Biodegradable ingestible systems and related electronics

Abstract

The present disclosure relates, in various aspects, to devices comprising biodegradable (e.g., bioresorbable) RFID antennas and dissolvable coatings. By employing fully biodegradable materials, the devices provided herein may obviate the need for device retrieval or battery replacement, thereby mitigating electronic waste. Moreover, the tags were compatible with standard gelatin or hydroxypropyl methylcellulose (HPMC) capsules, further enhancing clinical translational potential.

Description

[0001] BIODEGRADABLE INGESTIBLE SYSTEMS AND RELATED ELECTRONICS

[0002] RELATED APPLICATIONS

[0003] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 63 / 703,905, filed October 4, 2024, and entitled “PRIMARY AND SECONDARY BIODEGRADABLE BATTERIES AS POWER SOURCES FOR BIOELECTRONICS,” which is incorporated herein by reference in its entirety for all purposes.

[0004] GOVERNMENT SPONSORSHIP

[0005] This invention was made with government support under D24AC00040 awarded by the Advanced Research Projects Agency for Health (ARPA-H), and FA8650-21-2-7120 awarded by the Air Force Office of Scientific Research. The government has certain rights in the invention.

[0006] BACKGROUND

[0007] With environmental concerns and the ever-growing global demand for electrical energy, researchers are compelled to explore alternative solutions for electricity storage. Unfortunately, the widespread use of alkaline, lithium-ion, and chemistry of standard button batteries generate significant electronic waste. These batteries pose environmental threats, as their casings can be hazardous and toxic electrolytes can leak into water systems and release harmful gases. Exploring alternative materials and cell designs with adaptable form factors can pave the way for solutions that address electronic waste concern.

[0008] Medication nonadherence remains a critical healthcare challenge, contributing to approximately 125,000 preventable deaths and incurring over $100 billion in annual costs in the United States. Current adherence assessment strategies are constrained by limited scalability, suboptimal patient acceptability, and environmental sustainability concerns. While electronic medication tracking has the potential to improve the accuracy of adherence measurement, many existing technologies rely on external devices that require patient engagement, leading to usability challenges. Among these, ingestible sensors embedded in medication capsules offer a significant advancement by autonomously verifying ingestion events. This design raises multiple concerns: frequent ingestion of non-degradable materials increases the potential risk of gastrointestinal injury, particularly for patients on multiple medications requiring long-term monitoring, and the accumulation of electronic waste poses significant environmental challenges. Improved solutions would be desirable.

[0009] #14443731vl SUMMARY

[0010] Some aspects of the present disclosure provide a facile route for fabrication of printed biodegradable batteries using cellulose based cathode and bio- ionic liquid-based electrolyte using degradable metal anodes. The devices possess high operation voltage and capacity. Using natural waxes as encapsulation material gives a robust operation in bodily fluids and the components naturally degrade within the body.

[0011] In one aspect, a device is provided. According to some embodiments, the device comprises a biodegradable RFID antenna; and a coating surrounding the biodegradable RFID antenna and configured to dissolve within 48h of placement of the device within an internal organ of a subject, wherein the coating is configured to electromagnetically shield the biodegradable RFID antenna, such that the biodegradable RFID antenna is unable to receive a signal until the coating dissolves.

[0012] In some embodiments, the device comprises a biodegradable RFID antenna, a biodegradable battery, and a coating surrounding the biodegradable RFID antenna and configured to dissolve after placement of the device within an internal organ of a subject, wherein the coating is configured to electromagnetically shield the biodegradable RFID antenna, such that the biodegradable RFID antenna is unable to receive a signal until the coating dissolves.

[0013] BRIEF DESCRIPTION OF THE DRAWINGS

[0014] 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:

[0015] FIG. 1 illustrates a non-limiting, cross-sectional schematic illustration of a biodegradable RFID tag 101, according to some embodiments.

[0016] FIGS. 2A-2C depict one embodiment of a device 200 in various configurations, according to some embodiments. FIG. 2A shows the device in a retracted configuration within a capsule 202, according to some embodiments. FIG. 2B shows the device in a partially expanded

[0017] #14443731vl configuration, while FIG. 2C shows the device in a fully expanded configuration, according to some embodiments.

[0018] FIGS. 3A-3D provide non-limiting, schematic illustrations of a device exhibiting self- righting behavior, in an exemplary embodiment.

[0019] FIG. 4. Concept of biodegradable batteries, according to some embodiments. From left to right, the schematic summarizes the biomedical applications that have and are being developed in the Traverse Lab. High energy demanding applications require battery systems depending on the application. Bioresorbable and recycling of proposed battery system after performing its task within the body.

[0020] FIG. 5. Batteries for biomedical applications from past to future, according to some embodiments. Future applications demanding a shift from AgO2 batteries to biodegradable, high energy technology.

[0021] FIG. 6. Schematic representation of Mg primary batteries, according to some embodiments.

[0022] FIG. 7. Fabrication route for high performance biodegradable batteries, according to some embodiments, i) Laser structuring of Mg foils to design different types of anode geometry, ii) Cathode manufacturing methods using printing methods, iii) Full cell battery fabrication using 3D printing for casing and shell.

[0023] FIGS. 8A-8C. Preliminary work on Mg Alloy (AZ31)-MoO3 battery system, according to some embodiments. FIG. 8 A shows a schematic representation of the Mg-Mn03 nanopaper battery system. FIG. 8B shows an open circuit voltage comparison of battery with different electrolyte materials in gel electrolyte. PBS: Phosphate buffered saline, RGF: Real gastric fluid, SGF: Simulated gastric fluid, ChC12: choline chloride. FIG. 8C shows an open circuit voltage performance of our battery system compared with two commercial biocompatible batteries.

[0024] FIGS. 9A-9B. Preliminary work on in vivo test of battery in 3D capsule, according to some embodiments. FIG. 9A is a schematic illustration and real time images from the in vivo performance of the battery system. FIG. 9B shows an open circuit voltage performance of the battery before and after in vivo test. The device delivered into swine stomach and open circuit voltammetry was recorded after 12h residency time in stomach.

[0025] FIG. 10. A summary of Work Packages (WP) described herein, with tasks (T) and milestones (M) , according to some embodiments.

[0026] FIG. 11. Cathode materials design, according to some embodiments.

[0027] FIG. 12. Device biodegradation in SGF, according to some embodiments.

[0028] #14443731vl FIG. 13. Potential applications of a device described herein, according to some embodiments.

[0029] FIG. 14 shows a schematic illustration of a capsule based, biodegradable medication adherence tracking system with envisioned scenario for clinical use, according to some embodiments.

[0030] FIGS. 15A-15F show electrical characterization of biodegradable RFID tag, according to some embodiments.

[0031] FIGS. 16A-16F show CST full- wave electromagnetic simulation results for a RFID antenna design, showcasing five different configurations: 1) Flat, 2) Half-expanded, 3) Fully rolled with a molybdenum (Mo)-coated capsule, 4) Fully rolled with dissolved Mo coating, and 5) Truncated dipole arms, according to some embodiments.

[0032] FIG. 17 shows schematics for a modelled RFID tag, according to some embodiments.

[0033] FIGS. 18A-18G show cellulose based electrical shielding material fabrication and electrical characterization, according to some embodiments.

[0034] FIG. 19 provides a photograph of a printer in the process of printing an EMI shielding coating using industrial brush dispenser, according to some embodiments.

[0035] FIG. 20 shows a SEM image of HEC:Mo at a 1:11 ratio (left) and a zoomed in image of the film (right), according to some embodiments.

[0036] FIG. 21 shows a comparison of the metals and the composites for EMI Shielding performance between 700 MHz- 1200 MHz, according to some embodiments.

[0037] FIG. 22 shows the viscosity of molybdenum and tungsten-based EMI shielding inks, and the inset shows the ink applied using a brush, according to some embodiments.

[0038] FIG. 23A shows images of dissolution of EMI shielded capsule and RFID tag in SGF (pH 1.2) solution at 37 °C. At 75°C (corresponds to ~16 times relative to 37°C), the device and the components dissolved and disintegrated into small particles in a week, according to some embodiments.

[0039] FIGS. 23B-23G show an in vivo demonstration of biodegradable cellulose based RFID tag, according to some embodiments.

[0040] FIG. 24 shows an x-ray image of the animal in lateral recumbency, 24h after administration of the capsule, where the device was either partially dissolved or excreted from the GI tract, according to some embodiments.

[0041] #14443731vl FIG. 25A shows tag name acquisition using handheld reader connected to a smart phone ID verification (RFID Explorer, Technology Solutions (UK) Ltd.), according to some embodiments.

[0042] FIG. 25B shows an exemplary software interface for the tag reader, according to some embodiments.

[0043] FIGS. 26A-26H provides the electrical and mechanical characterization of conductive wax composites. FIG. 26A schematically illustrates conductive fillers and natural wax candidates with schematic illustration of mold preparation steps, according to some embodiments. FIG. 26B shows average sheet resistance measurements at varying metal volume ratios. FIGS 26C-26E show impedance spectroscopy of three different wax candidates in SGF (FIG. 26C), and SIF (FIG. 26E). FIG. 26F shows the results of mechanical characterization, comparing modulus (stiffness) between pure waxes, polymers and wax-metal composites. FIG. 26G shows the fracture strength comparison of the material family. FIG. 26H, summarizes selection wax-metal composite chosen for subsequent experiments.

[0044] FIG. 27A shows a schematic of the procedure for hook manufacturing technique, according to some embodiments.

[0045] FIG. 27B, shows penetration forces of the hooks in swine esophagus, stomach and duodenum, according to some embodiments.

[0046] FIG. 27C depicts insertion of the hooks into esophagus, stomach wall, and duodenum, revealing a robust anchoring the ex vivo GI tissue, according to some embodiments.

[0047] FIG. 27D presents representative histology images of H&E stained tissue sections of the esophagus, stomach and intestine penetrated by hook electrodes, according to some embodiments.

[0048] FIG. 27E demonstrates the degradability of the hooks over time, according to some embodiments.

[0049] FIG. 28A provides a detailed schematic illustration of GERD monitoring in vivo swine esophagus using tissue anchors provided herein, according to some embodiments.

[0050] FIG. 28B provides a schematic illustration and the photograph of a hook-based GERD sensor, according to some embodiments.

[0051] FIG. 28C shows impedance spectroscopy of measured using hooks inserted into in vivo esophagus tissue, according to some embodiments.

[0052] FIG. 28D shows impedance spectroscopy of the hooks measured in different GI bodily fluids, according to some embodiments.

[0053] #14443731vl FIG. 28E provides endoscopic images of GERD sensor in vivo before and after anchoring to swine esophagus, according to some embodiments.

[0054] FIG. 28F shows the device impedance response during GERD simulation at 1 kHz (left) and 10 kHz (right) on the esophagus model, according to some embodiments.

[0055] FIG. 29A provides a schematic illustration of the gastric slow wave (GSW) recording from the stomach using the hooks, hook electrodes anchored against the gastric mucosal surface, according to some embodiments.

[0056] FIG. 29B provides a photograph of the electrode array with hooks and the recording capsule, according to some embodiments.

[0057] FIG. 29C provides a photograph of the hook-based recording tool and image of the in vivo recording experiment, device placement into swine stomach. Zoomed in (dashed line) recordings show the cpm value for each pig, according to some embodiments.

[0058] FIG. 29D shows the gastric slow waves from 3 different swine captured over hooked channels of the electrode array in the swine stomach, according to some embodiments.

[0059] FIG. 29E shows a device configured to regulate hormones by delivering electrostimulation therapy in large animal models, according to some embodiments.

[0060] FIG. 29F provides a non-limiting exploded perspective illustration of the device, according to some embodiments.

[0061] FIG. 29G presents a photograph of the device, according to some embodiments.

[0062] FIG. 29H presents an X-ray image of the capsule with hooks anchored in duodenum, according to some embodiments.

[0063] FIG. 291 provides a schematic representation of ghrelin modulation using capsule size hook stimulator, according to some embodiments.

[0064] FIG. 29J shows the percentage change in the swine Ghrelin amount in different animals, according to some embodiments.

[0065] FIG. 29K provides representative histology images of H&E stained tissue section duodenum penetrated by the hooks, according to some embodiments.

[0066] FIG. 30A shows biodegradable batteries for ingestible electronics, according to some embodiments.

[0067] FIG. 30B shows long-distance ingestible device tracking, according to some embodiments.

[0068] FIG. 30C shows fully degradable, capsule based gastric electrical stimulation, according to some embodiments.

[0069] #14443731vl FIG. 30D shows dissolution and biosorption of the batteries, RF devices and capsule electronics, according to some embodiments.

[0070] FIG. 30E provides a schematic illustration of the Mg-MoO3 battery and the device architecture, according to some embodiments.

[0071] FIG. 31A shows 000 size and large area capsule battery device dimensions and optical images of two different sized battery systems, according to some embodiments.

[0072] FIG. 3 IB shows plots of discharge behaviors of 000-size battery, according to some embodiments.

[0073] FIG. 31C shows plots of discharge behaviors of large area capsule size battery at different current densities, according to some embodiments.

[0074] FIG. 3 ID provides a schematic diagram of in vivo retention study that investigates the battery capacities after days of retention in swine stomach, according to some embodiments.

[0075] FIG. 3 IE shows X-Ray images of arm-shape capsule loaded with batteries at day 0 and the retention day 3, according to some embodiments.

[0076] FIG. 3 IF is an endoscopic image visualizing the position of the capsule loaded with three 000-size batteries for investigation of retention, according to some embodiments.

[0077] FIG. 31G shows the change in the energy density and open circuit potential for the 000- size batteries in SGF and in vivo retention days spent in the stomach, according to some embodiments.

[0078] FIG. 31H shows an X-Ray image of 3D printed capsule loaded with large area capsule batteries at day 0, according to some embodiments.

[0079] FIG. 311 shows an X-Ray image of 3D printed capsule loaded with large area capsule batteries at the retention day 3, according to some embodiments.

[0080] FIG. 31 J shows the effect of retention on the energy density and open circuit potential for the large area batteries in SGF and in vivo retention days spent in the stomach., according to some embodiments.

[0081] FIG. 32A provides a schematic representation of fully degradable battery assisted RFID tag application, according to some embodiments.

[0082] FIG. 32B shows components and materials for battery assisted RFID tag device, according to some embodiments.

[0083] FIG. 32C shows optical images of the BA-RFID tag before administration, according to some embodiments.

[0084] #14443731vl FIG. 32D shows optical images of the BA-RFID tag before administration, according to some embodiments.

[0085] FIG. 32E shows antenna RF behavior (Si l) of the Mo based paper-clip antenna, according to some embodiments.

[0086] FIG. 32F provides a schematic illustration of battery assisted RFID tag application measuring from a long range, according to some embodiments.

[0087] FIG. 32G shows RSSI and frequency of a RFID tag measured over 4m distance, according to some embodiments.

[0088] FIG. 32H shows in vivo demonstration of the RFID tags for measuring the medication adherence, according to some embodiments.

[0089] FIG. 321 shows RSSI recorded in three different live swine, according to some embodiments.

[0090] FIG. 32J shows an X-Ray image of the BA-RFID tag delivered in esophagus, according to some embodiments.

[0091] FIG. 32K shows optical images of dissolution for BA-RFID tag in SGF at 37 °C. , according to some embodiments.

[0092] FIG. 33A provides a conceptual schematic of gastric electrical stimulation for regulating hunger hormone ghrelin, according to some embodiments.

[0093] FIG. 33B provides a schematic representation (i) and optical micrograph (ii), according to some embodiments.

[0094] FIG. 33C shows a degradable capsule system with capsule open and closed forms (iii), according to some embodiments.

[0095] FIG. 33D provides schematics of ingestible form factor stimulation PCB, according to some embodiments.

[0096] FIG. 33E show discharging at 1.5 mA performance of 2 biodegradable batteries in series, according to some embodiments.

[0097] FIG. 33F provides a schematic representation of in vivo GES application using fully degradable capsule electroceutical system, according to some embodiments.

[0098] FIG. 33G is a endoscope photograph showing a biodegradable capsule in swine gastric antrum, according to some embodiments.

[0099] FIG. 33H is an X-Ray image of the degradable capsule in swine stomach, according to some embodiments.

[0100] #14443731vl FIG. 331 shows H&E stains of biopsied stomach mucosa before and after electrical stimulation at the stimulation site, according to some embodiments.

[0101] FIG. 33J shows change in plasma ghrelin concentration over time after delivery of biodegradable battery powered stimulation capsule and sham, according to some embodiments.

[0102] FIG. 33K shows optical images of dissolution for biodegradable GES capsule in SGF at 37C, according to some embodiments.

[0103] DETAILED DESCRIPTION

[0104] This disclosure, relates, in various embodiments, to devices configured for use in medical applications that are configured to degrade within the body. Increasingly, the medical profession has become reliant on small-scale devices for sensing and / or drug delivery. However, these devices carry some risks, as they can injure subjects and / or require surgical intervention to recover them, if they fail to operate as intended. The devices provided herein, according to some embodiments, comprise components that are at least partially biodegradable. For example, the components may be biodegradable such that they are at least partially dissolvable in the body of a subject. In some embodiments, the biodegradable components provided herein are bioresorbable. The use of devices configured to biodegrade within the body, e.g., by bioresorption and / or dissolution can, in some embodiments, reduce or eliminate the risks associated with these devices. In some embodiments, the devices are completely resorbable. In others, a substantial portion (e.g., greater than or equal to 70%, 80%, 90% of the device) of the device is biodegradable (e.g., bioresorbable). Non-biodegradable portions of the device may be relatively small, e.g., so that they can pass through the digestive system without need for surgical intervention or recovery.

[0105] In some embodiments, the signal processing portion comprises a transmitter. The transmitter may be configured to transmit signals (e.g., RF signals) to an external controller unit. In some embodiments, the transmitter may be configured to transmit signals to an operator (e.g., via an external controller unit). In some embodiments, an operator may operate a device based, at least in part, on information transmitted by the device. Information transmitted by the device may include temperature information, pH information, chemical information, information regarding a state of the device, information regarding an orientation of the device, and / or any other appropriate form of information that may be determined by the device.

[0106] In some embodiments, the disclosure provides devices with one or more degradable components for signal transmission to or from a device. In some embodiments, the disclosure

[0107] #14443731vl provides one or more biodegradable (e.g., bioresorbable) components for signal transmission. For example, in some embodiments, the disclosure comprises one or more biodegradable (e.g., bioresorbable) radio frequency identification (RFID) tags or components thereof (e.g., RFID antennas). An RFID tag may comprise an RFID antenna, a substrate (e.g., on which the RFID antenna is deposited), and / or an RFID circuit. One or more components of the RFID tag may be biodegradable (e.g., bioresorbable). One or more components of the RFID tag may be dissolvable.

[0108] Any of a variety of RFID tag configurations may be used. In some embodiments, the degradable RFID tag is passive (e.g., the RFID tag is configured to be powered by receipt of a signal transmitted by an RFID reader). In some embodiments, the RFID tag is active or semiactive (e.g., is at least partially powered by power supply, such as a battery). As discussed in greater detail below, the disclosure provides biodegradable (e.g., bioresorbable batteries), according to some embodiments. The RFID tag may be configured for one-way or two-way communication with an RFID reader, depending on the embodiment.

[0109] The present disclosure generally relates, in various aspects, to devices comprising biodegradable (e.g., bioresorbable) RFID antennas and dissolvable coatings. By employing fully biodegradable materials, the devices provided herein may obviate the need for device retrieval or battery replacement, thereby mitigating electronic waste. Moreover, the tags are compatible with standard gelatin or hydroxypropyl methylcellulose (HPMC) capsules, further enhancing clinical translational potential.

[0110] FIG. 1 illustrates a non-limiting, cross-sectional schematic illustration of a biodegradable (e.g., bioresorbable) RFID tag 101, according to some embodiments. RFID tag 101 comprises a biodegradable (e.g., bioresorbable) RFID antenna 103 (comprising first portion 5003a and second portion 5003b, which are bifurcated portions of the same antenna, though their connection is not visible in the figure) disposed on a substrate 105. Atop substrate 105 and between first portion 5003a and second portion 5003b of antenna 103 is RFID circuit 109 (represented as an RFID chip), also disposed on substrate 105, in the form of a chip connected to antenna 103 by electronic connections 111. The portions of RFID tag 101 may be mechanically coupled, e.g., using an adhesive. For example, in some embodiments, antenna 103 and / or RFID circuit 109 are adhered to substrate 105 using an adhesive disposed on the substrate.

[0111] Any of a variety of suitable materials may be used to make a biodegradable (e.g., bioresorbable) RFID tag. According to some embodiments, a device comprises a biodegradable (e.g., bioresorbable) conductive material (e.g., as part of the RFID antenna and / or as part of a

[0112] #14443731vl circuit of the device). The conductive material may be used to form at least a portion of the RFID tag. For example, the conductive material may be used to form the RFID antenna, a portion of a circuit of a device, etc. In some embodiments, the conductive material is a pure conductive material, e.g., a pure metal. In some embodiments, the conductive material is a metal. Exemplary metals that may be used include, but are not limited to, W, Fe, Mg, Mo, Zn, and alloys thereof. The metal may be chosen to dissolve over time (e.g., via chemical reaction with the body fluid of a subject, such as stomach acid). In some embodiments, the metal is chosen to dissolve to form one or more non-toxic metal ions, e.g., which may be passed from or resorbed into the body of a subject, depending on the embodiment.

[0113] According to some embodiments, the conductive material is a conductive composite material. For example, the conductive composite material may be a composite comprising a first, conductive material and a second material. The first material may be a metal as described in the foregoing paragraph (e.g., W, Fe, Mg, Mo, Zn, or an alloy thereof). The second material may be a conductive material or a non-conductive material. In some embodiments, the second material is a polymer. For example, the second material may be a biodegradable (e.g., bioresorbable) polymer. Non-limiting examples of suitable bioresorbable polymers that may be used include, but are not limited to, polylactic acid (PLA), polycaprolactone (PCL), polyvinyl alcohol (PVA), poly(lactic-co-glycolic acid) (PLGA), polybutylene succinate (PBS), poly(glycerol sebacate) (PGS), gelatin, alginate, cellulosic materials (e.g., cellulose, cellulose acetate, methylcellulose), and mixtures and derivatives thereof. In some embodiments, the polymer is synthetic. According to some embodiments, the polymer is natural.

[0114] The composite may comprise a matrix phase (e.g., of the second material). In some embodiments, the first, conductive material, is embedded in the matrix phase. The conductive phase may, for example, comprise a plurality of conductive particles (e.g., metal filler particles) configured to provide a conductive pathway through the material. The first material and / or the second material may be biodegradable (e.g., bioresorbable), depending on the embodiment.

[0115] A suitable conductive material may have any of a variety of suitable sheet resistances. In some embodiments, a conductive material has a sheet resistance of greater than or equal to 0.1 Q / sq, greater than or equal to 1 Q / sq, greater than or equal to 10 Q / sq, greater than or equal to 100 Q / sq, greater than or equal to 200 Q / sq, greater than or equal to 300 Q / sq, greater than or equal to 400 Q / sq, greater than or equal to 500 Q / sq, greater than or equal to 600 Q / sq, greater than or equal to 700 Q / sq, greater than or equal to 800 Q / sq, or greater than or equal to 900 Q / sq. In some embodiments, a conductive material has a sheet resistance of less than or equal to 1000

[0116] #14443731vl Q / sq, less than or equal to 900 Q / sq, less than or equal to 800 Q / sq, less than or equal to 700

[0117] Q / sq, less than or equal to 600 Q / sq, less than or equal to 500 Q / sq, less than or equal to 400

[0118] Q / sq, less than or equal to 300 Q / sq, less than or equal to 200 Q / sq, less than or equal to 100

[0119] Q / sq, less than or equal to 10 Q / sq, or less than or equal to 10 Q / sq. Combinations of these ranges are also possible (e.g., greater than or equal to 0.1 Q / sq and less than or equal to 1000 Q / sq, or greater than or equal to 0.1 Q / sq and less than or equal to 100 Q / sq). Other ranges, both higher and lower than those described above, are also possible, as the disclosure is not so limited.

[0120] In some embodiments, the first, conductive material is a metal as described above. Where a conductive composite material is used, the first, conductive material may be included in the composite conductive material in any of a variety of suitable weight percentages. In some embodiments, a conductive composite material comprises a first, conductive material (e.g., a metal) in an amount of greater than or equal to 10 wt%, greater than or equal to 15 wt%, greater than or equal to 20 wt%, greater than or equal to 25 wt%, greater than or equal to 30 wt%, greater than or equal to 35 wt%, greater than or equal to 40 wt%, or greater than or equal to 45 wt% versus the weight of the conductive composite material. In some embodiments, a conductive composite material comprises a first, conductive material (e.g., a metal) in an amount of less than or equal to 50 wt%, less than or equal to 45 wt%, less than or equal to 40 wt%, less than or equal to 35 wt%, less than or equal to 30 wt%, less than or equal to 25 wt%, less than or equal to 20 wt%, or less than or equal to 15 wt% versus the weight of the conductive composite material. Combinations of these ranges are also possible (e.g., greater than or equal to 10 wt% and less than or equal to 50 wt%, or greater than or equal to 20 wt% and less than or equal to 40 wt%). Other ranges, both higher and lower than those described above, are also possible, as the disclosure is not so limited. According to some embodiments, the amount of conductive material in the composite material is chosen to improve rheological properties. For example, the amount of conductive material in the composite material may be chosen to ensure that the composite material can be processed via a coating technique.

