaglutide, liraglutide, dulaglitide, exenatide, factor VIII, small molecule drugs, progrstin, vaccines.

[0246] In certain embodiments, the therapeutic pay load may be released with a pulse release profile. For example, in some embodiments, the therapeutic payload may be released on the first day after administration and during another 24 hour period such as starting during the third day, the fourth day, or the fifth day, but is not substantially released on other days. Those skilled in the art would understand that other days and / or combinations of pulsing and continuous release are also possible.

[0247] The therapeutic payload may be released at a relatively constant average rate (e.g., a substantially zero-order average release rate) over a time period of at least about 24 hours. In certain embodiments, the therapeutic payload is released at a first-order release rate (e.g., the rate of release of the therapeutic payload is generally proportional to the concentration of the therapeutic payload) of a time period of at least about 24 hours. In some embodiments, at least a portion of the therapeutic payload loaded into the article is released continuously (e.g., at varying rates) over the residence time period of the article. Residence time periods are described in more detail, below.

[0248] In some embodiments, the therapeutic payload comprises one or more types of bacteria. The bacteria, whether naturally occurring or genetically modified, may undergo one or more chemical and / or biological reactions when exposed to a particular biomarker (or if the particular is removed or is not present), which may subsequently result in additional chemical and / or biological reactions.

[0249] In various embodiments, the therapeutic payload comprises Escherichia coli (e.g., E. coli, E. coli Nissle 1917 (EcN)). In some embodiments, the bacteria may be suitable as bacterial biosensors as described in International Patent Application No. PCT / US2022 / 026406 filed on April 26, 2022, which is herein incorporated by reference in its entirety. For example, various embodiments comprise a biosensor for detecting the presence (or absence) of a chemical and / or biological species, such a biomolecule or a biomarker. In some embodiments, the biosensor is a bacterial biosensor comprising one or more bacteria, wherein the bacteria can detect the presence (or absence) of one or more chemical and / or biological species (e.g., biomarkers). In some embodiments, the bacteria comprise bioengineered bacteria, wherein the bacteria has been genetically modified (e.g., plasmid insertion) to detect the presence (or absence) of one or more chemical and / or biological species. The bacteria, whether naturally occurring or genetically modified, may undergo one or more chemical and / or biological reactions when exposed to a particular biomarker (or if the particular is removed or is not present), which may subsequently result in additional chemical and / or biological reactions. In some embodiments, the presence of a biomarker (e.g., nitric oxide, NO) may cause a first chemical and / or biological reaction. In some embodiments, the presence of the biomarker may cause the first chemical and / or biological reaction to produce a species involved in a second chemical and / or biological reaction. In some such embodiments, the second chemical and / or biological reaction includes a regulatory molecule (e.g., a protein / peptide) involved in the regulation of DNA and / or RNA, such as a promotor. In some such embodiments, the regulatory molecule may be produced from the first and / or second chemical and / or biological reaction and may then bind to a promotor to initiate transcription. This may result in the production of a specific enzyme, which may, in some cases, facilitate the generation of a signal within the bacteria.

[0250] By way of example, the first chemical and / or biological reaction can be a first biological reaction (e.g., provided to the bacteria by a plasmid) in which NO is the biomarker. The NO may bind or react with a species characteristic of the first biological reaction to produce a regulatory molecule, such as a promoter. The promoter may activate a second chemical and / or biological reaction, such as a second biological reaction, which may subsequently generate a signal, for example by activating (or deactivating) a biolumine scent molecule (e.g., green fluorescent protein, GFP). Of course, other biomarkers and chemical and / or biological reactions are possible and are described elsewhere herein.

[0251] The bacterial biosensors may be configured, in some cases, to detect a variety of biomolecules or biomarkers. In some embodiments, the bacterial biosensors are configured to detect NO. In some embodiments, the bacterial biosensors are configured to detect reactive oxygen species (ROS), such as peroxides, hydroxyl radicals, and / or superoxide. In some embodiments, the bacterial biosensors are configured to detect thiosulfate and / or tetrathionate. Other species the bacterial biosensors may be configured to detect include, but are not limited to, inflammatory markers, proteins, DNA, RNA, hormones, chemical analytes, or the like.

[0252] In some embodiments, a plurality of bacterial and / or enzymatic biosensors are configured for non-blood-based detection of a gastrointestinal inflammatory process and / or disease state of the subject. However, in some embodiments, one or more biosensors may be configured to detect one or more components or blood and / or serum.

[0253] Advantageously, the devices described herein may be configured to detect two or more different biomolecules and / or biomarkers. For example, in an illustrative set of embodiments, the detection of a single biomolecule by a first biosensor may indicate a first disease state of the subject. In some embodiments, the detection of two different biomolecules by two different biosensors may indicate a second disease state, different than the first disease state, of the subject. In some embodiments, the plurality of sealable chambers, biosensors, and photodetectors advantageously provide a combinatorial approach to disease detection and monitoring in a subject. For example, different combinations of positive results (e.g., a detectable signal produced by a biosensor) by different biosensors may be correlated with different diseases and / or disease states.

[0254] In an exemplary illustration of the above noted detection, in some embodiments, a first detectable signal produced by a first biosensor corresponds to a first disease state. In some embodiments, a second detectable signal produced by a second biosensor (different than the first biosensor) corresponds to a second disease state, different than the first disease state. In some embodiments, the presence of the first detectable signal and the second detectable signal corresponds to a third disease state, different than the first disease state and the second disease state. In some embodiments, the presence of a third detectable signal produced by a third biosensor corresponds for a fourth disease state. In some embodiments, the presence of the first detectable signal and / or the second detectable signal and the third detectable signal corresponds to a fifth disease state. Other combinations and diseases / disease states are also possible.

[0255] A variety of suitable bacteria may be suitable for bacterial biosensors. In various embodiments, the bacterial biosensor comprises Escherichia coli (e.g., E. coli, E. coli Nissle 1917 (EcN)). However, other bacteria may be suitable for the bacterial biosensors. Non-limiting examples of other suitable bacteria include Bacteroidetes, Firmicutes, Actinobacteria, Proteobacteria. Other bacteria are possible as this disclosure is not so limited.

[0256] In some embodiments, the biosensor may comprise yeast, such as Saccharomyces cerevisiae (such as S. cerevisiae boulardii ) and / or other endogenous fungi, (e.g Candida albicans), without limitation. Other yeast are possible.

[0257] In some embodiments, one or more biosensors comprises an enzymatic biosensor or a non-enzymatic biosensor. An enzymatic biosensor may comprise an enzyme that recognizes a biomarker to produce an output that can be sensed by the electronic component of the device. In some embodiments, output comprises a signal generated through: 1) the enzymatic conversion of the biomarker into a new product; 2) biomarker- mediated inhibition or activation of the enzyme; or 3) biomarker-mediated modification of enzyme properties. By contrast, a non-enzymatic biosensor does not require interaction between an enzyme and a biomarker. For example, in some embodiments, a non-enzymatic biosensor may comprise a protein channel that facilitates signal flow (or output) when in the presence of an particular biomarker. In some embodiments, a non- enzymatic biosensor comprises an antibody or a binding protein that recognizes the presence of a biomarker. In some embodiments, the non-enzymatic biosensor comprises a nucleic acid that hybridizes to an analyte or otherwise binds to it (e.g., as an aptamer). In some embodiments, the non-enzymatic biosensor comprises of a transcription factor that alters gene expression upon binding to an analyte.

[0258] In some embodiments, the biosensors (e.g., bacterial biosensors) are configured to generate a luminescent signal, such a bioluminescent signal. Advantageously, a bioluminescent signal may be encoded into the biosensor so that light (or the absence thereof) may indicate the presence (or absence) of a biomarker detected by the biosensor.

[0259] In some embodiments, the therapeutic payload may comprise yeast, such as Saccharomyces cerevisiae (such as S. cerevisiae boulardii ) and / or other endogenous fungi, (e.g Candida albicans), without limitation. Other yeast are possible.

[0260] Various systems and devices described herein comprise a plurality of reservoirs (e.g., a sealable reservoir). Each sealable chamber may independently comprise one or more therapeutic payloads as described above and elsewhere herein. Each reservoir may be sealed e.g., to reduce or prevent undesired exposure of the one or more therapeutic pay loads to moisture or other liquids. In some embodiments, at least one of the plurality of reservoirs is sized and adapted to contain a therapeutic payload. In some embodiments, the therapeutic pay load is fluidically isolated (e.g., sealed) from an external fluid.

[0261] In some embodiments, the plurality of reservoirs have a total combined volume of greater than or equal to 1 pL and less than or equal to 500 pL. In some embodiments, the plurality of reservoirs have a total combined volume of greater than or equal to 1 pL and less than or equal to 40 pL. In some embodiments, each reservoir is adapted and designed to maintain therapeutic efficacy of the therapeutic payload for greater than or equal to 60 days under physiological conditions.

[0262] Each reservoir of the plurality of sealable reservoirs may independently be sized and shaped with a particular dimension. In some embodiments, at least some of the reservoirs of the plurality of sealable reservoirs has a volume of greater than or equal to 0.1 pL, greater than or equal to 0.2 pL, greater than or equal to 0.3 pL, greater than or equal to 0.5 pL, greater than or equal to 1, pL, greater than or equal to 5 pL, greater than or equal to 10 pL, greater than or equal to 20 pL, greater than or equal to 30 pL, greater than or equal to 40 pL, greater than or equal to 50 pL, greater than or equal to 100 pL, or greater than or equal to 250 pL. In some embodiments, at least some of the chambers of the plurality of sealable chambers has a volume of less than or equal to 250 pL, less than or equal to 100 pL, less than or equal to 50 pL, less than or equal to 40 pL, less than or equal to 30 pL, less than or equal to 20 pL, less than or equal to 10 pL, less than or equal to 5 pL, less than or equal to 1 pL, less than or equal to 0.5 pL, less than or equal to 0.3 pL, less than or equal to 0.2 pL, or less than or equal to 0.1 pL. Combinations of the above-referenced ranges are also possible (e.g., greater than or equal to 0.1 pL and less than or equal to 250 pL). Advantageously, a relatively small sized chamber (e.g., less than or equal to 5 pL may lower the power requirements of the system or device. Of course, other ranges are possible as this disclosure is not so limited. In some embodiments, some of the chambers of the plurality of chambers has a volume within the above-referenced ranges. In some embodiments, all of the chambers has a volume within the above-referenced ranges.

[0263] In some embodiments, the article further comprises an enteric layer associated with each reservoir.

[0264] In some embodiments, the reservoir further comprises a reservoir body. In some embodiments the reservoir body comprises an organic polymer. In some embodiments the organic polymer is selected from the group consisting of polymethyl methacrylate, polyethylene, polypropylene, tetrafluoroethylene, hexafluoropropylene, polyether ether ketone, polyethylenimine, cyclic olefin copolymer, polycarbonate, polypropylene, copolymers thereof, and combinations thereof.

[0265] The organic polymer is, in some embodiments, biocompatible. The term “biocompatible," as used in reference to the organic polymer, refers to a polymer that does not invoke a substantial adverse reaction (e.g., deleterious immune response) from an organism (e.g., a mammal), a tissue culture or a collection of cells, or invokes only a reaction that does not exceed an acceptable level. In some embodiments, the organic polymer comprises organic polymers, networks of organic polymers, and / or multi-block combinations of organic polymer segments, that may comprise organic polymers or organic polymer segments that are for example: polyesters - such as including but not limited to, polycaprolactone, polypropylene fumarate), poly(glycerol sebacate), poly (lactide), poly (glycol acid), poly (lactic-glycolic acid), polybutyrate, and polyhydroxyalkanoate; polyethers -such as including but not limited to, poly(ethylene oxide) and poly(propylene oxide); poly siloxanes - such as including but not limited to, poly (dimethylsiloxane); polyamides - such as including but not limited to, poly (caprolactam); polyolefins - such as including but not limited to, polyethylene; polycarbonates - such as including but not limited to poly (propylene oxide); poly ketals; polyvinyl alcohols; polyoxetanes; polyacrylates / methacrylates - such as including but not limited to, poly(methyl methacrylate) and poly(ethyl-vinyl acetate); polyanhydrides; and polyurethanes. In some embodiments, the organic polymer is cross-linked.

[0266] In some embodiments the reservoir body comprises an inorganic material. In some embodiments the inorganic material is selected from the group consisting of metals, ceramics, aluminum, and glass. In some embodiments the metal comprises a transition metal. In some embodiments the metal comprises an alloy. As defined herein, an “alloy” refers to any metallic substance composed of two or more elements as either a compound or a solution. In some embodiments, the alloy comprises one or more of iron, manganese nickel, chromium, molybdenum, titanium, vanadium, tungsten, cobalt, and niobium. In some embodiments, the alloy may comprise additional elements, for example, non-metallic elements. In some embodiments, the metal is selected from the group consisting of steel, gold, and copper.

[0267] In some embodiments, the triggerable release mechanism comprises a metal seal. In some embodiments, release of the therapeutic payload from within each reservoir comprises electrochemical dissolution of the metal seal. In some embodiments, the triggerable release mechanism releases the therapeutic payload from within each reservoir using less than or equal to 10 J per trigger. In some embodiments, the triggerable release mechanism releases the therapeutic payload from within each reservoir using less than or equal to 1 per trigger. In some embodiments, the triggerable release mechanism releases the therapeutic payload from within each reservoir using less than or equal to 100 mJ per trigger. In some embodiments the release of the therapeutic payload occurs with and less than or equal to 6 hours after triggering.

[0268] In some embodiments, the article is a gastric retention device. In some embodiments, the article is a gastrointestinal retention device.

[0269] In some embodiments, the article is administered to a subject (e.g., orally). In certain embodiments, the system may be administered surgically (e.g., implanted), orally, rectally, vaginally, nasally, or uretherally. In certain embodiments, the system is administered such that at least a portion of the system resides at a location internal to the subject (e.g., the gastrointestinal tract). In some embodiments, the location internally of the subject is the colon, the duodenum, the ileum, the jejunum, the stomach, or the esophagus.

[0270] As described above and herein, in some embodiments, a therapeutic pay load may be released at the location internal to the subject.

[0271] As described above and herein, the article is configured to reside within a subject for at least a period of time. The term residence time period generally refers to the length of time during which the article (or a component of the article) described herein is resided at a location internally of a subject as measured from the time initially present in the location internally of the subject to the time at which the article (or such component of the article being referenced) no longer resides at the location internally of the subject due to, for example, degradation, dissolution, and / or exit of the article or such component(s) of the article being referenced from the location internally of the subject. In an illustrative embodiment, the article may be orally administered such that the article resides at a location internally of the subject such as the stomach above the pylorus and exits through the pylorus into the intestine (e.g., after degradation of at least a portion of the article), where the residence time period is measured as the length of time between when the article initially resides in the stomach and when the article (or a component of the article being referenced) exits through the pylorus.

[0272] In some embodiments, the residence time period of at least a portion of the article is at least about 24 hours, at least about 48 hours, at least about 3 days, at 7 days, at least about 10 days, at least about 1 month, at least about 6 months, or at least about 1 year. In certain embodiments, the residence time period is less than or equal to about 2 years, less than or equal to about 1 year, less than or equal to about 6 months, less than or equal to about 1 month, less than or equal to about 10 days, less than or equal to about 7 days, less than or equal to about 3 days, or less than or equal to about 48 hours. Any and all closed ranges that have endpoints within any of the above-referenced ranges are also possible (e.g., between about 24 hours and about 2 years, between about 24 hours and about 1 year, between about 48 hours and about 7 days, between about 3 days and about 1 month, between about 7 days and about 6 months, between about 1 month and about 1 year). Other ranges are also possible.

[0273] Ingestible and / or implantable low power battery and signaling systems are generally provided. As would be understood by those of ordinary skill in the art, data sent over a wireless medium are generally important as, in some embodiments, the data comprises a user’s (and / or patient’s) private health information. In some cases, a command can invoke the operation of the ingestible device that directly affects the user’ s health just as a therapeutic does. Advantageously, the systems and methods described herein may provide, in some embodiments, secure communication such that only authorized users and / or medical professionals can read sensor data and / or send valid commands to a system. Advantageously, the system and methods described herein may provide, in some embodiments, an energy -efficient security protocol to further improve the wireless communication (e.g., of an ingestible and / or implantable article). In some embodiments, the security protocol advantageously provides data encryption to protect sensor and command information and mutual authentication to prevent unauthorized access to both ingestible and external devices. In some embodiments, the security protocol uses low energy by, at least in part, adopting Speck, a lightweight block cipher that is optimized for software implementation, and symmetric challenge-response protocol as a base protocol.

[0274] In some embodiments, an ingestible and / or implantable electronic article is provided. In some embodiments, the article comprises a capsule suitable for administration to a location internal to a subject.

[0275] In some embodiments, the article comprises a power source.

[0276] In some embodiments, the article comprises a short-range wireless component (e.g., electrical communication with the power source).

[0277] For example, as shown illustratively in FIG. 66, article 100 comprises capsule 110, power source 120, and a short-range wireless component 130.

[0278] In some embodiments, the article comprises a microcontroller. In some embodiments, the microcontroller is configured to duty-cycle the short-range wireless component. In some embodiments, the duty-cycle is greater than or equal to 1 second, greater than or equal to 2 seconds, greater than or equal to 5 seconds, greater than or equal to 10 seconds, greater than or equal to 30 seconds, greater than or equal to 60 seconds, or greater than or equal to 90 seconds. In some embodiments, the duty-cycle is less than or equal to 180 seconds, less than or equal to 90 seconds, less than or equal to 60 seconds, less than or equal to 30 seconds, less than or equal to 10 seconds, or less than or equal to 5 seconds. Combinations of the above-referenced ranges are also possible (e.g., greater than or equal to 1 second and less than or equal to 180 seconds). Other ranges are also possible.

[0279] In some embodiments, the microcontroller is configured for Bluetooth communication. In some embodiments, the microcontroller comprises a wake-up receiver configured as a wireless switch for a Bluetooth transceiver. Other wireless protocols are also possible, as described below.

[0280] In some embodiments, the microcontroller is configured for a periodic wireless connection. In some embodiments, the microcontroller is configured for periodic advertising for a wireless connection.

[0281] In some embodiments, the microcontroller comprises a mutual authentication protocol. In some embodiments, the mutual authentication protocol comprises a symmetric challenge -response protocol. In some embodiments, the mutual authentication protocol comprises a random number generator.

[0282] In some embodiments, the article is configured to send pre-shared authentication keys e.g., to a receiving device, if present, located external to the subject. In some embodiments, the article sends the pre-shared authentication keys the short-range wireless component in electrical communication with the microcontroller. The receiving device may comprise, in some embodiments, a consumer electronic device such as cellular phones (e.g., smartphones, iPhones, Android phones), digital cameras, tablets (e.g., iPads), laptop computers, home automation devices, watches (e.g., smartwatches), and / or desktop computers. However, the articles and methods are not limited to use with consumer-level electronics and may be used with other systems and devices as well.

[0283] In some embodiments, the articles described herein use relatively low energy consumption. For example, in some embodiments, the energy consumption for a 10 day, 30 day, 60 day, or 90 day or greater operation of the article is less than or equal to 500 J (e.g., less than or equal to 400 J, less than or equal to 300 J, less than or equal to 200 J, or less than or equal to 100). For example, in some embodiments, the article described herein may operate for greater than or equal to 90 days and have a total energy consumption of less than or equal to 500 J. Those of ordinary skill in the art would understand that operation of the article generally refers to regular use (e.g., sending / receiving signals, sharing authentication keys, operating a wireless component) of the article (e.g., in accordance with the embodiments described herein).

[0284] In some embodiments, operation of the microcontroller utilizes less than or equal to 1 microJoule, less than or equal to 0.5 microJoule, less than or equal to 0.3 microJoule, less than or equal to 0.2 microJoule, or less than or equal to 0.1 microJoule of power for each authentication (e.g., such that power source has a lifetime at the location internal to the subject of greater than or equal to 10 days, greater than or equal to 30 days, greater than or equal to 60 days, or greater than or equal to 90 days). In some embodiments, operation of the microcontroller utilizes greater than or equal to 0.01 microJoule, greater than or equal to 0.1 microJoule, greater than or equal to 0.2 microJoule, greater than or equal to 0.3 microJoule, or greater than or equal to 0.5 micro Joule of power for each authentication (e.g., such that power source has a lifetime at the location internal to the subject of greater than or equal to 10 days, greater than or equal to 30 days, greater than or equal to 60 days, or greater than or equal to 90 days). Combinations of the above-references ranges are also possible (e.g., less than or equal to 1 microJoule and greater than or equal to 0.01 microJoule).

[0285] In some embodiments, the article comprises various components described herein (e.g., microcontroller, power source, etc.) such that the power source has a lifetime (e.g., power sufficient to operate the device) at the location internal to the subject of greater than or equal to 1 days, greater than or equal to 5 days, greater than or equal to 10 days, greater than or equal to 30 days, greater than or equal to 60 days, greater than or equal to 90 days, or greater than or equal to 180 days. In some embodiments, the power source has a lifetime (e.g., power sufficient to operate the device) at the location internal to the subject of less than or equal to 360 days, less than or equal to 180 days, less than or equal to 90 days, less than or equal to 60 days, less than or equal to 30 days, less than or equal to 10 days, or less than or equal to 5 days. Combinations of the above referenced ranges are also possible (e.g., greater than or equal to 1 day and less than or equal to 360 days). Other ranges are also possible.

[0286] In some embodiments, the ingestible electronic article is configured for gastric residence for greater than or equal to 24 hours. In some embodiments, the short-range wireless component operates at a frequency of greater than or equal to 100 kHz and less than or equal to 3 GHz. For example, in some embodiments, the short-range wireless component operates at a frequency of greater than or equal to 100 kHz, greater than or equal to 500 kHz, greater than or equal to 1 MHz, greater than or equal to 5 MHz, greater than or equal to 10 MHz, greater than or equal to 50 MHz, greater than or equal to 100 MHz, greater than or equal to 500 MHz, greater than or equal to 1 GHz, greater than or equal to 2 GHz, or greater than or equal to 2.4 GHz. In some embodiments, the short-range wireless component operates at a frequency of less than or equal to 3 GHz, less than or equal to 2.4 GHz, less than or equal to 2 GHz, less than or equal to 1 GHz, less than or equal to 500 MHz, less than or equal to 100 MHz, less than or equal to 50 MHz, less than or equal to 10 MHz, less than or equal to 5 MHz, less than or equal to 1 MHz, or less than or equal to 500 kHz. Combinations of the above referenced ranges are also possible (e.g., greater than or equal to 100 kHz and less than or equal to 3 GHz). Other ranges are also possible.

[0287] As described herein, in some embodiments, the structure is configured to adopt a shape and / or size compatible with oral administration to and / or ingestion by a subject. In some embodiments, the structure has a shape with a capacity for folding and / or packing into stable encapsulated forms. For example, in some embodiments the structure is designed to maximally pack and fill a capsule or other soluble container (e.g., a containing structure). In some embodiments, the structure has a shape that maximally fills and / or packs into a capsule or other soluble container.

[0288] In some embodiments, the system comprises the structure and a containing structure. Based on the application, a capsule may be manufactured to particular specifications or a standard size, including, but not limited to, a 000, 00, 0, 1, 2, 3, 4, and 5, as well as larger veterinary capsules Su07, 7, 10, 12el, 11, 12, 13, 110ml, 90ml, and 36ml. In some embodiments, the structure may be provided in capsules, coated or not. The capsule material may be either hard or soft, and as will be appreciated by those skilled in the art, typically comprises a tasteless, easily administered and water soluble compound such as gelatin, starch or a cellulosic material.

[0289] In some embodiments, the capsule is sized and adapted for implantation in and / or ingestion by a subject.

[0290] As will be apparent from the description throughout this disclosure, the invention(s) includes many variations of the above description, not limited to any particular type of electronic component (e.g., microcontroller, PCB, wireless component, etc.).

[0291] In some embodiments, one or more of the electronic components described herein comprises a (micro)controller and / or (micro)processor. In some embodiments, the controller is configured (e.g., programmed) to receive and transmit data commands to / from one or more components of the component and / or the smartphone (or other consumer electronic device). In some embodiments, the data includes one or more signals from one or more sensors. In some embodiments, the controller may be configured to adjust various parameters based on external metrics e.g., in response to a signal from a sensor in electrical communication with the controller.

[0292] The embodiments described herein can be implemented in any of numerous ways. For example, the embodiments may be implemented by any suitable type of analog and / or digital circuitry. In some embodiments, the embodiments may be implemented using hardware or a combination of hardware and software. When implemented using software, suitable software code can be executed on processing circuitry including any suitable processor (e.g., a microprocessor) or collection of processors, whether provided in a single computer or distributed among multiple computers (or other consumer electronic devices). It should be appreciated that any component or collection of components that perform the functions described above can be generically considered as one or more controllers that control the above-discussed functions. The one or more controllers can be implemented in numerous ways, such as with dedicated hardware or with one or more processors programmed using microcode or software to perform the functions recited above. The one or more embodiments can be implemented in numerous ways, such as with dedicated hardware, or with general purpose hardware (e.g., one or more processors) that is programmed using microcode or software to perform the functions recited above.

[0293] In some embodiments, the embodiments described herein comprise wireless capabilities for enabling suitable communication with other devices / sy stems (e.g., for controlling aspects of the electronic component(s), controlling a source of electromagnetic radiation, controlling a sensor or other component). Wireless devices are generally known in the art and may include, in some cases, LTE, WiFi and / or Bluetooth systems. In some embodiments, the systems and / or devices described herein comprise such a wireless device (e.g., a short-range wireless component).

[0294] In some embodiments, the embodiments described herein may be configured to adjust various parameters in response to an input from a user and / or a signal from a sensor and / or an externally located consumer electronic device.

[0295] In some embodiments, the system is associated with and / or comprises a power source. The power source may include any appropriate material(s), such as one or more batteries, photovoltaic cells, etc. Non-limiting examples of suitable batteries include Li- polymer (e.g., with between 100 and 1000 mAh of battery life), Li-ion, nickel cadmium, nickel metal hydride, silver oxide, or the like. In some cases, the battery may apply a voltage (e.g., to a degradable material as described herein) in response to a physiological and / or external metric and / or signal (e.g., by a user). For example, the voltage may be used to trigger the exit of the resident structure by e.g., applying a voltage to thermally sensitive degradable component as described herein. For example, the average magnitude of the voltage applied to the degradable component(s) may be between 0.001 to 0.01 V, between 0.01 to 0.1 V, between 0.1 V and 10.0 V, between 1.0 V and 8.0 V, between 2.0 V and 5.0 V, between 0.1 V and 5.0 V, between 0.1 V and 1.5 V, between 0.1 V and 1.0 V, between 1.0 V and 3.0 V, between 3.0 V and 8.0 V, or any other appropriate range.

[0296] Any electronic component circuitry may be implemented by any suitable type of analog and / or digital circuitry. For example, the electronic component circuitry may be implemented using hardware or a combination of hardware and software. When implemented using software, suitable software code can be executed on any suitable processor (e.g., a microprocessor) or collection of processors. The one or more electronic components can be implemented in numerous ways, such as with dedicated hardware, or with general purpose hardware (e.g., one or more processors) that is programmed using microcode or software to perform the functions recited above.

[0297] In this respect, it should be appreciated that one implementation of the embodiments described herein comprises at least one computer-readable storage medium (e.g., RAM, ROM, EEPROM, flash memory or other memory technology, or other tangible, non-transitory computer-readable storage medium) encoded with a computer program (i.e., a plurality of executable instructions) that, when executed on one or more processors, performs the above-discussed functions of one or more embodiments. In addition, it should be appreciated that the reference to a computer program which, when executed, performs any of the above-discussed functions, is not limited to an application program running on a host computer. Rather, the terms computer program and software are used herein in a generic sense to reference any type of computer code (e.g., application software, firmware, microcode, or any other form of computer instruction) that can be employed to program one or more processors to implement aspects of the techniques discussed herein.

[0298] In some embodiments, the systems described herein are administered to a subject (e.g., surgically, endoscopically, orally). In certain embodiments, the system may be administered surgically (e.g., implanted), orally (e.g., swallowed, endoscopically), rectally, vaginally, nasally, or uretherally. In certain embodiments, the system is administered such that at least a portion of the system resides at a location internal to the subject (e.g., the gastrointestinal tract). In some embodiments, the location internal to the subject is the colon, the duodenum, the ileum, the jejunum, the stomach, or the esophagus. By way of example, and without wishing to be limited by such an exemplary set of embodiments, the system may be administered to a subject orally where it, in some cases, travels to the stomach of the subject, sinks to the bottom of the subject’s stomach.

[0299] In some embodiments, the systems described herein are designed such that the system resides at a location internal to a subject (i.e. a residence time period) for at least 24 hours, at least 48 hours, at least 3 days, at 7 days, at least 1 month, at least 6 months, or at least 1 year. In certain embodiments, the residence time period is less than or equal to 2 years, less than or equal to 1 year, less than or equal to 6 months, less than or equal to 1 month, less than or equal to 7 days, less than or equal to 3 days, or less than or equal to 48 hours. Any and all closed ranges that have endpoints within any of the abovereferenced ranges are also possible (e.g., between 24 hours and 2 years, between 24 hours and 1 year, between 48 hours and 7 days, between 3 days and 1 month, between 7 days and 6 months, between 1 month and 1 year). Other ranges are also possible.

[0300] The following examples are intended to illustrate certain embodiments of the present invention, but do not exemplify the full scope of the invention.

[0301] EXAMPLE 1 Energy-efficient ingestible drug delivery system in the dynamic gastrointestinal environment.

[0302] 1.1. Abstract. Ingestible electronics serve as useful tools for detecting physiological and pathophysiological signals, and providing an alternative therapeutic modality supporting automated and / or external actuation of drug release. These devices are useful especially when treatments cannot be done externally. Moreover, ingestible devices can be easily delivered via oral administration to provide close or direct access to target organs, and do not require invasive surgical procedures associated with implantable devices.

[0303] 1.2. Introduction. Ingestible electronics are promising platforms for on-demand health monitoring and drug delivery. However, these devices and their actuators must operate in the gastrointestinal (GI) environment, which has a pH range of 1 to 8. Drug delivery systems using electrochemical dissolution of metal films are particularly susceptible to pH changes. Optimal operation in this dynamic environment stands to transform our capacity to help patients across a range of conditions. This disclosure describes an energy-efficient ingestible electronic electrochemical drug delivery system to support subjects through operation in this dynamic environment. The disclosed system consists of a drug reservoir sealed with an electrochemically dissolvable gold membrane and an electronic subsystem. An electronic subsystem controls the rate of gold dissolution by sensing and adapting to the pH of the GI environment and provides an option for energy -efficient drug delivery, reducing energy consumption by up to 42.8 %. Integrating the electronics with electrochemical drug delivery enables the proposed system to adapt to the dynamic physiological environments which makes it suitable for drug and / or therapeutic delivery at different locations in the GI tract.

[0304] Developing and using ingestible electronics for clinical applications is challenging due to the constraints on the dimensions of capsules to ensure their safe transit and the limited energy density of power sources. Actuators, which enable diagnostic and therapeutic functions such as drug delivery, biopsy, insufflation, electrical stimulation, and locomotion, are an important part of ingestible electronics but can take up a significant amount of space and energy. Electronically controlled drug delivery actuators, such as micro-pumps and reservoir-based drug delivery systems, can be controlled wirelessly or through preprogrammed algorithms and offer advantages over passive drug delivery methods. The disclosed reservoir-based system is sealed with an electrochemically dissolvable gold film which has a small form factor and low power requirements, and can protect sensitive payloads such as unstable drugs or living cells from the harsh environment of the GI tract due to the hermetic seal provided by the gold film. The disclosed technology is biocompatible, reliable, and safe for use in implantable drug delivery devices. However, the dynamic nature of the GI environment significantly impacts the gold dissolution characteristics, leading to large variations in the gold dissolution time and energy consumption. This may be compensated for with additional sensors and circuitry in order to achieve more reliable actuation.

[0305] Herein is disclosed an energy-efficient drug delivery system based on electrochemical gold dissolution for ingestible electronics. The proposed drug delivery system consists of a drug reservoir sealed with an electrochemically dissolvable gold membrane and an electronic subsystem. The electronics subsystem can control the gold dissolution time and energy by modulating the driving voltage to an optimal level based on the pH level sensed from the GI tract and the user’s command through wireless communication as shown in FIG. 1. The proposed drug delivery system can be used as a platform in any part of the GI tract not only to deliver therapeutics such as drugs or biologies but also to sample GI fluids or to contain biosensors.

[0306] Section 1.3 describes the design of the millimeter- size freestanding gold membrane that seals the drug reservoir and its electrochemical dissolution to release the pay load. The gold dissolution time and energy at different driving voltage have been characterized in the simulated GI fluid at different pH. Section 1.4, describes the electronics that can sense pH and modulate driving voltage to control the gold dissolution time and energy. Section 1.5 describes the fully integrated energy-efficient ingestible electronics drug delivery system and its performance in the ex vivo stomach. Conclusions are provided in Section 1.6.

[0307] 1.3. Design and Characterization of Drug Reservior

[0308] 1.3.1. Design of Drug Reservoir The drug reservoir consists of a plastic reservoir, a dissolvable gold membrane, and a flexible printed circuit board (PCB) as shown in FIG. 2a. The gold membrane seals the reservoir and protects the payload in the reservoir. Upon receiving the release command from the external user, the gold membrane is dissolved electrochemically to release the payload. The gold membrane comprises 300 nm of gold film and 25 pm of SU-8 film. The SU-8 film is patterned photolithographically into a mesh structure with 150 pm by 150 pm openings to provide mechanical support for the gold film. The gold membrane is attached to the plastic reservoir with an adhesive film, and the flexible PCB is electrically connected to the gold film with conductive epoxy. The cathode on the flexible PCB is electroplated with platinum using the pulse plating method. The final diameter of the dissolvable gold membrane exposed to the external environment after encapsulation is 2.4 mm as shown in FIG. 2b.

[0309] 1.3.2. Electrochemical dissolution of gold membrane

[0310] The payload release from the drug reservoir is achieved via the electrochemical dissolution of the gold film. The electrochemical system in the proposed device consists of the anode (gold), the cathode (platinum), and the electrolyte (GI fluid) as shown in FIG. 3a. The gold anode is inert in the GI environment when no electric potential is applied. In the GI fluid which contains chloride ions, when the anode potential is raised to 1.04 V with respect to a saturated calomel reference electrode, the gold oxidizes and dissolves as water-soluble chlorogold complexes. At the platinum cathode, the hydrogen ions reduce to hydrogen gas. The following electrochemical reactions summarize the gold dissolution process.