[0121] The second material (e.g., the matrix phase) may be configured to bioresorb, while the first phase biodegrades, according to some, specific embodiments. The second material (e.g., the matrix phase) may be configured to biodegrade, while the first phase bioresorbs, according to some, specific embodiments. In some embodiments, the second material is a biodegradable (e.g., bioresorbable) polymer matrix. Non-limiting examples of suitable bioresorbable materials for the coating include polyethylene glycol, polyvinylpyrrolidone, polylactic acid,

[0122] #14443731vl polysaccharaides (e.g., maltose, lactose, starch, cellulose), acacia, methyl cellulose, gelatin, tragacanth, clays, HPMC, stearic acid, sodium stearate, magnesium stearate, talc, polyethylene glycol, mineral oil, preservatives (e.g., phenol, paraben, cetrimide), antioxidants (e.g., gallic acid, tocopherol), derivatives thereof, and combinations thereof. According to some embodiments, the bioresorbable polymer matrix comprises a polysaccharide.

[0123] According to some embodiments, the second material is a wax. For example, in some embodiments, the second material comprises beeswax, candlilla wax, and / or carnauba wax.

[0124] The second material may be included in the conductive composite material in any of a variety of appropriate weight percentages. Where a conductive composite material is used, the second material may be included in the composite material in any of a variety of suitable weight percentages. In some embodiments, a conductive composite material comprises a second material (e.g., a matrix material) in an amount of greater than or equal to 50 wt%, greater than or equal to 55 wt%, greater than or equal to 60 wt%, greater than or equal to 65 wt%, greater than or equal to 70 wt%, greater than or equal to 75 wt%, greater than or equal to 80 wt%, or greater than or equal to 85 wt% versus the weight of the conductive composite material. In some embodiments, a conductive composite material comprises a second material (e.g., a matrix material) in an amount of less than or equal to 90 wt%, less than or equal to 85 wt%, less than or equal to 80 wt%, less than or equal to 75 wt%, less than or equal to 70 wt%, less than or equal to 65 wt%, less than or equal to 60 wt%, or less than or equal to 55 wt% versus the weight of the conductive composite material. Combinations of these ranges are also possible (e.g., greater than or equal to 50 wt% and less than or equal to 90 wt%, or greater than or equal to 60 wt% and less than or equal to 80 wt%). Other ranges, both higher and lower than those described above, are also possible, as the disclosure is not so limited.

[0125] The following paragraph provides a specific set of embodiments. In one aspect, a device is provided. The device may comprise a biodegradable (e.g., bioresorbable) RFID antenna. In some embodiments, the biodegradable (e.g., bioresorbable) RFID antenna comprises a metal, e.g., W, Fe, Mg, and / or Zn. For example, in some embodiments, a bioresorbable RFID antenna comprises Zn. In some embodiments, at least a portion of the metal is degraded, dissolved, or otherwise mechanically weakens in a gastric environment of a subject. In some embodiments, the gastric environment of the subject is located in the colon, the duodenum, the ileum, the jejunum, the stomach, or the esophagus of the subject. Of course, it should be understood that the disclosure is not limited to the foregoing set of embodiments.

[0126] #14443731vl In some embodiments, the biodegradable component (antenna, battery, capsule, etc.) is degraded, dissolved, or otherwise mechanically weakens in a gastric environment of a subject.

[0127] A “subject” refers to any animal such as a mammal (e.g., a human). Non-limiting examples of subjects include a human, a non-human primate, a cow, a horse, a pig, a sheep, a goat, a dog, a cat or a rodent such as a mouse, a rat, a hamster, a bird, a fish, or a guinea pig. Generally, the invention is directed toward use with humans. In some embodiments, a subject may demonstrate health benefits, e.g., upon administration of devices described herein.

[0128] In some embodiments, one or more components of the article (e.g., the antenna, the battery) is substantially non-toxic. The term “non-toxic” refers to a substance that is not toxic. Toxic reagents include, e.g., oxidative stressors, nitrosative stressors, proteasome inhibitors, inhibitors of mitochondrial function, ionophores, inhibitors of vacuolar ATPases, inducers of endoplasmic reticulum (ER) stress, and inhibitors of endoplasmic reticulum associated degradation (ERAD). In some embodiments a toxic reagent selectively causes damage to nervous system tissue. Toxic reagents include compounds that are directly toxic and reagents that are metabolized to or give rise to substances that are directly toxic. It will be understood that the term “toxic compounds" typically refers to reagents that are not ordinarily present in a cell’s normal environment at sufficient levels to exert detectable damaging effects. However, in some cases, the toxic reagents may be present in a cell’s normal environment but at concentrations significantly less than present in the auxiliary materials described herein. Typically, toxic reagents exert damaging effects when present at a relatively low concentration, e.g., at or below 1 mM, e.g., at or below 500 microM, e.g., at or below 100 microM. It will be understood that a toxic reagents typically has a threshold concentration below which it does not exert detectable damaging effects. The particular threshold concentration will vary depending on the agent and, potentially, other factors such as cell type, other agents present in the environment, etc.

[0129] The present disclosure recognizes that, according to some embodiments, it may be desirable to shield a degradable component for signal transmission to or from a device. One form of electromagnetic shielding is a Faraday cage — a conductive enclosure that shields the device from electromagnetic signals. In some embodiments, the disclosure provides conductive coatings suitable for use as Faraday cages. A conductive coating may comprise a conductive material (e.g., a conductive composite material comprising a first, conductive material and a second matrix phase as described above).

[0130] #14443731vl The device may further comprise a coating surrounding the RFID antenna. The coating may be configured to electromagnetically shield the RFID antenna such that the antenna is unable to receive a signal until the coating dissolves. For example, in some embodiments, the coating acts as a Faraday cage. The coating may be conductive. For example, the coating may comprise a composite of a bioresorbable metal filler disposed within a polymer matrix. The bioresorbable metal filler may comprise particles of Mo, W, Fe, Mg, Zn, and / or an alloy thereof. In some embodiments, the polymer matrix comprises a polysaccharide. Non-limiting examples of suitable materials for the coating include polyethylene glycol, polyvinylpyrrolidone, polylactic acid, polysaccharaides (e.g., maltose, lactose, starch, cellulose), acacia, methyl cellulose, gelatin, tragacanth, clays, HPMC, stearic acid, sodium stearate, magnesium stearate, talc, polyethylene glycol, mineral oil, preservatives (e.g., phenol, paraben, cetrimide), antioxidants (e.g., gallic acid, tocopherol), derivatives thereof, and combinations thereof.

[0131] According to some embodiments, the coating is applied to a containing structure of the device. A containing structure be configured to aid with administration of the device to a subject. In some cases, the device may be administered to a subject. In some embodiments, the device is administered orally, rectally, vaginally, nasally, or uretherally. In some embodiments, the device comprises a containing structure (e.g., a capsule). In some embodiments, the device is contained within a containing structure (e.g., during administration) and, upon reaching the location internal to the subject (e.g., in the gastrointestinal tract), at least a portion of the containing structure degrades such that the device obtains a configuration configured for gastric residence. In some embodiments, the device is administered directly to a subject (e.g., without a containing structure). The biodegradable (e.g., bioresorbable) RFID antenna may be contained within the capsule. The containing structure may comprise the coating. For example, the containing structure may be the coating, or the coating may be deposited on the capsule (e.g., on an exterior surface of the capsule, or on an interior surface of the capsule. Thus, when the capsule is administered to a subject (e.g., orally) the coating and the capsule may disintegrate, removing the electromagnetic barrier between the biodegradable (e.g., bioresorbable) RFID antenna and a transmitter or receiver external to the subject. Thus, dissolution of the coating may allow the biodegradable (e.g., bioresorbable) RFID antenna to become active, and to transmit or receive a signal from outside the subject.

[0132] The coating may be configured to dissolve after placement of the device within an organ internal to a subject (e.g., within 10 min, 30 min, Ih, 12h, 24h, 48h, or 72h of placement of the device within the internal organ). For example, in some embodiments, the matrix of the coating

[0133] #14443731vl dissolves while the particles of the coating react with stomach acid to produce biocompatible side-products. In some embodiments, a coating is configured to dissolve within a period of less than or equal to 72 hours, less than or equal to 66 hours, less than or equal to 60 hours, less than or equal to 54 hours, less than or equal to 48 hours, less than or equal to 42 hours, less than or equal to 36 hours, less than or equal to 30 hours, less than or equal to 24 hours, less than or equal to 18 hours, less than or equal to 12 hours, less than or equal to 6 hours, less than or equal to 3 hours, less than or equal to 1 hour, or less than or equal to 30 minutes. In some embodiments, a coating is configured to dissolve within a period of greater than or equal to 10 minutes, greater than or equal to 30 minutes, greater than or equal to 1 hour, greater than or equal to 3 hours, greater than or equal to 6 hours, greater than or equal to 12 hours, greater than or equal to 18 hours, greater than or equal to 24 hours, greater than or equal to 30 hours, greater than or equal to 36 hours, greater than or equal to 42 hours, greater than or equal to 48 hours, greater than or equal to 54 hours, greater than or equal to 60 hours, or greater than or equal to 66 hours. Combinations of these ranges are also possible (e.g., greater than or equal to 10 minutes and less than or equal to 72 hours, or greater than or equal to 1 hour and less than or equal to 72 hours). Other ranges, both higher and lower than those described above, are also possible, as the disclosure is not so limited.

[0134] The biodegradable RFID antenna may be configured to dissolve and / or bioresorb (e.g., after release from the coating). In some embodiments, a biodegradable RFID antenna is configured to dissolve within a period of less than or equal to 72 hours, less than or equal to 66 hours, less than or equal to 60 hours, less than or equal to 54 hours, less than or equal to 48 hours, less than or equal to 42 hours, less than or equal to 36 hours, less than or equal to 30 hours, less than or equal to 24 hours, less than or equal to 18 hours, less than or equal to 12 hours, less than or equal to 6 hours, less than or equal to 3 hours, less than or equal to 1 hour, or less than or equal to 30 minutes. In some embodiments, a biodegradable RFID antenna is configured to dissolve within a period of greater than or equal to 10 minutes, greater than or equal to 30 minutes, greater than or equal to 1 hour, greater than or equal to 3 hours, greater than or equal to 6 hours, greater than or equal to 12 hours, greater than or equal to 18 hours, greater than or equal to 24 hours, greater than or equal to 30 hours, greater than or equal to 36 hours, greater than or equal to 42 hours, greater than or equal to 48 hours, greater than or equal to 54 hours, greater than or equal to 60 hours, or greater than or equal to 66 hours. Combinations of these ranges are also possible (e.g., greater than or equal to 10 minutes and less than or equal to 72 hours, or greater than or equal to 1 hour and less than or equal to 72 hours). Other ranges,

[0135] #14443731vl both higher and lower than those described above, are also possible, as the disclosure is not so limited.

[0136] Certain of the structures, systems, and methods 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 structures and systems described herein may offer certain advantages as compared to traditional compositions and structures and systems 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 biodegrade into one or more forms configured for passing through a gastrointestinal tract. In certain embodiments, the structures and systems 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 systems, structures, and methods described herein are compatible with subjects, including, but not limited to, humans and non-human animals. In further embodiments, the systems and structures 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.

[0137] Thus, in some embodiments, the entire device is configured to completely dissolve within the subject. For example, the entire device may be configured to dissolve before the device completes its journey within the gastrointestinal tract of a subject. In some embodiments, a device is configured to dissolve within a period of less than or equal to 1 year, 6 months, 3 months, 1 month, 2 weeks, less than or equal to 1 week, less than or equal to 6 days, less than or equal to 5 days, less than or equal to 4 days, less than or equal to 72 hours, less than or equal to 66 hours, less than or equal to 60 hours, less than or equal to 54 hours, less than or equal to 48 hours, less than or equal to 42 hours, less than or equal to 36 hours, less than or equal to 30 hours, less than or equal to 24 hours, less than or equal to 18 hours, less than or equal to 12

[0138] #14443731vl hours, less than or equal to 6 hours, less than or equal to 3 hours, less than or equal to 1 hour, or less than or equal to 30 minutes of placement of the device within the internal organ of a subject. In some embodiments, a device is configured to dissolve within a period of greater than or equal to 10 minutes, greater than or equal to 30 minutes, greater than or equal to 1 hour, greater than or equal to 3 hours, greater than or equal to 6 hours, greater than or equal to 12 hours, greater than or equal to 18 hours, greater than or equal to 24 hours, greater than or equal to 30 hours, greater than or equal to 36 hours, greater than or equal to 42 hours, greater than or equal to 48 hours, greater than or equal to 54 hours, greater than or equal to 60 hours, greater than or equal to 66 hours, greater than or equal to 72 hours, greater than or equal to 4 days, greater than or equal to 5 days, greater than or equal to 6 days, or greater than or equal to 1 week of placement of the device within the internal organ of a subject. Combinations of these ranges are also possible (e.g., greater than or equal to 10 minutes and less than or equal to 2 weeks, or greater than or equal to 1 hour and less than or equal to 72 hours). Other ranges, both higher and lower than those described above, are also possible, as the disclosure is not so limited.The containing structure may be configured to dissolve after placement of the device within an organ internal to a subject (e.g., within 1 min, 5 min, 10 min, 30 min, Ih, 12h, 24h, 48h, or 72h of placement of the device within the internal organ). In some embodiments, a containing structure is configured to dissolve within a period of less than or equal to 72 hours, less than or equal to 66 hours, less than or equal to 60 hours, less than or equal to 54 hours, less than or equal to 48 hours, less than or equal to 42 hours, less than or equal to 36 hours, less than or equal to 30 hours, less than or equal to 24 hours, less than or equal to 18 hours, less than or equal to 12 hours, less than or equal to 6 hours, less than or equal to 3 hours, less than or equal to 1 hour, or less than or equal to 30 minutes of placement of the device within the internal organ of a subject. In some embodiments, a containing structure is configured to dissolve within a period of greater than or equal to 1 minute, greater than or equal to 5 minutes, greater than or equal to 10 minutes, greater than or equal to 30 minutes, greater than or equal to 1 hour, greater than or equal to 3 hours, greater than or equal to 6 hours, greater than or equal to 12 hours, greater than or equal to 18 hours, greater than or equal to 24 hours, greater than or equal to 30 hours, greater than or equal to 36 hours, greater than or equal to 42 hours, greater than or equal to 48 hours, greater than or equal to 54 hours, greater than or equal to 60 hours, or greater than or equal to 66 hours of placement of the device within the internal organ of a subject. Combinations of these ranges are also possible (e.g., greater than or equal to 1 minute and less than or equal to 72 hours, or greater than or equal

[0139] #14443731vl to 1 hour and less than or equal to 72 hours). Other ranges, both higher and lower than those described above, are also possible, as the disclosure is not so limited.

[0140] According to some embodiments, the RFID tag comprises a substrate. The substrate may comprise any of a variety of suitable materials. According to some embodiments, the substrate comprises a non-conductive material. For example, the substrate may comprise a biodegradable (e.g., bioresorbable), non-conductive substrate material. Examples of non-limiting biodegradable (e.g., bioresorbable) non-conductive substrate materials that can be used, alone or in combination, include, but are not limited to, cellulosic materials (e.g., cellulose, cellulose acetate, methylcellulose) and biodegradable (e.g., bioresorbable) polymers (e.g., polybutylene succinate (PBS), alginate, gelatin, and poly(glycolide-co-lactide) (PLGA)).

[0141] According to some embodiments, an RFID tag comprises an RFID circuit (e.g., in the form of an RFID chip). The RFID chip may be biodegradable (e.g., bioresorbable). However, this is not necessary; in some embodiments the RFID chip is simply small enough to be able to safely pass through a subject after bioresorption of one or more other portions of a device. Any of a variety of suitable RFID circuits may be used, depending on the embodiment, as the disclosure is not so limited.

[0142] According to some embodiments, the RFID tag comprises an adhesive. The adhesive may serve any of a variety of suitable purposes. For example, in some embodiments the adhesive is configured to adhere the RFID antenna, the RFID circuit, and / or the RFID substrate together. The adhesive may be bioresorbable. For example, in some embodiments, the adhesive comprises a bioresorbable polymer (e.g., polybutylene succinate (PBS), alginate, gelatin, and poly(glycolide-co-lactide) (PLGA)).

[0143] The device may comprise a battery configured to dissolve within a subject. Presented herein, in some aspects, is a cellulose based Mg primary and Zn secondary batteries that can disintegrate in the body or degrade in soil. The development of biodegradable (e.g., bioresorbable), or otherwise transient electronics offers several advantages: it eliminates the need for secondary surgeries to remove implants, thereby reducing the risk of infection. This field opens exciting new avenues for biodegradable and green electronics that can seamlessly integrate with the body and degrade after a predetermined period of operation.

[0144] Previous systems have not utilized fully packaged biodegradable battery technology. Furthermore, the devices were not tested in large mammals. Additionally, previous systems have not reported toxicity and dissolution data using mass spectroscopy or analytical methods.

[0145] #14443731vl According to some embodiments, a device comprises a biodegradable (e.g., bioresorbable) battery. According to some embodiments, the biodegradable (e.g., bioresorbable) battery is configured to completely dissolve within a subject. For example, in some embodiments, a battery provided herein is configured to dissolve within a period of less than or equal to 72 hours, less than or equal to 66 hours, less than or equal to 60 hours, less than or equal to 54 hours, less than or equal to 48 hours, less than or equal to 42 hours, less than or equal to 36 hours, less than or equal to 30 hours, less than or equal to 24 hours, less than or equal to 18 hours, less than or equal to 12 hours, less than or equal to 6 hours, less than or equal to 3 hours, less than or equal to 1 hour, or less than or equal to 30 minutes. In some embodiments, a battery provided herein is configured to dissolve within a period of greater than or equal to 10 minutes, greater than or equal to 30 minutes, greater than or equal to 1 hour, greater than or equal to 3 hours, greater than or equal to 6 hours, greater than or equal to 12 hours, greater than or equal to 18 hours, greater than or equal to 24 hours, greater than or equal to 30 hours, greater than or equal to 36 hours, greater than or equal to 42 hours, greater than or equal to 48 hours, greater than or equal to 54 hours, greater than or equal to 60 hours, or greater than or equal to 66 hours. Combinations of these ranges are also possible (e.g., greater than or equal to 10 minutes and less than or equal to 72 hours, or greater than or equal to 1 hour and less than or equal to 72 hours). Other ranges, both higher and lower than those described above, are also possible, as the disclosure is not so limited.

[0146] The biodegradable (e.g., bioresorbable) battery may have any of a variety of configurations.

[0147] Generally, a battery comprises an anode. The anode may comprise any of a variety of anode active materials. As used herein, the terms “anode active material” and “anode active species” both refer to any electrochemically active species associated with the anode. For example, the anode may comprise a material comprising a bioresorbable metal (e.g., magnesium), wherein the bioresorbable metal is the anode active material. Any of a variety of anode active materials may be used, including but not limited to Mg, Zn, Mn, Fe, and / or alloys thereof. As an example, in some embodiments, the anode active material is an alloy of Mg, Zn, and Al (e.g., AZ31). In some embodiments, the anode active species comprises magnesium metal (e.g., Mg foil). In some embodiments, the anode active species comprises a magnesium alloy.

[0148] Generally, a battery comprises a cathode. The cathode may comprise any of a variety of cathode active materials. As used herein, the terms “cathode active material” and “cathode

[0149] #14443731vl active species” both refer to any electrochemically active species associated with the cathode. For example, the cathode may comprise MoO3, M0S2, Mo (and / or alloys thereof), and / or Mn (and / or alloys thereof).

[0150] According to some embodiments, the cathode comprises cellulose. For example, the cathode may comprise a composite of cellulose with a cathode active material. In some embodiments, the cathode is a composite of nanofibrillated cellulose with a cathode active material. For example, in some embodiments, cathode is a nanopaper composite cathode. In some embodiments, the cathode is a composite of microfibrillated cellulose with a cathode active material. In some embodiments, the cathode is a composite of nanocrystalline cellulose with a cathode active material.

[0151] The nanofibrillated cellulose may comprise cellulose nanofibrils that, in some embodiments, have a relatively high aspect ratio. In some embodiments, the nanofibrillated cellulose comprises cellulose nanofibrils having an average aspect ratio of greater than or equal to 10 : 1, greater than or equal to 20 : 1, greater than or equal to 30 : 1, greater than or equal to 40 : 1, greater than or equal to 50 : 1, greater than or equal to 60 : 1, greater than or equal to 70 : 1, greater than or equal to 80 :1, or greater than or equal to 90 :1. In some embodiments, the nanofibrillated cellulose comprises cellulose nanofibrils having an average aspect ratio of less than or equal to 100 :1, less than or equal to 90 :1, less than or equal to 80 :1, less than or equal to 70 :1, less than or equal to 60 :1, less than or equal to 50 :1, less than or equal to 40 :1, less than or equal to 30 :1, or less than or equal to 20 :1. Combinations of these ranges are also possible (e.g., greater than or equal to 10 :1 and less than or equal to 100 :1, or greater than or equal to 10 :1 and less than or equal to 90 : 1). Other ranges, both higher and lower than those described above, are also possible, as the disclosure is not so limited.

[0152] The CNFs have a high aspect ratio and exhibit gel-like characteristics (e.g., gel-like rheological properties) in water, with pseudoplastic properties.

[0153] According to some embodiments, the cellulose is modified cellulose. For example, according to some embodiments, the cellulose is carboxymethylated.

[0154] According to some embodiments the cathode further comprises activated carbon.

[0155] The cathode active material, the cellulose, and / or the activated carbon may be included in the cathode in any of a variety of suitable weight percentages. In some embodiments, a cathode comprises cathode active material (e.g., comprising MoOs) in an amount of greater than or equal to 50 wt%, greater than or equal to 60 wt%, greater than or equal to 70 wt%, greater than or equal to 80 wt%, or greater than or equal to 90 wt% versus the weight of the cathode. In some

[0156] #14443731vl embodiments, a cathode comprises cathode active material in an amount of less than or equal to 100 wt%, less than or equal to 90 wt%, less than or equal to 80 wt%, less than or equal to 70 wt%, or less than or equal to 60 wt% versus the weight of the cathode. Combinations of these ranges are also possible (e.g., greater than or equal to 50 wt% and less than or equal to 100 wt%, or greater than or equal to 60 wt% and less than or equal to 80 wt%). Other ranges, both higher and lower than those described above, are also possible, as the disclosure is not so limited.

[0157] In some embodiments, a cathode comprises cellulose (e.g., nanofibrillated cellulose) in an amount of greater than or equal to 0 wt%, greater than or equal to 2 wt%, greater than or equal to 5 wt%, greater than or equal to 8 wt%, greater than or equal to 10 wt%, greater than or equal to 12 wt%, greater than or equal to 15 wt%, or greater than or equal to 18 wt% versus the weight of the cathode. In some embodiments, a cathode comprises cellulose in an amount of less than or equal to 20 wt%, less than or equal to 18 wt%, less than or equal to 15 wt%, less than or equal to 12 wt%, less than or equal to 10 wt%, less than or equal to 8 wt%, less than or equal to 5 wt%, or less than or equal to 2 wt% versus the weight of the cathode. Combinations of these ranges are also possible (e.g., greater than or equal to 0 wt% and less than or equal to 20 wt%, or greater than or equal to 5 wt% and less than or equal to 15 wt%). Other ranges, both higher and lower than those described above, are also possible, as the disclosure is not so limited.

[0158] In some embodiments, a cathode comprises activated carbon in an amount of greater than or equal to 0 wt%, greater than or equal to 2 wt%, greater than or equal to 5 wt%, greater than or equal to 8 wt%, greater than or equal to 10 wt%, greater than or equal to 12 wt%, greater than or equal to 15 wt%, or greater than or equal to 18 wt% versus the weight of the cathode. In some embodiments, a cathode comprises activated carbon in an amount of less than or equal to 20 wt%, less than or equal to 18 wt%, less than or equal to 15 wt%, less than or equal to 12 wt%, less than or equal to 10 wt%, less than or equal to 8 wt%, less than or equal to 5 wt%, or less than or equal to 2 wt% versus the weight of the cathode. Combinations of these ranges are also possible (e.g., greater than or equal to 0 wt% and less than or equal to 20 wt%, or greater than or equal to 5 wt% and less than or equal to 15 wt%). Other ranges, both higher and lower than those described above, are also possible, as the disclosure is not so limited.

[0159] In some embodiments, the battery comprises an electrolyte. The electrolyte may be disposed, e.g., between the cathode and the anode. Any of a variety of suitable electrolytes may be used. For example, in some embodiments, the electrolyte is an ionic liquid. According to some embodiments, the electrolyte is bioresorbable. For example, in some embodiments the

[0160] #14443731vl electrolyte is a bioresorbable ionic liquid. Non-limiting examples of bioresorbable ionic liquids that may be used include, but are not limited to: choline based ionic liquids and ester-based or amide-based ionic liquids. According to some embodiments, the electrolyte is included in a gel. The gel may be bioresorbable. For example, in some embodiments the gel comprises alginate, PBS, gelatin, or any of a variety of other suitable bioresorbable polymers.

[0161] According to some embodiments, the disclosure comprises one or more current collectors. A current collector may be placed adjacent to an electrode (e.g., an anode or a cathode of the battery). In some embodiments the current collector comprises a conductive material configured to transmit current to or from the battery. The current collector may be biodegradable (e.g., bioresorbable). According to some embodiments, the current collector comprises a conductive material, as described above. For example, the current collector may comprise a conductive metal (e.g., a metal foil) or a conductive composite material, depending on the embodiment.

[0162] In some embodiments, the device comprises a tissue-engaging component configured to engage with a surface (e.g., a surface of a tissue) at the location internal to the subject such that it is retained at that location. According to some embodiments, the device is configured to be retained at a location internal to a subject. In some embodiments, the tissue-engaging component(s) of the device comprise one or more tissue anchors.

[0163] Tissue anchoring would provide important advantages for various applications of the devices provided herein. However, tissue anchoring is challenging, since tissue anchors can damage tissue and / or fail to provide a sufficiently high pull-out force to ensure that the device is not de-anchored. Furthermore, it would be an improvement for tissue anchors to be electrically conductive. And it would be an improvement for tissue anchors to be biodegradable (e.g., bioresorbable), e.g., because damaged tissue anchors would degrade on their own without requiring a surgical intervention. The disclosure provides new devices that provide advantageous combinations of these features.

[0164] The disclosure provides, in various embodiments, tissue-engaging components that are biodegradable (e.g., bioresorbable). In some embodiments, a tissue-engaging component (e.g., a tissue anchor) provided herein is configured to dissolve within a period of less than or equal to 72 hours, less than or equal to 66 hours, less than or equal to 60 hours, less than or equal to 54 hours, less than or equal to 48 hours, less than or equal to 42 hours, less than or equal to 36 hours, less than or equal to 30 hours, less than or equal to 24 hours, less than or equal to 18 hours, less than or equal to 12 hours, less than or equal to 6 hours, less than or equal to 3 hours,

[0165] #14443731vl less than or equal to 1 hour, or less than or equal to 30 minutes. In some embodiments, a tissueengaging component (e.g., a tissue anchor) provided herein is configured to dissolve within a period of greater than or equal to 10 minutes, greater than or equal to 30 minutes, greater than or equal to 1 hour, greater than or equal to 3 hours, greater than or equal to 6 hours, greater than or equal to 12 hours, greater than or equal to 18 hours, greater than or equal to 24 hours, greater than or equal to 30 hours, greater than or equal to 36 hours, greater than or equal to 42 hours, greater than or equal to 48 hours, greater than or equal to 54 hours, greater than or equal to 60 hours, or greater than or equal to 66 hours. Combinations of these ranges are also possible (e.g., greater than or equal to 10 minutes and less than or equal to 72 hours, or greater than or equal to 1 hour and less than or equal to 72 hours). Other ranges, both higher and lower than those described above, are also possible, as the disclosure is not so limited.

[0166] In some embodiments, the disclosure relates to a device comprising one or more tissue anchors. The tissue anchors may be configured to anchor the device to an organ (e.g., a gastrointestinal organ such as the stomach. Such devices, including the tissue anchors, may be biodegradable (e.g., may be configured to dissolve within the organ), thereby eliminating the need for surgical retrieval and reducing long-term electronic waste in the GI tract. For example, such devices, including the tissue anchors, may be bioresorbable. Biodegradable electrodes offer the advantage of gradual degradation, while maintaining secure attachment to mucosal surfaces or tissue during their functional lifespan.

[0167] The tissue anchor may be fabricated using any of a variety of suitable methods, including but not limited to 3D molding soft lithography techniques, may offer the advantage of allowing full integration of the tissue anchor with the device.

[0168] Any of a variety of tissue anchors may be used (e.g., hooks, clips, supports). In a particular, non-limiting embodiment, a device comprises a plurality of tissue anchors in the form of hooks configured to anchor the device to tissue. In some embodiments, the hooks are configured penetrate through tissue of a subject (e.g., to penetrate the tissue of the organ in which the device resides). The tissue anchors may form part of a sensor, e.g., an induction sensor. The sensor may be used to detector or monitor a disease condition (e.g., gastroesophageal reflux disease (GERD)). In some embodiments, the tissue anchors form part of a stimulation tool and are configured to provide a stimulation (e.g., an electrical stimulation) to the tissue on which they anchor the device. Subsequently, the device may be configured to disintegrate and may be at least partially bioresorbed in the body.

[0169] #14443731vl A tissue engaging component provided herein (e.g., a tissue anchor) provided herein may be conductive. Conductive tissue engaging components may, in some embodiments, be advantageous for providing electrical stimulation and / or for use of the tissue-engaging component as an electrical sensor (e.g., an induction sensor). The tissue-engaging component may comprise any of the conductive materials described above. For example, in some embodiments, the tissue engaging component comprises a conductive composite material comprising a wax matrix and a plurality of conductive metal filler particles.

[0170] Advantageously, the systems comprising one or more tissue anchors described herein may be anchored to (e.g., inserted into) a surface of tissue at a location internal to a subject, and may maintain contact with the tissue under relatively high applied forces and / or relatively high change in orientation (e.g., by compressive forces exerted by the gastrointestinal tract and / or under high flow rates within the gastrointestinal tract). In some embodiments, the systems described herein do not substantially block orifices within the gastrointestinal tract (e.g., in the pylorus) e.g., restricting flow and permitting longer contact times. Natural replenishment of the walls of the gastrointestinal tract may permit desirable detachment and / or expulsion of the systems and devices described herein, without the need for surgical and / or endoscopic retrieval.

[0171] For example, in some embodiments, the tissue anchor is anchored to (e.g., inserted into) a surface of a tissue at a location internal to a subject and maintains contact with the tissue (e.g., the device remains anchored) under a change of orientation of the device of greater than or equal to 1 degree, greater than or equal to 2 degrees, greater than or equal to 5 degrees, greater than or equal to 10 degrees, greater than or equal to 15 degrees, greater than or equal to 20 degrees, greater than or equal to 25 degrees, or greater than or equal to 30 degrees. In certain embodiments, the device may remain anchored under a change of orientation of the device of less than or equal to 45 degrees, less than or equal to 30 degrees, less than or equal to 25 degrees, less than or equal to 20 degrees, less than or equal to 15 degrees, less than or equal to 10 degrees, less than or equal to 5 degrees, or less than or equal to 2 degrees. Combinations of the above-referenced ranges are also possible (e.g., greater than or equal to 1 degree and less than or equal to 45 degrees, greater than or equal to 2 degrees and less than or equal to 30 degrees). Other ranges are also possible.

[0172] In certain embodiments, the device (e.g., comprising the tissue anchor) is configured to be retained at the location internal to the subject under a normal retention force of greater than or equal to 0.002 N, greater than or equal to 0.004 N, greater than or equal to 0.006 N, greater than or equal to 0.008 N, greater than or equal to 0.01 N, greater than or equal to 0.012 N, greater

[0173] #14443731vl than or equal to 0.014 N, greater than or equal to 0.016 N, greater than or equal to 0.018 N, greater than or equal to 0.02 N, greater than or equal to 0.025 N, greater than or equal to 0.03 N, greater than or equal to 0.04 N, greater than or equal to 0.05 N, greater than or equal to 0.1 N, greater than or equal to 0.15 N, greater than or equal to 0.2 N, greater than or equal to 0.25 N, greater than or equal to 0.3 N, greater than or equal to 0.35 N, greater than or equal to 0.4 N, greater than or equal to 0.5 N, greater than or equal to 0.6 N, greater than or equal to 0.7 N, greater than or equal to 0.8 N, or greater than or equal to 0.9 N of normally applied force per tissue anchor. In some embodiments, the device has a normal retention force of less than or equal to 1 N, less than or equal to 0.9 N, less than or equal to 0.8 N, less than or equal to 0.7 N, less than or equal to 0.6 N, less than or equal to 0.5 N, less than or equal to 0.4 N, less than or equal to 0.35 N, less than or equal to 0.3 N, less than or equal to 0.25 N, less than or equal to 0.2 N, less than or equal to 0.15 N, less than or equal to 0.1 N, less than or equal to 0.05 N, less than or equal to 0.04 N, less than or equal to 0.03 N, less than or equal to 0.025 N, less than or equal to 0.02 N, less than or equal to 0.018 N, less than or equal to 0.016 N, less than or equal to 0.014 N, less than or equal to 0.012 N, less than or equal to 0.01 N, less than or equal to 0.008 N, less than or equal to 0.006, or less than or equal to 0.004 N of normally applied force per tissue anchor. Combinations of the above referenced ranges are also possible (e.g., greater than or equal to 0.002 N and less than or equal to 1 N, greater than or equal to 0.02 N and less than or equal to 0.08 N, greater than or equal to 0.1 N and less than or equal to 1 N). Other ranges are also possible. The normal retention force as described herein may be determined by inserting the tissue anchor of the device into a surface of tissue (e.g., ex vivo swine stomach) to a penetration depth of at least 0.9 mm and then pulling the device, in a direction orthogonal to the surface of the tissue until the device dislodges from the tissue. The maximum force before dislodging the device is the normal retention force.

[0174] In some embodiments, the device (e.g., comprising the tissue anchor) is configured to be retained at the location internal to the subject under an orthogonal retention force of greater than or equal to 0.002 N, greater than or equal to 0.004 N, greater than or equal to 0.006 N, greater than or equal to 0.008 N, greater than or equal to 0.01 N, greater than or equal to 0.012 N, greater than or equal to 0.014 N, greater than or equal to 0.016 N, greater than or equal to 0.018 N, greater than or equal to 0.02 N, greater than or equal to 0.025 N, greater than or equal to 0.03 N, greater than or equal to 0.04 N, greater than or equal to 0.05 N, greater than or equal to 0.1 N, greater than or equal to 0.15 N, greater than or equal to 0.2 N, greater than or equal to 0.25 N, greater than or equal to 0.3 N, greater than or equal to 0.35 N, greater than or equal to 0.4 N,

[0175] #14443731vl greater than or equal to 0.5 N, greater than or equal to 0.6 N, greater than or equal to 0.7 N, greater than or equal to 0.8 N, or greater than or equal to 0.9 N of normally applied force per tissue anchor. In some embodiments, the device has an orthogonal retention force of less than or equal to 1 N, less than or equal to 0.9 N, less than or equal to 0.8 N, less than or equal to 0.7 N, less than or equal to 0.6 N, less than or equal to 0.5 N, less than or equal to 0.4 N, less than or equal to 0.35 N, less than or equal to 0.3 N, less than or equal to 0.25 N, less than or equal to 0.2 N, less than or equal to 0.15 N, less than or equal to 0.1 N, less than or equal to 0.05 N, less than or equal to 0.04 N, less than or equal to 0.03 N, less than or equal to 0.025 N, less than or equal to 0.02 N, less than or equal to 0.018 N, less than or equal to 0.016 N, less than or equal to 0.014 N, less than or equal to 0.012 N, less than or equal to 0.01 N, less than or equal to 0.008 N, less than or equal to 0.006, or less than or equal to 0.004 N of normally applied force per tissue anchor. Combinations of the above referenced ranges are also possible (e.g., greater than or equal to 0.002 N and less than or equal to 1 N, greater than or equal to 0.02 N and less than or equal to 0.08 N, greater than or equal to 0.1 N and less than or equal to 1 N). Other ranges are also possible. The orthogonal retention force as described herein may be determined by inserting the tissue anchor of the device into a surface of tissue (e.g., ex vivo swine stomach) to a penetration depth of at least 0.9 mm and then applying a force to the device, in a direction parallel to the surface of the tissue, until the device dislodges from the tissue. The maximum force before dislodging the device is the orthogonal retention force.

[0176] In some embodiments, the device is configured to remain anchored to the surface of the tissue located internal to the subject under less than or equal to 30 degrees change in orientation and less than or equal to 1 N of applied (e.g., normal, orthogonal) force.

[0177] In some embodiments, the device comprises two or more tissue anchors. In some cases, the device may comprise a single device comprising two or more tissue anchors. In certain embodiments, the force required to dislodge the device (e.g., the normal retention force, the orthogonal retention force) may be increased by increasing the number of tissue anchors associated with the device. Without wishing to be bound by theory, the spacing between tissue anchors may be related to the retention force (e.g., the normal retention force, the orthogonal retention force) of the device.

[0178] The tissue anchor may have any suitable dimension and / or shape. For example, in some embodiments, the largest dimension (e.g., the length) of the tissue anchor may be less than or equal to 1 cm, less than or equal to 0.8 cm, less than or equal to 0.6 cm, less than or equal to 0.5 cm, or less than or equal to 0.4 cm. In certain embodiments, the largest dimension (e.g., the

[0179] #14443731vl length) of the tissue anchor may be greater than or equal to 0.2 cm, greater than or equal to 0.4 cm, greater than or equal to 0.5 cm, greater than or equal to 0.6 cm, or greater than or equal to 0.8 cm. Combinations of the above-referenced ranges are also possible (e.g., greater than or equal to 0.2 cm and less than or equal to 1 cm). Other ranges are also possible.

[0180] In some cases, the tissue anchor may be configured to have an optimal penetration depth (e.g., the depth at which the tissue anchor is disposed beneath the surface of a tissue located internal to a subject). In some embodiments, the tissue anchor has a penetration depth of greater than or equal to 0.5 mm, greater than or equal to 0.6 mm, greater than or equal to 0.7 mm, greater than or equal to 0.8 mm, greater than or equal to 0.9 mm, greater than or equal to 1 mm, greater than or equal to 1.2 mm, greater than or equal to 1.4 mm, greater than or equal to 1.5 mm, greater than or equal to 1.7 mm, greater than or equal to 1.9 mm, greater than or equal to 2 mm, greater than or equal to 2.2 mm, greater than or equal to 2.4 mm, greater than or equal to

[0181] 2.5 mm, greater than or equal to 3 mm, greater than or equal to 3.5 mm, greater than or equal to

[0182] 4 mm, greater than or equal to 4.5 mm, or greater than or equal to 5 mm. In certain embodiments, the tissue anchor has a penetration depth of less than or equal to 6 mm, less than or equal to 5 mm, less than or equal to 4.5 mm, less than or equal to 4 mm, less than or equal to

[0183] 3.5 mm, less than or equal to 3 mm, less than or equal to 2.5 mm, less than or equal to 2.4 mm, less than or equal to 2.2 mm, less than or equal to 2 mm, less than or equal to 1.9 mm, less than or equal to 1.7 mm, less than or equal to 1.5 mm, less than or equal to 1.4 mm, less than or equal to 1.2 mm, less than or equal to 1 mm, less than or equal to 0.9 mm, less than or equal to 0.8 mm, less than or equal to 0.7 mm, or less than or equal to 0.6 mm. Combinations of the abovereferenced ranges are also possible (e.g., greater than or equal to 0.5 mm and less than or equal to 6 mm, greater than or equal to 0.9 mm and less than or equal to 2.5 mm). Other ranges are also possible.

[0184] Advantageously, the devices comprising a tissue anchor described herein may be retained for a relatively long period of time under physiological conditions and fluid flows (e.g., exposed to a fluid flowing at approximately 0.1 m / s). For example, in some embodiments, the device comprising a tissue anchor is retained at a surface of tissue located internal to a subject for greater than or equal to 1 hour, greater than or equal to 2 hours, greater than or equal to 4 hours, greater than or equal to 8 hours, greater than or equal to 12 hours, greater than or equal to 24 hours, greater than or equal to 2 days, greater than or equal to 3 days, greater than or equal to

[0185] 5 days, greater than or equal to 7 days, or greater than or equal to 10 days. In certain embodiments, the device is retained for less than or equal to 14 days, less than or equal to 10

[0186] #14443731vl days, less than or equal to 7 days, less than or equal to 5 days, less than or equal to 3 days, less than or equal to 2 days, less than or equal to 24 hours, less than or equal to 12 hours, less than or equal to 8 hours, less than or equal to 4 hours, or less than or equal to 2 hours. Combinations of the above referenced ranges are also possible (e.g., greater than or equal to 1 hour and less than or equal to 14 days). Other ranges are also possible.

[0187] In some embodiments, the device has a particular configuration including a particular size and / or shape such that the device can be administered to a subject (e.g., orally). In some embodiments, the device is configured to adopt a shape and / or size in vivo that slows or prevents further transit in a body (e.g., gastric) cavity (e.g., passage from the body of the stomach through the pylorus). In some embodiments, the device adopts a shape and / or size configured for retention (e.g., gastric residence). In some embodiments, the device adopts the shape and / or size for retention upon release from a soluble capsule / container and / or soluble retaining structure / element. In some embodiments, the device is configured for adopting a shape and / or size configured for gastric residence after being stored in its encapsulated shape and / or size for durations greater than 24 hours, including up to about one year. In some embodiments, the mechanical properties of the device are optimized for safe transient retention of all or a portion of the device in an internal cavity such as the gastric cavity for durations greater than 24 hours, including up to about one year.

[0188] Certain embodiments of structures and systems described herein may offer certain advantages as compared to traditional compositions and structures and systems 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 (e.g., upon detection of a signal from a sensor); 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 devices and systems 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 systems, devices, and methods described

[0189] #14443731vl herein are compatible with subjects, including, but not limited to, humans and non-human animals.

[0190] The devices and systems described herein may be modular / multi-component (i.e., formed of multiple interconnected subcomponents.) In some embodiments, the device comprises one or more sensors, three or more arms, a central core, and / or a drug release component. In some embodiments, the device is configured for adopting a shape and / or size configured for gastric deployment (after being stored in its encapsulated / folded shape and / or size) for the residence time period. In some embodiments, the residence time period is greater than or equal to 24 hours, greater than or equal to 48 hours, greater than or equal to 3 days, greater than or equal to 7 days, greater than or equal to 1 month, greater than or equal to 6 months, or greater than or equal to 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. Combinations of the above-referenced ranges are also possible (e.g., greater than or equal to 24 hours and less than or equal to 2 years, greater than or equal to 24 hours and less than or equal to 1 year, greater than or equal to 48 hours and less than or equal to 7 days, greater than or equal to 3 days and less than or equal to 1 month, greater than or equal to 7 days and less than or equal to 6 months, greater than or equal to 1 month and less than or equal to 1 year). Other ranges are also possible.

[0191] In some embodiments, a device includes a central core and a plurality of arms attached to and configured to rotate relative to the central core. In some embodiments, the central core and / or distal portions of the arms may be equipped with drug release components (sometimes referred to herein as a tissue interfacing component, e.g., that may comprise needles) configured to deliver an active pharmaceutical compound to the esophagus, or other structure, without perforation. However, embodiments without drug release components, (e.g., embodiments generally intended for data collection and / or monitoring) are also envisioned. The device may be able to fold into a retracted form that can be easily delivered to the esophagus or other anatomical structure in any appropriate manner. Upon reaching the esophagus, or other desired location within a subject’s body, the device may be permitted to transform from the retracted configuration into an expanded configuration in which the arms of the device may pivot away from the central body. In some embodiments, this results in penetration of the drug release component (e.g., the penetration of a needle of the drug release component) into the esophageal mucosa and delivery of an active pharmaceutical compound to the esophageal mucosa.

[0192] #14443731vl However, in some embodiments, the expanded configuration may be used principally for improved gastric retention without injection. Penetration of the drug release components into the esophageal mucosa and subsequent delivery of the active pharmaceutical compound may occur immediately upon transformation into the expanded configuration. However, in some embodiments, penetration of the drug release component instead occurs in response to external signals or conditions.

[0193] In some embodiments, the tissue interfacing component comprises a needle, a biopsy component, a projectile, a plurality of microneedles, a hook, a mucoadhesive patch, or combinations thereof. In certain embodiments, as described herein and above, the tissue interfacing component is configured to penetrate tissue (e.g., skin, tongue, tissue of the GI tract such as GI mucosal tissue). In some embodiments, the tissue in penetrated with a force of greater than or equal to 1 mN and less than or equal to 20 N (e.g., greater than or equal to 10 mN and less than or equal to 20 mN, greater than or equal to 1 mN and less than or equal to 100 mN, greater than or equal to 20 mN and less than or equal to 1 N, greater than or equal to 1 N and less than or equal to 20 N, greater than or equal to 10 N and less than or equal to 20 N).

[0194] In certain embodiments, tissue interfacing component 130 comprises an active pharmaceutical agent. In some embodiments, the active pharmaceutical agent may be present in the tissue interfacing component at relatively high amounts (e.g., greater than or equal to 10 wt%, greater than or equal to 80 wt%, or greater than or equal to 90 wt% API versus the total weight of the tissue interfacing component). The self-righting articles described herein may, in some cases, be administered to a subject e.g., such that the pharmaceutical agent is delivered to the subject. For example, in some cases, the article may be administered to the subject and a pharmaceutical agent is released from the article at a location internal to the subject. Administration of the articles and release of pharmaceutical agents are described in more detail herein.

[0195] In some embodiments, the tissue interfacing component (e.g., associated with a selfactuating component) may comprise a relatively high loading of active pharmaceutical ingredients (e.g., drugs). For example, in certain embodiments, the tissue interfacing component comprises a solid therapeutic agent (e.g., a solid API) and, optionally, a support material (e.g., a binder such as a polymer) such that the solid therapeutic agent is present in the component in a relatively high amount (e.g., greater than or equal to 80 wt%) versus the total weight of the tissue interfacing component. Such tissue-interfacing components may be useful for delivery of API doses (e.g., to a subject). Advantageously, in some embodiments, the reduction of volume

[0196] #14443731vl required to deliver the required API dose as compared to a liquid formulation permits the creation of solid needle delivery systems for a wide variety of drugs in a variety of places / tissues (e.g., tongue, GI mucosal tissue, skin) and / or reduces and / or eliminates the application of an external force in order to inject a drug solution through the small opening in the needle. In some cases, a physiologically relevant dose may be present in a single tissue interfacing component (e.g., having a relatively high API loading). In some embodiments, as described above and herein, the system comprises a component (e.g., a tissue interfacing component) comprising a solid therapeutic agent (e.g., a solid API) and a second material (e.g., a support(ing) material for the solid API such as a binder and / or a polymer) such that the solid therapeutic agent is present in the component in an amount of greater than or equal to 10 wt% versus the total weight of the tissue interfacing component. Such tissue-interfacing components may be useful for delivery of API doses (e.g., to a subject). Advantageously, in some embodiments, the reduction of volume required to deliver the required API dose as compared to a liquid formulation permits the creation of solid needle delivery systems for a wide variety of drugs in a variety of places / tissues (e.g., tongue, GI mucosal tissue, skin) and / or reduces and / or eliminates the application of an external force in order to inject a drug solution through the small opening in the needle.

[0197] In some cases, a physiologically relevant dose may be present in a single tissue interfacing component (e.g., having a relatively high API loading). In certain embodiments, the API is substantially solid (e.g., a powder, a compressed powder, a crystalline solid, an amorphous solid) i.e. a solid therapeutic agent. In some embodiments, the API may be in liquid form.

[0198] In response to an external signal or condition, the device may reconfigure from the expanded configuration with a larger transverse dimension (e.g., a width or diameter) to the retracted configuration with a smaller transverse dimension to permit the device to subsequently pass through the gastrointestinal tract or to otherwise be removed from the esophagus or other anatomical structure.

[0199] FIGS. 2A-2C depict one embodiment of a device 200 in various configurations. FIG. 2A shows the device in a retracted configuration within a capsule 202. FIG. 2B shows the device in a partially expanded configuration, while FIG. 2C shows the device in a fully expanded configuration. In some embodiments, a device may include a central core and a plurality of arms that are rotatably coupled to a central core. In some embodiments, the plurality of arms comprises two, three, four, five, six, eight, ten, or more arms. In some embodiments, the arms may be biased away from the central core via one or more flexible elastic components. For

[0200] #14443731vl example, referring to the exemplary embodiment of FIGS. 2A-2C, device 200 includes central core 204 and plurality of arms 206. Depending on the particular embodiment, a flexible elastic component may be attached to and extend between an associated arm and the central core and / or between adjacent arms. For example, in FIGS. 2A-2C, the arms 206 may be coupled to one another with one or more elastic components, such as beams 210. In either case, elastic energy stored in a flexible elastic component when the device is in a retracted configuration may apply a force to the associated arms to bias the device from the retracted configuration to the expanded configuration during deployment. Thus, the arms may be biased radially outward from the body by the associated flexible elastic components.

[0201] Specifically, as shown in FIGS. 2A-2C, the beams may have a L shape, or other angled shape, such that the straight portions of the beam are aligned with and extend along at least a portion of a length of adjacent arms. The beams, or other elastic components, may be attached to the arms using any appropriate method including adhesives, welding, mechanical interlocking features, interference fits and / or any other appropriate attachment method. While the use of flexible elastic beams is described in relation to the figures, other appropriate flexible elastic components that may be used include but are not limited to springs (such as torsion springs) connected between an arm and central core, elastic living hinges disposed between an arm and central core, and / or any other flexible elastic structure configured to bias the arms away from the central core. Accordingly, it should be understood that various components and configurations may be used to apply the desired deployment forces to a device.

[0202] In some embodiments, a device may also include one or more biasing components that, when signaled, apply a force to the arms to bias the arms towards a central core of the device such that the device is biased from the expanded configuration to the retracted configuration. Biasing components, such as actuated springs 208 of FIGS. 2A-2C, may couple the arms to the central core. In embodiments such as that presented in FIGS. 2A-2C, the actuated springs 208 are torsional springs, which including one or more coils with the opposing ends attached to the core and a corresponding arm as shown in the figure. The spring, or other biasing component, may be attached to the core and arms using any appropriate attachment method similar to those noted above for the elastic component. The force applied by the biasing components may be sufficient to overcome a force applied by the elastic beams, or other elastic component, that is applied in an opposing direction, to apply an overall force that biases the device into the retracted configuration. In some embodiments, the biasing components may apply a force to the arms to bias the device from the expanded configuration to the retracted configuration without

[0203] #14443731vl heating. For example, deformation of the biasing components may result in a restoring force that biases the arms towards the core.