[0311] Anode (gold): Au(s) + 4CI“(aq) AuCl- 4 (aq) + 3c“

[0312] Cathode (platinum): 2H+(aq) + 2c“ — H2(g)

[0313] The dissolution of the electrochemical gold was characterized in vitro in simulated gastric fluid (SGF) using a potentiostat (DY2000, Digi-Ivy). The driving voltage range for the electrochemical gold dissolution was determined with the linear sweep voltammetry (LSV) technique measured in SGF of pH 1 (100 mM hydrochloric acid) at 35-38°C. An exemplary drug reservoir device, according to one embodiment, is shown in FIG. 2. The current density, which is proportional to the rate of dissolution of gold, begins to rise near 1.1 V and reaches a maxima near 1.5 V as shown in FIG. 4(a). When the driving voltage is higher than 1.5 V, the current density drastically drops due to the passivation of the gold surface. Thus, the driving voltage range to effectively dissolve the gold film is from 1.1 V to 1.5 V.

[0314] 1.3.3. Driving voltage modulation for energy-efficient gold dissolution

[0315] In one set of embodiments, the driving voltage range for gold dissolution occurs in energy-save mode (1.1 V) or fast mode (1.4 V). For each driving mode, the energy and time of gold dissolution was measured in SGF of pH 1 at 35-38°C as shown in FIG. 4b. A gold membrane anode and platinum cathode fabricated on a silicon wafer were used as shown in FIG. 3b. They have the same structure and dimensions as the gold membrane and platinum cathode on the drug reservoir shown in FIG. 2. At higher driving voltage, the dissolution energy is higher but the dissolution occurs at a faster rate. At lower driving voltage, the gold dissolves slower but also consumes less energy. The energy consumption in the energy-save driving mode is 38.8 % lower compared to the energy in the fast mode.

[0316] The pH of the GI fluid varies over a wide range from pH 1 to pH 8 depending on the location in the GI tract and the feeding state. To evaluate the performance of the proposed drug delivery system under these physiological variations, the gold dissolution time and energy at two driving modes were measured in SGF of pH 1 to 4 with a fixed chloride ion concentration of 100 mM as shown in FIG. 4(c). A gold membrane model on a silicon wafer as shownin FIG. 3b was used for this purpose. The dissolution energy and time are negatively correlated over the entire pH range. If the pH and the desired dissolution time are known at the time of payload release, the most energy -efficient driving voltage can be estimated based on the measured data shown in FIG. 4c. To summarize, an energy -efficient gold dissolution can be achieved at the cost of dissolution speed by modulating the driving voltage regardless of the pH level. And vice versa, faster gold dissolution can be achieved at the cost of higher energy consumption. Either one of the two driving modes can be selected based on the application requirements.

[0317] 1.4. Electronic System Design 1.4.1. System architecture and implementation

[0318] FIG. 5a shows the block diagram of the proposed electronic subsystem comprising the following key blocks: a pH sensor, a wireless transceiver (TRx), a 3.6 V battery, a microcontroller unit (MCU), and a voltage driver for gold dissolution (DC-DC buck converter). The pH sensor block includes an ISFET-based pH sensor, a silver-silver chloride reference electrode, and a sensor interface. When the sensor interface applies the appropriate bias to the ISFET (drain current = 100 pA and drain-to-source voltage = 500 mV), the ISFET generates a voltage signal proportional to the GI tract’s pH. This ISFET voltage signal is read by the MCU and used to determine the driving voltage. The output voltage of the buck converter is modulated to the determined driving voltage using the general purpose input / output (GPIO) pins of the MCU. The buck converter was selected as the voltage driver over other types of voltage converters, like a low drop out (LDO) regulator or a switched capacitor voltage converter, because of its high energy efficiency in generating a stable DC driving voltage.

[0319] Each key block of the electronic subsystem is implemented on a circular two- layer PCB with a diameter of 9.6 mm as shown in FIG. 5b. Off-the-shelf components were used for MCU (ATmega328P, Microchip Technology), TRx (SX1231H, Semtech), ISFET-based pH sensor (MSFET 3330M-2, Microsens SA), silver-silver chloride reference electrode (117-23, Creative Materials), and DC-DC buck converter (TPS62841, Texas Instruments). The circular PCBs are inter-connected using electrical wires and the gold membrane of the drug reservoir is electrically connected to the electronic subsystem using flexible connectors. The final assembled capsule with the electronic subsystem and the drug reservoir has comparable dimensions with other commercially available ingestible electronic devices.

[0320] 1.4.2. MCU operation scenario

[0321] A timing diagram for the MCU operation scenario is shown in FIG. 5c. Upon powering up, TRx turns on periodically in intervals of 60 seconds to listen for the delivery signal from an external transceiver while the other blocks remain in a low power, sleep mode to conserve energy. Upon receiving the delivery command, the MCU turns on the ISFET pH sensor and reads the pH value of the GI environment. Taking pH and user’s desired dissolution time as inputs, the MCU determines the driving mode based on the relationship between pH, driving voltage, time, and energy described in FIG. 4c. The MCU turns on the gold dissolution driving circuit and sets the output voltage of the DC-DC buck converter to the driving voltage (1.1 V or 1.4 V) corresponding to the determined driving mode. Prior to the gold dissolution, TRx sends the pH and estimated dissolution time to the user. The driving voltage is applied to the gold membrane of the selected reservoir for the preset dissolution time. Once the gold dissolution is completed, the system sends a signal to the user notifying the completion of the pay load delivery.

[0322] 1.5. Results and Discussion

[0323] 1.5.1. Ex vivo experimental setup

[0324] The prototype was deployed in the stomach harvested from a Yorkshire pig 30 minutes after euthanasia. The method of euthanasia was approved by the Massachusetts Institute of Technology Committee on Animal Care protocol. Pigs were anesthetized prior to euthanasia with an intravenous administration of sodium pentobarbital (~100 mg / kg). To contain SGF in the stomach for the experiment, retort stands and hemostats were used to fix the stomach as shown in FIG. 6. SGF and the prototype were delivered via the upper opening of the stomach. 200 ml of SGF of pH 1 was used in the ex vivo experiment. The stomach and SGF were heated to 35-38°C during the experiment. The delivery signal, carrying the information of the desired dissolution time, was transmitted to the capsule prototype located in the ex vivo stomach from the external transceiver with a 915 MHz panel antenna as shown in FIG. 6.

[0325] 1.5.2. Measurement Results

[0326] The dissolution of the gold membrane on the drug reservoir prototype was evaluated using the proposed electronic subsystem in the ex vivo stomach. The output of the DCDC buck converter and the system ground were connected to the gold membrane and the platinum cathode, respectively. The buck converter applied the selected driving voltage to the gold membrane with respect to the platinum cathode. The dissolution current flowing from the gold membrane anode to the platinum cathode at each driving mode was measured at the output of the buck converter using a current profiler (Power Profiler Kit II, Nordic Semiconductor). The buck converter was powered using a source measurement unit (2450, Keithley). A dissolution current of 15 pA was used as a proxy for the completion of gold dissolution. The dissolution energy was calculated from the measured dissolution current and the driving voltage. The energy consumption at the output of the buck converter is the gold dissolution energy, and the energy at its input comprises of both the dissolution energy and the energy dissipated as heat in the buck converter.

[0327] The dissolution energy in the ex vivo experiment for the two driving modes is shown in FIG. 7a. The dissolution energy in the energy-save mode is 42.8 % less than in the fast mode. The measured results match closely with the in vitro data shown in FIG. 4b. The energy consumption at the input of the buck converter in the energy- saving mode is 37.2 % lower compared to that in the fast mode. This discrepancy in energy consumption at the input and output of the buck converter stems from the variations in the energy conversion efficiency of the converter at different output currents. The energy conversion efficiency of the buck converter in the energy-save and fast mode was measured to be 78.9 % and 90.3 %, respectively. The gold membrane before and after dissolution is shown in FIG. 7b. The proposed system successfully demonstrated two different driving modes for energy-efficient gold dissolution, with the energy savings in the 1.1 V driving mode enabling the operation of roughly twice as many reservoirs, leading to a doubled capacity for drug storage and / or delivery.

[0328] 1.6. Conclusions

[0329] This disclosure describes a dynamic ingestible electronic system capable of supporting the energy-efficient delivery of therapeutics in the changing pH environment of the GI tract using electrochemical gold dissolution. This system includes a drug reservoir that is sealed with an electrochemically dissolvable gold membrane, as well as an electronic system that controls the dissolution of the gold membrane based on the pH level in the GI tract and the user’s command. The electronic system can modulate the driving voltage to optimize the gold dissolution time and energy. The proposed system was tested in an ex vivo porcine stomach and was able to successfully release the payload in a controlled manner. The energy-save mode uses 37.2 % less energy than the fast mode, thereby increasing the number of drug reservoirs that can be operated with same energy by a factor of two, which leads to double the amount of available drug storage or delivery.

[0330] The proposed therapeutic delivery system is a versatile and innovative solution that can be used in any part of the gastrointestinal tract to deliver therapeutics, sample fluids, or contain biosensors. It is capable of delivering multiple types of therapeutics in different chambers, which could provide a number of benefits such as more precise dosing, the ability to reduce the need for multiple medications, and improved patient adherence to treatment regimens. The proposed system can be integrated with a gastric resident structure in order to reside in the stomach for an extended period of time, and it could also incorporate sensors to create a closed loop oral drug delivery system that adjusts the drug delivery in real-time based on the patient’s condition. Its energy efficient design could make it especially useful for long term ingestible devices with multiple functions.

[0331] EXAMPLE 2

[0332] Devices and materials for live cell protection and delivery in the gastrointestinal tract Microbial therapeutics are the next generation of therapies being developed for many diseases (ranging from infectious disease to cancer therapy), however microbes are fragile and are susceptible to damage when dosed orally into the gastrointestinal tract. Current approaches to protect microbial cells during dosing rely on genetic modifications or microencapsulation of microbial cells. However, these approaches do not allow protection and release to be tuned precisely and independently of the specific microbial cells used.

[0333] In some embodiments, the present disclosure relates to devices comprising chambers and films that isolate on-board microbial cells from the outside environment. In other embodiments, the present disclosure relates to films that can be triggered to release the live microbial cells via an electronic or chemical input.

[0334] 2.1. Bacteria sealed in chambers with gold films

[0335] 2.1.1. Optimization of gold films

[0336] The skilled artisan will appreciate that maintaining microbial cell viability following microencapsulation (e.g., within a device comprising chambers) is challenging, as is, controlling the controlled release of said microbial cells from said encapsulation vehicles. It has now been discovered that sealing microbial cells in chambers with low permeability to water vapor sealed with electrochemically triggerable gold films and / or sealing microbial cells in chambers with low permeability to low pH ingress sealed with triggerable pH-dependent polymer films, increases microbial cell viability and permits controlled release of said cells over various time scales.

[0337] In some embodiments, the devices disclosed herein comprise a sub-micron thick gold membrane. Initial experiments showed that while triggerable, the freestanding gold layer was fragile to mechanical perturbations leading to premature ingress of liquid into the chamber. To overcome this challenge, the incorporation of secondary support layers was further explored. Exemplary support layer tested included dissolvable (polyvinyl alcohol [PVA], magnesium) and non-dis solvable (SU-8, polyimide) layers. While the dissolvable layers provided sufficient mechanical support, they suffered from extended dissolution times (>10 hours to days) that were incompatible with the target on-demand actuation of the payload. The non-dis solvable SU-8 layer proved to be functional and led to longer stability of the gold layer (Table 1). An exemplary process for manufacturing and attaching this improved sealing layer is illustrated in FIG. 8.

[0338] Various parameters were investigated including: SU-8 layer thickness, SU-8 mesh size, adhesive, chamber body material, external sealant (see FIG. 8 in green) to improve the mechanical stability. For the SU-8 layer thicknesses ranging from the original 10 pm up to 40 um were explored. Both 25 pm and 40 pm thicknesses showed better handling performance (rigid when free-standing) but 40 pm led to some delamination during layer manufacturing (FIG. 9). Based on this observation, 25 pm was chosen as the improved SU-8 layer thickness that gave the best mechanical robustness to the gold film and handling performance. Various mesh sizes of the SU-8 layer ranging from 150 pm up to 600 pm were also explored (FIG. 10). The mesh size refers to the side length of a square unit cell (FIG. 11). At the SU-8 thickness of 25 pm, the smallest mesh size (150 pm) showed the best performance in improving the mechanical robustness of the gold film (Table 1).

[0339] Table 1. The mechanical stability of the gold film with and without secondary support layers to gold film. The test setup is illustrated in FIG. 12.

[0340] Next, long-term confirmation experiments with various combinations of gold membrane + support layers were conducted. These mock chamber devices were loaded with methylene blue, sealed as indicated and left submerged in simulated gastric fluid, with regular agitation at 37°C for up to 97 days. Chamber integrity was assessed by visual inspection of the outer solution, with blue coloring indication premature release from the chamber. This combination (150 m of SU-8 mesh size + 25 pm of SU-8 mesh thickness + EpoTek 301 adhesive) led to no premature release of the dye before 97 days (FIG. 12, Table 1). Additionally, at the optimized SU-8 thickness, larger mesh sizes also did not show leaks for up to 35 days (FIG. 12, Table 1).

[0341] 2.1.2. Optimization of chamber material

[0342] As disclosed herein, it is now known that the biggest impact on bacterial stability in the context of the bacterial chamber device is moisture ingress. Despite the robustness of the bacterial powder in ideal dry conditions, total loss of viability occurred within 5 days when placed in a chamber device submerged in simulated gastric fluid. Without wishing to be bound by any particular theory, it is now believed that the moisture ingress through the walls of the device occurs via moisture vapor permeation in the bulk plastic. Theoretical calculations were conducted to determine the required moisture vapor transmission rates (MVTR) useful to achieve acceptable performance given the target form factor of the device (FIG. 13). These calculations corroborated the observed experimental results with the initial chamber device material (polymethylmethacrylate, PMMA) which was chosen for ease of device iteration (amenable to laser cutting). Based on these MVTR targets we selected a range of alternate chamber materials including: high density polyethylene (HDPE), polypropylene (PP), fluorinated ethylene propylene (FEP), polyetheretherketone (PEEK), polyetherimide (PEI), cyclic olefin copolymer (COC), aluminum and glass. All these materials have MVTRs significantly lower than PMMA but differ significantly in terms of machinability and adhesiveness (surface energy). Only the aforementioned polymers were selected for further testing due to ease of fabrication, however, the skilled artisan will appreciate that other non-polymer based materials may also be used (e.g., aluminum, glass, etc.).

[0343] Next, the materials were tested for compatibility with the gold sealing method, pre-evaluation with a color indicating desiccant, and final evaluation with the dry bacterial formulations. All materials passed the initial no-bacteria tests. For the bacterial evaluation, two tests were used: Test A, storage of a bacterial tablet and desiccant bead in a device fully made from the target material adhered with the previously chosen film adhesive that is compatible with the gold and Test B, storage of a bacterial tablet and desiccant bead in a device made from the target material but sealed on one side only with the previously optimized thin gold membrane (FIG. 14).

[0344] Most of the materials except for PEI passed test A (Figure 14) with PP and FEP performing the best (lowest variability and highest viability). This test accounts both for the MVTR of the material as well as for the seal quality specific to the material-adhesive interactions which include the as -manufactured surface finish. Next, Test B was applied to PP and FEP. Overall, the test suffered from technical challenges (bulk ingress of fluid) related to the manufacturability of devices in these materials (cannot be laser cut). Nevertheless, one of the FEP test devices showed for the first-time successful retention of high viability of the bacterial formulation in a device submerged in simulated gastric fluid at 37 °C for >10 days. Specifically, the viability observed is comparable (>40%) to the one observed for the formulation when stored in an ideal container (glass vial with surplus desiccant). This result demonstrates that the overall target design is viable and meets the target viability milestone (>10%). Specifically, these tests confirm that a single -300 nm thick gold film is sufficient to protect the bacterial formulation from the outside environment.

[0345] 2.1.3. Electrochemical triggering and release of bacteria via gold films

[0346] The gold films developed to seal and protect the bacteria inside a chamber can also be used for the electrochemical triggering of bacterial release. This additional function requires developing companion printed circuit boards (PCBs) as well as methods to electrically connect the PCBs to the gold films without damaging their sealing properties (FIG. 15) PCB Ver.l

[0347] A key feature of this design is a low-profile connector that allows for the necessarily destructive testing of the payload PCB while allowing reuse of the main control PCB. The board has flexible substrate that will allow conformal adhesion to the gold / SU-8 membrane. The center gold-plated copper ring will be connected to the gold membrane via conductive epoxy or hot solder. The gold cathode at the edge will be plated with platinum.

[0348] PCB Ver.2

[0349] Without wishing to be bound by any particular theory, it is believed that the structure of the flex PCB is a major cause of unreliable encapsulation results. The major change in the new version of the flex PCB is the location of the anode ring; the anode ring was placed at the bottom layer of the flex PCB so that the anode ring is not exposed to the outside (FIG. 15). The anode of the previous version of the flex PCB had a viatype structure, and the proper encapsulation of the sidewall and the annular ring at the top layer was challenging (FIG. 15). The encapsulation area with the new version flex PCB is confined to the junction between the flex PCB and the gold membrane, and is expected to allow the encapsulation process to be more reliable.

[0350] The gold film is electrochemically dissolved to release the payload sealed inside the chamber. The associated electrochemical system consists of the anode (gold membrane), the cathode (ground), and the electrolyte (gastric fluid). The anode, the gold membrane, will be dissolved when a DC driving voltage is applied across the anode and the cathode. The range of the DC driving voltage for the electrochemical gold dissolution was be determined with the cyclic voltammetry (CV) technique measured in 0.01 M HC1 + 90 mM NaCl solution (pH 2). The gold dissolution occurs in the voltage range of 1.2 V to 1.5 V vs. RHE in the 3-electrode system, and 0.8 V to 1.65 V in the 2-electrode system, respectively (FIG. 18). To minimize the total time required for the gold dissolution, the driving voltage for gold dissolution was set at around the peak voltage of 1.65 V in the 2-electrode system, where the dissolution rate is at maximum. However, if the driving voltage is higher than the peak voltage, the reaction rate drops dramatically. To avoid the reaction rate decrease due to the voltage fluctuation that may be caused by circuit or the environmental noise, the supply voltage was set at 1.5 V. The driving voltage waveform can be DC, AC, square pulse, etc, as long as the voltage level stays within the active range.