[0204] According to certain embodiments, a device in the expanded configuration may be retained in a location internal to a subject such as the gastrointestinal tract of the subject, relative to a device in the retracted configuration. In other words, in some embodiments, the device may be placed in the expanded configuration to facilitate long-term gastric retention of the device. According to certain embodiments, the device can remain in a stomach until signaled to exit the stomach. In some embodiments, a device in the expanded configuration can be placed in an injection mode, wherein the arms remain in an expanded configuration, but their position is adjusted to better stabilize the capsule upon injection.

[0205] The phrase “location internal to a subject” as used herein generally refers to an internal cavity (e.g., the mouth, the esophagus, the small intestine, the colon, the duodenum, the ileum, the jejunum, the stomach, or the rectum) of the subject. In some embodiments, the location internal to the subject is proximate (e.g., adjacent, directly adjacent) a gastric orifice such as the pylorus. In some embodiments, the device is configured to reside adjacent the gastric orifice such as the pylorus (e.g., the device has a largest cross-sectional area which does not permit passage through the pylorus). Those of ordinary skill in the art would understand, based upon the teachings of this specification, that a device is retained at a location internal to a subject when it does not substantially transit from said location absent a physical, chemical, or mechanical change to the device. By way of example and without wishing to be bound by a literal interpretation of such, a device is retained a location internal to a subject when it remains substantially proximate (e.g., adjacent, in contact with) that location over the duration of a residence time period (e.g., greater than or equal to 24 hours). By contrast, by way of a comparative example and without wishing to be bound by a literal interpretation of such, a device is not considered retained at a location internal to a subject as it transits the gastrointestinal tract (e.g., driven by gastrointestinal forces and / or motion such that it moves through the gastrointestinal tract). For example, a device that remains internal to a subject but transits the gastrointestinal tract over e.g., greater than or equal to 24 hours is not intended to be a device that is retained at a location internal to a subject for said greater than or equal to 24 hours, despite being internal to the subject. By way of example, a device that remains proximate the pylorus of the subject e.g., greater than or equal to 24 hours is intended to be considered a device that is retained at the location internal to the subject for said greater than or equal to 24 hours. Other residence time periods are also possible and are described in more detail below.

[0206] #14443731vl Those of ordinary skill in the art would understand, based upon the teachings of this specification, that residence does not require a strict adherence to a geometrically defined relative to location internal to a subject such that the device may move (e.g., as a result of gastrointestinal forces / motion) while being retained at the location internal to the subject. By way of example, and without wishing to be bound by a literal interpretation of such, a device is said to be retained e.g., in the stomach of the subject as long as the structure remains in the stomach and does not exit the stomach (e.g., via the pylorus) during the desired residence time period. In some embodiments, the structures described herein comprise a component that undergoes a change (e.g., a mechanical change) such that the device exits the location internal to the subject (e.g., passes through the pylorus).

[0207] In some embodiments, the location internally of the subject is the colon, the duodenum, the ileum, the jejunum, the stomach, the small intestine, the large intestine, the rectum, the mouth, or the esophagus.

[0208] As described above and herein, in some embodiments, a pharmaceutical agent may be released at the location internal to the subject.

[0209] In an exemplary set of embodiments, the device is administered such that the device enters the stomach of the subject and is retained in the stomach for a residence period (e.g., of greater than or equal to 24 hours). In some embodiments, the device may be configured to sense physiological conditions about the subject such as e.g., subject temperature (e.g., gastric internal temperature), local pH, local pressure, and / or other biophysical characteristics. For example, the device may comprise (and / or be in electronic communication with) one or more sensors configured to determine one or more physiological conditions about the subject. In some embodiments, the device comprises one or more sensors (e.g., a biomolecular sensor, a gas sensor, a temperature sensor, a pressure sensor, a motion sensor, an accelerometer, a pH sensor, a biochemical sensor), a wireless identification microchip, and / or an imaging system (e.g., a camera). In some embodiments, the device is configured to generate and / or receive a signal from the one or more sensors and generate an electrical signal to one or more arms. In some embodiments, the signal triggers the device to change the one or more arms into a deployed configuration. In some embodiments, the signal triggers the device to reorient (e.g., via the one or more arms) such that a tissue interfacing component is positioned relative to a tissue located internal to a subject. In some embodiments, the signal triggers the device to delivery (e.g., via injection) the tissue interfacing component into the tissue located internal to the subject. In some embodiments, the tissue interfacing component delivers a therapeutic agent.

[0210] #14443731vl In some embodiments, the signal provides an orientation of the device to a microcontroller (e.g., for activation of the one or more arms). In some embodiments, the signal mediates the exit of the device from the stomach through the pylorus (e.g., after delivery of a therapeutic agent)

[0211] In some embodiments, a central core of the device comprises a tissue-engaging surface. The tissue-engaging surface may be associated with a drug release component, as described in greater detail below. According to certain embodiments, the injection mode of the device stabilizes the device such that the tissue-engaging surface contacts a tissue of a subject at a location internal to a subject.

[0212] In some embodiments, a device may be deployed in a body of a subject through ingestion. For example, a device may be enclosed within a capsule, such as a gelatin or other dissolvable capsule, in the retracted configuration. A subject may swallow the encapsulated device, introducing the device into the gastrointestinal tract. The capsule may be configured to dissolve after a predetermined time or upon reaching a predetermined environment, allowing the device to be deployed at a predetermined location within the body of the subject. However, in some embodiments, the device may be deployed in the body endoscopically, surgically, or in any other appropriate manner, as the disclosure is not limited in regards to the method of deploying the device to a desired location within a subject’s body.

[0213] For example, as shown in FIG. 2A, a capsule 202, such as a dissolvable gelatin capsule, may at least partially surround the central core and the arms, retaining the arms in the retracted configuration prior to deployment. In this configuration, the L- shaped beams may be deformed such that elastic energy is stored in the structure and a biasing force is applied to the arms that biases the arms towards an expanded configuration as elaborated on below. While the elastic components and biasing elements are shown in the drawings as L-shaped beams and springs (respectively), it should be appreciated that any suitable geometries and / or structures may be used for the elastic components and the biasing components as the disclosure is not limited in this regard.

[0214] The arms may be rotatably coupled to the central core in any appropriate manner that permits the arms to pivot outward away from the central core to selectively reconfigure the device between a retracted configuration and an expanded configuration. In some instances, the arms may rotate about an axis of rotation that is approximately perpendicular to a direction of a longitudinal axis of the central core. In some embodiments, such as the exemplary embodiments of FIGS. 2A-2C, beams 210 may be L-shaped beams that may couple two adjacent arms, such

[0215] #14443731vl that each arm is perpendicular to its two adjacent arms. When the arms are brought into the retracted configuration, the L- shaped beams may be deformed relative to their undeformed neutral configuration. Thus, in a retracted configuration, the arms may be biased outwards away from the central core into the expanded configuration by the L- shaped beams or other elastic component. For example, a capsule 202 may retain the device in a retracted configuration (FIG. 2A). In such a configuration, beams 210 may be deformed, storing elastic energy. When the capsule is removed (e.g., when a gelatin capsule is dissolved in the esophagus), the stored elastic energy of the beams may cause the arms to unfold (FIG. 2B), causing the device to expand. In a fully expanded configuration (FIG. 2C), the arms may be substantially perpendicular to the long axis of the central core.

[0216] In the expanded configuration, one or more biasing components associated with each arm, i.e., biasing springs 208, may exert a torque on the arms 206 to urge the arms back towards the central core 204. A spring 208 may be coupled to the central core 204 on one side and to an arm 206 on an opposite side. The spring may be operatively coupled to the arm and / or the core through the use of an adhesive, an interference fit with a hole, simply being placed into contact with the arm with a portion of the arm disposed between the L-shaped beam or other elastic component and the spring, or any other suitable method of associating the biasing component with the corresponding arm.

[0217] Using such a configuration, when the biasing components (e.g., springs), are in a first state, the torque exerted on the arms by the biasing components (which may bias the arms towards the central core) may be less than the torque exerted on the arms by the elastic components 210 (which may bias the arms away from the core). As such, the device 200 may remain in an expanded configuration when the springs are in the first state. In contrast, when device 200 is in the second state, the plurality of arms 206 may become biased towards the central core 204. This may cause them to transition into the retracted configuration. Specifically, the torque exerted on the arms 206 by the biasing components 208 (which may bias the arms towards the central core) may be greater than the torque exerted on the arms 206 by the elastic components 210 (which may bias the arms away from the core), which may cause the arms to retract towards the central core. In some case, the transition between the first state and the second state of the biasing components may be actuated, as described in greater detail below.

[0218] In some embodiments, there may be competing forces exerted by the elastic beams (or other elastic component) and the biasing components. In some embodiments, the relative strength of the force applied by the biasing component may be increased in response to an

[0219] #14443731vl external signal (e.g., a signal originating from outside the device). In other embodiments, the relative strength of the force applied by the biasing component may be increased in response to an external condition. For example, the force applied to the biasing component may be increased in response to an external force, or in response to an external chemical environment. Thus, the device may be biased toward the retracted configuration by increasing the force applied by the biasing components to be greater than the threshold temperature. This may correspondingly cause an overall force applied to the arms to be directed towards the core to bias the device into the retracted configuration. The biasing components may be actuated by any of a variety of methods recognized in the art. The device may be electromagnetically actuated. For example, the device may comprise an electromagnet that can be switched on remotely, in order to apply a biasing force to the arms. The device may be electro-mechanically actuated. In some embodiments, the biasing components are hydraulically actuated. In some embodiments, the biasing components are pneumatically activated. In various embodiments, the biasing components are chemically actuated. In some embodiments, the biasing components are piezoelectrically actuated. The biasing component may also be actuated thermally. For instance, in some embodiments, the biasing components may comprise biasing components that tend to deform in response to temperature changes. Exemplary thermal actuators include shapememory alloys and bimetallic strips. The biasing components may also be actuated by magnetostriction. In some embodiments, the biasing components are actuated by electroactive polymers. The biasing components are actuated by bladders, in some embodiments. According to certain embodiments, the biasing components are actuated by micro-electromechanical systems (MEMS). In some cases, all biasing components of a device are actuated identically. However, in other embodiments, combinations of distinct types of actuation may be used. For example, in some embodiments, some biasing components may be thermally activated, while other biasing components may be hydraulically actuated. The application is not so limited.

[0220] Biasing components may have any of a variety of appropriate forms. In some embodiments, a biasing component may comprise an actuated spring, a bimetallic strip, a LJ- shaped structure, an L-shaped structure, or any other suitably shaped structure extending between the core of a device and an associated arm, or another appropriately shaped component capable of applying a desired force. Further the various parameters of the component including material properties, dimensions, overall geometry, and other appropriate parameters may be selected to provide a desired restoring force upon actuation. Accordingly, it should be

[0221] #14443731vl understood that a biasing component is not limited to only the specific structures described herein.

[0222] As an alternative to elastic components and biasing components, in some embodiments, the transition of the arms between the retracted and the expanded configuration is electro- mechanically actuated. For example, in some embodiments, a device comprises an electromechanical actuator configured to translate a rigid body in a direction parallel to a central axis of a device. For example, FIGS. 3A-3D present translation an exemplary embodiment of device 300 comprising rigid body 302 configured to be translated in a direction parallel to central axis 304 of device 300.

[0223] The rigid body may enclose at least part of a lateral cross-section of the central core of the device, in some embodiments. For example, the rigid body may totally enclose the lateral cross-section of the central core of the device. As another example, the rigid body may enclose an interior portion of a lateral cross-section of the central core of the device (e.g., the rigid body may enclose a lead screw of a motor, or may form a portion of a lead screw of a motor that encloses). The configuration of the rigid body to enclose a lateral cross-section of the central core may advantageously allow translation of the rigid body along the central axis of the device, in a direction parallel to the central axis of the device. As one example, in some embodiments, the central core comprises a cylindrical portion, and the rigid body is a ring or a cylinder surrounding the central core and centered on the central axis of the device. As another example, in some embodiments, the central core comprises a prismatic portion. For example, the prismatic portion may have a shape corresponding to a triangular prism, a rectangular prism, a hexagonal prism, or another prism having any other appropriate number of sides. In some embodiments the rigid body is a polygon corresponding to the prismatic portion of the central core. For example, in some embodiments the corresponding polygon may be a triangle, a rectangle, a hexagon, or another polygon corresponding to the cross-sectional dimensions of the prismatic portion.

[0224] The rigid body may be coupled to a proximal end of an arm-connector, in some embodiments. For example, in FIGS. 3A-3D, rigid body 302 is connected to arm connectors 306. In some embodiments, a distal end of the arm-connector is coupled to an arm of the plurality of arms of the device. As used herein, ‘coupling’ of two parts may be achieved either by direct connection between those parts, or via one or more intervening components. Exemplary intervening components that may be positioned between arm-connectors, arms, and / or rigid bodies, include hinges or sliders. The arm-connector may be rigid, such that

[0225] #14443731vl translation of the rigid body in a direction parallel to the central axis of the device applies a force to the arm, causing it to rotate relative to the device. In some embodiments, the rigid body is connected to a plurality of arm connectors. The plurality of arm connectors may be connected at a plurality of distal ends to the plurality of arms of the device. Thus, motion of the rigid body may result in simultaneous rotation of the arms with respect to the device. For example, in FIGS. 3A-3D, arm connectors 306 are connected at distal ends to arms 310. Thus, motion of rigid body 302 may result in simultaneous rotation of arms 310. In some embodiments, at least one arm connector is connected to each arm of the plurality of arms of the device.

[0226] In some embodiments, the device is configured such that translation of the rigid body in a first direction parallel to the central axis of the device will cause the arms to transition to an expanded configuration. In some embodiments, the device is configurated such that translation of the rigid body in a second direction, opposite to the first direction, will cause the arms to transition to a closed configuration.

[0227] The rigid body may be translated by any of a variety of appropriate methods. In some embodiments, an electro-mechanical actuator may be used to translate the rigid body. For example, in some embodiments, a motor of the device may be used to translate the rigid body. The motor may be, for example, a DC geared motor. In some embodiments, the motor may comprise a lead screw. In some embodiments, the lead screw is configured to move the rigid body. In some embodiments, the lead screw is configured to actuate a drug release component as described below, e.g., by moving a locking mechanism, as described below. In some embodiments, a piezoelectric, electromagnetic, pneumatic, and / or hydraulic actuator may be used to translate the rigid body. The disclosure is not, in this way limited.

[0228] It should also be understood that while annular rigid bodies corresponding to crosssections of portions of the central core of the device are described herein, the rigid body is not limited to this shape. For example, the rigid body may have an X-shape, wherein the rigid body is translated via application of force to a center of the rigid body, while proximal ends of the arm-connectors are coupled to the X-shape away from the center of the X-shape. In some embodiments, the device comprises a plurality of rigid bodies. In certain embodiments, the rigid bodies of the plurality of rigid bodies of the device may be configured to be translated in a direction parallel to a central axis of the device. In some embodiments, rigid bodies of the plurality of rigid bodies are configured to change the configuration of one or more arms of the plurality of arms.

[0229] #14443731vl In some embodiments, a device described herein may orient itself during a change in configuration. For instance, the device descried herein may exhibit self-righting behavior during a transition from a retracted configuration to an expanded configuration. FIGS. 3A-3C demonstrate this behavior, in an exemplary embodiment. In FIG. 3A, exemplary device 300 has an initially horizontal orientation and is in the retracted configuration. In FIG. 3B, device 300 begins to transition from the retracted configuration to the expanded configuration, resulting in a change in orientation of central axis 304 of device 300. Finally, in FIG. 3C, device 300 is oriented such that central axis 304 is substantially aligned with a vertical axis. In some embodiments, a device in the expanded configuration is self-righting, as described in greater detail below.

[0230] In some embodiments, the device may comprise an arm-locking component. The armlocking component may be configured to hold one or more arms in a retracted configuration. For example, the arm- locking component may comprise a hydrogel configured to hold one or more arms in the retracted configuration. According to certain embodiments, the arm-locking component is chemically sensitive. For example, the arm-locking component may be configured to respond in the presence of a particular chemical (e.g., a toxic chemical, as described below). In some embodiments, the arm-locking component may be configured to respond to a change in pH. The arm-locking component may respond to the chemical and / or the change in pH by swelling, shrinking, and / or degrading. In some embodiments, the response of the arm-locking component to the chemical and / or the change in pH may result in the opening of the arms. For example, in some embodiments, the arm-locking mechanisms are configured to degrade in response to the chemical and / or the change in pH, releasing the arms into the expanded configuration.

[0231] While the use of a device in the esophagus of a subject is described above, it should be understood that the current disclosure is not limited to using devices only in the esophagus and / or gastrointestinal tract of a subject. For example, the disclosed devices may be used in any appropriate anatomical structure in the body where it may be desirable to have a device transition between an expanded configuration and a retracted configuration for delivery of an active pharmaceutical compound and / or sensing applications. Other appropriate types of anatomical structures where the disclosed medical devices may be used include, but are not limited to, a stomach, small intestine, large intestine, trachea, colon, ureters, urethra, and any tubular viscus of a subject.

[0232] #14443731vl It should be understood that the various components of a device may be made from any appropriate material compatible with the anatomical structures with which the device will interact during use and exhibiting appropriate properties for a desired application. In some embodiments, the arms and the central core may comprise any suitable material and may have appropriate dimensions to provide a desired rigidity during deployment and use. Appropriate materials may include, but are not limited to: polymeric materials such as poly( > -caprolactone) (PCL), thermoplastic polyurethanes (TPUs), poly(vinyl alcohol) (PVA), polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), silicone-based elastomers with high shore hardness, metals (e.g., titanium), and / or any other suitable material.

[0233] An elastic component may be made from any sufficiently elastic material and may have any appropriate construction to provide a desired biasing force to bias a device to an expanded configuration. Appropriate materials may include, but are not limited to: elastic and / or elastomeric polymers such as thermoplastic polyurethane , silicon-based elastomers, polydimethylsiloxane (PDMS), and other appropriate polymers; flexible metals such as stainless steel, titanium, alloys thereof, and other metals compatible with the anatomical structure with which the device may interact; and / or any other appropriate elastic material. Depending on the specific material and corresponding elasticity, the elastic components may take any number of different forms including, but not limited to, springs, beams, solid components, components with portions having reduced cross sections to form living hinges, and / or any other appropriate structure exhibiting a desired combination of flexibility and stiffness to provide the desired functionality.

[0234] In some applications, it may be desirable to be able to quickly reconfigure a device. Actuation time of the device may refer to the amount of time for the device to reconfigure from the expanded configuration to the retracted configuration action of actuated biasing components of the device. In some embodiments, the actuation time of the a device may be less than 10 minutes, 5 minutes, 1 minute, 10 seconds, and / or any other appropriate time period. Additionally, in some embodiments, the above-noted actuation times may be greater than 0.5 seconds, 1 second, and / or any other appropriate time period. Combinations of the foregoing are contemplated including, for example, actuation times that are between or equal to 0.5 seconds and 1 minute, 0.5 seconds and 10 minutes, and / or any other appropriate time period including time periods both greater and less than those noted above.

[0235] In some embodiments, an active pharmaceutical composition is released from a drug release component of a device. The drug release component may be comprised by a central core

[0236] #14443731vl of a device. For example, the drug release component may be associated with a tissue-engaging surface of the device. According to certain embodiments, the drug release component is a selfactuating component. However, in some embodiments, the drug release component is actuated by an electro-mechanical actuator (e.g., a motor) and / or a circuit as described elsewhere herein. Advantageously, the release components described herein may be useful as a general platform for delivery of a wide variety of active pharmaceutical compositions that are typically delivered via injection directly into tissue.

[0237] Self-actuating drug release components may include, for example, self-actuating tissue interfacing components such as self-actuating needles tissue anchor. In some embodiments, the device comprises a spring (e.g., a coil spring, wave springs, Belleville washers, a beam, a membrane, a material having particular mechanical recovery characteristics). The spring may, in some cases, be operably linked to the tissue interfacing component. 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 compressive force on the material / component, the material / component substantially returns to an uncompressed length of the material / component under ambient conditions (e.g., within 80%, within 90%, within 95% of the length of the material / component prior to compression).

[0238] Externally-actuated drug release components may include, for example, tissue interfacing components such as needles. In some embodiments, the device comprises a spring as described above, which is configured to be released and / or compressed by a motor. As in the case of selfactuating drug release components, the spring may, in some cases, be operably linked to the tissue interfacing component. In some embodiments, externally-actuated drug release components comprise tissue interfacing components that are translated into tissue. For example, the tissue interfacing component may anchored to (e.g., inserted into) tissue using a motor.

[0239] According to some embodiments, the drug release component is coupled to a drug reservoir component. For example, the drug release component may be connected to the drug reservoir component. It should be understood that as used herein, connected components may be directly connected (e.g., they may directly contact one another), or they may be indirectly connected (e.g., they may be separated via one or more intervening components). In some embodiments, the drug release component is directly connected to the drug reservoir component. In some embodiments, the drug reservoir component is removable from the drug release component. However, the drug reservoir component may be integrally formed with the drug

[0240] #14443731vl release component, or may be a portion of the drug release component, in some embodiments. The disclosure is not so limited. The drug reservoir component may have any of a variety of suitable geometries, and may be configured to retain the active pharmaceutical composition. In some embodiments, the active pharmaceutical composition may be transmitted from the drug reservoir component to the drug release component, such that the drug reservoir component acts as an additional source of the active pharmaceutical composition. Although the drug reservoir component may be configured to retain the active pharmaceutical composition, this is not a requirement of all drug reservoir components. In some embodiments, the drug reservoir component does not comprise an active pharmaceutical composition. For example, the drug reservoir component may be empty. In some embodiments, the drug reservoir component is not configured to comprise an active pharmaceutical composition. For example, the drug reservoir component may simply be incorporated to provide an appropriate connection between the drug release component and the device. The disclosure is not so limited.

[0241] In some embodiments, the drug reservoir component is configured to retain the drug release component within the device until a time when the device is configured to deliver the active pharmaceutical composition.

[0242] In some such embodiments, an active pharmaceutical ingredient is delivered into the tissue by the tissue interfacing components. For example, in some embodiments, the device comprises an active pharmaceutical ingredient such that, upon release of the spring at a location internal of a subject, the active pharmaceutical ingredient is released (e.g., into tissue proximate the location internal of the subject).

[0243] In some embodiments, a tissue interfacing component comprises an active pharmaceutical ingredient. In some embodiments, the tissue interfacing component comprises greater than or equal to 70 wt%, greater than or equal to 75 wt%, greater than or equal to 80 wt%, greater than or equal to 85 wt%, greater than or equal to 90 wt%, greater than or equal to 95 wt%, or more of an active pharmaceutical agent. In some embodiments, the tissue interfacing component comprises less than or equal to 99 wt%, less than or equal to 95 wt%, less than or equal to 90 wt%, less than or equal to 85 wt%, less than or equal to 80 wt%, less than or equal to 75 wt%, or less of an active pharmaceutical agent. Combinations of these ranges are possible. For example, in some embodiments, the tissue interfacing component comprises greater than or equal to 70 wt% and less than or equal to 99 wt% of an active pharmaceutical agent.

[0244] In some embodiments, the device is self-righting. The self-righting device generally has a geometric center. In certain embodiments, the density, mass, and / or volume of the first portion

[0245] #14443731vl and / or the second portion is selected such that the self-righting device exhibits self-righting behavior. According to certain embodiments, a device exhibits self-righting behavior via transitioning from a retracted configuration to an expanded configuration. For example, in some embodiments, a device in the retracted configuration may support itself using one or more of its arms, as it transitions from the retracted configuration to the expanded configuration. The transition from the retracted configuration to the expanded configuration may result in rotation of the central axis of the device, self-righting the device. The process is exemplified in FIGS. 3A-3D, which show a transition of the device from a fully retracted configuration (FIG. 3A) to a fully expanded configuration (FIG. 3C). In some embodiments, following self-righting, a drug release component can be extended from a tissue-interfacing surface, such that it can be exposed to tissue, as shown in FIG. 3D.

[0246] It should be understood that in some embodiments, the arms of the device may operate independently. Therefore, in some embodiments, the transition from the retracted configuration to the expanded configuration occurs as a result of a transition of some (but not all) arms to an expanded state. Thus, in some embodiments, a subset of the arms of the plurality of arms may be used to self-right the device.

[0247] In some embodiments, the device comprises one or more vents (e.g., to permit the flow of air and / or fluid through the self-righting device). In some embodiments, the self-righting device comprises one or more (e.g., two or more, three or more, four or more) vents associated with at least a portion (e.g., the first portion, the second portion) of the device. In some such embodiments, the vent permits a fluid (e.g., gastric fluid) to enter at least a portion of the device such that e.g., the self-actuating component and / or the spring are exposed to the fluid (e.g., such that the self-actuating component and / or the spring actuate). In some embodiments, the device has a particular largest cross-sectional dimension. In some embodiments, the largest cross- sectional dimension of the device is less than or equal to 30 cm, less than or equal to 20 cm, less than equal to 10 cm, less than or equal to 5 cm, less than or equal to 2 cm, less than or equal to 1.1 cm, less than or equal to 1 cm, less than or equal to 0.8 cm, or less. In certain embodiments, the largest cross-sectional dimension of the device is greater than or equal to 0.1 cm, greater than or equal to 0.2 cm, greater than or equal to 0.4 cm, greater than or equal to 0.6 cm, greater than or equal to 0.8 cm, greater than or equal to 1 cm, greater than or equal to 1.1 cm, greater than or equal to 2 cm, greater than or equal to 2 cm, greater than or equal to 5 cm, greater than or equal to 10 cm, greater than or equal to 20 cm, or greater. Combinations of the above referenced ranges are also possible. For example, in some embodiments, the largest cross-sectional

[0248] #14443731vl dimension of the device is greater than or equal to 0.1 cm and less than or equal to 30 cm. Other ranges are also possible.