[0351] Table 2. Standard reduction potential of the electrochemical reactions. E° is reported in the 3 electrode system with respect to the standard hydrogen electrode.

[0352] | Reaction | Equation | EG|

[0353] In addition, the driving voltage of 1.5V can prevent any other side electrochemical reactions such as oxygen evolution reaction (OER) or chlorine gas evolution reaction (CER) and thus minimize the energy consumption. The standard potential of OER and CER are 1.23 V and 1.396 V, respectively, which are higher than the potential for gold dissolution reaction. (Table 2) When a voltage higher than 1.396 V is applied, the supplied energy will be used towards not only gold dissolution but also OER and CER. To improve the energy efficiency (ratio of the energy used towards gold dissolution and the total supplied energy) and minimize the total supplied energy, it is necessary to maintain the driving voltage below the onset potential of OER. The onset potential of OER and CER in the 2-electrode system can be inferred by comparing with the potential in the 3-electrode system. In FIG. 18, the peak voltage difference in the 3- and 2-electrode systems is around 0.15 V, which could be attributed from the cathodic overpotential of Pt for hydrogen evolution reaction (HER) in 2-electrode system. It is known that the onset potential of OER for pure gold electrode is close to 1.65 V vs. RHE and this gives us an approximate onset potential of OER and CER to be 1.8 V and 1.97 V in the 2-electrode system. Thus, by setting the driving voltage at 1.5V in the 2-electrode system, the OER and CER reactions can be avoided, thus minimizing the energy consumption and preventing any toxic chlorine gas generation.

[0354] Next, the electrochemical behavior of gold dissolution at the optimal driving voltage under different conditions was analyzed (FIG. 19). The characteristics of gastric fluid, such as pH or ion concentration, vary over a wide range. For instance, the gastric pH can range from pH 1 to 7. The 1) total energy, 2) average current during the gold dissolution, and 3) total time for the gold dissolution completion under pH 1-4 of SGF to operate the electronic triggering mechanism reliably under various physiological conditions were measured. The total energy is constant at any condition since the amount of gold to dissolve is does not change. The total energy is the multiplication of the voltage and the total charge to be delivered to the gold. The total charge to be delivered to the gold is same as the total number of electrons required to oxidize and dissolve the gold, which is linearly proportional to total amount of the gold to dissolve. Thus, the total energy is constant under any condition at the same driving voltage. However, the average current during the degradation decreases at high pH since the reduction reaction rate of hydrogen ions at the cathode decreases. As the current can be interpreted as the rate of gold dissolution, total time to degrade the gold membrane increases at high pH.

[0355] Next, the electrochemical dissolution of the gold membrane with SU-8 layer was demonstrated at the optimal driving voltage of 1.5 V. (FIG. 20).

[0356] Next, integration of the chambers, gold membranes and custom printed circuit boards with bacteria into a device that can electronically control bacterial release was demonstrated (FIG. 21). These fully integrated tests also allowed direct evaluation of the power requirements compared to theoretically expected values of gold dissolution (FIG. 22).

[0357] 2.1.3. Additional functionalities inside chamber (other than payload delivery) - hydrogen gate, Zn release, hydration sensor.

[0358] Since the printed circuit boards have been demonstrated to successfully couple to the gold films in the geometry of bacterial chambers, these electronic connection can also be used to trigger other functionalities that can interface with the on-board bacterial such as hydration and exposure to additional metal ions (FIG. 23).

[0359] 2.1.4. Polymer-based protection of bacterial chambers from low pH environments and environmental-triggered release.

[0360] Bacterial chambers can also be protected from the outside environment by polymer films. The use of polymers also allows selection of chemical properties (e.g. ionizable groups) to enable environmental-based degradation of the protective polymer film (e.g. exposure to neutral pH) and exposure (and / or release) of the bacterial to the external environment. Traditionally, these types of enteric polymers are used to spray coat tablets to protect small molecules from low pH exposure. As disclosed herein, aspects of the present invention relate to methods and processes comprising solventcasting of free-standing polymer films and adhesive films that allows them to be assembled onto the bacterial chambers at any stage of device assembly. Importantly, this allows inclusion of these protective polymer films next to fragile functional components (e.g. porous filter membranes) without the fouling that would occur through the traditional spray coating process. Additionally, these free-standing polymer films allow loading and sealing of bacterial chambers without exposing the fragile bacterial cargo to solvents (e.g. organic and / or aqueous) normally required in spray coating. FIG. 24 details the assembly process of the polymer films onto bacterial chambers, their protective properties against low pH and ability to dissolve at neutral pH without fouling an underlying porous membrane. FIG. 25 shows the ability of the polymer films to successfully protect the viability of on-board bacteria as well as their function (measured through the presence of a constitutively active bioluminescent genetic circuit) despite being exposed to low pH for an extended period of time.

[0361] EXAMPLE 3

[0362] FIGs. 26-30 generally relate to the testing of tether-based devices to assess in vivo gastric retention of the base station and self-insertion of the satellite into the intestine. The concept of a GLresident system with triggerable disassembly is presented as shown in FIG. 26, according to some embodiments. The differences between tether-based devices and gastric-only based devices (e.g., Star-only) are described (see FIG. 27). In some embodiments, the base of the tethered-base system resides in the stomach and the satellite (e.g., tethered component) in the intestine. In some embodiments, the base and satellite both reside in the stomach with gastric-based devices. In some embodiments, the pH on payload release is neutral in the tether-based devices. In some embodiments, the pH on pay load release is acidic (e.g., low pH) in the gastric-based devices.

[0363] A percutaneous endoscopic gastrostomy (PEG) testing platform was used evaluate the tether-based device designs, as shown in FIG. 28, according to some embodiments.

[0364] Various modes of failure observed for tether-based devices are shown, as illustrated in FIG. 29. For example, in some embodiments, the tether-based devices failed via fast reflux of large diameter tubes. In some embodiments, the tether-based devices failed via delayed reflux. In some embodiments, the tether-based devices failed via tangling of small diameter tubes; and in some embodiments, the tether-based devices failed due to the nitinol wire escaping the silicone tube.

[0365] In vivo results of tether-based devices inserted into the stomach of 50-80 kg pigs over a period of 3 to 10 days are presented in FIG. 30. The tether length was varied from about 30 cm to about 80 cm, according to some embodiments. In some embodiments, the tether diameter was varied from about 0.6 mm to about 4 mm, according to some embodiments. Exemplary tether materials tested, include, but are not limited to, polyurethane, silicone, and nitinol in silicone tubing. In some embodiments, the device was anchored using the PEG tube. In other embodiments, the device was anchored using a Gl-resident short star. In some embodiments, the satellite device tested was about 5 mm x 5 mm to about 16 mm x 8 mm. In some embodiments, no satellite device was tested. In some embodiments, tether-based devices comprising a tether length of 30 cm, a tether diameter of 0.94 mm, a tether material of nitinol in silicone tubing, and a satellite device about 5 mm x 5 mm that are anchored to the stomach using a Gl-resident short star comprising are retained within the SI for at least 10 days.

[0366] EXAMPLE 4 FIGs. 31-37 generally relate to gastric-only devices with ultra-long gastrointestinal tract (GI) residence times. FIG. 31 illustrates the benefits of gastric-only devices, according to some embodiments. As described in FIG. 31, tether-based devices are useful for small payloads and small accessory subsystems; whereas gastric-based devices (e.g., star-only) are useful for larger payloads and accessory subsystems, according to some embodiments.

[0367] FIGs. 32a and 32b illustrate gastric-only device design and prototyping according to some embodiments. For example, in some embodiments, the cross-section of the armcoupling and disassembly mechanism is presented. In other embodiments, the positioning and placement of the nitinol arms with coupling holes is presented. In some embodiments, the positioning and placement of the pinned arm couple plate described. In other embodiments, the number of arms (e.g., 2 arms, 3 arms, etc.) and the angle thereinbetween (e.g., 120 degrees, 180 degrees, etc.) are also presented.

[0368] FIGs. 33a and 33b illustrate common failure modes for the gastric-only devices and mitigation strategies to overcome said failures. For example, in some embodiments, devices may comprise a third arm to mitigate an observed passage risk (e.g., premature passage into the small intestine).

[0369] FIG. 34a illustrates modeling studies were performed to identify the bend radius that induced the least amount of fatigue. The results from this example are provided in FIG. 34. For example, FIG. 34a shows that modeling studies were performed for devices having a 0 mm bend radius (e.g., sharp edge), a 1 mm bend radius, and a 2.2 mm bend radius, according to some embodiments. FIG. 34a also shows that devices with a 2.2 mm bend radius did not exhibit fatigue during in vitro testing and remains intact following retention for 46 days within a pigs stomach, according to some embodiments. FIGs. 34b and 34c show cycles until failure of devices with non-passivated and passivated arms. Fig. 34d shows a PEEK arm holder where the NiTi arms are passivated with PEEK. The arms are coupled to the capsule with a PEEK arm holder with a 2 mm bend radius. In vivo images are shown and demoinstrate the reliability of the passivated arms for ultralong residency in vivo.

[0370] FIG. 35 shows results of device integrity of gastric-only devices following 36 days of gastric residency in the stomach of swine. Exemplary gastric devices tested comprised a 1 mm bend radius, as described elsewhere herein. Following 36 days in residence, one of three devices exhibited an arm failure and all three device moisture indicators suggested humidity ingress occurred, according to some embodiments.

[0371] FIG. 36 shows device integrity of gastric-only devices between 0 days and 62 days of gastric residency in the stomach of swine. In some embodiments, devices with a 2.2 mm bend radius remained intact in the stomach for at least 62 days (top row of pictures). In some embodiments, devices with a 1.5 mm bend radius remain intact in the stomach for at least 19 days (bottom row of pictures). In some embodiments, devices with a 2.2 mm bend radius remain intact in the stomach for at least 14 days. In some embodiments, the device migrates to the pylorus after about 19 days in residency. In some embodiments, the device migrates to the S.I. after about 26 days of residency. In some embodiments, the device does not cause adverse reactions (e.g., inflammation) after at least 62 days gastric residency.

[0372] FIG. 37 shows a failure analysis and redesign of an exemplary gastric-only device, according to some embodiments. As shown in FIG. 37, the first design iteration exhibited device failure in vivo due to separation of the arms from the device body (see x-ray images at day 17). The arms appeared intact without fatigue failure. In some embodiments, device failure was overcome by redesign of the attachment point as shown in FIG. 37 (see CAD images and photomicrograph in right bottom image). In some embodiments, redesigned devices remain intact following at least 35 days gastric residence (see bottom left image).

[0373] EXAMPLE 5

[0374] FIGs. 38-42 generally relate to the actuation of disassembly of an exemplary gastric-only device as contemplated herein, according to some embodiments. FIG. 38 shows an exemplary actuation mechanism for the disassembly of the gastric-only devices comprising a top port comprising degradable dowel and gold film and a bottom port comprising a metal coupling dowel, degradable sugar, and gold film. In some embodiments, the device port design (e.g., top port and bottom port) is assembled as illustrated in FIG. 38 (see 1. Assembly). In some embodiments, the device retention within the stomach is achieved as illustrated in FIG. 38 (see 2. Retention). In some embodiments, device disassembly is triggered as illustrated in FIG. 38 (see 3. Disassembly Triggered). In some embodiments, the device falls apart as illustrated in FIG. 38 (4. Fall apart). As shown in FIG. 38 (4. Fall apart), in some embodiments, the “cap” or “top port” dissociates from the primary body of the capsule. As used herein, the term “cap” or “top port” are synonymous and may refer to any segment of the capsule configured to dissociate from the primary capsule body. In some embodiments, the cap dimension 1 is about 9 mm. In some embodiments, the cap dimension 2 is about 9 mm. In some embodiments, the body dimension 1 is about 11 mm. In some embodiments, the body dimension 2 is about 29 mm. In some embodiments, the one or more arms dimension 1 is about 3 mm. In some embodiments, the one or more arms dimension 2 is about 29 mm. In some embodiments, the device disassembly time is less than 10 minutes. In some embodiments, the device disassembly time is less than 15 minutes.

[0375] FIG. 39 shows a graphical illustration of an exemplary actuation mechanism of device disassembly, according to some embodiments. In some embodiments, the mechanism for separating the top port from the bottom port, which allows the arms to disengage, is illustrated in a series of CAD drawings as shown.

[0376] FIG. 40 describes the in vivo delivery, disassembly and passage of at least one exemplary gastric-only device in a large animal survival model, according to some embodiments. In some embodiments, FIG. 40 (from top left to bottom right) shows (i) x-ray images indicating that the at least one device is intact in the stomach after delivery (see Benchtop evaluation and delivery), (ii) x-ray and endoscopic images indicating that the at least one device is still intact following 1 day after delivery (see In vivo evaluation after 1 day), (iii) endoscopic images showing bubbles were released following remote triggered disassembly of the at least one device (see Triggering disassembly in vivo), (iv) endoscopic images showing the cap separating from the body following in vivo triggered disassembly (see Monitoring), (v) photographs of the at least one device post-retrieval indicating that electrodes degraded and cap separated but arms were still intact, and (vi) photographs of the at least one device after a 37 °C water soak indicating incomplete disassembly in acute terminal setting.

[0377] FIG. 41 describes the in vivo delivery, disassembly and passage of at least one second exemplary gastric-only device in a large animal survival model, according to some embodiments In some embodiments, FIG. 41 (from top left to bottom right) shows (i) x-ray images indicating that the at least one second device is intact in the stomach after delivery (see Benchtop evaluation and delivery), (ii) x-ray and endoscopic images indicating that the at least one second device is still intact following 2 day after delivery (see In vivo evaluation after 2 day), (iii) endoscopic images showing bubbles were released following remote triggered disassembly of the at least one second device (see Triggering disassembly in vivo), and (iv) x-ray images showing (a, left) the capsule body only in small intestine (SI) (e.g., no arms) and (b, right) at least one arm present in the colon, with the other two arms appearing to have passed fully through the animals digestive tract.

[0378] FIG. 42 shows the results of additional in vivo studies performed using other exemplary gastric-only devices, according to some embodiments. In some embodiments, FIG. 42 (top, left to right) shows (i) x-ray images illustrating that exemplary devices remain intact following delivery to the stomach, (ii) a photograph of a retrieved exemplary device that failed to disassemble following remote triggering after 9 days residency in the stomach, and (iii) photographs of said exemplary devices following in vitro disassembly and subsequent failure analysis which revealed that the SS dissolved within 1.5 hours and disassembly took between 4-5 hours. In some embodiments, FIG. 42 (bottom, left to right) shows endoscopic and x-ray images of intact exemplary devices within the stomach after delivery and photographs of retrieved devices following 4 days of gastric residency. In some embodiments, failure analysis reveals that the stainless steal port was intact but that leakage was likely through the cap / capsule seam.

[0379] EXAMPLE 6

[0380] FIGs. 43-50 generally relate to the gastric retention studies and triggered disassembly studies performed as of the filing date of the present disclosure. For example, FIG. 43 provides a list of in vivo retention studies and in vivo triggered disassembly studies completed are presented.

[0381] FIG. 44. shows a plot of the study number as a function of the total number of days devices were in gastric residency, according to some embodiments.

[0382] FIG. 45a shows a table summarizing the arm coupling geometries tested, the number of arms employed, the arm lengths tested, whether or not the device passed through an animals stomach (or failed), and the number of days the intact device was retained in the gut of a test animal without failure, according to some embodiments. FIG. 45b shows data of three independent in vivo studies of gastric residence, according to some embodiments. FIG. 45c provides a table and plot summarizing the retention time of various article designs within a pig stomach, according to some embodiments.

[0383] FIG. 46. shows an overview of the localization tracking from gastric retention to disassembly and passage of exemplary gastric-only devices, according to some embodiments. As shown in FIG. 46 (left) CAD drawings illustrate the device in the deployed position and following disassembly, according to some embodiments. FIG. 46 (middle) shows CAD drawings illustrating the release mechanism that separates the cap from the body, according to some embodiments. FIG. 46 (right, top) shows a drawing illustrating oral delivery of an exemplary device and x-ray images confirming device integrity following said oral delivery, according to some embodiments. FIG. 46 (right, bottom) shows a drawing illustrating a disassembled device and endoscopic photographs confirming disassembly following remote triggering, according to some embodiments. In some embodiments, the cap dimension 1 is about 9 mm. In some embodiments, the cap dimension 2 is about 9 mm. In some embodiments, the body dimension 1 is about 11 mm. In some embodiments, the body dimension 2 is about 32 mm. In some embodiments, the one or more arms dimension 1 is about 3 mm. In some embodiments, the one or more arms dimension 2 is about 33 mm.

[0384] FIG. 47 shows the mechanical disassembly of the gastric-only device, according to some embodiments. FIG. 47 (left) shows CAD drawings illustrating the degradable linking dowels, coupling pins, and nitinol arms with coupling holes, according to some embodiments. FIG. 47 (middle) shows CAD drawings of the disassembly of the cap from the body of the capsule, according to some embodiments. FIG. 47 (bottom) shows a series of endoscopic photographs illustrating device disassembly following remote triggering, according to some embodiments. FIG. 47 (top, right) provides a table describing the time to trigger dowel dissolution and arm removal from said devices, according to some embodiments.

[0385] FIG. 48a shows the results from a series of benchtop device integrity tests, according to some embodiments. FIG. 48a (left) shows the results from a sealed moisture ingress test at day 164, according to some embodiments. FIG. 48a (middle) shows the results from a disassembly ingress test following days 0, 14, and 17, according to some embodiments. Partial disassembly was observed at day 14 and full disassembly at day 17 when exposed to SGF at 37 °C, according to some embodiments. FIG. 48a (right) shows the results from a fatigue test in which devices were soaked in SGF at 37 °C prior to fatigue testing, according to some embodiments. FIG. 48b shows another sealed moisture ingress test. The device was a sealed polypropylene capsule and had a relative humidity of less than 60% at least until day 264. The device failed between days 264 and 275.

[0386] FIGs. 49a and 49b show the results from the fatigue test described in FIG. 48a (right), according to some embodiments.

[0387] FIG. 50 shows an overview of the decision tree used to evaluate the tethered gastric devices, according to some embodiments.

[0388] EXAMPLE 7

[0389] FIGs. 51-53 generally relate to articles with payload volumes of >120 pF (>20 pL per dose). Design requirements for the pay load chamber for an exemplary device are described in FIG. 51.

[0390] FIG. 52 illustrates the differences between an exemplary tethered device and an exemplary gastric-only (e.g., star-only) device. In some embodiments, the tethered device comprises a capsule comprises a base station and a statellite, wherein the satellite is tethered to the base station (e.g., tethered design). In some embodiments, the gastric only devices comprises a capsule comprising the base station and the satellite, wherein the satellite is on-board the base station (e.g., gastric-only design). In some embodiments, the gastric-only design allows delivery of the target dose and larger accessory subsystems than tethered designs.

[0391] FIG. 53 illustrates an exemplary gastric-only device, according to some embodiments. In some embodiments, the device comprises a metal-sealed polypropylene chamber comprising a payload (FIG. 53b), wherein the payload is released via electrochemical dissolution of the metal seal.

[0392] EXAMPLE 8

[0393] FIGs. 54-60 generally relate to articles with payloads that are stable for > 60 days in vivo. FIG. 4 highlights the key design requirements for maintaining payload stability within the pay load chamber, according to some embodiments. Without wishing to be bound by any particular theory, it is generally believed that maintaining payload stability is due, at least in part, to (i) the intrinsic stability of the payload (e.g., bacteria), (ii) the permeability of the chamber materials, and (iii) the mechanical robustness of the triggerable seal (see FIG. 54).

[0394] FIG. 55 shows several plots illustrating stabilization of biological payloads (e.g., E. coli Nissle 1917) with species-specific materials (e.g., maltodextrin, melibiose, etc.), according to some embodiments. In some embodiments, formulations comprising species-specific materials allows these payloads to survive drying, elevated temperatures, organic solvents and even ionizing radiation and allows these payloads to undergo tableting and pharmaceutical methodologies involving organic solvents as described by Jimenez et al. “Synthetic extremophiles: Species- specific formulations for microbial therapeutcis and beyond” bioRxiv 2022.1130.518573, which is herein incorporated by reference in its entirety. In some embodiments, the species-specific materials comprise melibiose, maltodextrin, caffeine, yeast extract, and / or combinations thereof (e.g., melibiose and yeast extract). For example, FIG. 55a shows the percent viability of E. coli Nissle 1917 formulated with Form D powder (which comprises a mixture of melibiose and caffeine) is preserved (e.g., nearly 100% viability), relative to the viability of formulations comprising maltodextrin (< 0.01% viability) and melibiose (e.g., < 10% viability). FIG. 55b also shows that the temporal dynamics of E. coli Nissle 1917 viability is prolonged at 37°C over a 210-day period when formulated with Form D and Form E, relative to maltodextrin and melibiose alone.

[0395] FIG. 56 demonstrates incorporation of enteric polymers into the articles of the present disclosure, according to some embodiments. Any suitable enteric polymer known to those of skill in the art are contemplated herein. In some embodiments, enteric polymers are useful for protecting a payload (e.g., bacterial cell or drug) from gastric fluids of the stomach. For example, FIG. 56a shows a photograph illustrating that pH sensitive beads coated with enteric films remain green, indicative of neutral pH, when exposed to simulated gastric fluid (SGF) for 18 hrs. On the other hand, the same uncoated beads turn red, indicative of an acidic pH, under the same conditions. FIG. 56b further shows that bacteria-containing capsules coated in enteric films maintain high cell viability when exposed to SGF or simulated intestinal fluid (SIF), whereas unprotected capsules exhibited significant loss in viability when exposed to SGF.

[0396] FIG. 57 shows results of an experimental validation study evaluating the effect of the moisture vapor transmission rate (MVTR) on bacterial chamber performance, according to some embodiments. For example, FIG. 57 shows exemplary results from the study, which suggests, polypropylene can serve as the chamber material, according to some embodiments.

[0397] FIG. 58 shows bacterial cell viability data as a function of time and chamber material according to some embodiments. In some embodiments, the effect of chamber material on cell viability can be assessed using a setup shown in FIG. 58a, in other embodiments, the effect of chamber material on cell viability is assessed using a set up in FIG. 58b. Regardless of the setup, the results repeatedly show that bacterial cells loaded into chambers comprising polypropylene (e.g. PP) exhibit the highest cell viability following either 22 days (FIG. 58a) or 10 days (FIG. 58b) days of exposure to SGF.

[0398] FIG. 59 shows bacterial cell viability data as a function of time and metal film mechanical robustness, according to some embodiments. In some embodiments, the metal film is a gold film. In some embodiments, the gold film has a thickness of greater than 10 microns. In some embodiments, capsules having gold films having a thickness of greater than 10 micron exhibit improved cell viability both in vivo and in vitro. For example, FIG. 59a shows that capsules with sealed chambers exhibit greater cell viability in vitro and in vivo compared to capsules with exposed chambers. FIG. 59b shows that metal films with thickness of 1 micron or less have tears that render the chamber exposed. FIG. 59c shows the capsule at 0- and 5-days post ingestion.

[0399] FIG. 60 shows bacterial cell viability data as a function of stainless-steel seal geometry, according to some embodiments. In some embodiments, the stainless- steel seal comprises a hard-edge geometry. In some embodiments, the stainless-steel seal comprises a tapered-edge geometry. In some embodiments, the stainless- steel seal comprises a no support geometry (FIG. 60a). FIG. 60c shows that the percent cell viability is highest for capsules comprising the tapered edge geometry.

[0400] EXAMPLE 9 FIGs. 61-65 generally relate to articles capable of releasing a payload via a triggerable release mechanism (e.g., an electronic trigger signal). FIG. 61 illustrates additional key design requirements for releasing the payload via an electronic signal, according to some embodiments. As described in FIG. 61, and without wishing to be bound by any particular theory, it is generally believed that releasing the payload via electronic signal requires (i) a low energy system, (ii) a robust chemical environment (e.g., pH change), and (iii) a reliable release mechanism.

[0401] FIG. 62 demonstrates the use of electrochemical dissolution of a metal seal as a low energy system for payload release, according to some embodiments. In particular, FIG. 62a shows an illustration depicting the electrochemical reactions involved in the dissolution of gold when exposed to gastric fluid. FIG. 62b shows a computer automated drawing (CAD) illustrating an exemplary design integrating the gold membrane with MVP electronics via a PCB wrap-around to enable a current to be applied to the gold membrane. FIG. 62c shows the photographs of the final assembly of the exemplary device as described in FIG. 62b.

[0402] FIG. 63 shows the efficacy of electrochemical dissolution as proposed in FIG. 62, according to some embodiments. FIG. 63a shows a plot of the current as a function of time for an exemplary device (e.g., similar to devices described in Example 12). FIGs. 63b and 63c show photographs of the seals following electrochemical dissolution. Devices used in FIG. 63b were sealed with a first sealing method and devices used in FIG. 63c were sealed using a second sealing method. Comparison of FIGs. 63b and 63c reveals that membranes sealed with the second sealing method were more uniformly dissolved related to those sealed using the first sealing method (e.g., the “previous sealing method” as recited in FIG. 63c). This example demonstrates that electrochemical dissolution of the metal seal allows low energy actuation (e.g., < 50 mJ per trigger), according to some embodiments.

[0403] FIG. 64 illustrates the use of a Ag / AgCl counter electrode to reduce pH dependent dissolution time is presented. FIG. 64a shows a photograph of an exemplary device with a gold membrane anode and a platinum black cathode. FIG. 64b shows a plot of the total energy dissipated as a function of pH, a plot of the total dissolution time as a function of pH, and the average dissolution current as a function of pH. From these plots it is clear that lower pHs favor faster dissolution times, and produce higher energies and higher dissolution currents. FIG. 64c shows that use of a gold membrane anode and a gold chloride cathode reduces the pH dependence observed with the gold / platinum system.

[0404] FIG. 65 shows results from an efficacy study using the electrochemical dissolution mechanism, according to some embodiments. FIG. 65a shows a series of graphics illustrating the experiment as conducted. For example, the leftmost panels (top and bottom) illustrate a control sample in which a bacterial pill (e.g., free bacteria that is not loaded within a chamber) is added to a solution of PBS. The middle panels (top and bottom) illustrate a bacterial payload within a chamber sealed with a metal seal connected to a battery. The rightmost panels (top and bottom) illustrate dissolution of the seal and release of the bacterial payload. FIG. 65b shows a plot of the release kinetics of the control and test samples. In particular, bacterial release from the pill was faster and more uncontrolled than bacteria released from the triggered device.

[0405] EXAMPLE 10

[0406] Energy-Efficient Lightweight Security Protocol

[0407] In typical wireless communication, the transmitted / received information may be vulnerable to being eavesdropped on by nearby devices other than the intended recipient. Under a more adverse scenario, another device can inject its data into the shared messages, making the two devices think they are communicating securely with one another (man-in-the-middle attack). In wireless communications, in some cases, interception of data may be inevitable. Hence, mutual authentication is generally desirable between an external device and an ingestible device to prevent over-the-air messages from being understood or controlled by unknown devices.

[0408] An energy-efficient mutual authentication protocol was implemented based on a symmetric challenge -response protocol to protect our ingestible system from wireless security attacks. In one example, protocol was implemented on the ARM Cortex-M4 microcontroller of the Bluetooth Low Energy (BLE) chip (Nordic Semiconductor, nRF52832). The protocol is elaborated in FIG. 67. Here the ingestible device and the external device have already agreed upon a common pre- shared key, and the mutual authentication is done by proofing its possession. In more detail, FIG. 67 shows (i) The authentication is initiated by the ingestible device sending a cryptographically secure 64-bit random number RA to the external device as a challenge. Generally, the RA may be non-repeatable, (ii) On the externaldevice end, the device generates another independent cryptographically secure 62-bit random number RB. Upon receiving RA, the external device concatenates RA, RB, and the 2-bit user’s command (cmd). The concatenation of RA, RB, and cmd, in this specific order, is denoted by RA||RB||cmd and is 128 bits in length (64 + 62 + 2 bits). Finally, the external device encrypts this concatenated value with the pre-shared key to generate a 128-bit Ci and shares it back to the ingestible device.

[0409] (iii) The ingestible device, upon receiving Ci, decrypts it and verifies its correctness by comparing the most significant 64 bits of the decrypted data with RA. If Ci was corrupted during transmission, the above matching would fail with extremely high probability; hence, any data corruption would be detected. In the case of mismatch of RA, the authentication fails, and the ingestible device closes BLE connection to reduce unnecessary energy consumption. In this example, only the party possessing the key can successfully perform the correct encryption / decry ption. Hence, receiving the correct encrypted value indicates that the other party communicating possesses the same key.

[0410] (iv) Conversely, if RA is verified, the ingestible device authenticates the external device and performs the received command, such as therapeutic release. Then, the ingestible device re-sends a message C2 made by encrypting RB, RA, and its response (ack) (in this order). Again, the external device decrypts this message and checks its validity by verifying whether RB is received correctly.

[0411] The principal idea of the protocol is that every execution involves random numbers (RA and RB) generated by each party. So, no two sets of messages exchanged between both parties are the same (thus, preventing any replay attack).

[0412] To summarize, only three times of data transmission is necessary for mutual authentication and data exchange of command (cmd) and corresponding response (ack), thus making it practical for low-power implementation.

[0413] A. Energy -Efficient Cryptographic Implementation

[0414] The implementation described generally uses Advanced Encryption Standard (AES). AES is a symmetric encryption algorithm that was selected in 2001 by the National Institute of Standards and Technology (NIST). However, in recent years, lightweight ciphers have grown in popularity because of their low area / power / latency requirements. Hence, a Speck cipher was used in this Example. Speck is generally a family of lightweight block ciphers publicly released by the National Security Agency (NS A). The rationale for choosing Speck is that it is optimized for performance in software implementations. Based on the embedded implementation on the ARM Cortex- M4 microcontroller (Table I), Speck required more than 6x less energy for encryption and 18x less energy for decryption as compared to AES with the same 128-bit security level.

[0415] Table I. Performance Comparison between Embedded Implementations of AES and Speck

[0416] B. Generation of Cryptographically Secure Random Numbers

[0417] In order to effectively generate cryptographically secure-random numbers, the existing implementation of the Speck cipher was used as a Pseudo-Random Number Generator (PRNG). It generates pseudo-random numbers by encrypting a counting variable (counter). The value of the counter increases by one whenever the BLE radio is newly connected and requires a new random number.

[0418] In conclusion, the energy-efficient security protocol prevents eavesdropping from unauthorized devices. To prolong the lifetime of the ingestible device, the protocol is implemented in low energy by applying a lightweight cipher, Speck, and a base protocol of symmetric challenge-response without compromising the security level. The security protocol enables stable and secure wireless communication at 2.4 GHz that allows authorized users to access their own ingestible devices by using their mobile devices with BLE.

[0419] EXAMPLE 11

[0420] This example demonstrates the (1) choice of wireless communication method; 2) implementation of a duty-cycling-based low-power communication system and its energy estimation; 3) analysis of the energy budget by considering capsule form factor and battery solutions.

[0421] Wireless communication methods.

[0422] To be applied to ingestible electronics, wireless communication should generally be possible through across 10 cm of tissue by considering the distance between the ingestible device and the external transceiver while minimizing the power consumption. Its transceiver and devices may be small enough to be implemented in a 000 capsule with the form factor of ~9.9 mm X 26 mm (or form factor consistent with FDA-approved ingestible electronics like a video capsule endoscope). It may be tolerant to misalignment in consideration of the free movement of the capsule inside the stomach. It is important to minimize the number of external devices for user convenience.

[0423] By considering these requirements, wireless communication sources were evaluated that have been used for implantable systems and have device dimensions smaller than a 000 capsule to guide our solution for the ingestible electronic device. First, magnetic fields and infrared sources may present some field challenges for this application since they generally require strict alignments of fields or a narrow beam. Importantly, large 1 xl x0.5 inch rare earth magnets are often carried by service men / women. Therefore, this may represent a potential alternative for actuation / triggering. Ultrasound may overcome the alignment requirements through animal tests in pigs, but it generally requires the user to carry external devices including a transducer. As such, efforts focused on radio-frequency (RF) communication. And within RF communication it is important to note that 433-MHz carrier frequency (a commonly used frequency for device communication), the user would potentially need to carry an external transceiver operating at 433 MHz (if they don’t carry one already) in addition to a mobile phone as standard mobile phones generally do not provide 433-MHz band communication. On the other hand, Bluetooth Low Energy (BLE) uses a 2.4 GHz ISM band, and it can directly communicate with a mobile phone system that users already carry. Also, BLE systems have a smaller antenna than 433-MHz antennas given their shorter wavelength. Therefore, BLE was chosen for our ingestible electronics system.

[0424] FIG. 68 shows a comparison between wireless communication sources that are applicable to implantable electronics.

[0425] Implementation of duty-cycled BLE system.

[0426] As described above, RF communication using BLE reduces the burden of carrying external devices by enabling direct communication between the mobile phone and ingestible electronics and alleviates the requirements on strict alignment between devices, maximizing user convenience. Its antenna size is generlaly smaller than those of sub-GHz transceivers thanks to shorter wavelength and chip-type commercial antennas can be as small as 3.2 mm x 1.6 mm. The use of a small antenna makes it possible to implement BLE transceiver inside a 000 capsule.

[0427] Its high carrier frequency of 2.4 GHz requires the circuit speed to be higher, which leads to high power consumption. For instance, an exemplary BLE device named nRF52832 from Nordic Semiconductor consumes a 5.3 mA peak current in TX mode with 0 dBm output power and 5.4 mA peak current in RX mode. To be more specific, the current consumption during advertising mode with 20-msecond interval already reaches 359 uA on average, which leads to 1.11 mW by considering 3.1 V supply voltage (e.g., from two silver oxide batteries in series connection). In this case, the energy consumption for 60 days is estimated to be about 5769 J, and this is over 9 times higher than the capsule energy budget (625 J).

[0428] To reduce the energy consumption, two different strategies were implemented: (1) wake-up approach and (2) duty-cycling approach. For the wake-up approach, the wake-up receiver works as a wireless switch that turns on the BLE transceiver. This approach reduced the overall power consumption since a power-hungry circuit of commercial BLE can be almost always turned off while the low-power wake-up receiver is on to receive communication request. Since the wake-up receiver is mostly turned on, it is generally important to reduce its power consumption. To implement a low-power wake-up receiver with off-the-shelf solutions, other communication sources with lower carrier frequency and higher channel gain compared to RF signal such as ultrasound may be used. The duty-cycling approach was added to the BLE system to make it meet the low-energy requirement for ingestible electronics. Here the capsule BLE is duty-cycled and advertises itself periodically for the possible scanning event from mobiles to enable the BLE connection. Mobile’s scanning may last long enough to be aligned with the capsules advertisements, and this increases the latency involved in establishing a communication link. With a lower duty ratio, the overall energy of the ingestible electronics generally decreases as a function of longer latency, without wishing to be bound by such theory.