[0249] In some embodiments, the device is administered (e.g., orally) to a subject. In some such embodiments, the device may comprise one or more active pharmaceutical ingredients. In certain embodiments, the active pharmaceutical ingredient is released at a location internal of the subject (e.g., within the G.I. tract).

[0250] In certain embodiments, one or more sensors are associated with the device, as described in greater detail below.

[0251] In some cases, one or more of the first portion and / or second portion may be magnetic.

[0252] The device may comprise a circuit, in some embodiments. For example, the device may comprise a circuit configured to control an electro -mechanic al actuator, such as a motor, and / or a sensor. In some embodiments, the circuit is a printed circuit. For example, the circuit may be printed onto a flexible substrate.

[0253] In some embodiments, the circuit comprises a processor. The processor may be a microcontroller unit (MCU). Processors are described in greater detail elsewhere herein. According to certain embodiments, the processor may be configured to control and / or interact with circuit portions. For example, in some embodiments, an actuator in electrical communication with a microcontroller may be opened or closed based upon a signal received from the microcontroller. Advantageously, for example, the actuator being electrically controllable by a microcontroller may avoid false-positive detections and / or undesired openings or closings.

[0254] In some embodiments, the circuit comprises a signal processing portion. The signal processing portion may be configured to receive an external signal. The external signal may be sent by a remote operator. For example, the external signal may be a radio frequency (RF) signal. In some embodiments, the external signal may be used to trigger a change in configuration of a device. For example, the external signal may be used to trigger a transition between a retracted configuration and an expanded configuration. Any appropriate triggering mechanism may be used. For example, the circuit may comprise a switch that may be actuated by the external signal, triggering action by an electro-mechanical actuator. In some embodiments, actuation of a switch by an external signal may result in a change in state of the device.

[0255] In some embodiments, the comprises a motor control portion. The motor control portion may be configured to actuate an electro-mechanical actuator (e.g., a motor). In some

[0256] #14443731vl embodiments, an electro-mechanical actuator may be controlled by an external operator using the motor control portion of the circuit. For example, the motor control portion may be configured to actuate an electro-mechanical actuator used to transition a device between a retracted configuration and an expanded configuration. The motor control portion may be configured to actuate an electro-mechanical actuator that allows a drug release component to interface with tissue, in some embodiments. According to certain embodiments, the motor control portion may be configured to respond to a signal produced by a sensor. For example, in some embodiments, the motor control portion is configured to actuate a drug release component, at least in part in response to a signal received by a sensor.

[0257] In some embodiments, the motor control portion is configured to actuate more than one electro-mechanical actuator. For example, the motor control portion may be configured to actuate a first electro-mechanical actuator (e.g., a first motor) and a second electro-mechanical actuator (e.g., a second motor), in some embodiments. The motor control portion is configured to actuate a first electro-mechanical actuator that can change a configuration of the device between a retracted configuration and an expanded configuration, in some embodiments. The motor control portion is configured to actuate a second electro-mechanical actuator that can actuate a drug release component, in some embodiments. In some embodiments, the motor control portion is configured to actuate the first electro-mechanical actuator in response to an external signal and the second electro-mechanical actuator in response to a signal produced from a sensor of the device. For example, in some embodiments, the motor control portion is configured to actuate the first electro-mechanical actuator in response to a signal received from an external operator and to actuate the second electro-mechanical actuator in response to a signal produced by a sensor of the device. In some embodiments, the motor management portion is be configured to receive information from the signal management portion. For example, the motor management portion may be configured to receive signals from an external operator. In some embodiments, the motor management portion is configured to transmit information to the signal management portion (e.g., the motor management portion may be configured to transmit information regarding a state of the motors to the signal management portion) in order to transmit the information to the external operator.

[0258] In some embodiments, the circuit comprises a sensor management portion. The sensor management portion may be electrically connected to sensors of the device. The sensor management portion may receive signals from the sensors of the device. In some embodiments, the sensor management portion is configured to process signals from individual sensors (e.g., by

[0259] #14443731vl consolidating signals from similar sensors to provide higher-resolution information). In some embodiments, the sensor processing circuit is configured to process information from the sensors (e.g., by filtering signal from the sensors). In some embodiments, the sensor management portion is configured to control the sensors (e.g., by turning the sensors off or on). The sensor management portion may be used to transmit information to the signal processing portion. For example, the sensor management portion may be used configured to transmit data from the sensor or sensors to an external operator.

[0260] In some embodiments, the circuit comprises a voltage management portion. The voltage management portion may comprise components constructed an arranged to amplify, modulate, or convert voltages associated with signals (e.g., external signals, or signals generated by sensors of the device) into voltages appropriate to actuate the device. The voltage management portion may be configured, for example, to output a uniform voltage to a motor control portion of a device in response to a continuously changing input received in the form of a signal from a sensor of the device. In some embodiments, the voltage management portion is electrically connected to a voltage source of the device. For example, the voltage management portion may be electrically connected to a battery of the device. In some embodiments, the device may comprise a power management portion, configured to supply power to an electro-mechanical actuator of the device. For example, the power management portion may comprise a supercapacitor and a voltage regulator electrically connected to the electro-mechanical actuator.

[0261] According to certain embodiments, the device comprises spatial sensors. For example, the device may comprise an accelerometer. In some embodiments, the device comprises a gyro. In some embodiments, the device comprises a magnetometer. In some embodiments, signals from these sensors may be configured to provide information regarding the orientation and / or spatial position of the device.

[0262] In some embodiments, the device comprises environmental sensors. Environmental sensors may detect environmental conditions external to the device. Environmental conditions external to the device may include temperature, pressure, humidity, and / or pH. In some embodiments, the device comprises a temperature sensor. In some embodiments, the device comprises a pressure sensor. In some embodiments, the device comprises a humidity sensor. In some embodiments, the device comprises a pH sensor. According to certain embodiments, environmental sensors may be used to determine the location of the device (e.g., within the gastrointestinal tract of a subject). Alternatively or additionally, environmental sensors may be used to monitor degradation of a capsule, e.g., a capsule comprising a device.

[0263] #14443731vl In some embodiments, one or more of the sensors of the device are operatively connected to the device. For example, the sensor may be operatively coupled to a drug release component of a device, in some embodiments.

[0264] According to some embodiments, the devices described herein are compatible with one or more active pharmaceutical ingredients (APIs), e.g., 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. While much of the specification describes the use of therapeutic agents, other agents listed herein are also possible. The tFor example, 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.

[0265] In some embodiments, the device comprises an active pharmaceutical composition (e.g., a therapeutic agent), also referred to herein as an active pharmaceutical ingredient (API). The active pharmaceutical composition may be configured for release during internal residence of the device. For example, the active pharmaceutical agent may be configured for release at a location internal to a subject. In some embodiments, the active pharmaceutical composition is configured for release under a set of physiological conditions.

[0266] The active pharmaceutical composition may comprise one or more active pharmaceutical agents. The active pharmaceutical composition may have a solid form. For example, the active pharmaceutical composition may comprise one or more active pharmaceutical agents having a solid form. The active pharmaceutical composition may have a liquid form. For example, the active pharmaceutical composition may comprise a dissolved active pharmaceutical agent. The active pharmaceutical composition may be configured to be delivered via a drug release component as described herein.

[0267] 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 (e.g., HMG co- A reductase inhibitors (statins) like rosuvastatin, nonsteroidal anti-inflammatory drugs like meloxicam, selective serotonin reuptake inhibitors like escitalopram, blood thinning agents like clopidogrel, steroids like prednisone, antipsychotics

[0268] #14443731vl like aripiprazole and risperidone, analgesics like buprenorphine, antagonists like naloxone, montelukast, and memantine, cardiac glycosides like digoxin, alpha blockers like tamsulosin, cholesterol absorption inhibitors like ezetimibe, metabolites like colchicine, antihistamines like loratadine and cetirizine, opioids like loperamide, proton-pump inhibitors like omeprazole, anti(retro)viral agents like entecavir, dolutegravir, rilpivirine, and cabotegravir, antibiotics like doxycycline, ciprofloxacin, and azithromycin, anti-malarial agents, and synthroid / levothyroxine); substance abuse treatment (e.g., methadone and varenicline); family planning (e.g., hormonal contraception); performance enhancement (e.g., stimulants like caffeine); and nutrition and supplements (e.g., protein, folic acid, calcium, iodine, iron, zinc, thiamine, niacin, vitamin C, vitamin D, and other vitamin or mineral supplements).

[0269] 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, antiproliferatives, such as anti-cancer agents, antihistamines, antimigraine drugs, hormones, prostaglandins, antimicrobials (including antibiotics, antifungals, antivirals, antiparasitics), antimuscarinics, anxioltyics, bacteriostatics, immunosuppressant agents, sedatives, hypnotics,

[0270] #14443731vl antipsychotics, bronchodilators, anti-asthma drugs, cardiovascular drugs, anesthetics, anticoagulants, inhibitors of an enzyme, steroidal agents, steroidal or non-steroidal antiinflammatory agents, corticosteroids, dopaminergics, electrolytes, gastro-intestinal 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.

[0271] In another embodiment, the therapeutic agent is an immunosuppressive agent. Exemplary immunosuppressive agents include glucocorticoids, cytostatics (such as alkylating agents, antimetabolites, and cytotoxic antibodies), antibodies (such as those directed against T- cell receptors or 11-2 receptors), drugs acting on immunophilins (such as cyclosporine, tacrolimus, and sirolimus) and other drugs (such as interferons, opioids, TNF binding proteins, mycophenolate, and other small molecules such as fingolimod).

[0272] In certain embodiments, the therapeutic agent is a hormone or derivative thereof. Nonlimiting examples of hormones include insulin, growth hormone (e.g., human growth hormone), vasopressin, melatonin, thyroxine, thyrotropin-releasing hormone, glycoprotein hormones (e.g., luteinzing hormone, follicle-stimulating hormone, thyroid-stimulating hormone), eicosanoids, estrogen, progestin, testosterone, estradiol, cortisol, adrenaline, and other steroids.

[0273] 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.

[0274] 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, subunit vaccines, recombinant vaccines, polysaccharide vaccines, and conjugate vaccines, toxoid vaccines, influenza vaccine, shingles vaccine, prevnar pneumonia vaccine, mmr vaccine, tetanus vaccine, hepatitis vaccine, HIV vaccine Ad4-env Clade C, HIV vaccine Ad4-mGag, DNA vaccines, RNA vaccines, etanercept, infliximab, filgastrim, glatiramer acetate, rituximab, bevacizumab, any molecule encapsulated in a nanoparticle, epinephrine,

[0275] #14443731vl lysozyme, glucose-6-phosphate dehydrogenase, other enzymes, certolizumab pegol, ustekinumab, ixekizumab, golimumab, brodalumab, gusellu,ab, secikinumab, omalizumab, tnf- alpha inhibitors, interleukin inhibitors, vedolizumab, octreotide, teriperatide, crispr cas9, insulin glargine, insulin detemir, insulin lispro, insulin aspart, human insulin, antisense oligonucleotides, and ondansetron.

[0276] In an exemplary embodiment, the therapeutic agent is insulin.

[0277] In certain embodiments, the therapeutic agent is present in the device in an amount greater than or equal to 1 gram, greater than or equal to 2 grams, greater than or equal to 3 grams, greater than or equal to 5 grams, greater than or equal to 10 grams, greater than or equal to 20 grams, greater than or equal to 30 grams, greater than or equal to 40 grams, greater than or equal to 50 grams, greater than or equal to 60 grams, greater than or equal to 70 grams, or greater than or equal to 80 grams, greater than or equal to 90 grams. In some embodiments, the therapeutic agent is present in the device in an amount of less than or equal to 100 grams, less than or equal to 90 grams, less than or equal to 80 grams, less than or equal to 70 grams, less than or equal to 60 grams, less than or equal to 50 grams, less than or equal to 40 grams, less than or equal to 30 grams, less than or equal to 20 grams, less than or equal to 10 grams, less than or equal to 5 grams, less than or equal to 3 grams, or less than or equal to 2 grams.

[0278] Combinations of the above-referenced ranges are also possible (e.g., greater than or equal to 1 gram and less than or equal to 100 grams, greater than or equal to 2 grams and less than or equal to 100 grams, greater than or equal to 3 grams and less than or equal to 100 grams). Other ranges are also possible.

[0279] In some embodiments, the devices described herein comprises two or more types of therapeutic agents. For example, in some embodiments, a first therapeutic agent and a second therapeutic agent are present in the device such that the total amount of the first and second therapeutic agent is in one or more ranges described above (e.g., the total amount of therapeutic agent is greater than or equal to 1 gram and less than or equal to 100 grams). In some embodiments, each therapeutic agent is present in an amount such that the total amount of therapeutic agents is greater than or equal to 1 gram. In some embodiments, each therapeutic agent is present in an amount as described above (e.g., each therapeutic agent is present in an amount of greater than or equal to 1 gram and less than or equal to 100 grams).

[0280] In certain embodiments, the therapeutic agent is present in the device at a concentration such that, upon release from the device, the therapeutic agent elicits a therapeutic response.

[0281] #14443731vl In some embodiments, a subject may demonstrate health benefits, e.g., upon administration of the device and / or upon eliciting a therapeutic response.

[0282] Active pharmaceutical compositions for use in accordance with the present disclosure may include a pharmaceutically acceptable excipient. As used herein, the term “pharmaceutically acceptable excipient” means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable excipients are sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, methylcellulose, hydroxypropylmethylcellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; detergents such as Tween 80; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen free water; isotonic saline; citric acid, acetate salts, Ringer’s solution; ethyl alcohol; and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0283] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution, ethanol, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0284] The injectable formulations can be sterilized, for example, by filtration through a bacteria retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0285] #14443731vl In some embodiments, the device may be configured to adjust various parameters based on physiological and / or external metrics. For example, in some embodiments, the device is configured to adjust the rate and / or amount of a pharmaceutical agent released from the device (e.g., stored within one or more reservoirs associated with the device) e.g., in response to a signal from a sensor in electrical or wireless communication with and / or associated with (e.g., embedded within) the device. In some embodiments, the device adjusts the rate and / or amount of a pharmaceutical agent released from the device in response to an input from the user and / or a signal from the sensor. In some embodiments, the device is associated with one or more reservoirs configured for the release of a pharmaceutical agent. In some embodiments, the one or more reservoirs may release a portion of the pharmaceutical agent contained therein in response to a signal received from a sensor in electrical or wireless communication with the device.

[0286] In some embodiments, the device is configured to adjust the position and / or orientation of the device (e.g., via the one or more arms) e.g., in response to a signal from a sensor in electrical or wireless communication with and / or associated with (e.g., embedded within) the device.

[0287] Non-limiting examples of suitable sensors for use with the structures and methods described herein include temperature sensors (e.g., monitoring internal temperature, ambient temperature, temperature of a component associated with the device such as a thermally sensitive polymer), physiological / biometric sensors (e.g., heart rate, electrical activity, neuronal activity), accelerometers (e.g., for measuring breathing rate, activity levels, sleeping behavior / patterns, device orientation), and environmental sensors (e.g., pH, biologic concentration, chemical concentration).

[0288] Any device circuitry may be implemented by any suitable type of analog and / or digital circuitry. For example, the device 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 devices 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.

[0289] The above-described embodiments of the technology described herein can be implemented in any of numerous ways. For example, the embodiments may be implemented using hardware, software or a combination thereof. When implemented in software, the

[0290] #14443731vl software code can be executed on any suitable processor or collection of processors, whether provided in a single computing device or distributed among multiple computing devices. Such processors may be implemented as integrated circuits, with one or more processors in an integrated circuit component, including commercially available integrated circuit components known in the art by names such as CPU chips, GPU chips, MPU chips, microprocessor, microcontroller, or co-processor. Alternatively, a processor may be implemented in custom circuitry, such as an ASIC, or semicustom circuitry resulting from configuring a programmable logic device. As yet a further alternative, a processor may be a portion of a larger circuit or semiconductor device, whether commercially available, semi-custom or custom. As a specific example, some commercially available microprocessors have multiple cores such that one or a subset of those cores may constitute a processor. Though, a processor may be implemented using circuitry in any suitable format.

[0291] Further, it should be appreciated that a computing device may be embodied in any of a number of forms, such as a rack-mounted computer, a desktop computer, a laptop computer, or a tablet computer. Additionally, a computing device may be embedded in a device not generally regarded as a computing device but with suitable processing capabilities, including a Personal Digital Assistant (PDA), a smart phone, tablet, or any other suitable portable or fixed electronic device.

[0292] Also, a computing device may have one or more input and output devices. These devices can be used, among other things, to present a user interface. Examples of output devices that can be used to provide a user interface include display screens for visual presentation of output and speakers or other sound generating devices for audible presentation of output. Examples of input devices that can be used for a user interface include keyboards, individual buttons, and pointing devices, such as mice, touch pads, and digitizing tablets. As another example, a computing device may receive input information through speech recognition or in other audible format.

[0293] Such computing devices may be interconnected by one or more networks in any suitable form, including as a local area network or a wide area network, such as an enterprise network or the Internet. Such networks may be based on any suitable technology and may operate according to any suitable protocol and may include wireless networks, wired networks or fiber optic networks. For example, in some embodiments, the device comprises wireless capabilities for permitting suitable communication with other devices / sy stems (e.g., for controlling aspects of the device, controlling / monitoring physiological conditions of the subject (e.g., at the location

[0294] #14443731vl internal to the subject), etc.). Wireless devices are generally known in the art and may include, in some cases, LTE, WiFi and / or Bluetooth systems. In some embodiments, the devices described herein comprise such a wireless device.

[0295] Also, the various methods or processes outlined herein may be coded as software that is executable on one or more processors that employ any one of a variety of operating systems or platforms. Additionally, such software may be written using any of a number of suitable programming languages and / or programming or scripting tools, and also may be compiled as executable machine language code or intermediate code that is executed on a framework or virtual machine.

[0296] In this respect, the embodiments described herein may be embodied as a computer readable storage medium (or multiple computer readable media) (e.g., a computer memory, one or more floppy discs, compact discs (CD), optical discs, digital video disks (DVD), magnetic tapes, flash memories, RAM, ROM, EEPROM, circuit configurations in Field Programmable Gate Arrays or other semiconductor devices, or other tangible computer storage medium) encoded with one or more programs that, when executed on one or more computers or other processors, perform methods that implement the various embodiments discussed above. As is apparent from the foregoing examples, a computer readable storage medium may retain information for a sufficient time to provide computer-executable instructions in a non-transitory form. Such a computer readable storage medium or media can be transportable, such that the program or programs stored thereon can be loaded onto one or more different computing devices or other processors to implement various aspects of the present disclosure as discussed above. As used herein, the term "computer-readable storage medium" encompasses only a non- transitory computer-readable medium that can be considered to be a manufacture (i.e., article of manufacture) or a machine. Alternatively or additionally, the disclosure may be embodied as a computer readable medium other than a computer-readable storage medium, such as a propagating signal.

[0297] The terms “program” or “software” are used herein in a generic sense to refer to any type of computer code or set of computer-executable instructions that can be employed to program a computing device or other processor to implement various aspects of the present disclosure as discussed above. Additionally, it should be appreciated that according to one aspect of this embodiment, one or more computer programs that when executed perform methods of the present disclosure need not reside on a single computing device or processor, but may be

[0298] #14443731vl distributed in a modular fashion amongst a number of different computers or processors to implement various aspects of the present disclosure.

[0299] Computer-executable instructions may be in many forms, such as program modules, executed by one or more computers or other devices. Generally, program modules include routines, programs, objects, components, data structures, etc. that perform particular tasks or implement particular abstract data types. Typically the functionality of the program modules may be combined or distributed as desired in various embodiments.

[0300] The embodiments described herein may be embodied as a method, of which an example has been provided. The acts performed as part of the method 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 performing some acts simultaneously, even though shown as sequential acts in illustrative embodiments.

[0301] Further, some actions are described as taken by a “user.” It should be appreciated that a “user” need not be a single individual, and that in some embodiments, actions attributable to a “user” may be performed by a team of individuals and / or an individual in combination with computer-assisted tools or other mechanisms.

[0302] EXAMPLE 1

[0303] Purpose and Aims

[0304] It is believed that the convergence of materials science and engineering with chemistry and biology holds immense potential for breakthrough energy technologies. Advances in biological interfaces are paving the way for next-generation clinical applications, where green energy technologies have the potential to catalyze further advancements. With environmental concerns and the ever-growing global demand for electrical energy, researchers are compelled to explore alternative solutions for electricity storage. Unfortunately, the widespread use of alkaline, lithium-ion, and chemistry of standard button batteries generate significant electronic waste. These batteries pose environmental threats, as their casings can be hazardous and toxic electrolytes can leak into water systems and release harmful gases. While replacing current battery technology entirely might be a formidable challenge, exploring alternative materials and cell designs with adaptable form factors can pave the way for solutions that address these concerns. Notably, a new field is emerging at the intersection of energy technology and bioresorbable materials, where novel battery technologies can be developed to meet the growing

[0305] #14443731vl energy demands of biomedical electronics. The development of bioresorbable, or transient, electronics offers several advantages: it eliminates the need for secondary surgeries to remove implants, thereby reducing the risk of infection. This field opens exciting new avenues for biodegradable and green electronics that can seamlessly integrate with the body and degrade after a predetermined period of operation.

[0306] Use of primary and secondary batteries as power sources in implantable medical electronics remains widespread despite significant concerns with biocompatibility and environmental impact. Existing FDA regulations for batteries in medical applications primarily focus on conventional lithium-ion (LIB) and silver oxide batteries. This focus is due to concerns over toxicity and waster accumulation. To address these issues, bioresorbable magnesium (Mg) batteries offer a promising alternative.

[0307] Mg is a prime candidate for bioresorbable batteries due to its unique properties:

[0308] • Biocompatibility: Mg is essential for human health (minimum daily intake: 100 mg / day), and its battery chemistry produces non-toxic byproducts . It also exhibits low thrombogenicity, minimizing the risk of blood clot formation.

[0309] • High energy density: Mg-air batteries possess the highest theoretical voltage (3.10 V) among metal-air batteries and boast an impressive energy density of 6800 Wh / kg .

[0310] • Abundance and affordability: Mg is the fifth most abundant element on Earth, ensuring a sustainable supply and a lower cost compared to lithium.

[0311] Motivated by these advantages, the development of a bioresorbable Mg battery system for biomedical applications was undertaken. The research plan outlined the following objectives:

[0312] • Electrolyte optimization and full-cell performance evaluation: identify the most suitable bio-ionic liquid electrolytes and investigate full-cell performance, targeting specific metrics such as voltage, capacity, and cycle life.

[0313] • Device development: This phase encompasses the sustainable fabrication of high- capacitance, thin cathodes using printing methods, as well as the standardization of encapsulation materials compatible with biodegradable implant and ingestible platforms.

[0314] • In vivo evaluation: conduct in vivo studies to assess the lifetime and performance of biodegradable batteries in both capsule and implantable electronic devices.

[0315] This research will generally contribute to the advancement of bioresorbable battery technologies, opening up promising avenues for future biomedical applications. FIG. 4 describes the overall goals of the project. These include developing of stimulation electrodes,

[0316] #14443731vl contraceptive implants, electronic drug delivery and ingestible electronics. All of these applications generally consume relatively large amounts of power (> 1 mW) when they are turned on and actively used in the tissue, organs or on the skin. Since LIB and silver oxide batteries face issues with toxicity and low energy densities, we propose a bioresorbable battery using Mg-MoCL batteries which employs high performance using bio ionic liquid electrolytes and body-resistant encapsulations. After the potential use time in the bio-applications such systems will undergo controlled degradation processes activated by bodily fluids, enzymes or hydrolysis such gastric fluid, pepsin and interstitial fluids etc. The suggested production methodology represents a generic manufacturing platform for an electro -functional and green future technology of relevance for e.g. process chemistry, synthesis as well as the previously mentioned application areas.