[0429] FIG. 69 shows the overall block diagram of an exemplary system, including the mobile and ingestible electronics. The BLE component has an internal module called the Real-Time Counter (RTC), and this module can use the system clock to generate timing events every 60s while only consuming 2 uA. These low-frequency timing events were used to control the BLE radio activity and briefly enable advertising once per RTC period, which is known as “duty cycling.”

[0430] In exemplary BLE design, the capsule BLE works as a server that stores data internally, and mobile BLE works as a client that can access data inside a capsule remotely. At the same time, the mobile BLE works as a central device (called initiator after BLE connection) which scans for Bluetooth devices to connect. The capsule BLE works as a peripheral device (called responder after BLE connection) which can be scanned by the mobile BLE.

[0431] As shown in FIG. 70, the capsule BLE advertises itself by sending 5 continuous advertising packets over 1 second as a peripheral and repeats advertisement every 60 second. Mobile BLE performs on-demand scanning according to the user input to mobile application as a Central. Once two events of advertising and scanning are aligned together, two BLE devices can be connected and perform data communication to receive a command from the mobile and to receive a corresponding response from the capsule. As described above, by increasing the duty cycling period (Tadv_event), the on- average power of radio operation decreases, and the system power consumption is further reduced. 60 seconds was chosen as Tadv_event for the design, but other duty cycles are also possible.

[0432] Security enhancement in BLE communication using mutual authentication.

[0433] In BLE communication, information is generally shared over the air, and it can be seen by nearby devices other than the intended recipient (passive eavesdropping). Furthermore, an attacking device can inject its own data before passing the message along, making the two devices think they are communicating securely with each other (man-in-the-middle attack or active eavesdropping). In wireless communications, interception of data may be inevitable. Hence, mutual authentication is useful between the mobile and the capsules BLEs to prevent over-the-air messages from being understood or controlled by unknown devices.

[0434] To protect the system from eavesdropping, an energy-efficient mutual authentication protocol based on a symmetric challenge-response protocol. The protocol was implemented on the ARM Cortex-M4 microcontroller of the BLE chip. Her,e capsule and mobile have the pre-shared key and authentication is done by proofing the possession of this secret key. To be specific, unilateral authentication was used as follows:

[0435] Capsule -> Mobile : rA(challenge)

[0436] Capsule <- Mobile : EK(rA) (response)

[0437] Capsule-. DK(EK(rA)) (proofing)

[0438] The capsule sends a random number (r^) to the mobile as a challenge. Then, mobile encrypts rAusing the pre-shared key and encryption algorithm. It then sends the key back to the capsule as a response. If the mobile used the pre-shared key and the same encryption algorithm that the capsule is using, then the capsule will get rAas a result of decryption that is paired with the encryption algorithm. In other words, if the decryption result matches rA, it means the mobile is the authenticated device that has a pre- shared key, and the capsule allows the mobile to request commands. (Only the party possessing the key can successfully perform the correct encryption / decryption. Hence, receiving the correct encrypted value indicates that the other party communicating possesses the same key.)

[0439] This authentication process generally prevents replay attacks. Since the capsule uses a new rAwhenever there is a new BLE connection, its response for authentication also changes. Therefore, even if an attacker captures the previous response and replays it next time, it does not authenticate the attacker. In some cases, a 128-bit secret key was used, which leads to 128-bit secret level, and it will take the order of 2128trials to break the system with a brute-force attack based on trial-and-error to guess the pre-shared key (without wishing to be bound by theory). As such, the capsule BLE with 60-second duty cycling allows only 86,400 (< 217) times of trials for 60 days of operation time, and this is a relatively short-term period to be broken by brute-force attack.

[0440] The exemplary system implemented mutual authentication for both capsule and the mobile, and authentication works right after two devices are connected. As shown in FIG. 71, the capsule starts the BLE communication by sending a rAto mobile. Mobile encrypts rAbut including its self-generated random number rBfor the capsule’s authentication and user command with the pre- shared key and sends it back to the capsule. Then the capsule decrypts the message and proofs if rAis correct. In the case of incorrect rA, capsule unauthorizes mobile and finishes BLE connection to reduce unnecessary energy consumption. On the other hand, if rAis correct, the capsule authenticates mobile and performs the received command such as drug release. The capsule re-sends a message made by encrypting rB, rA, and its response (ack). Again, mobile decrypts this message and check if the authorized capsule got the command by proofing if rBis correct and check ack. The principal idea of the protocol is that every execution of the protocol involves random numbers generated by each party. So, no two sets of messages exchanged between both parties are the same (thus, preventing replayattack). To sum up, only three times of data sending or receiving is necessary for mutual authentication as well as data exchange of command (cmd) and corresponding response (ack) and it is helpful for low-power implementation.

[0441] Analysis on energy consumption of ingestible electronics. As described above, the capsule BLE is currently designed to advertise itself every 60 seconds. BLE communication can also be requested from during this advertising time. To characterize the system’s energy consumption, it was assumed that the capsule BLE will communicate every 60 seconds (although other time periods are also possible). It represents the worst-case scenario when there is a continuous adversarial attack for energy-draining, which leads to 86,400 times of communication for 60 days even though authorized mobile will ask connection for tens of times just to request for drug release, status assessment and capsule disassembly at last. BLE output power was also maximized to +4 dBm to evaluate the highest energy consumption. 3.1 V was supplied to the ingestible electronics from two silver oxide batteries in series, for energy measurement. The evaluation board named nRF52-DK includes nRF52832, the target BLE IC, and it was used to prototype the capsule BLE and to characterize energy consumption.

[0442] Table II. shows the energy measurement results and the estimated energy level of capsule BLE for 60-day operation. According to our measurements, the capsule BLE consumed 3 uA during standby mode, 150 uA during each advertisement period, and 300 uA for 1 cycle of BLE connection, communication, data processing, and authentication. The estimated energy levels for a 60-day operation can be calculated by using the equation below. The current capsule BLE is expected to consume 209 J in total as shown in Table II.

[0443] E60d=lavgx3.1

[0444] Current Duration On-average Energy for

[0445] Mode ON) (TON) current (Iavg) 60 days (E60d)

[0446] Standby 3 uA Steady 3 uA 48 J

[0447] Radio

[0448] 150 uA 1 sec / 60 sec 2.5 uA 40 J

[0449] (advertising)

[0450] Radio 300 uA 1.5 sec / 60 sec 7.5 uA* 121 J (connection, communication, processing)

[0451] Total - 209 J

[0452] Table II. Energy consumption of current capsule BLE. (* The power for random number generation has not been calculated.)

[0453] To achieve this energy level, the following low-power solutions were used. First, a switching DC / DC converter that is designed inside the BLE chip instead of using LDO to increase power conversion efficiency. Second, a preliminary mobile app was designed that allows the user to enter commands in advance before BLE connection and this mobile app can automatically respond to the capsule BLE after connection. This reduces radio operation time and corresponding energy consumption for both BLE devices. Third, SPECK was used which is a lightweight block cypher for energy-efficient implementation.

[0454] The required clock cycles for encryption and decryption for both cyphers were measured then converted each clock-cycle number into energy consumption by using the following equation, where the term “3.1 V X 51.6 uA / MHz X f clock” presents the processing power of the core processor while reading from RAM.

[0455] Energy = 3.1 V x 51.6

[0456] 160 pj I Cycle X Nclock Cycle

[0457] As shown in Table IV, we could see that SPECK required more than 6 times less energy for encryption and 18 times less energy for decryption when compared to AES with the same security level of 128 bit. Therefore, we selected SPECK for our energyefficient mutual authentication protocol.

[0458] Clock Cycle Number Energy Consumption [J]

[0459] Cypher AES-128 SPECK-128 AES-128 SPECK-128

[0460] Encryption 8866 1334 1.418u 0.213u

[0461] Decryption 29745 1574 4.758u 0.252u Table IV. Clock cycle and energy consumption comparison between two block cyphers, AES and SPECK with 128-bit security level.

[0462] Analysis on capsule energy budget.

[0463] To secure more battery capacity, coin-type batteries inside a 000 capsule may be stacked, such that the diameter of batteries is shorter than the diameter of a 000 capsule, or 9.9 mm.

[0464] Various batteries of which size is comparable to a 000 capsule to find the battery solution as shown in Table V. Lithium battery provides high energy density, but it is less suitable to be used for the capsule design since the diameter of the lithium battery with the shortest diameter (10 mm) is longer than that of the capsule (9.9 mm). Second, the diameter of an alkaline battery (7.9 mm) can be shorter than that of the size of a 000 capsule (9.9 mm), but it has lower energy density. On the other hand, silver oxide batteries providing shorter diameter of 6.8 mm is appropriate for capsule design and provides high energy density of 1.66 J / mm3. Also, these are recognized as safer from a toxicity perspective as compared across four different batteries in Table V. Therefore, silver oxide batteries were used.

[0465] However, silver oxide batteries may have a low dischargeable current which is limited to 40 uA to guarantee its full battery capacity. When connecting two silver oxide batteries in parallel, the maximum dischargeable current increases to 80 uA. In this case, the use of lithium-ion batteries together with silver oxide batteries may provide higher current and the current limit of lithium-ion battery is 6 times higher than that of silver oxide battery.

[0466] Battery Supply Supply Current Battery Energy

[0467] Form Factor

[0468] Type Voltage Limit Capacity Density

[0469] ~ 10 mm* 324 J

[0470] Lithium 3 V - 1.65 J / mm3

[0471] X 2.5 mm (30 mAh)

[0472] ~ 7.9 mm* 243 J

[0473] Alkaline 1.5 V - 1.38 J / mm3

[0474] X 3.6 mm (45 mAh) Silver ~ 6.8 mm 156 J

[0475] 1.55 V 40 uA 1.66 J / mm3oxide X 2.6 mm (28 mAh)

[0476] Lithium- ~ 6.8 mm 250 uA 59.4 J

[0477] 3 V 0.78 J / mm3ion x 2.1 mm (50 % capacity) (5.5 mAh)

[0478] Table V. Comparison between various batteries of which sizes are comparable to 000 capsule form factor (~9.9 mm X 26 mm). (*considering lithium battery and alkaline battery with minimum lengths)

[0479] As shown in FIG. 72, 2 pairs of silver oxide batteries may be used in parallel to generate 3.1 V for electronics supplies with 625 J of energy. Alongside this, in case the drug release circuitry or the capsule decomposition circuitry requires a high current over 80 uA, which is a dischargeable current from a silver oxide battery without degrading the battery lifetime, a separate 3-V lithium-ion battery may be used together with silver oxide batteries. In this orientation, it can provide 655 J of energy for the entire 60-day operation. As previously described in Table IV, the capsule electronics design is expected to consume 333 J, within the energy budget of 625-655 J.

[0480] Secure user interface

[0481] By using the preliminary mobile app, the user can request a BLE connection and send a command to an ingestible electronics (capsule BLE) via security-enhanced BLE communication described above.

[0482] Two BLEs are working as follows: once the user pushes one of the LED buttons in the mobile application, the mobile BLE starts scanning the capsule’s advertising events. After two BLEs are connected, the capsule BLE starts data communication by sending a random number to the mobile BLE as a challenge for the mobile’s authentication. Then the mobile sends back the encrypted response, including the command based on the LED button the user pressed before the BLE connection. If the mobile is proven to be an authenticated device by the capsule BLE, then the capsule BLE turns on one of the LEDs upon the user command. As shown in FIG. 73, it was demonstrated that a mobile device with the correct key successfully controlled the capsule BLE by making it turn on the LED1, while the mobile with the incorrect key failed to control capsule BLE. Random number generators have not been implemented yet from both the mobile and the capsule side. But we successfully showed that our preliminary mobile application controlled the capsule system through security-enhanced BLE communication.

[0483] Implementation of a random number generator for the authentication protocol

[0484] As described above, a capsule was designed with an energy -efficient mutual authentication protocol based on symmetric challenge-response protocol. Both the capsule and mobile devices have the pre-shared key (k), and authentication is done by proofing the possession of this secret key.

[0485] Capsule -> Mobile : rA(challenge)

[0486] Capsule «- Mobile : EK(rA) (response)

[0487] Capsule-. DK(EK(A) = rAl (proofing)

[0488] On the assumption that rAis chosen by a random process only the device with the pre- shared key can generate a correct response for each challenge to be authenticated. However, if rAis not a random number, an adversary can intercept the correct response from the mobile, re-transmit it to the capsule device, and it can be authenticated when the capsule is transmitting the same rAagain, which is called a replay attack. Therefore, it is important for the capsule device to have rAas a random number to mitigate this type of attack, and a random number generator was implemented.

[0489] Two different random number generators were considered: 1) a true random number generator (TRNG) and 2) a pseudo-random number generator (PRNG). The first generator is supported by the BLE-MCU (nRF52832) and produces true random numbers using internal thermal noise. It consumes approximately ~ 1.488 p] to generate an 8-byte (64-bit) random number as shown in the equation below. 3.1 V x 0.5 mA x 120 psec / byte x 8 bytes

[0490] = 1.488 pj

[0491] Over the course of 60 days and attempting to authenticate at every opportunity when the capsule BLE is on once every minute, this results in the total energy consumption of ~0.129 J (Please refer to Table 1.3.1). Alternatively, PRNG can be another solution to generate random numbers, one based on the encryption algorithm. PRNG generates pseudo-random numbers by encrypting a counting variable (N). The value of this counting variable (N) increases by one whenever the BLE radio is newly connected and requires a new random number as a challenge, as shown in FIG. 74.

[0492] When implementing a PRNG, a large enough size of the counting variable may be used to prevent its overflow so the PRNG will not generate the same sequence of pseudo-random numbers that have already been used. As with TRNG, the user can attempt to be authenticated once every minute over the 60-day operation time, which corresponds to 86,400 authentication attempts. Therefore, the PRNG could generate up to 86,400 random numbers in the worst-case scenario. In this design, the variable (N) has a size of 64 bits and can increase up to 264, which is higher than 86,400. Therefore, the counting variable (N) will not overflow. The same sequence of counting numbers and pseudo-random number sequences will not be generated, making the wireless communication system secure against replay attacks. It is important to note that, in some embodiments, only the device with a pre- shared key and the same encryption algorithm can generate the correct response against the challenge generated from this PRNG for the authentication.

[0493] Using PRNG the overhead of resources such as memory may also be minimized by re-using the Speck encryption algorithm implemented for the authentication protocol. PRNG consumes ~0.213 j j to generate each random number (64 bit) and a total of 0.018 J total over 60 days. This energy level is lower than the energy consumed by the TRNG as shown in Table VI. Therefore, we implemented a mutual authentication protocol that works with the PRNG to generate rAfor mobile authentication.

[0494] Table VI. Energy comparison between the two random number generators

[0495] Random number Energy for single generation Energy for 60 days generatorngie) ERNG 60d= 86,400 x ERNG singie)

[0496] TRNG -1.488 mJ -0.129 J

[0497] PRNG -0.213 mJ -0.018 J Overall energy consumption of the capsule BLE remains the same, even including the PRNG energy consumption, as shown in Table VII. The random number generator may work in a mobile device to generate a random number rBfor capsule authentication. Independently, a time-out function that the capsule BLE can automatically end the BLE connection after a given period may be used. This function may advantageously save energy in case of no response or long response delay from the mobile BLE.

[0498] Table VII. Energy consumption of the capsule BLE, including the PRNG

[0499] Current Duration On-average Energy for

[0500] Mode UON) TON) current (Javg) 60 days (E60d)

[0501] Standby 3 uA Steady 3 uA 48 J

[0502] Radio

[0503] 150 uA 1 sec / 60 sec 2.5 uA 40 J

[0504] (advertising)

[0505] Radio

[0506] (connection, 300 uA 1.5 sec / 60 sec 7.5 uA 121 J communication, processing)

[0507] Total - 209 J

[0508] Characterization of received signal strength

[0509] The received signal strength was also characterized. Before doing so, the output power of the BLE transmitter was measured, the antenna spec was designed, and the initial target antenna was chosen, which is used for the link analysis. The resonant frequencies of the antenna was measured and the received signal strengths were characterized by performing in-vitro and in-vivo experiments. 1) BLE output power and signal characteristics

[0510] To measure the BLE output signal, a spectrum analyzer (Keysight N9020A) was directly connected to the evaluation board of the target BLE chip (Nordic Semiconductor nRF52-DK), as shown in FIG. 75. FIG. 76A shows the output spectrum of a single BLE channel (channel 37 in this case). As defined in the BLE specification, the output was measured to be GFSK-modulated and showed two peaks in two different frequencies with a 500-kHz difference to transmit binary data information. As shown in FIG. 76B, the entire 40 channels of BLE from 2.402 GHz to 2.48 GHz were observed. Specifically, BLE is using 3 of these channels (channel #37 at 2.402 GHz, channel #38 at 2.426 GHz, and channel #39 at 2.48 GHz) for general advertisement, and another 37 channels (channel #0 ~ #36) are available for use during connected communication. One of the 37 channels is chosen by adaptive frequency hopping to avoid any collisions with other BLE or WiFi devices using the same 2.4-GHz ISM band. Therefore, the antenna and the received signal strengths were characterized over the overall channel bandwidth from 2.402 GHz to 2.48 GHz, which will be described in the next section.