[0317] Survey of the field

[0318] In the biomedical field, the power delivery to an implantable sensor or electronic capsule is limited with battery type, volume and capacity and these challenges urge researchers to investigate new ways for generation and storage of electricity. Commercial batteries have been used since the first applications of implanted electronics. The pacemaker was using Ni-Cd batteries when it was developed in 1958. Solid-state batteries have been used to supply power to sensory and communication systems, where adequate energy delivery is required within the limited volume of the electronic pill. Silver oxide batteries or galvanic cells often take up the majority of the space in the pill due to the power consumption needs of the device. The main obstacle here is that the battery biocompatibility and safety, as well as utilizing novel materials with controlled manufacturing methods such as printing. In a typical electronic pill, coin size commercial batteries have been used, which occupy a significant volume. Batteries from Li / MnCL, Zn / AgCL and rechargeable Li-ion batteries have large packaging, poor rigidity, electrolyte toxicity and volume issues are still prominent downsides of current technology. Biocompatible energy storage systems proposed such as galvanic cells from biocompatible zinc electrodes, including gastric batteries. The limited energy density and cycle life as well as the need for energy harvesting circuitry are big obstacle to deliver enough energy to the commercial electronics. Flexible Zn-Mo biodegradable battery and bioresorbable supercapacitors are proposed however the energy capacity provided from such cells are limited even though the devices are providing some level of flexibility. Zn batteries are another promising device architecture. Zinc foil can be used as anode and high cyclic stability aimed to be maintained as

[0319] #14443731vl rechargeable battery structure. The dendrite formation, cyclic stability and biocompatibility of such devices however remains in question, especially considering that the electrolytes are based on organic solvents and corrosive liquids. FIG. 5 summarizes the history of providing battery technology and current trends to be used in electronic implants. A multitude of factors have been identified for a decades long research, where in the last decade there has been an enormous increase in biobased green solutions.

[0320] Ongoing work demonstrates magnesium bioresorbable batteries area safe, alternative solution to energy storage in biomedical electronics. The first reported bioresorbable battery uses Mg foil as the anode, with Fe, W, or Mo foils as the cathode, and saline solution as the electrolyte. The reported Mg-Mo cell configurations can achieve an operating voltage of 0.45 V. The low voltage outputs and energy densities in these devices are due to the use of cathodes with low electrochemical potential and water-based electrolytes. Cathode materials such as MoO3 and MnCh offer increased electrochemical potential to mitigate the limitations of Fe, W, and Mo cathodes on voltage outputs and energy densities. Nevertheless a true high energy density device platform remains elusive. Recently, researchers used I2 as cathode to increase the operating voltage. Another strategy presented at the work of Kaltenbrunner et. al., where stretchable materials presented to demonstrate a biodegradable battery using an Mg-MoCF system with PBS / alginate electrolytes. However, each work suffers from bulk designs, waterbased electrolytes and bulky full cell device configurations. In another example of a biodegradable battery within the context of textile electronics, an Mg-FeMn fiber battery exhibited a voltage 0.98 V, lacking stability and high operation voltage. Another approach was taken into consideration in the field of biodegradable batteries using conductive polymers. The researchers proposed a path to claim polypyrrole and PEDOT dissolution within enzymatic media, however, the issue of low operation voltage and concern regarding the polymer system’s biodegradability are the main issues.

[0321] The structure of an Mg-nanopaper battery as shown in FIG. 6, consists of three parts: The Mg or Mg alloy anode such as AZ31, the air cathode and the electrolyte. The anodic reaction occurs, and Mg produces Mg+2and cathodic reaction reduces O2 in air (Mg— >Mg+2+ 2c’). As for the cathode side, the reaction would be O2 + 2H2O + 4c’ 40 H’). For the selection of high capacitance cathode material (for the initial study MoO3 was selected), the reaction would be MoO3 + xMn++ nxc’ MxMoO3.

[0322] Although theoretical potential of Mg / Mg+2is -2.69 V to Ag / AgCl, the measured potential is ranging from 1.2 V to 1.5 V in such battery systems. This behavior is due to the corrosion

[0323] #14443731vl mechanism of anode into a side product of Mg(0H)2, using water based electrolyte systems. For example, the work of Huang et al. reached 1.6V with PBS electrolyte with MoO3 cathode, Jia et al., 1.4 V achieved using ionic liquid with silk electrolyte and Au cathode, and PEDOT as a cathode in reference. Recently Rogers et.al demonstrated ionic liquid electrolyte with iodine cathode composite. None of these devices can replace current technology to power implantable systems that uses analog front-end circuitry or Bluetooth modules. It therefore was aimed to overcome the obstacles of limiting operating voltage issue in the previously demonstrated Mg primary batteries, implementing two new methods. High performance bio ionic liquids were included in the gel electrolyte system to increase the voltage window and attaining high capacitance cathode using nanopaper composite material.

[0324] After a successful device operation, the transient electronics undergo a degradation process or in other words disappear into the body when they complete their function. The degradation is dependent on different factors including the environmental conditions (the presence of ions and compounds, enzymes, pH, temperature, etc.). For the metals, the degradation mechanism is through a corrosion process, in which metal in contact with water / biofluids, electrochemical reactions take place to form metal cations and side products such as oxides, H2 gas, hydroxides. For example, Mg (Mg+2) participates in water reduction (2H2O + 2e’ — > H2 + 2OH") as an anodic reaction, resulting a H2 gas and a surface layer, metal hydroxide MgOH2. These byproducts can be eroded by body fluids, enzymes or reactive ions present within the body such as CT. Capacitive cathode materials such as MoO3 or MnCh undergo dissolution in aqueous electrolytes. For the natural biopolymers, gelatin, alginate, and cellulose can disintegrate with the processes of dissolution, enzymatic reaction, hydrolysis, and oxidative reaction.

[0325] Project description

[0326] This project aims to move from silver oxide batteries, using bioresorbable materials in the form of battery components to full cell battery as the primary means of powering biomedical technologies. It was proposed for new full cell configurations of bioresorbable materials using printing methods and new material combinations. Printing enables the direct fabrication of complex planar and spatial structures on flat and curved surfaces with high yield, which leads to rapid prototyping, lower costs, and mass fabrication of electronics. One aim was to increase the energy density of proposed batteries using thin nanopaper electrodes and ionic liquid-based gel electrolytes. FIG. 7 represents (z to zzz) the fabrication procedures of capsule or implantable

[0327] #14443731vl device size bioresorbable batteries. Easy to cut and design Mg and Mg alloy foils with different thicknesses will be used as anode metals for the battery devices. Cold laser tools in the lab were capable of cutting magnesium foils of different types and thicknesses without increasing the risk of sparking and creating hazardous gases. This allows safe prototyping of anode foils. As a cathode, a MoO3 based nanopaper composite (FIG. 11) was proposed. Cellulose nanofibrils (CNF) were used as mechanically robust nanonetwork to provide scaffold for the conductive capacitive cathode material. CNF is an excellent binder for energy storage technologies, and it allows desired rheology for printed electronics. The CNFs have a high aspect ratio and exhibit gel-like characteristics in water, with pseudoplastic properties. For electronic applications, the most useful CNF is either the carboxymethylated CNF or the introduction of charged carboxyl groups.

[0328] Use of CNF instead of other synthetic polymers and carbohydrates for cathode manufacturing allows us to easily tune the material thickness. For the electrolyte, an edible gel electrolyte using choline chloride based ionic liquid will be used to maintain the high ionic conductivity and increase the potential window. Ionic liquids have been incorporated into new battery technologies in order to increase voltage window and eliminate water related side reactions within the cell structure). Here, choline chloride / DE Eactic acid was employed within the polymer network of gelatin. This composite permitted use of the ionic polymer network as both ion source and a separator. It was aimed to use established printed techniques to print nanopaper cathode using blade coating or screen printing. Next, as a last step of manufacturing, 3D printing was used to assembly the battery parts. For the encapsulation materials, biodegradable hydrogels and natural wax materials as encapsulation to control the degradation may be used.

[0329] Overall, it was proposed a holistic approach to understand all the possibilities of Mg based biodegradable batteries devices, attacking the problem at different levels: The fabrication and optimization of from the device electrochemistry point of view, delving into the bioresorbable effects both on the single-cell level and then system level, and finally transferring the devices to biomedical device prototypes. The primary final goal of the bioresorbable battery technology is to transition from electrochemical device approach to a concept to a complete bioresorbable biomedical application.

[0330] At the work packages I and II (FIG. 10), the project focused on thorough development of batteries using the high-performance bio-IE and will aim to create the highest capacity device possible. The experimental and theoretical work of WP1 progressed naturally with encapsulation

[0331] #14443731vl material and testing of WP2. In WP3, stability of encapsulated batteries in simulated and real gastric fluid and other biofluids to estimate complete biodegradation was explored. In WP3, long term stability of bioresorbable devices and asses the biocompatibility within the body was explored. In WP4, animal studies were conducted and demonstrated in vivo applications for ingestible electronics and battery enabled drug delivery for the implant concept. For the risk management part of the battery system, minimal risk is associated with battery fabrication, preliminary tests were carried out on Mg Foils as robust anodes and full cell device structure.

[0332] Successful applications of electronic pills and implantable designs will give the opportunity to study GI monitoring and electronic medicine applications. In vitro performance tests will be carried out by mimicking the stomach environment and the electrochemical performance of the devices will be evaluated. Establishing a continuous sensor mechanism is challenging because of the harshness of the GI environment, miniaturization of the current technology, and system rigidity. Therefore, to evaluate the functionality of bioresorbable batteries that are encapsulated in hydrogels and ingestible capsules, the prototype device will be orally administered to pigs. A gastric endoscope will be applied to observe the devices. All animal experiments will be carried out under the approval of the Committee on Animal Care at MIT.

[0333] Preliminary and previous results

[0334] Layer by layer manufacturing method for fabrication of 7.5 mm diameter size bioresorbable battery used a low cost, 50 m magnesium alloy AZ31 as anode, 100 pm MoO3 nanopaper cathode. Gelatin-based electrolytes were prepared to investigate the performance of the proposed battery system. Simulated gastric fluid, real gastric fluid, PBS, and choline chloride based ionic liquids are used as electrolytes within the gel polymer network. For ionic liquids, the choline chloride based ionic liquids are synthesized in lab.

[0335] Although, Mg- MoO3 nanopaper cathodes are currently early stage if development. However, full cell devices already demonstrated 1.7- 1.8 V open circuit voltages using new bioionic liquids (FIG. 8B). The presented preliminary tests provide a starting point for further development of encapsulated, battery powered biomedical applications. When compared to the voltage with commercial coin size batteries, such as Renata 377, AgO2 and Energizer Zn, the ingestible capsule shows better performance during the open circuit potential measurement test (FIG. 8C).

[0336] #14443731vl Risk Management: have reduced risk in WP1 by conducting preliminary tests focused on functionality and material flexibility. The main risks include a) low levels of improvement with process variation, and b) difficult translation to humidity and oxygen sensitive packaging. The fabrication processes themselves will receive a great deal of attention, as well as the effect of different ionic liquid-based gel electrolytes on the produced batteries.

[0337] Ingestible electronics should be cost competitive with existing treatment methods while maintaining a similar or better level of subject risk. Progress on safety, new technologies, and extensive clinical trials for medical device approval are quite an impactful on ingestible electronics. To do so, the sensor systems require high energy and the current battery technologies take up a lot of space (up to 60%) within the capsule to provide enough capacity. Included a preliminary animal residency study to test the performance robustness of the biodegradable batteries. In a typical experiment, it was possible to insertthe thin, capsule size battery in a 3D printed degradable capsule. Then, deploy the capsule in the stomach for 12 hours. Here, the robustness of the encapsulation of the battery and the capsule shell were tested. After 12h hours of residency in stomach (gastric fluid, pH 1.2 and 37 °C), removed the battery and measured the open circuit potential. As shown in FIG. 9B, the battery preserved its 83% of open circuit voltage performance, which shows a quite promising first results to achieve the aim of high-performance bioresorbable batteries to be used in life sciences.

[0338] FIG. 10 provides a summary of Work Packages (WP) described herein, with tasks (T) and milestones (M). FIG. 11 provides non-limiting cathode materials design. FIG. 12 illustrates device biodegradation in SGF. And FIG. 13 provides non-limiting applications of a device described herein.

[0339] This battery ensures that the components after dissolution within the bodily fluid or in the organ remains safe in terms of daily intake or maximum dosage. For example, a typical 7.5 mm ingestible battery with a cell capacity of ~ 6 mAh cm'2utilizes 30 mg Mg, 20 mg of Mo, 14.7 mg of MoO3, 4.2 mg of activated carbon and 2.1 mg of CNF and 0.1 g carbohydrate hydrogel and natural wax (beeswax or candelilla wax) (FIG. 12).

[0340] Significance

[0341] Battery technology in the biomedical field has been extensively studied and utilized in the applications. These technologies are mostly regarded as unsafe and tried to solve energy delivery problem for the use cases. Achieving certain level of power delivery to the devices using bioresorbable and safe batteries will be significant contribution to the field. Although

[0342] #14443731vl wireless methods, nanogenerators, RFID can deliver some power, the energy required for the biomedical applications are quite demanding, where such technologies theoretically cannot meet with the demand. This success could lead to new generation power delivery technology and bioresorbable biomedical devices that can disintegrate within the body. The success of this approach would also serve as a foundation of a new area that scientists working on both organic and inorganic materials can enter. This project aims at finding completely new battery technology to deliver power, and the fundamental materials science findings must be communicated both to the materials community and to the physiology and medical community.

[0343] Currently, it has been a decade for the investigation of biodegradable batteries, yet a high energy density capacity device technology is lacking. Several devices demonstrated however, the discharging current either is too low or the operation voltage is around below 1.2V. The success of this approach would also serve as a foundation of a new applications that scientists working on both implantable and ingestible electronics. This success could lead to a new generation of bioresorbable batteries with much higher energy densities that can dissolve in bodily fluids. This would enable electronic medicine that is compact and minimally invasive. Such devices will dramatically simplify the surgical procedure for implantation and eliminate secondary surgery after implantation as well as provide new trajectories in ionic and electronic biomedical devices. Many applications such as defense, subject specific drug delivery, and secure self-destructing data systems would be enabled by viable biodegradable batteries.

[0344] EXAMPLE 2

[0345] This example illustrates the use of a non-limiting device comprising a non-limiting, bioresorbable RFID tag contained within a shielded coating. A switching mechanism was conceptualized by introducing an EMI (Electromagnetic Interference) shielding coating that encapsulated an RFID tag and a gelatin carrier capsule. FIG. 14 shows an envisioned medical use of case of the non-limiting device. Specifically, FIG. 14 shows a schematic illustration of a capsule based, biodegradable medication adherence tracking system with envisioned scenario for clinical use. In step 1 a Bio-RFID capsule is administered. In step 2, the shielding coating dissolves and the payload is released. In step 3, the Tag ID and frequency range were monitored, and the payload is recorded for tracking adherence. In step 4, the coating, tag, and capsule dissolve and were biosorbed.

[0346] The device comprises i) a Zinc based RFID tag, ii) an RFID chip, iii) a 000 capsule and payload of interest (drug, sugar, dye etc.), and iiv) a bioresorbable EMI shielding material. The

[0347] #14443731vl tag can be incorporated into a gelatin or HPMC (hydroxypropyl methylcellulose) capsule along with the payload. Once it is encapsulated with ingestible EMI shielding coating, the tag signal is blocked, which is the OFF state. In the “On State”, the bioresorbable RFID tag can be queried via an external reader and used to monitor events using RFID chip data. In the event of ingestion, the EMI shielding coating dissolves and the bioresorbable device can accept queries from the external reader, confirming the ingestion. During manufacturing, the RFID tag can be loaded with information regarding drug dosage, manufacture date, serial number and any other relevant information. Following payload delivery, a healthcare professional can track the medication dose that is delivered with the capsule using an external reader. Upon dissolution of the capsule, the device is exposed to GI fluids, the EMI coating, capsule and RFID tag can be dissolved in the stomach and all device components can be degraded or absorbed in the body.

[0348] Further details were provided below.

[0349] Bioresorbable RFID tag

[0350] The Bio-RFID tag was a compact device that comprised thin cellulose acetate substrate (35pm), a bio-adhesive PGS to bond the substrate with zinc traces, and Impinj Monza M700 RFID chip (~ 400 pm x 400 pm, -24 dBm). FIGS. 15A-15F show electrical characterization of bioresorbable RFID tag. FIG. 15A shows an antenna device architecture and simulated RF performance in equivalent tissue models (Sn). FIG. 15B shows a schematic representation of RFID working principle. FIG. 15C shows RSSI measurement of RFID tags in air, in gelatin capsule and ex vivo in stomach, FIG. 15D shows FEM simulation of a device in 000 capsule. FIGS. 15E-15F show device dissolution in real gastric fluid (RGF) (FIG. 15E) and simulated gastric fluid (SGF) (FIG. 15F) at pH=1.2 and 37 °C at 25 rpm.

[0351] FIG. 15A demonstrates a schematic illustration of the device layers and characterization of the tag. The tag included a Zinc antenna bonded to a cellulose acetate substrate using bioadhesive Polyglycol Sebacate (PGS), an RFID chip and a PEGA encapsulation. The electrical connection between the zinc antenna and RFID chip was maintained by wire bonding and was supported with epoxy. This Zinc based RFID tag resonated at a frequency of 915 MHz. Simulations (CST Microwave Studio) were performed using different scenarios (RFID Antenna Design and. Simulation, below).

[0352] FIG. 15B presents a non-limiting schematic illustration showing the operation scheme of the RFID tags. A signal was sent from an RFID reader and received by the RFID tag. The RFID tag backscattered the signal to the reader. In order to verify the performance and specifically to

[0353] #14443731vl read the tag name and the operational frequency range, the transmitted power was set to 30 dBm and the tag to reader distance was set to ~20 cm. The measurement setup was based on a programmable RFID reader (Rain R700) and a circularly polarized panel antenna with a gain of 9 (dBi). The setup could adjust the emitted power up to 33 dBm (constrained by the Federal Communications Commission at 30 dBm), within the frequency range of 860-928 MHz. The Received Singal Strength Indicator (RSSI) for the RFID tag was monitored in air, rolled in a 000-gelatin capsule and inside of an ex- vivo swine stomach. FIG. 15C shows RSSI measurement of RFID tags in air, in gelatin capsule and ex vivo in stomach. For all cases, RSSI values ranged in between 50-65 dBm for SGF and ex vivo cases, indicating that the RFID tag had sufficient performance for continuous reading.

[0354] FIG. 15D shows the FEA simulation results when the tag was bent at an angle that permitted it to fit in a 000 capsule. Bending the device to 168 degrees, to match that observed during capsule loading (FEM Mechanical Simulations, below), showed that the electrode structures had the highest von Mises stress N / m2at the zinc arm, indicating that the connectivity of the RFID chip to the substrate was unaffected during loading of the capsule.

[0355] FIGS. 15E-15F demonstrate a series of images that show the process of dissolution of a tag during immersion in RGF and SGF at 37°C. The zinc antenna and the encapsulation dissolved in less than a week, while the substrate degraded over several weeks. This agreed with the degradation mechanisms of the respective materials: Zinc degraded at a rate of 120 nm / day via the chemical reaction: [Zn + 2H2O Zn(OH)2 + H2]. Although flexible substrate degradation via hydrolysis may take months, the substrate’s dimensions (10 mm x 15 mm) and its softening upon wetting, facilitated its passage through the GI tract. The designed absence of thick encapsulation layers or humidity barriers permitted the full device to be absorbed or passed with minimal complications.

[0356] RFID Antenna Design and. Simulation

[0357] A commercially available tag reader was employed and a custom transponder was engineered to explore these dynamics further for the proposed ingestible biodegradable RFID technology. The focus was enhancing the tag antenna design to optimize the system for biomedical applications, where efficiency and size were often considered. Presented here is the design process and simulation results of an RFID antenna in the CST full-wave electromagnetic simulation platform.

[0358] #14443731vl Zinc was employed as the biodegradable conducting material for the antenna, which was matched for resonant operation with a commercial tag chip, the Monza R6-P from Impinj. FIGS. 16A-16F show CST full- wave electromagnetic simulation results for a RFID antenna design, showcasing five different configurations: 1) Flat, 2) Half-expanded, 3) Fully rolled with a molybdenum (Mo)-coated capsule, 4) Fully rolled with dissolved Mo coating, and 5) Truncated dipole arms. As depicted in FIGS. 16A and 16B, the disclosed RFID design features a compact layout with a small loop connected to the tag IC and a parallel extended dipole antenna.

[0359] Six different operational cases were explored: 1) the flat state, 2) partially expanded, 3) fully rolled within the Mo-coated capsule, 4) fully rolled with the Mo coating dissolved but not yet expanded, 5) truncated dipole arms, and 6) a hypothetical state of a fully expanded RFID in the stomach but without any surrounding liquid. To assess the antenna's functionality in a realistic environment, an electromagnetic model was used that simulated the surrounding tissue layers once the antenna reached the stomach. This model included skin, fat, gastric fluid (or mucus), and stomach muscle, with the RFID positioned 15 cm from the skin surface. For example, the stomach had a relative electric permittivity of 65 and an electrical conductivity of 1.19 S / m. A discrete port on the RFID was configured to match the Monza R6-P tag IC's resistance at 1.2 fcfl and a lumped element was incorporated with 1.23 pF capacitance, reflecting the IC’s equivalent input capacitance. These electromagnetic simulations helped optimize the disclosed RFID design and understand its effective performance within the gastrointestinal tract.

[0360] The antenna used zinc as its current-carrying material, mounted on a flexible polymer substrate. The Impinj Monza R6-P tag IC was accurately modeled in CST using the appropriate impedance model. In FIG. 16B, simulations included a GI tract tissue model comprising a 2 mm skin layer and 30 mm of fat, with the antenna placed 15 cm below the skin surface and immersed in gastric fluid and stomach muscle tissue. A dry state was also assessed for performance variations; results are shown in FIG. 16C. The lateral dimension of the tissue model, set at one electromagnetic wavelength from the antenna, aimed to minimize boundary reflections, simulating realistic in-vivo conditions. FIG. 16C illustrates the simulated Si l parameter under six different conditions to demonstrate the antenna's robustness, with non-solid curves indicating hypothetical scenarios. Surface current distribution at the resonant frequency is shown in FIG. 16D, while 3D and 2D far-field radiation patterns were shown in FIG. 16E and FIG. 16F, respectively.

[0361] From the Si l simulation results shown in FIG. 16C, it was evident that when the RFID was lightly rolled, its performance remained consistent with a minimum SI 1 of — 15 dB at the

[0362] #14443731vl resonant frequency of 943 MHz. However, as the antenna was fully rolled to a diameter of 8.5 mm, a degradation in performance was observed, although the resonance remained detectable in the Si l results. When the antenna was encapsulated within a dissolvable Mo-coated capsule, the signal was completely nullified, demonstrating the material's effective theoretical shielding capabilities.

[0363] The design intentionally matched the aqueous environment surrounding the antenna to mimic real-case scenarios. Nevertheless, it was beneficial also to simulate a worst-case scenario, where the antenna's environment was dry without any gastric fluid or mucus as illustrated in FIG. 16C. The dry state resulted in an increase in SI 1, which reduced the sensitivity of the antenna's backscattering signal. FIG. 16D displays the surface current distribution of the RFID during resonant operation, highlighting that most of the current flow through the small loop was responsible for resonance, validated further by the simulated Si l results with truncated dipole arms as shown in FIG. 16C.

[0364] The Si l parameter measured the ratio of input power that was radiated out by the passive transponder. However, RFID radiation is not inherently omnidirectional. Electromagnetic (EM) energy was transmitted from the reader antenna to the tag antenna, which was reflected back with the tag's information modulated into the signal. This signal was then detected and amplified. To comprehensively evaluate the backscattering signal, the radiation pattern of the antenna was assessed. Given that the largest dimension of the antenna was 25 mm and the electromagnetic wavelength in tissue was approximately 4 cm, the far- field range of the antenna was calculated using the equation 2D2 / which equalled 3 cm. With an operational distance of at least 15 cm, the antenna functioned within the far-field range.

[0365] In the far field, EM power attenuated radially, following the inverse square law relative to the distance from the antenna. As shown in FIG. 16E, the far-field radiation pattern of the proposed RFID antenna features peaked along the azimuth plane, with a noticeable null along 0 = 0°. Examination of the 2D cuts in the pattern along the = 0° and = 90° planes, as shown in FIG. 16F, revealed a donut-shaped pattern typical of a loop antenna, in contrast to the pattern of a dipole antenna. This observation aligned with the simulated current distribution. Unlike traditional dipole-type RFID, which peaked along the zenith plane, a loop-type RFID radiated with its peak along the azimuth plane.

[0366] FEM Mechanical Simulations

[0367] #14443731vl This analysis used COMSOL Multiphysics 5.6 to simulate the stresses experienced by the part bending to fit inside a capsule. The part was modelled as two layers. The bottom layer was made of cellulose acetate with a thickness of 35 pm, while the top layer was composed of zinc foil with a thickness of 25 pm. The model's origin was positioned at the center of the part, with the z-axis oriented vertically and the x-axis directed to the right. A visualization of the modelled part in COMSOL is provided in FIG. 17. FIG. 17 shows schematics for the modelled RFID tag.

[0368] The mechanical properties of the materials were input into the model based on values from the manufacturer and reputable online sources, summarized in Table 1 below.

[0369] TABLE 1:

[0370] The deformation of the object was simulated in three dimensions using the Solid Mechanics interface. The spatial frame coordinates were shown by X, while the material frame coordinates were shown by x. The displacement vector u related the material coordinates to the spatial position after deformation, as described by the equation below. x = X + u(X,t)

[0371] The governing equation for this system was expressed as follows, where s denoted the stress tensor (specifically the second Piola- Kirchhoff stress), and Fv represented the body force.

[0372] 0 = V ■ s + Fv

[0373] To simulate bending, a fixed constraint was applied to the right side of the part, constraining it fully. The equation below described this constraint. u = 0

[0374] A prescribed rotation was applied to the left side, around the y-axis with the center of rotation located at the right side of the part. The expression for the displacement of points on the rigid body was given by the equation below where X were the material coordinates, Xcwas the center of rotation, ucwas the displacement at the center of rotation, and u was the displacement, I was the unit matrix, R was the rotation matrix u = uc+ (R — I)(X — Xc)

[0375] #14443731vl To accurately model the bending of the part within the capsule, the angle of rotation was calculated using the following equation, where r was the bending radius, 0 was the bending angle in degrees, and L was the length of the side.

[0376] 360L 9 = -

[0377] 2nr

[0378] Based on this calculation, a rotation angle of 168 degrees was selected to accurately reflect the bending condition within the capsule.

[0379] From the simulation described above, the von Mises stresses were calculated according to the equation below, where a was the Cauchy stress tensor components.

[0380] Cellulose Based EMI Shielding Coating

[0381] Following the design of a RFID Tag system, a biodegradable EMI shielding coating was then introduced to block the signal prior to capsule dissolution and to permit signal activation following coating dissolution. The ink comprised a polymer matrix of 2-Hydroxyethyl cellulose (HEC) and bioresorbable metal fillers. In the cellulose family, HEC was chosen due to its solubility in ethanol, viscosity to facilitate gelatin capsule coating, as well as its dissolution rate in an acidic environment.

[0382] FIGS. 18A-18G show cellulose based electrical shielding material fabrication and electrical characterization. FIG. 18A shows the steps of preparing the shielded capsules, which can be easily scaled using a dip, brush or spray coating method, as needed. FIG. 18B shows sheet resistance vs. HEC to metal particle ratio with different metal particle sizes. FIG. 18C shows a summary of lowest sheet resistance values vs. the filler metal type and size. FIG. 18D shows shielding data spectrum between the frequencies of 700 MHz and 1.2 GHz. FIG. 18E shows Total Shielding Effectiveness at 915 MHz for composite thin films (40 pm) using W and Mo. FIG. 18G shows a schematic representation of shielding effectiveness on a shielded capsule. FIG. 18F shows the homogenous distribution of the Mo particles leads to high conductivity, which results in more absorption of the incident EM waves. FIG. 18G shows coated capsule layers and representative thickness values.

[0383] #14443731vl It was also possible to print such inks using direct ink writing using a brush, which would allow mass manufacturing of the coated capsules. (FIG. 19). FIG. 19 provides a photograph of a printer in the process of printing an EMI shielding coating using industrial brush dispenser.

[0384] It was determined that a viscosity of 1-300 Pa.s (8% w / v HEC to solvent) was suitable for capsule coating. Blade coating the composites at a controlled thickness produced uniform films. The composite containing 1-5 pm Mo particles exhibited strong performance and low sheet resistance (0.8 Ohms / sq) at the mass ratio of 1:11 (FIGS. 18B-18C), followed by W particles with size of 1-5 pm. When the ratio passed beyond 1 to 11, the sheet resistance increased possibly due to non-uniform dispersion of particles. FIG. 20 shows a SEM image of HEC: Mo at a 1:11 ratio (left) and a zoomed in image of the film (right). The HEC / Mo composite with a Mo size of 3-7 pm showed the lowest sheet resistance of 6.63 Ohms / sq when the ratio was 1:11.

[0385] To explore the EMI shielding properties of bioresorbable composites, thin films of HEC / Mo and W, each having thicknesses of 40-50 pm, were then fabricated. A pair of wideband near-field probes were utilized with a vector network analyzer to investigate the radio frequency (RF) transmission properties of the composites. To effectively reduce environmental RF noise interference, a Faraday cage was constructed using aluminum foil to encase the probing setup. Then, between 700 MHz and 1.2 GHz was scanned to analyze the S21 response in the mid-field range, especially at the 915 MHz (FIG. 18D). The recorded EMI SE of HEC: W and HEC: Mo with a metal particle size of 1-5 pm is given in FIG. 18E. HEC with Mo showed 25 dB at 915 MHz which was higher than the W composite that of 15 dB. This indicated the HEC: Mo was a good candidate for shielding applications. A comparison using different metals (including foils and polymer films) at the ultra high frequency (UHF) band is given in FIG. 21. FIG. 21 shows a comparison of the metals and the composites for EMI Shielding performance between 700 MHz- 1200 MHz. Films of (3N) W, Zn and Mo materials effectively attenuated RF signals, (measured S12 parameters) demonstrating their suitability for applications requiring high shielding effectiveness. However, printable inks were required for applications in curved substrates. Several materials, specifically conductive polymers in the CNT and MXene families, have been proposed as a thin film shielding material for the X-Band and THz range. The UHF band is a known biomedical frequency and commercial RFID tags mainly work at this range. The measured EMI SE for Mo particles was comparable to PEDOT-based polymers but had the added benefit of full biodegradability.

[0386] #14443731vl FIG. 22 shows the viscosity of molybdenum and tungsten-based EMI shielding inks, and the inset shows the ink applied using a brush.

[0387] Composites using microparticles of Mo represented a better choice compared to those of other bioresorbable metals and conductive polymers due to their high conductivity, biodegradability, resistance to the formation of thick oxides, relatively slow absorption and low cost. Application of Mo based composites to ingestible capsules created a continuous conductive layer, preventing RF transmission to and from the interior of the capsule (FIG. 18F) until layer dissolution. FIG. 18G shows a cross-section of an example capsule architecture, which reserves ~98 % volume for the loading of a drug payload.

[0388] Dissolution, degradation and in vivo Studies of SAFARI

[0389] To understand the dissolution mechanics of the full system, the degradability of the capsule and its component layers was tested in vitro at physiological temperature (37 °C) in SGF. The EMI encapsulation coating dissolved immediately after wetting during in vivo tests (10-20 minutes). The tag’s zinc layer and Mo coating parts disintegrated into pieces in 24 hours. Accelerated biosorption was demonstrated at an elevated temperature to convey a complete picture of dissolution. FIG. 23A shows images of dissolution of EMI shielded capsule and RFID tag in SGF (pH 1.2) solution at 37 °C. At 75°C (corresponds to ~16 times relative to 37°C), the device and the components dissolved and disintegrated into small particles in a week. The materials were bioresorbable due to hydrolysis or enzymatic degradation in physiological and gastric conditions. Zn and Mo undergo hydrolysis to form oxides (Zn+2H2O — Zn (OH)2 +H2, (Mo +4H2O — >MoO4'2+ 8H++ 6e“). The substrate CA is a biodegradable commercial polymer that dissolves in water, upon swelling and permits laser processed electronics. Bioadhesive PGS is a biocompatible synthetic polymer that undergoes surface erosion and is effectively used in drug delivery. The commercial cost-effective gelatin and HPMC (hydroxypropyl methylcellulose) capsules were considered biodegradable and their dissolution time varies depending on the pH. HEC acted as a binder in the coating formulation and is a cellulosic material that degrades into glucose under the effect of enzymatic degradation.

[0390] Coated devices were then tested in vivo. Swine models were selected due to the similarity of their GI tract size to that of humans. First, the shielded 000 size capsules were administered into the stomach. FIGS. 23B-23G show an in vivo demonstration of bioresorbable cellulose based RFID tag. FIG. 23B shows a schematic representation of device measurement in vivo swine and endoscopic images of capsule dissolution and RFID tag under test. FIG. 23C

[0391] #14443731vl shows an x-ray image of the ingested capsule. FIG. 23D shows an RSSI recording of the devices after the EMI coating dissolution. FIG. 23E shows a recorded frequency spectrum of the RFID devices communicated through the swine stomach. FIG. 23F shows time dependent concentration of Zn and Mo ions in SGF immersion test by ICP-OES (n=2). FIG. 23G shows serum Zn and Mo concentration after the device administration in swine models (n=3), ppm, parts per million.

[0392] FIG. 23B shows the steps of dissolution of the device in swine stomach and data recording. Endoscopic images were taken to assess the dissolution trend of the coating and to investigate the RFID tag. After the administration of the capsule, and upon contact with the gastric fluid, the EMI shielding coating swelled due to the cellulose content (i). Then, the coating partially dissolved (ii), and the tag was fully exposed for passive communication (iii). Once the tag was exposed, the panel antenna started to record the tag data and following frequency range. An X-Ray image of the capsule in a swine stomach is shown in FIG. 23C. The image was taken immediately after administration. In general, the tag and parts of the shielded capsule disintegrated in the stomach up to 24h after administration (FIG. 24). FIG. 24 shows an x-ray image of the animal in lateral recumbency, 24h after administration of the capsule, where the device was either partially dissolved or excreted from the GI tract. The administrated RFID tags’ names were recorded prior to capsule ingestion, to simplify the data recording during in vivo testing.

[0393] To acquire tag properties in live animals, the same measurement setup was maintained. FIGS. 23D-23E show the RSSI data recorded from a known tag ID, showing the dB level of the different devices operating in the stomach. In addition, the frequency data of the tags during operation were recorded, while the capsule dissolved until the tag was immersed in gastric fluid (FIG. 23D). When the device was fully immersed in gastric fluid or floating inside the stomach, the setup was still able to record the frequency range of 900 - 925 MHz. This showed the robust design of the proposed antenna configuration. Using the tag name, the payload along with the capsule was recorded into a cloud system and noted. This passive way of recording the ingestion event allows for electronic medication adherence and supports its application in digital health.

[0394] To gain additional insights into metal dissolution and degradation, inductive coupled plasma optical emission spectrometry (ICP-OES) analysis of the Zn antenna and Mo coating was performed and indicated material dissolution at 37°C, 25 rpm over various time points. These findings aligned with previous reports conducted in PBS and were consistent with SGF immersion images. The coated capsule with tag dissolved partially in 8 hours, exhibiting 2 ppm

[0395] #14443731vl Zinc and less than 1.5 ppm Mo (FIG. 23F). On Day I, results showed peak Zn and Mo concentrations up to 5 ppm. Dissolution of the device saturated on Day III, showing 7 ppm Zinc and 3 ppm of Mo. To validate device safety, the capsules were administered to swine and the Zn and Mo levels in blood serum were measured over time. A special diet was administered, providing approximately 2000 ppm Zn and 1 ppm Mo daily. Baseline blood serum levels were measured at 0.4 ppm Zn (n=4) and 0.05 ppm for Mo. The metal levels in serum were measured at 8 hours and 24 hours after the capsule administration (FIG. 23G). No significant increase in the serum Zn and Mo levels was observed since the daily dietary intake of these metals exceeded the amounts present in the device (mzn= 20-25 mg, UIMO = 30-50 mg). The measured serum metal concentrations aligned with previous studies on high Zn load diet. Mo accumulation in organs was unlikely, as studies on Mo implants (diameter, 250 pm), wire) in small animals have shown minimal accumulation and toxicity. For a molybdenum (Mo) foil-based implant (thickness, 25 pm), toxicity and Mo accumulation studies in a rodent model over 22 weeks postimplantation revealed no tissue damage, with only minimal accumulation observed in the organs. Additional studies indicate that even with high Mo diet in humans, excess molybdenum is efficiently excreted by the body.

[0396] Conclusion

[0397] This example illustrates the efficacy and usefulness of a fully bioresorbable RF device technology for ingestible electronics.

[0398] Experimental Section

[0399] Reagent and. Materials

[0400] Mo particles (Thermo Scientific, 3-7 pm and 1-5 pm size) and W particles (Alfa Aesar, 1-5 pm) were used for bioresorbable conductive coatings. Hydroxyethyl cellulose (HEC, Mw= 90000), glycerol, sebacic acid, DMSO were purchased from Sigma-Aldrich. Ethanol (%99, Decon labs) and DI water were used as solvent in all ink preparations. Cellulose acetate (35 pm) or PLA Polylactic acid (50 pm substrate, and zinc foil (25 pm) were purchased from Goodfellow Corporation. PEDOT: PSS (PH1000, 1.3 wt%) was purchased from Heraeus Clevios GmbH.

[0401] Ink Preparation

[0402] Polyglycol Sebacate bio-adhesive synthesis: PGS adhesive was synthesized using equimolar mixtures of glycerol and sebacic acid under 120°C and N2 for 24h to form the

[0403] #14443731vl prepolymer. The prepolymer was then spread on the CA substrate to maintain adhesion to a zinc film.

[0404] Gelatin based adhesive: 1g gelatin, 1g glycerol and 8 g of DI water was kept in oven at 70°C for Ih. Then, the mixture was mixed on a hot plate at 70°C with 250 rpm for 2 hours. After it was fully dissolved, the mixture was mixed for 10 minutes at 40°C to be used to bond the chip to the substrate.

[0405] Biodegradable, Conductive Ink Preparation: The ink was prepared by mixing HEC (0.8g) in ethanol (10 ml) at room temperature. After preparing a gel, Mo and W particles were subsequently added to the gel at different volume ratios and mixed using a Flacktek speed mixer (at 2500 rpm for 10 minutes). To compare conductive polymer EMI shielding, 10 ml PH1000 (Sigma- Aldrich) 0.1 g glycerol and DMSO (5 % v / v) were added to 10 ml PH1000. The ink was vigorously mixed overnight and drop-casted in petri dishes. The other metals, W, Mo films were purchased from Goodfellow Inc.

[0406] For conductivity measurements, samples were printed using a blade coater. First, a PET (125 pm) foil was placed on a coating bed, then the ink was spread with blade coater (distance kept as 0.2 mm between the glass bed and the PET foil). After the solvent evaporated in ambient air, the resulting film was 8x8 cm, and a film thickness range between 40- 80 pm was achieved. The film was peeled off from the substrate, cut to appropriate dimensions and placed on Ossila four-point probe test bench for sheet resistance, conductivity and EMI shielding measurements.

[0407] Coating of 000 Capsule: The coating experiments were performed using a brush. For brush painting of gelatin capsules, a mold was fabricated to maintain better control on deposition. Ecoflex 00-30 was mixed at a 1:1 ratio, poured in plastic cups and degassed. 000 capsules were then pressed in the mixture and cured overnight. After curing, the sacrificial gelatin capsule was removed, and an e-pill was replaced for coating. The ink was applied first to the upper face of the capsule. After evaporation of the solvent, the other half was coated with the ink. This process was repeated several times to create a continuous, pinhole free coating of composite ink onto gelatin capsules.

[0408] Immersion test, SGF preparation: SGF was prepared by dissolving 0.2% w / v NaCl in DI water and pH 1.2 was adjusted using HC1. For RGF tests, fresh gastric fluid was collected every other 2 days and replaced every 24 h.

[0409] Device Fabrication

[0410] #14443731vl A CA / PGS / Zn stack was used as a base for antenna manufacturing. A U4 LPKF laser system was used for patterning and cutting of RFID antenna. After patterning the zinc, unwanted parts were peeled off from the substrate and the zinc antenna on CA substrate was achieved. Impinj Monza RFID chips were gold wire bonded from the chip connections. At the other end, the gold bonding was left floating. The chip with gold connections was adhered to the substrate using a gelatin adhesive. The floating ends of the RFID chip with gold wires was placed on the zinc and connected using conductive Mo based ink. For the in vivo test to maintain a good electrical connection, a biocompatible Ag / AgCl ink was used for the connection. As a last step, PLGA (1 mg in 1ml acetone) was drop-casted on the RFID chip and electrical contacts. The resulting device was placed in a 000 gelatin or HPMC capsule, horizontally, and placed for the molds for depositing shielding material. A painting brush (size #1) was used to print bioresorbable EMI shielding inks. After one pass of printing with the brush, the coating dried for 1 hour. Then, the device was removed from the Ecoflex mold, and the other face of the capsule was placed in the mold. Another coating was applied to coat the entire capsule with the shielding ink.

[0411] Tag data measurement

[0412] A 902-928 MHz panel antenna (TE Connectivity, 9dBic) connected with Impinj RAIN R700 was used to communicate with the fabricated RFID tags. Impinj Itemtest software was used for capturing tag name, RSSI data and frequency. The tag name was also validated using a handheld tag reader (TSL 1128 UHF RFID Reader) to verify the electrical connection and tag name for ease of detection during in vivo demonstrators. FIG. 25 A shows tag name acquisition using handheld reader connected to a smart phone ID verification (RFID Explorer, Technology Solutions (UK) Ltd.). FIG. 25B shows an exemplary software interface for the tag reader.

[0413] EMI shielding measurement

[0414] The EMI shielding measurements were measured over the UHF band (700 MHz - 1.2 GHz) frequency using probes that were connected to a vector network analyzer (Keysight E5080B ENA). A pair of wide-band near-field probes (NFP-3 Near Field Probe Kit 30MHz - 3GHz, RIGOL) were used with the VNA to investigate the radio frequency transmission properties of various metallic shielding materials. To effectively reduce environmental RF noise interference, a Faraday cage was constructed using aluminum foil to encase the probing setups. This setup ensured that the measurements were precise and minimally impacted by external noise.

[0415] #14443731vl In vivo testing

[0416] All swine studies were approved by and performed in accordance with the Committee on Animal Care at the Massachusetts Institute of Technology. In vivo studies were performed in female Yorkshire swine, n= five (4-8 months, weighing -50-70 kg) due to the anatomical similarity of their GI tract to that of humans. Before any procedures, the animals were given a liquid diet (Ensure, Abbott Laboratories) for 24 hours, followed by an overnight fast. For capsule placement, animals were sedated using an intramuscular injection of midazolam 0.25 mg kg-1and dexmedetomidine 0.03 mg kg-1. Following sedation, the animal was intubated, placed on isoflurane (2%) in oxygen, connected to a vital sign monitoring system and provided thermal support. The device was endoscopically delivered through an overtube to the stomach and visualized using a PENTAX EC-3870TLK (160 cm) while the animal was positioned in the left lateral. After delivering the capsule and performing endoscopic imaging, the panel antenna was positioned 10 cm from the animal to capture tag events.

[0417] Finite Element Analysis

[0418] 3D FEA was used to simulate zinc tag bending using commercial software COMSOL Multiphysics. In the model, a Solid Mechanics Interface was used to calculate stress when the bending conditions matched with the bending conditions of a tag placed in a 000 capsule.

[0419] ICP-OES

[0420] Agilent 5100 DVD Inductively Coupled Plasma-Optical Emission Spectrometer was used to quantify the metals. For quantifying the amount of Zn and Mo in blood, samples were digested in immersion trace-grade nitric acid (HNO3; >69%; Sigma Aldrich) and heated 37° C overnight at 25 rpm. The addition of ultrapure H2O (18.2 megohm-cm) yielded a final solution of 2.0% nitric acid. Zn and Mo solutions (1000 pg / ml; Inorganic Ventures, Christiansburg, VA, USA) were used to create calibration curves.

[0421] Characterization Methods

[0422] SEM was conducted by Hitachi FlexSEM TM-1000 II (Tokyo, Japan) using low voltage imaging (3-5 kV) The rheological property of the electrode ink was measured by DHR-3 Rheometer (TA Instruments. New Castle, Delaware USA). Flow sweeps were implemented to test the viscosity from 1 1 / s to 100 1 / s. Optical microscope images were taken by (Keyence VHX-X1 Digital Microscope). The surface roughness and step height profiles were quantitatively analyzed by laser confocal scanning using a 3D surface profilometer (Keyence

[0423] #14443731vl VK-X3000. Osaka, Japan). Conductivity measurements were taken by Ossila Four Point Probe System. Thickness values were measured with micrometer (Mitutoyo).

[0424] EXAMPLE 3

[0425] This example demonstrates the manufacture and use of non-limiting devices comprising tissue anchors in the form of bioresorbable microhooks. The degradable microhooks in the device permitted secure tissue attachment and effective stimulation, demonstrating the therapeutic potential of this approach. The development of 3D bioresorbable tissue anchoring electronics holds multiple advantages for ingestible devices: it eliminates the need for secondary surgeries to remove the capsules, and minimizes electronic waste in the GI tract21,22. Collectively, these results underscore the versatility and impact of the bioresorbable tissueanchoring electronics, positioning them as a promising solution for next-generation GI bioelectronic devices and ingestible systems.

[0426] Reagent and Materials

[0427] Mo particles (Thermo Scientific, 3-7 pm and 1-5 pm size) and W particles (Alfa Aesar, 1-5 pm and Strem Chemicals, 0.5 pm) were used as metal fillers. Beeswax (8012-89-3), Candelilla wax (8006-44-8), Carnauba wax (8015-86-9), and PBS were purchased from Sigma- Aldrich. Simulated gastric fluid without pepsin and simulated intestinal fluid (SIF) were purchased from Ricca. Artificial Saliva (Fusuyama / Meyer) was purchased from Pickering Laboratories. DI water was used as a solvent in electrolyte preparations. Molybdenum foil (25 pm) was purchased from Goodfellow Corporation.

[0428] Ink Preparation

[0429] Biodegradable, Conductive Wax Preparation: After each natural wax was completely melted at 100 °C, Mo and W particles were added to the mixture at different volume ratios and mixed with a spatula by hand before the wax and conductive filler mixture returned to the oven for at least 15 minutes to re-melt. The wax and filler were then carefully re-mixed by hand before being poured into wax molds of varying size - square for sheet resistance, thin and rectangular for impedance, cylindrical molds for mechanical tests, and flat round cylinders for hook preparation / melt prep.

[0430] Immersion and dissolution test: For RGF tests, fresh gastric fluid was collected and used for electrolyte. SGF was changed every 3 days, hook full submerged in SGF Real Gastric fluid filtered with a 110 mm diameter filter paper.

[0431] #14443731vl 3D Printing

[0432] Two-photon polymerization 3D printer UpNano, Austria was used for hook manufacturing. SLA 3D printer Formlabs, Form 3 was used for the printing of molds, capsule body and cap parts. For 3D printing of biodegradable capsule and holders FDM-based 3D printer, Bambu Lab XI, USA was used.

[0433] Electrical and Mechanical Characterization of Biodegradable Wax Composites

[0434] Electrical Characterizations

[0435] The wax samples were left overnight for complete drying at room temperature before electrical characterizations. A 4-point probe system (Ossila, UK) measured the sheet resistance of each W-paste and Mo-paste sample. 3 measurements were averaged per sample.

[0436] Impedance measurements: Three-electrode electrochemical measurements were performed for composite characterizations with a potentiostat (PalmSens 4, PalmSens). A Pt wire counter electrode (ItalSens) and an Ag / AgCl (3 M KC1, ItalSens) were used as reference electrodes. The electrochemical impedance spectroscopy (EIS) was performed between frequencies 1 Hz and 100 kHz.

[0437] By screening natural wax-metal composites for desirable electrical and mechanical properties, carnauba wax with 35% molybdenum was identified as an advantageous formulation for biodegradable tissue interfacing electrodes. Tissue interfacing electrodes benefit from useful balances between high electrical conductivity, appropriate impedance for accurate sensing, high mechanical modulus, and high fracture strength. The conductive carnauba wax exhibited exceptional conductivity (sheet resistance = 0.6 Q / sq), mechanical robustness (3.2x stiffness of poly(lactic acid) (PLA), 7.4x fracture strength of polycaprolactone (PCL)), and versatile manufacturability through a single step of molding. This section compares the properties of various materials.

[0438] Three natural waxes — beeswax (E901, animal-based), candelilla wax (E902, plant-based from the Candelilla shrub), and carnauba wax (E903, plant-based from the Brazilian palm) — were studied as potential wax matrix to be combined with fillers for tissue anchors due to their unique combination of properties. These waxes were mixtures of long-chain fatty acids, esters of aliphatic alcohols and hydrocarbons selected for their proven biocompatibility and humidity barrier performance in life sciences and GI applications. These waxes are FDA-approved biocompatible food additives (E901-E903) with humidity barrier properties while remaining biodegradable. To create percolation networks and make the waxes conductive, tungsten (W)

[0439] #14443731vl and molybdenum (Mo) particles were added as fillers based on their biodegradability, biocompatibility, and high conductivity, and were introduced to the waxes to form wax-metal composites. The wax-metal composites were manufactured into a homogenous blend and poured into a mold.

[0440] FIGS. 26A-26H provides the electrical and mechanical characterization of conductive wax composites. FIG. 26A schematically illustrates conductive fillers and natural wax candidates with schematic illustration of mold preparation steps, according to some embodiments.

[0441] The electrical and mechanical properties of the wax-metal composites were highly dependent on the ratio of wax to metal. Wax-metal composites were first screened the composites at various metal contents. Increasing metal content generally increased conductivity; however, wax-metal separation was observed at high metal content, limiting moldability and conductivity of the tissue anchor as a whole. Next, the composites were electrically and mechanically characterized.

[0442] After characterizing the stable composites for sheet resistance and impedance, three top contenders were selected for further screening: carnauba wax with 35% Mo, beeswax with 20% W, and candelilla wax with 15% W. Sheet resistance helped reduce energy inefficiency and the impedance profile impacted the accuracy of the tissue anchors as sensor probes or stimulators (e.g., to ensure recording fidelity, and stimulation reliability).

[0443] First, the sheet resistance of all stable composites was measured using a four-point probe. FIG. 26B shows average sheet resistance measurements at varying metal volume ratios, with additional zoomed in FIG. 26C. The composites with the lowest sheet resistance were beeswax with 20% W at 0.1 / sq, carnauba wax with 30% Mo at 0.6 / sq and candelilla wax with 40% Mo at X Q / sq.