[0511] Characterization of battery lifetime

[0512] As described above, the lifetime of a silver-oxide battery generally degrades when draining currents higher than its specified dischargeable current limit of ~50 uA. However, the BLE drains high peak current over 1 mA during its radio operation, so it can shorten the battery lifetime. Therefore, the battery lifetime was measured when draining the batteries from simulated BLE current loads. The same battery configuration of the ingestible system was used with four silver oxide batteries with 56-mAh capacity. As shown in FIG. 77, the standby current was increased by 3.3 times and radio-mode current by 2 times, respectively, compared to the ingestible BLE. This increased the stress level applied to the batteries, which helped consider worse conditions than our actual BLE. Also, it shortened the testing time from 6 months to 2 months, enabling battery characterization as shown in Table VIII.

[0513] Table VIII. Comparison of the supply current and battery lifetime between actual BLE and simulated BLE.

[0514] Actual BLE Simulated BLE Multiplication Factor

[0515] Mode

[0516] Standby 3 uA 10 uA 3.3

[0517] Radio -10 mA 20 mA > 2

[0518] Ideal lifetime of the

[0519] 4308 hours 1292 hours

[0520] 56-mAh batteries 3.3

[0521] (179.5 days) (53.8 days)

[0522] (56 mAh / Iavg)

[0523] Table IX shows the battery characterization results. As the on-average current of the simulated BLE was 43.3 uA, the 56-mAh batteries were expected to survive for 53.8 days without any degradation. However, the test was terminated due to an unexpected malfunction of the recorder on the 46thday of testing, at which point the batteries were still charged and operating normally. If we assume that the batteries ran out on the 46thdate, the battery degradation factor isx100%).

[0524] Table IX. Test results of the battery lifetime.

[0525] Measured lifetime

[0526] Ideal lifetime of Degradation Factor of

[0527] 56-mAh batteries ((1 - TmeaSbaTidealbatt) X

[0528] 56-mAh batteries

[0529] 53.8 days 45 days

[0530] 16.4%

[0531] (1292 hours) (1080 hours)

[0532] As shown in Table X, the same degradation factor was applied to the energy budget of the ingestible system (625 J), and the estimated energy budget was 522 J. As stated in the previous report, our ingestible system is expected to consume 333 J for the 60-day operation of all Tasks 3, 4, and 5, and this is 63.8% of the estimated energy budget. This result validates that the ingestible system has enough energy for at least a 60-day operation even with the high peak current from the BLE operation.

[0533] Table X. Comparison between the estimated energy budget and the energy consumption of the ingestible system for 60 days. Ideal energy Estimated energy budget Energy consumption of budget Eest batt = E ideal batt x (1 - the ingestible system

[0534] 625 J 522 J 333 J (63.8% of Eest batt)

[0535] EXAMPLE 12

[0536] Custom wake-up receiver.

[0537] A custom wake-up receiver(Rx) ASIC was designed. The TSMC 65-nm CMOS process was used with the options of mixed-signal / RF and low-power (TSMC-65 MS / RF LP). The capsule BLE system with this wake-up Rx is shown in FIG. 13. When the user wants to trigger a drug release or read status from the capsule, the user can send a wake-up pattern (RWUP) by using an external BLE device through its advertising packet. If the sent RWUP has a high correlation with the pattern that the wake-up Rx already has, the wake-up Rx generates a wake-up signal (WU) and enables the commercial BLE-MCU, waking it from sleep-mode. Subsequently, the commercial BLE-MCU has direct access to the BLE physical layer and conducts BLE protocol operations normally. In this system, the commercial BLE stays in sleep mode until the custom Rx captures an advertisement packet, which keeps average theoretical system power draw below luA DC.

[0538] It is important to note that the RWUP may be updated by the external device during the connection session as shown in FIG. 78. This advantageously prevents user device impersonation and hardens system security against wake-up signal replay attacks. It should be noted that MCU code handles authentication, so if a successful wake up command is received but authentication fails, RWUP will not change. This means the final step for securing against wake-up circuit power drain attacks is to rate-limit the wake-up interface. The MCU may control this aspect with built-in hardware timer peripherals, in some cases.

[0539] (1) Strategies for low-power implementation

[0540] Only the wake-up Rx is active until RWUP is captured. Therefore, the sleep energy of the capsule electronics mostly that of the wake-up Rx. To design a highly performant system, the following four strategies were applied. First, the wake-up Rx is designed with a supply voltage of 0.7 V which is lower than the nominal supply voltage of the fabrication process (1.2 V) to reduce power consumption. Second, a low-power local oscillator was implimented by using a Flim Bulk Acoustic-Wave Resonator (FBAR). FBARs have a high quality factor (Q-factor), which enables generation of a stable carrier frequency of 2.48 GHz without the need of phase-locked loops (PLL). The FBAR die is provided by Broadcom and has the advantage of a small surface area of around 0.6 X 0.8 mm2, and can be stacked on top of the wake-up Rx die while not requiring additional area on the miniaturized capsule PCB. The FBAR die was measured using an on-die probe and a vector network analyzer, made a lumped-circuit model and showed the FBAR impedance based on the circuit model well matches the measured FBAR impedance. This lumped-circuit model for our low-power FBAR oscillator circuit design (FIGs. 79A-79C).

[0541] Third, the symbol rate of the wake-up data transmission was decreased for both low power and high sensitivity implementation. The mobile BLE device has a nominal BLE data rate of 1 Mbps. By making the BLE repeat the same bit we can effectively decrease the symbol rate. In this design the mobile BLE device will transmit the same bit 8 times consecutively, which decreases the symbol rate from 1 Mbps to 125 kbps. This generally relaxes the speed requirements on the RF interface circuitry, reducing power consumption. Also, the Rx circuit has a narrow bandwidth, so signal to noise ratio improves dramatically without the cost of additional power.

[0542] Fourth, the energy consumption may be further reduced by duty-cycling the wake-up Rx. For example, the mobile device sends advertisements periodically with intervals of 30 msec as shown in FIG. 80. Consequently, the wake-up Rx is enabled for TRX to catch the signal. TRX can be elongated to provide resiliency to packet loss. In the case of duty cycling the wake-up Rx with a 30-sec period (Tduty), can reduce its power consumption by 1000 times compared to always-on performance. This is the selected duty cycle for the sake of RF communication performance but can be further slowed for the sake of security. The system is also capable of falling back to the validated MCU- controlled wake-up strategy if a power drain attack is detected (in the form of receiving a wake-up signal followed by an unsuccessful authentication). Wake-up control can be returned to the low power Rx as appropriate. (2) Implementation of the wake-up Rx.

[0543] The overall architecture of the designed wake-up Rx is shown in FIG. 81. The low-noise amplifier (LNA) amplifies the 2.48-GHz RF signal received by the capsule antenna. The output of the LNA is mixed to transform the RF signal into an intermediate frequency (IF) signal around 9.73 MHz. Next, the IF amplifier (IF_Amp) amplifies the IF signal so that the Frequency Shift Keying (FSK) demodulator can produce a message in the baseband. The following comparator that consists of a baseband amplifier (BB Amp) and a Schmitt Trigger feeds 10 banks of correlators with an oversampling ratio of 10 to search for the device RWUP. Schmitt triggers are binary buffers with hysteresis, so they act as a final safeguard against noise propagating through the multistage amplifier circuit. If the decoded input data matches the device RWUP, the authentication correlator subsystem exceeds its threshold and produces a wake-up signal (Wu). The 10-x oversampling accounts for baseband synchronization with the external BLE transmitter. Here it is worth noting that the required clock signals are generated from the FBAR oscillator.

[0544] FIG. 82 shows the time-domain simulation results. As shown in the last waveform (LO_+), the FBAR oscillator started to oscillate with its start-up time of 3 us. As described above, the RF signal passes through LNA, mixer, IF amplifier, FSK demodulator, and is then transformed into digital bits as shown in the output waveform of the Schmitt Trigger, or Schmitt_Out_tran of FIG. 82.

[0545] The wake-up Rx is designed under the following specifications. First, the target Rx sensitivity is set to be -90 dBm. According to our previous animal tests, it was found that the received signal strengths are around -70 dBm and -90 dBm between the external BLE device and the capsule BLE. In order to receive the weakest signal, the sensitivity level was targeted at -90 dBm. To achieve this low sensitivity level, the low-noise- amplifier-first architecture was chosen. The LNA in the first stage of the signal chain increases the signal level against the noise power and improves the sensitivity at the cost of higher power consumed by the LNA. Erom simulations, the wake-up Rx achieved the sensitivity level (Psensitivity) °f ”93 dBm and its sensitivity level can be calculated as below.

[0546] ^sensitivity -174 dBm + 101og10(Bie / / ) + NFeff+ SNRrequired • NFeff = 10 dB (simulated)

[0547] • BWeff = 0.5 MHz (simulated)

[0548] • SNRrequired = 14 dB (for BER<10“3GFSK)

[0549] Second, it was determined that the symbol rate of the wake-up pattern to be 125 kbps by considering the false alarm rate and the security level. In this system, the wakeup pattern (RWUP) is transmitted through an advertising packet of the external BLE, where the user has full control over 31 bytes (or 248 bits) of data with 1-Mbps data rate. Since it was chosen to send the wake-up pattern at 125 kbps, the external BLE will repeat the same bit 8 times, leading the maximum wake-up pattern length (LWUP) to 31 bits. It indicates 31 bits of security level which is enough for the wake-up Rx when considering the main security function of the mutual authentication during the BLE communication. On the other hand, these 31 bits of LWUP also determine the false alarm rate as 0.156 per month. It indicates that there will be unlikely a false alarm during the 2- month operation. It can be calculated that the false alarm rate can be calculated as below.

[0550] Assuming that the bits are independent and random, each bit has a 50% probability of being ‘1’ or ‘O’.

[0551] 1

[0552] = (-)31 x(30.25 msec X 125 kbps — 31 + 1) x 31 / 30 sec

[0553] = 0.000001805

[0554] = 0.156 alarms I month

[0555] Third, the active power of the wake-up Rx is ~1 mW. The power breakdown of the individual components is shown in FIG. 83. By applying a duty cycle with a period of 30 sec, an average power consumption of 1 uW can be achieved. Compared to the commercial BLE system it can be expected to save 74.6% of total sleep energy expended. Here it was assumed that the user may wake the system 10 times over 60-day operation time, resulting in the energy consumptions of 4.65 mJ and 13.95 mJ in BLE advertising mode and communication.

[0556] Table XL Energy comparison between two ingestible BLE systems: (1) a system based on commercial BLE part and (2) another system including a wake-up Rx.

[0557] Commercial BLE Only With Wake-Up Rx

[0558] On-average Energy for On-average Energy for

[0559] Mode power (Pavg) 60 days (E60d) power (Pavg) 60 days (E60d)

[0560] Duty-cycling

[0561] 9.3 uW 48 J 9.3 uW 48 J clock

[0562] Radio l uW 5.1 J

[0563] (wake-up listen)

[0564] Radio

[0565] 7.75 uW 40 J - 4.65 mJ*

[0566] (advertising)

[0567] Radio (connection, 23.25 uW 121 J - 13.95 mJ* communication, processing)

[0568] Total 209 J 53.1 J

[0569] EXAMPLE 13

[0570] The example describes an article, according to some embodiments. Fig. 84. shows an image of a disassembled article, including a container configured to be water-tight when sealed and multiple electrical subsystems. The electrical subsystems may be associated with a triggerable release mechanism.

[0571] FIG. 85 shows an image of an assembled article in communication with an external component. In this instance, the external component provides a signal to initial a triggerable release mechanism of the article to release a pay load from an interior volume (e.g., a reservoir) of the article.

[0572] EXAMPLE 14 This example describes arrangement of components of articles, according to some embodiments.

[0573] FIG. 86 shows a schematic diagram of an drug delivery article. The drug delivery article includes a reservoir body partially disposed between a payload and a physiological medium (i.e., the host medium as shown). The article further includes a sealing component adjacent the reservoir body and arranged such that the sealing component and the reservoir body isolates payload contained therein from the physiological medium. The article further includes an actuator configured such that, upon application of energy from the actuator to the sealing component, at least a portion of the sealing component may be removed. In such a manner, the payload is at least partially exposed to the physiological medium, or other encompassing system. FIG. 87 shows partial removal of the sealing component and the associated exposure and release of the pay load from the interior volume of the article (e.g., from the reservoir body) to the host medium. FIG. 87 does not show the actuator.

[0574] FIG. 88 shows another schematic diagram of an alternative example of a drug delivery article. The drug delivery article includes a reservoir body partially disposed between a pay load and a physiological medium (i.e., the host medium as shown). The article further includes a sealing component adjacent the reservoir body and arranged such that the sealing component and the reservoir body isolates payload contained therein from the physiological medium. The article further includes an interface (e.g., an energy delivery interface configured such that, upon application of energy from one or more external systems (i.e., the one external as shown) to the interface, at least a portion of the sealing component may be removed. In such a manner, the payload is at least partially exposed to the physiological medium, or other encompassing system. Such a release may again be seen in FIG. 87.

[0575] FIG. 89 shows an exemplary article having three retention arms. The arms are coupled to a trigger wire. The device is configured to dissolve the trigger wire upon receipt of a signal, which may release the arms and facilitate release of the article from a location internal to a subject.

[0576] EXAMPLE 15 This example describes the mechanical robustness of a sealing component of an article, according to some embodiments.

[0577] Fig. 90a shows a test set up for quantifying mechanical robustness to puncture thin metal foils using a force measurement device (Admet) in a certain device geometry. FIG. 90b shows the max load before puncture of different metal foil films compared to a Gold+SU-8 film using the test jig in Fig. 90a.

[0578] Fig. 91 show a first (left) and second (right) sub-component testing device for in vivo evaluation of sealing robustness. The second design provided for more replicates per animal and simpler retrieval.

[0579] Fig. 92a shows a test of in vivo robustness of a payload chamber device with integrated electronics and shows that external facing electrical connections are not robust and cannot be triggered as demonstrated in Fig. 92b. The remaining viability of the internal bacterial payload is maintained however with noticeable degradation in performance compared to a chamber-only device. Despite this degradation in performance, overall viability remains significantly higher than previous unoptimized devices based on gold foil seals. VI refers to the “no support” variant and V2 refers to the “tapered edge” variant (see Fig. 60a). Fig. 92b shows (left) a design of printed circuit board (PCB) integration into a 1 -chamber device via a PCB “wrap-around” approach, (middle) The device shows comparable electrochemical triggering performance to benchtop assessments of stainless- steel electrochemical performance in terms of energy consumption, (right) Data demonstrating this version of the device also supports triggering and release of a bacterial payload like the previous gold-sealed device. Additionally, inclusion of disintegrants into the tablet formulation enhance the kinetics of bacterial release. CFU: colony forming units.

[0580] Fig. 93 shows a CV graph (top left), a DC dissolution graph (top right), before and after DC dissolution (bottom left), and a summary of DC dissolution of gold anode and Ag / AgCl cathode in SGF of pH 2 and pH 5 (bottom right).

[0581] Fig. 94 shows a device image for in vivo electrochemical gold dissolution of gold membrane (left) and a result summary (right).

[0582] Fig. 95 shows test conditions and result summary of testing two pre-treatment methods for the gold electrode. Fig. 96 shows a summary of the characteristics of different metal membranes for ingestible therapeutic delivery.

[0583] EXAMPLE 16

[0584] This example describes an in vivo experiment showing successful triggered release after 11 day in vivo exposure, according to some embodiments.

[0585] Fig. 97 describes a first (left) and second(right) design for an electrical-integrated device for in vivo testing. Both designs perform as expected in vitro as manufactured, but the constant mechanical and chemical degradation in the stomach leads to failure of the triggering in the first design. The second design internalizes all printed circuit board components to ruggedize the device for successful function after >10 days in vivo (swine stomach).

[0586] Figs. 98-100 shows the viability of bacterial tablets of the second design from Fig. 97 in the electronics bay after in vivo exposure for >10 days. During in vivo testing formulated bacteria tablets were loaded both in the triggerable payload chambers as well as in the electronics bay as a control. The control tablets show that the devices sealed with epoxy (left) do not maintain high bacterial viability reproducibly. However, the devices that are melt sealed (right) successfully maintain a high baseline viability which is indicative of the expected total viability in the payload compartment. Fig. 99 shows the triggered electronic release of viable bacteria from devices resident in the stomach of pigs from >10 days. Devices were recovered, triggered electronically and the released cells were evaluated by plating. Data is shown as a percent of the total cells expected from the viability data in the control tablets (Fig. 1.5.4) for each device. This data shows that at 1 hour, the devices release a consistent dose of bacteria relative to the mean (50% - 200% of the means). Fig. 100 shows the electrical power consumption of devices triggered after residence in pigs for >10 days, (left) Total energy consumed during a 30- minute triggering routine, (middle) Time-current traces for run A summarized in the left panel, (right) Time-current traces for run B summarized in the left panel.

[0587] EXAMPLE 17

[0588] This example describes various parameters of articles, according to some embodiments. Fig. 101. Chamber dimensions. Initial chamber dimensions posed challenges of spring actuation, because the chamber was too narrow for full spring actuation. To overcome these challenges, the chamber was expanded, and the launching mechanism was improved. Afterwards, the device was able to be sealed without premature breakage. Upon triggering in vitro, the spring was able to successfully eject a mock payload from the chamber.

[0589] Fig. 102. Mitigation of jamming. Misalignment issues were observed in the device due to overconstraint of the pogo-pins on the PCB and the pogo-pin holder. To overcome this, the device was redesigned to function without the pogo-pin holder. A new foil was designed which was insensitive to alignment, facilitating guaranteed contact. Specifically, it was designed into a “U-shape” to increase surface area of the electrodes controlling chamber triggering.

[0590] Fig. 103. Device design to facilitate improved liquid resistance and module for gastric retention. To overcome potential challenges with humidity and water ingress, the device was redesigned with the following: additional flanges on interfaces between the sleeve wrap, capsule, and the cap; the sleeve wrap height was elongated to enable better sealing between itself and the capsule; the chamber alignment (between sleeve wrap and the chamber itself) feature was redesigned to maximize the surface area of contact between the adhesive and the foil. These additions facilitated more effective sealing of the device through additional material that was melted and used to seal device interfaces. Moreover, the device manufacturing process was optimized with the following: inclusion of internal epoxy application at the joints; maximizing curing time; and improving sealing efficiency via a clamping process throughout. To facilitate gastric retention, a minimal fixture was designed that could be applied to the bottom side of the capsule via UV-cured epoxy. This facilitated addition of flexible arms for gastric retention of at least 8 days.

[0591] Figs. 104a-104b. Demonstration of wirelessly triggered release. The capacity of the device to be wirelessly triggered and release a live therapeutic payload was evaluated in a porcine intestinal clamp model. Here, two devices were administered: a functional test device and a non-functional control device. Both devices were placed in clamped intestinal compartments, and intestinal contents were collected as a baseline. The intestines were then placed back into the animal, and the devices were triggered. After 2 h, intestinal contents were collected and plated. Compared to controls, bacteria growth was observed only in the test device after 2 h, suggesting successful release of a live therapeutic payload.

[0592] EXAMPLE 18

[0593] This example describes the electronic functioning of an article over a long time at a location internal to a subject, according to some embodiments.

[0594] Fig. 105a shows plots of electronic signals from two studies of two separate articles within respective pigs. The first article was present within the stomach of the pig for 86 days. The second article was present within the stomach of the pig for 82 days. Fig. 105b shows the electronic signal received from an article during a feeding event. The decrease in temperature measured at the article during the feeding event demonstrates the article is functioning in the stomach of the pig.

[0595] While several embodiments of the present invention have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and / or structures for performing the functions and / or obtaining the results and / or one or more of the advantages described herein, and each of such variations and / or modifications is deemed to be within the scope of the present invention. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and / or configurations will depend upon the specific application or applications for which the teachings of the present invention is / are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, the invention may be practiced otherwise than as specifically described and claimed. The present invention is directed to each individual feature, system, article, material, and / or method described herein. In addition, any combination of two or more such features, systems, articles, materials, and / or methods, if such features, systems, articles, materials, and / or methods are not mutually inconsistent, is included within the scope of the present invention. The indefinite articles “a” and “an,” as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean “at least one.”

[0596] The phrase “and / or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified unless clearly indicated to the contrary. Thus, as a non-limiting example, a reference to “A and / or B,” when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A without B (optionally including elements other than B); in another embodiment, to B without A (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0597] As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of’ or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e. “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law.

[0598] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and / or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0599] As used herein, “wt%” is an abbreviation of weight percentage. As used herein, “at%” is an abbreviation of atomic percentage.

[0600] Some embodiments may be embodied as a method, of which various examples have been described. The acts performed as part of the methods may be ordered in any suitable way. Accordingly, embodiments may be constructed in which acts are performed in an order different than illustrated, which may include different (e.g., more or less) acts than those that are described, and / or that may involve performing some acts simultaneously, even though the acts are shown as being performed sequentially in the embodiments specifically described above.

[0601] Use of ordinal terms such as “first,” “second,” “third,” etc., in the claims to modify a claim element does not by itself connote any priority, precedence, or order of one claim element over another or the temporal order in which acts of a method are performed, but are used merely as labels to distinguish one claim element having a certain name from another element having a same name (but for use of the ordinal term) to distinguish the claim elements.

[0602] In the claims, as well as in the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of’ and “consisting essentially of’ shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

Claims

CLAIMSWhat is claimed is:

1. An article, comprising: one or more reservoirs, each reservoir comprising a therapeutic pay load, the one or more reservoirs having a total combined volume of greater than or equal to 10 microliters; one or more triggerable release mechanisms associated with each of the reservoirs such that, upon receipt of a signal, each triggerable release mechanism releases the therapeutic pay load from the one or more reservoirs; and an electrical system associated with the triggerable release mechanisms, the electrical system comprising a short-range wireless component; wherein each reservoir is adapted and designed to maintain therapeutic efficacy of the therapeutic payload for greater than or equal to 10 days under physiological conditions.

2. The article of claim 1, wherein the electrical system is contained within a container, wherein the container is configured to maintain a relative humidity within an interior volume defined by the container of less than or equal to 80% for at least 1 day when the container is at a location internal to the subject.

3. The article of claim 1 or 2, wherein the electrical system is contained within a container, wherein the container is configured to maintain a relative humidity within an interior volume defined by the container of less than or equal to 60% for at least 264 days when the container is at a location internal to the subject.

4. The article of any one of claims 1-3, wherein the electrical system comprises two or more electronic components, wherein each of the two or more electronic components are configured to communicate with the triggerable release mechanisms and / or other electronic components.

5. A system comprising two or more of the articles as in any preceding claim, wherein the two or more articles are in communication with each other.

6. An article, comprising: one or more reservoirs, each reservoir configured to contain a therapeutic payload, the one or more reservoirs having a total combined volume of greater than or equal to 10 microliters; one or more triggerable release mechanisms associated with each of the reservoirs such that, upon receipt of a signal, each triggerable release mechanism is configured to release the therapeutic pay load from the one or more reservoirs; and an electrical system associated with the triggerable release mechanisms, the electrical system comprising short-range wireless component; wherein each reservoir is adapted and designed to maintain therapeutic efficacy of the therapeutic payload for greater than or equal to 10 days under physiological conditions.

7. A drug delivery article, comprising: a reservoir body at least partially disposed between a payload and a physiological medium, or other encompassing system; a sealing component adjacent the reservoir body such that the sealing component and / or the reservoir body isolate the payload from the physiological medium, or other encompassing system; an actuator associated with the sealing component, wherein, upon application of energy from the actuator to the sealing component, at least a portion of the sealing component is removed and the payload is at least partially exposed to the physiological medium, or other encompassing system.

8. A drug delivery article, comprising: a reservoir body at least partially disposed between a payload and a physiological medium, or other encompassing system; a sealing component adjacent the reservoir body such that the sealing component and / or the reservoir body isolate the payload from the physiological medium, or other encompassing system; an energy delivery interface associated with the sealing component and one or more systems external to the drug delivery article,wherein, upon application of energy from the one or more systems to the energy delivery interface, the payload is at least partially exposed to the physiological medium, or other encompassing system.

9. A drug delivery article, comprising: a reservoir body comprising a payload portion and an opening; a dissolvable metal layer adjacent the opening such that the dissolvable metal layer seals the payload portion; a working electrode in electrical communication with the metal layer; a power source in electrical communication with the working electrode; wherein, upon application of a voltage from the power source to the metal layer, the metal layer degrades such that the dissolvable metal layer at least partially dissolves.

10. A method for delivering a drug, comprising: administering to a subject a drug delivery article comprising a reservoir body, the reservoir body comprising a pay load portion, an opening, and a dissolvable metal layer adjacent the opening; applying a voltage to the dissolvable metal layer such that the dissolvable metal layer dissolves, releasing the contents of the payload portion to a location internal to the subject.

11. The drug delivery article or method as in any preceding claim, wherein the dissolvable metal layer comprises gold.

12. The drug delivery article or method as in any preceding claim, wherein the dissolvable metal layer comprises a metal.

13. The drug delivery article or method as in any preceding claim, wherein the dissolvable metal layer is selected from the group consisting of carbon steel, carbon steel coated in gold, and copper.

14. The drug delivery article or method as in any preceding claim, comprising a therapeutic payload disposed within the payload portion.

15. The drug delivery article or method as in any preceding claim, wherein the therapeutic payload comprises one or more types of bacteria.

16. The drug delivery article or method as in any preceding claim, wherein dissolution of the dissolvable metal layer comprises less than or equal to 10 J of power.

17. The drug delivery article or method as in any preceding claim, wherein dissolution of the dissolvable metal layer comprises less than or equal to 1 J of power.

18. The drug delivery article or method as in any preceding claim, wherein dissolution of the dissolvable metal layer comprises less than or equal to 100 mJ of power.

19. The drug delivery article or method as in any preceding claim, wherein each pay load portion has a volume of greater than or equal to 1 microliter and less than or equal to 100 microliters.

20. The drug delivery article or method as in any preceding claim, wherein release of the therapeutic payload occurs within less than or equal to 6 hours after application of the voltage from the power source.

21. The drug delivery article or method as in any preceding claim, wherein each payload portion is adapted and designed to maintain therapeutic efficacy of the therapeutic payload for greater than or equal to 10 days under physiological conditions.

22. The drug delivery article or method as in any preceding claim, wherein each payload portion is adapted and designed to maintain therapeutic efficacy of the therapeutic payload for greater than or equal to 60 days under physiological conditions.

23. The drug delivery article or method as in any preceding claim, wherein the drug delivery article further comprises a conductive epoxy adjacent one or more electronic component.

24. The drug delivery article or method as in any preceding claim, wherein the drug delivery article further comprises an encapsulation epoxy adjacent the one or more electronic component.

25. The drug delivery article or method as in any preceding claim, wherein the one or more electronic component comprises a printed circuit board (PCB).

26. The drug delivery article or method as in any preceding claim, wherein the one or more electronic component comprises the working electrode.

27. The drug delivery article or method as in any preceding claim, wherein the one or more electronic component comprises the power source.

28. The drug delivery article or method as in any preceding claim, wherein the one or more electronic component is mechanically pressfit into the drug delivery article.

29. The drug delivery article or method as in any preceding claim, wherein the one more electronic component is connected to the drug delivery article using a bonding method.

30. The drug delivery article or method as in any preceding claim, wherein the opening has a diameter of greater than or equal to 1 mm and less than or equal to 5 mm.

31. The drug delivery article or method as in any preceding claim, wherein the voltage is greater than or equal to 1 V and less than or equal to 2 V.

32. The drug delivery article or method as in any preceding claim, further comprising an antenna associated with the one or more electronic component configured to receive a wireless signal wherein, upon receipt of the wireless signal, the electronic component triggers the release of the therapeutic payload.

33. The drug delivery article or method as in any preceding claim, wherein the drug delivery article comprises two or more reservoir bodies.

34. The drug delivery article or method as in any preceding claim, wherein the working electrode comprises platinum black.

35. The drug delivery article or method as in any preceding claim, wherein the working electrode comprises silver foil coated in silver / silver chloride.

36. The drug delivery article or method as in any preceding claim, further comprising a photoresist layer adjacent the metal layer.

37. The drug delivery article or method as in any preceding claim, wherein metal layers comprising carbon steel do not comprise the photoresist layer.

38. The drug delivery article or method as in any preceding claim, wherein the metal layer has a thickness of greater than or equal to 100 nm and less than or equal to 50 microns.

39. The drug delivery article or method as in any preceding claim, wherein the photoresist layer comprises a photoresist mesh.

40. The drug delivery article or method as in any preceding claim, wherein the photoresist layer has a thickness of greater than or equal to 10 microns and less than or equal to 100 microns.

41. The drug delivery article or method as in any preceding claim, wherein the dissolvable metal layer and / or photoresist layer have a low permeability to water vapor and / or low pH fluids.

42. The drug delivery article or method as in any preceding claim, wherein the dissolvable metal layer supports sealing of the reservoir body.

43. An article configured for triggerable gastric exit, comprising: a capsule comprising a releasable cap, the releasable cap comprising one or more coupling components; one or more retention arms, each retention arm mechanically coupled to the capsule via the one or more coupling components; a spring disposed within the cap; and a degradable component associated with the spring, such that upon degradation of the degradable component, the spring ejects the cap from the capsule and the one or more retention arms disassociate from the capsule, wherein, prior to degradation of the degradable component, the article is configured to be retained at a location internal to a subject for at least 7 days.

44. The article as in claim 1, wherein the degradable component comprises a degradable material selected from the group consisting of sugar, gelatin, and isomalt.

45. The article as in any preceding claim, wherein the degradable component degrades upon exposure to a gastric fluid.

46. The article as in any preceding claim, wherein the degradable component degrades in response to an external wireless signal received by the gastric residence article.

47. The article as in any preceding claim, wherein the gastric residence article is configured to be retained and electronically functional at a location internal to the subject for at least 30 days, at least 60 days, or at least 90 days prior to degradation of the degradable component.

48. The article as in any preceding claim, wherein the capsule comprises a therapeutic payload.

49. The article as in any preceding claim, wherein the therapeutic payload comprises one or more types of bacteria.

50. The article as in any preceding claim, wherein the location internal to the subject is the stomach of the subject.

51. The article as in any preceding claim, wherein the gastric residence article has a retention configuration such that the gastric residence article is unable to pass through the pylorus of the subject until release of the cap from the capsule.

52. The article as in any preceding claim, wherein the degradable component is fluidically isolated from the gastric fluid at the location internal to the subject until the external wireless signal is received by the gastric residence article.

53. The article as in any preceding claim, further comprising an electronic component.

54. The article as in any preceding claim, further comprising a tether, the tether configured to extend from the capsule into an intestine of the subject.

55. The article as in any preceding claim, wherein the tether comprises one or more therapeutic pay loads.

56. The article as in any preceding claim, wherein the one or more retention arms comprises a super elastic material.

57. The article as in any preceding claim, wherein the one or more retention arms comprises a corrosion resistant material.

58. The article as in any preceding claim, wherein the one or more retention arms comprises a fatigue resistant material.

59. The article as in any preceding claim, wherein the article is a gastric retention device.

60. The article as in any preceding claim, wherein the article is a gastrointestinal retention device.

61. An article, comprising: one or more reservoirs, each reservoir comprising a therapeutic pay load, the one or more reservoirs having a total combined volume of greater than or equal to 10 microliters; and one or more triggerable release mechanisms associated with each reservoir such that, upon receipt of an external signal, each triggerable release mechanism releases the therapeutic pay load from the one or more reservoirs; wherein each reservoir is adapted and designed to maintain therapeutic efficacy of the therapeutic payload for greater than or equal to 10 days under physiological conditions.

62. The article as in claim 61, further comprising a semi-permeable membrane associated with each reservoir, each semi-permeable membrane having low permeability to water vapor and / or low pH fluids.

63. The article as in any preceding claim, further comprising a triggerable seal associated with each reservoir.

64. The article as in any preceding claim, wherein the therapeutic payload comprises one or more types of bacteria.

65. The article as in any preceding claim, wherein each reservoir has a volume of greater than or equal to 1 microliter and less than or equal to 500 microliters.

66. The article as in any preceding claim, wherein each reservoir has a volume of greater than or equal to 1 microliter and less than or equal to 250 microliters.

67. The article as in any preceding claim, wherein each reservoir is adapted and designed to maintain therapeutic efficacy of the therapeutic payload for greater than or equal to 60 days under physiological conditions.

68. The article as in any preceding claim, further comprising an enteric layer associated with each reservoir.

69. The article as in any preceding claim, wherein the reservoir further comprises a reservoir body.

70. The article as in claim 69, wherein the reservoir body comprises an organic polymer.

71. The article of claim 70, wherein the organic polymer is selected from the group consisting of polymethyl methacrylate, polyethylene, polypropylene, tetrafluoroethylene, hexafluoropropylene, polyether ether ketone, polyethylenimine, cyclic olefin copolymer, polycarbonate, polypropylene, copolymers thereof, and combinations thereof.

72. The article of any one of claims 69-71, wherein the reservoir body comprises an inorganic material.

73. The article of claim 72, wherein the inorganic material is selected from the group consisting of metals, ceramics, aluminum, and glass.

74. The article of claim 73, wherein the metal is selected from the group consisting of steel, gold, and copper.

75. The article as in any preceding claim, wherein the semi-permeable membrane has a thickness of greater than or equal to 1 micron.

76. The article as in any preceding claim, wherein the triggerable release mechanism comprises a metal seal.

77. The article as in any preceding claim, wherein release of the therapeutic pay load from within each reservoir comprises electrochemical dissolution of the metal seal.

78. The article as in any preceding claim, wherein the triggerable release mechanism releases the therapeutic payload from within each reservoir using less than or equal to 10J per trigger.

79. The article as in any preceding claim, wherein the triggerable release mechanism releases the therapeutic payload from within each reservoir using less than or equal to 1 J per trigger.

80. The article as in any preceding claim, wherein the triggerable release mechanism releases the therapeutic payload from within each reservoir using less than or equal to 100 mJ per trigger.

81. The article as in any preceding claim, wherein release of the therapeutic pay load occurs within less than or equal to 6 hours after triggering.

82. The article as in any preceding claim, wherein the article is a gastric retention device.

83. The article as in any preceding claim, wherein article is a gastrointestinal retention device.

84. The article as in any one of the preceding claims, wherein the electrical system comprises a central processor, a wireless component, power source, a power management system, a system wakeup controller, an actuator, and / or an electronic sensor.

85. The article as in any one of the preceding claims, wherein each of the one or more reservoirs is configured to maintain a relative humidity within an interior volume defined by the reservoir of less than or equal to 80% for at least 1 day when the container is at a location internal to the subject.

86. A drug delivery article, comprising:a reservoir body at least partially disposed between a payload and a physiological medium, or other encompassing system; a sealing component adjacent the reservoir body such that the sealing component and the reservoir body isolate the payload from the physiological medium, or other encompassing system, wherein the sealing component comprises an interface associated with one or more systems internal to the drug delivery article, wherein the article is configured such that, upon receipt of a signal to the one or more systems, the payload is at least partially exposed to the physiological medium, or other encompassing system.

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