[0444] Next, the six best performing composites for sheet resistance and recorded their impedance profiles from 1 Hz to 100 kHz using electrochemical impedance spectroscopy in simulated gastric fluid (SGF) and intestinal fluid (SIF). Given the focus on developing ingestible electronic devices, impedance measurements were made in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) as electrolyte. While the 30% carnauba wax composite exhibited the lowest sheet resistance, the 35% carnauba wax composite with 1-5 pm Mo demonstrated the lowest impedance across the entire frequency range, making it a promising candidate for further optimization. FIGS 26C-26E show impedance spectroscopy of three different wax candidates in SGF (FIG. 26C), and SIF (FIG. 26E). The inset of FIG. 26C illustrates the three-electrode

[0445] #14443731vl electrochemical setup, CE: counter electrode; WE: working electrode; RE: reference electrode. The three best composites across the frequency spectrum in both fluids, and especially within the low frequency range (IHz-l kHz), were carnauba with 35% Mo, beeswax with 20% W, and candelilla with 15% W. Zwater, i KHZ = 2500 Q. Carnauba with 35% Mo had the lowest impedance profile in both SGF (FIG. 26C) and SIF (FIG. 26E); notably, carnauba with 35% Mo in SIF had an impedance profile at least one order of magnitude smaller than other composites.

[0446] Mold preparation for mechanical test samples

[0447] Carnauba with 35% Mo was selected as a final formulation for subsequent experiments by advancing the three best performing composites in electrical characterization and screening for sufficiently high mechanical modulus and high fracture strength. Sufficiently high mechanical modulus reduce the risk of buckling and tissue rupture and facilitate the efficient transmission of actuation forces by mitigating deformation under load. High fracture strength was limits the risk of failure of the system during movement, insertion, or retention.

[0448] Compressive test samples were designed to mimic the ASTM D695 standard for testing compressive properties of rigid plastics and composites. The compressive test molds were SEA 3D (Formlabs, Form 3, Silicone) printed to result in test samples of 10 mm diameter and 25 mm height. The molds were sprayed with release agent, left to dry, and the intended material was placed inside as powder or small pieces. To match vacuum compression molding conditions, the filled molds were degassed overnight in a vacuum oven above the melting point of the cast material. Once solidified, the molds were peeled and the top meniscus of the test samples were sanded flat, thus resulting in the compressive test samples. The diameter and length of the samples were recorded with calipers (n=3 each), finishing the mechanical sample preparation.

[0449] Mechanical Characterizations

[0450] The wax and polymer samples were mechanically characterized for axial compression modulus and fracture strength. The molded cylinders were loaded into a column force testing machine (Admet 5952 machine frame) with a 1000 lb load cell. The sample was compressed at a rate of 3.00 mm / sec until failure by fracture. The collected force-position data were analyzed in Matlab. The data were preprocessed by low-pass filtering. To calculate the axial compression modulus, the linear region of the plot was selected. The selected linear region was fit with a first- order linear regression, ensuring R2> 0.99, and the slope was extracted as stiffness. The recorded initial diameter and length was used to calculate axial stress and strain and subsequently the axial compression modulus (Eq. (1)). To calculate the fracture strength, the maximum axial stress was recorded (Eq. (2)). The modulus and strength values for each material

[0451] #14443731vl were averaged (n=3), thus characterizing the critical mechanical properties of the studied materials.

[0452] In equations 1-2:

[0453] E = Modulus (Pa) a = Stress (Pa) e = Strain (Unitless)

[0454] F = Load (N) k = Stiffness (F / m) dQ= Initial diameter (m)

[0455] A = Initial cross-sectional area (m2)

[0456] Lo= Initial length (m) L = Displacement (m)

[0457] Sf = Fracture strength (Pa)

[0458] Carnauba with 35% Mo surpassed the two contending composites on both mechanical metrics and surpassed or matched commonly used materials for tissue interfacing structures, corroborating the reputation of carnauba as the one of the hardest natural wax.

[0459] FIG. 26F shows the results of mechanical characterization, comparing modulus (stiffness) between pure waxes, polymers and wax-metal composites. FIG. 26G shows the fracture strength comparison of the material family. Data were presented as means ± (standard deviation). Dots in FIGS 26F-26G represent individual replicates (n = 3 or 4). FIG. 26H, summarizes selection wax-metal composite chosen for subsequent experiments.

[0460] Compared to the lowest sheet resistance composite (beeswax with 20% W) the selected carnauba composite has 5.86x modulus and 5.8 lx fracture strength. The selected composite exhibited 3.2x stiffness of PLA and 7.4x fracture strength of PCL.

[0461] Finally, the composite selection for the tissue anchor was tested to demonstrate long term stability and conductivity in SGF and SIF. The carnauba composite did not exhibit significant

[0462] #14443731vl changes in sheet resistance. In contrast, meanwhile the beeswax with 20% W composite exhibited large changes in sheet resistance after immersion into SGF and SIF (AR / RO > X% in < day 3).

[0463] The combined results (softness and changes in resistance) suggest carnauba wax as a promising metal-wax composite material, and subsequent experiments focused on this material.

[0464] Fabrication of Tissue Anchoring, biodegradable conductive 3D hooks

[0465] 3D Hook Fabrication

[0466] Tissue anchoring components in the form of hooks were fabricated using vacuum compression molding with replica molds. The replica mold was prepared from pattern parts printed with two-photon lithography (UpNano, Austria). All parts were designed using SolidWorks. The pattern parts were placed in a custom SLA 3D printed container (Formlabs, Form 3, Silicone), post-baked overnight at 70 °C, and sprayed with release agent. After drying, the container was filled with degassed silicon replication resin. Once cured, the pattern parts were removed from the silicon mold, resulting in the replica mold.

[0467] For the casting, a round block of conductive carnauba wax / Mo composite was prepared by pouring the molten wax into an SLA 3D printed container. To perform the casting, the replica mold was first sprayed with release agent and left to dry. The preheated mold was placed in the vacuum compression chamber with a round block of casting material on top. The chamber was heated to 405 °C, thus softening the round block and extruding the material into the mold. After cooling, the mold was removed from the chamber. The top surface of the mold was scraped using a hot knife and razor blade. The cast parts were then demolded, resulting in wax hooks.

[0468] Assembly of the recording, sensing, and stimulation devices

[0469] For the recording device, an article in accordance with some embodiments described herein (“MiGut”) base was fabricated. To attach the wax hooks, the MiGut surface was first cleaned with isopropyl alcohol. The hooks were placed onto the MiGut pads using an Ag / AgCl paste (Ercon E2414), and fillet bonded using Loctite 3936. The adhesive completely covered the exposed portion of the MiGut pads, thus isolating the wax hooks for electrical recording.

[0470] For the sensing device, a backing was fused deposition modeling (FDM) 3D (Bambu Lab XI, USA) printed using PLA filament. The current collectors were placed into the sockets on the backing. To connect the hooks to the molybdenum current collector, the free surfaces of the foils were covered by a small piece of conductive carnauba wax. The piece of conductive wax was heated using a soldering iron and the hooks were quickly placed on top of the foil, welding the

[0471] #14443731vl hooks to the current collector. To stabilize the hooks, the surrounding PLA was melted using a soldering iron onto the base of the hooks. The connection was further strengthened using a custom zein-based degradable adhesive by fillet bonding around the hook base and leaving to dry. To connect the current collectors to the impedance spectroscopy system, a wire was placed into the channel behind the foils alongside Ag / AgCl paste. The PLA surrounding the wire was again melted onto the wire and bonded with the custom zein-based adhesive to strengthen the connection.

[0472] For the stimulation device, a 3D printed capsule (Formlabs, Form 3, Clear) and PLA cap were 3D printed to contain the stimulation PCB and silver oxide battery (Renata, 393). To form an electrical connection to the wax hooks, the ProtoLaser U4 was employed to cut the electrode outline using 25 pm thick molybdenum foil, resulting in molybdenum current collectors. To connect the hooks to the molybdenum current collector, the free surfaces of the foils were covered by a small piece of conductive carnauba wax. Afterwards, the wires from the current collectors and battery were soldered onto the PCB. The capsule lip was dipped in molten PCL and the cap was placed onto the lip, forming a degradable bond. The device was dipped in molten beeswax until the hook base to protect from premature degradation or opening. To protect the subject and device during passage to the duodenum, and a 3D printed cover was placed on top of the cap and bonded by lightly brushing with molten PEG 4000 (Sigma- Aldrich, 4 kDa).

[0473] The result was a bioresorbable device comprising a plurality of tissue anchoring components comprising conductive wax and configured to act as sensors and / or stimulating components after anchoring of the device using the tissue anchoring components.

[0474] Synthesis of zein based, bioresorbable adhesive: The zein-based adhesive was composed of 115% w / v zein (Sigma- Aldrich,), 17% w / v glycerol, 6% w / v calcium chloride, and 23% w / v microcrystalline cellulose, given relative to ethanol volume. 70% Ethanol was warmed and calcium chloride was dissolved. Zein was slowly added while stirring. Once all the zein was dissolved, the remaining components were added. A shear mixer was used to homogenize the mixture.

[0475] In vivo testing

[0476] All swine studies were approved by and performed in accordance with the Committee on Animal Care at the Massachusetts Institute of Technology. In vivo studies were performed in female Yorkshire pigs, n=3pigs (4-8 months, weighing -50-70 kg) for each device application. Prior to any procedure, the animals were placed on a liquid diet (Ensure, Abbot Laboratories) for

[0477] #14443731vl 24 h and then fasted overnight. Before device placement, animals were anaesthetized using an intramuscular injection of midazolam 0.25 mg kg-1and dexmedetomidine 0.03 mg kg-1. For terminal settings Telazol® (tiletamine and zolazepam, 5mg / kg) and xylazine

[0478] (2mg / kg). Following sedation, ophthalmic ointment was applied to both eyes and animals were placed on thermal support. The animal was intubated and placed on wasoflurane (2%) in oxygen and monitored using vital sign monitoring system during the entire procedure. The devices were delivered orally into the stomach, using an endoscope and imaged to visualize the stomach with the animal in the left lateral position. For the hook placement during gastric slow wave recording, a ventral midline laparotomy was employed to anchor the recording electrode array to the stomach wall. To access the gastric mucosa, an incision (8-10 cm) was made to access the stomach wall.

[0479] Characterization Methods

[0480] SEM and EDX was conducted by Hitachi FlexSEM TM-1000 II (Tokyo, Japan) using low voltage imaging (3-5 kV). Thickness values were measured with micrometer (Mitutoyo).

[0481] In Vivo Electronics

[0482] Stimulation PCB: Schematic diagrams and the board layouts for the ingestible stimulation platform were designed using Altium. The components included 0201 -inch footprint passive components (capacitors, resistors), a Hall switch (NMP100), a timer (555), dc-dc converter, and a current amplifier.

[0483] In vivo hormone study

[0484] Before and after administration of the device to anesthetized swine, approximately 8 mL of blood was sampled. Starting 10 minutes before the device anchoring, samples were collected every 10 min during a 70-min electrostimulation session from the intravascular ear catheter. Each sample was collected in P800 tubes stored at -80°C before enzyme-linked immunosorbent assay (ELISA) analysis. Ghrelin-acylated porcine ELISA kit (Biovendor, RA594062400R) was used for assessing hormone change. Samples thawed in room temperature and were diluted 1:1 using dilution buffer provided by the kit. Next, 100 pL of acylated ghrelin conjugate solution was added. The strips were covered with a cover sheet and incubated for 20 h at 4 °C. After incubation, the strips were washed with wash buffer five times, and 200 pL of Ellman’s reagent was added to each well. The absorbance was measured for each each well at wavelengths between 405 nm and 414 nm. The absorbance was measured every 30 min until the maximum absorbance reached a minimum of 0.5 A.U., blank subtracted. The average absorbance for each

[0485] #14443731vl standard and sample well was calculated, and a standard curve (ghrelin concentration versus absorbance) was plotted.

[0486] Histology

[0487] Histological analysis was performed on esophagus, stomach and small intestine (duodenum). Biopsies were taken from the hook-anchored mucosa from GI tissues from MIT animal facility. The biopsies from different organs were placed in formalin for 96 hours and then transferred to 70% ethanol. Tissue samples were embedded in paraffin, cut into tissue sections, stained with H&E, and analyzed using an Aperio AT2 slide scanner (Leica Biosystems).

[0488] In vitro cytotoxicity

[0489] Fluorescent LIVE / DEAD staining and MTT [3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide] viability assays were used to assess the cytotoxicity.

[0490] Results of manufacture and testing of tissue anchors

[0491] A schematic of the procedure for hook manufacturing technique is shown in FIG. 27A. 3D printing method using 2PP technique defines the sharp hook geometry for preparing the negative 3D mold. (FIG. 27A-i). The hook fabrication began by preparing an epoxy using soft lithography, followed by using molten Carnauba wax-Mo composite to fill the mold cavity (FIG. 27A-ii). Using molding, a replica of the hook dimensions was created, incorporating silicone epoxy. The mold’s openings were filled with the cast in Mo / wax using vacuum compression molding. Vacuum compression during the melting of the wax permitted filling the volume of the hook openings, after which the silicone was peeled off to reveal the bioresorbable, conductive hooks (FIG. 27A-ii to iii). Similar tissue interfacing microelectrode structures, such as a microneedle array (diameter, >100 um) and a Utah array (diameter >100 um, and 1000 um in length), could be fabricated using the same manufacturing technique. FIG. 27A-iii shows the scanning electron microscopy (SEM) and optical images of a representative Mo / wax-based hook, revealing a homogeneous dispersion of Mo microparticles in Carnauba wax.

[0492] The wax hook penetration and removal forces were measured ex vivo in swine GI tissue. FIG. 27B, shows penetration forces of the hooks in swine esophagus, stomach and duodenum (n=3), Means ± SD. The force required to insert a wax hook 2 mm into swine esophagus was 0.108 ± 0.016 N, into stomach was 0.094 ± 0.010 N, and into duodenum was 0.113 ± 0.039 N (n = 3). Removing the inserted hooks required a force of 1.28 N at a displacement of 7.57 mm away from the tissue surface, wherein the hook fractured. FIG. 27C depicts insertion of the hooks into esophagus, stomach wall, and duodenum, revealing a robust anchoring the ex vivo GI

[0493] #14443731vl tissue. For histological analysis, hematoxylin and eosin (H&E)-stained sections of hook anchored sites were analyzed. Major GI organs (esophagus, stomach and small intestine) show no discernible immune reactions to hook penetration. FIG. 27D presents representative histology images of H&E stained tissue sections of the esophagus, stomach and intestine penetrated by hook electrodes. No tissue damage was found in vivo histological analysis. The conductive carnauba wax exhibited exceptional conductivity (0.6 Q / sq), mechanical robustness (3.2x stiffness of PLA, 7.4x fracture strength of PCL), and versatile manufacturability through a single step of molding.

[0494] To assess the biocompatibility of the hooks, in vitro cytotoxicity tests were conducted on cultured mouse embryonic fibroblast cells (NIH / 3T3), revealing cell viability. The results indicated that 80 ± 3% of the cells remained alive after 24 hours of exposure to Mo / camauba samples.

[0495] FIG. 27E demonstrates the degradability of the hooks over time, showing a photographic series of images of the hook during accelerated tests of bioresorption in SGF at 37°C and indicate degradation of the hooks over time. All the materials associated with the E-hooks were biodegradable: (1) The use of Mo as a metal undergoes hydrolysis to form oxides, degrading in several weeks then fully disappears at a rate of 20 nm / day and reacts with water (Mo +4H2O — >MoO4'2+ 8H++ 6e“)27. (2) carnauba wax dissolves (e.g., into fatty acids). The complete degradation of the natural wax occurs over a period of a month in SGF, In the absence of thick encapsulation layers or humidity barriers, the device gradually disintegrates into small fragments in weeks, dissolved fatty acid component of the carnauba wax can be absorbed by the GI tract and the remaining parts will be excreted during the digestion process. Images of dissolution of in SGF (pH 1.2) solution at 37 °C.

[0496] 2.3 GERD Impedance sensor

[0497] As an example, a device for detecting a sensor for detecting gastroesophageal reflux events associated with gastroesophageal reflux disease (GERD). GERD can be monitored by using temporary diagnostic interfaces that reliably detect reflux events while minimizing risks to subjects. GERD can cause irritation to the esophageal lining, leading to problems such as ulceration, esophageal narrowing, GI bleeding. Here, the conductive wax hooks of a device were used for real-time monitoring of reflux events in the esophagus. FIG. 28A provides a detailed schematic illustration of GERD monitoring in vivo swine esophagus using tissue anchors provided herein. FIG. 28B provides a schematic illustration and the photograph of a hook-based GERD sensor, according to some embodiments. The device anchored to the esophagus and

[0498] #14443731vl measured impedance change to detect which fluids were dominant in the esophageal environment, thus informing subjects and clinicians in case of GERD events. The sensor reliably detects reflux events while completely degrading, eliminating the risk of clinical removal.

[0499] The GERD sensor was fabricated by assembling the conductive carnauba wax / Mo hooks onto a degradable PLA backing with a footprint of 7.5 x 10 mm. The PLA backing was small enough to fit in a porcine esophagus while maintaining an electrode separation of 7.6 mm (FIG. 28B).

[0500] A biodegradable sensor platform device using 3D anchoring hooks that can monitor pH change, demonstrating sensitivity in bodily fluids was designed. Prior to vivo performance of GERD model sensor, impedance spectroscopy was performed between 1 Hz to 100 kHz both in vivo and ex vivo. FIG. 28C shows impedance spectroscopy of measured using hooks inserted into in vivo esophagus tissue. FIG. 28D shows impedance spectroscopy of the hooks measured in different GI bodily fluids. Another aspect of the impedance sensitivity was investigating the material performance in different bodily fluids. Three-electrode electrochemical impedance spectroscopy measurements show that the impedance sensor showed a significant response to SGF and RGF (FIG. 28D). The anchoring hook sensors were also tested on an in vivo swine model. The hook anchoring never dislodged or lost electrical contact during in vivo testing. FIG. 28E provides endoscopic images of GERD sensor in vivo before and after anchoring to swine esophagus.

[0501] The gastrointestinal (GI) retention feature and impedance of degradable hooks made the device an ideal platform for GERD sensors. The GERD impedance sensor was tested on a swine esophagus model. FIG. 28F shows the device impedance response during GERD simulation at 1 kHz (left) and 10 kHz (right) on the esophagus model. Device performance on a GERD model was tested by recording the change of liquid in the esophagus via endoscopy. The GERD model was simulated by periodically spraying water and real gastric fluid into the esophagus and demonstrated that the 3D hook device could reliably detect sequential GERD incidents. FIG. 28F depicts that the hook impedance sensor accurately differentiates between water and gastric fluid by responding to the impedance change during the constant frequency scan. The device responds to the fluid change within a short timeframe (~20 seconds) in both 1 kHz and 10 kHz. Single frequency impedance measurements showing notable impedance changes (Zwater, i KHZ = 2500 □; ZGF, I KHZ = 2000 □). Examining the impedance plot at 10 kHz, a notable change in the impedance was observed when spraying the gastric fluid (Zwater, io KHZ = 1300 □; ZGF, IO KHZ = 750 □), showing sensitivity of the device to environmental change, and specifically differentiating

[0502] #14443731vl the ionic content of the liquid medium in real time. When the water was present in the esophagus the impedance increased and during the gastric fluid reflux, the impedance dropped significantly, indicating the response of highly ionic conductive medium. The response could be differentiated from artificial saliva. Results indicate that the impedance sensor precisely detected gastric reflux, demonstrating a noninvasive method for GERD monitoring. This platform shows the first 3D biodegradable, anchoring sensor device that fully degrades in GI tract for monitoring GERD events.

[0503] Gastric slow wave recording and electroceutical therapy capsule using 3D wax electrodes

[0504] Measuring bioelectrical signals through the GI tract was challenging and technologies for recording gastric slow wave propagation was useful to investigate GI disorders such as gastroparesis and chronic nausea. Surface electrodes demonstrated as part of the ingestible electronic devices, promoting non-invasive approaches of monitoring physiological signal recording approaches.

[0505] This experiment incorporated the hooks into capsule electronics by attaching the hooks to top of the electrode arrays. FIG. 29A provides a schematic illustration of the gastric slow wave (GSW) recording from the stomach using the hooks, hook electrodes anchored against the gastric mucosal surface. FIG. 29B provides a photograph of the electrode array with hooks and the recording capsule.

[0506] Leveraging the hooks’ low impedance and superior tissue contact properties, gastric slow waves were recorded from the swine models. The propagation of the slow waves recorded from central stomach and electrode were placed towards gastric antrum. FIG. 29C provides a photograph of the hook-based recording tool and image of the in vivo recording experiment, device placement into swine stomach. Zoomed in (dashed line) recordings show the cpm value for each pig. The gastric slow waves from 3 different swine captured over hooked channels of the electrode array in the swine stomach is shown in FIG. 29D. The averaged frequency of the slow waves was 3.22 cpm and amplitude was 2.49 mV. (fswine i = 3.42cpm, fSwine2 = 2.95 cpm), fswine 3 = 3.30 cpm; Vswine 1 = 1.37 mV, Vswine 2 = 1.94 mV, Vswine 3 = 4. 16 mV).

[0507] Gastric electrical stimulation

[0508] Gastric electrical stimulation (GES) may be sued to treat gastroparesis. A device in the form of a fully bioresorbable capsule equipped with a plurality of tissue anchors in the form of hooks used as GES electrodes was prepared. The device comprised a silver oxide battery and a 3D printed casing. The device was configured to regulate hormones by delivering

[0509] #14443731vl electrostimulation therapy in large animal models, as is schematically represented in FIG. 29E. FIG. 29F provides a non-limiting exploded perspective illustration of the device, according to some embodiments. FIG. 29G presents a photograph of the device. The hook structure forms a stable interconnection between the tissue and stimulation parts of the capsule electronics. Two hooks were connected to output of the PCB via Mo foil pads and hooks were encapsulated with a zein based adhesive. The carrier capsule, which hosted an Ag2O battery and PCB was kept in minimum dimensions to maintain easy excretion process (7 mm in diameter). This configuration was designed to keep the tissue contacting interface as bioresorbable. The dimensions of the entire capsule, including the hooks were 18 mm in length and 7 mm in diameter (FIG. 29G).

[0510] Using in vivo swine models, the device was delivered to initiate electrostimulation through duodenum. The device was monitored by measuring the trend in the plasma ghrelin levels. To further validate the stimulation effect of the capsule, plasma ghrelin levels were monitored for a 60-minute period while the device was delivering 20 minutes of stimulation. Performance was demonstrated using three different swine. During each experiment, the device was anchored to the duodenum of each subject using endoscopy and confirmed with X-Ray radiography. FIG. 29H presents an X-ray image of the capsule with hooks anchored in duodenum. In FIG. 29H, VD means ventrodorsal and L means left lateral. The electrical stimulation PCB utilized a magnetic switch, power management for optimizing the GES signal power consumption, signal generation using a 555 timer, passive components and voltage to current converter. The overall output of this PCB was square wave voltage (0.3ms pulse, Frequency 14Hz, Amplitude: 0.5 mA), which is the FDA approved protocol, and the capsule electronics could maintain the stimulation continuously for 8 hours with a single silver oxide battery.

[0511] FIG. 291 provides a schematic representation of ghrelin modulation using capsule size hook stimulator. During the electrical stimulation, the plasma ghrelin levels of the swine was increased, by approximately 80% after 20 min of electrostimulation. FIG. 29J shows the percentage change in the swine Ghrelin amount in different animals. Data are presented as mean ± (standard deviation); dots represent individual replicates (n = 3 or 4). FIG. 29K provides representative histology images of H&E stained tissue section duodenum penetrated by the hooks.

[0512] Plasma ghrelin levels continued to increase for the first 10-30 minutes and dropped after the capsule was removed. The results demonstrate the potential clinical use of the biodegradable wax hooks for electroceutical device interface in the field of regulating the hunger hormones. No

[0513] #14443731vl tissue damage was found in the stimulation area during the in vivo histology analysis (FIG. 29K).

[0514] In summary, this work introduces a versatile and bioresorbable 3D tissue-anchoring electronic platform that demonstrates robust functionality across multiple gastrointestinal applications. Through in vivo validation in swine models, this experiment highlights the platform’s ability to perform sensing, electrophysiological monitoring, and targeted electrostimulation — all while ensuring stable mucosal attachment and natural biodegradation over time.

[0515] EXAMPLE 4

[0516] The applications system has been successfully demonstrated in vivo using swine models, suggesting a straightforward pathway toward clinical trials. This innovative approach opens avenues for exploring applications such as device localization, measurement of detection range for ingestible electronics, and battery-assisted stimulation. This design leverages battery assisted RFID based intra-body communication using bioresorbable materials and fully degradable capsule based electroceuticals. This study validates the battery technology’s ability to power ingestible devices beyond simple demonstrators, presenting a viable platform for next- generation communication systems in the GI tract and permitting advanced bioelectronics for effective, electroceutical delivery using bioresorbable devices and components.

[0517] Results and Discussion

[0518] FIGS. 30A-30E depict a schematic illustration of capsule based biodegradable capsule electronics system with envisioned scenario for clinical use. FIGS. 30A-30C illustrate the development of ingestible batteries and medical use of case of batteries in ingestible device technologies. FIG. 31A Biodegradable batteries for ingestible electronics. FIG. 3 IB is a longdistance ingestible device tracking for medication adherence. FIG. 31C shows fully degradable, capsule based gastric electrical stimulation.

[0519] Here, it is envisioned that once the batteries placed into a capsule and permit two specific application for ingestible electronics, a fully degradable capsule stimulation system and battery assisted RFID tags for tracking of the medication. After both devices are exposed to gastric fluid, can be dissolved in the stomach and all device components can be degraded or absorbed in the body FIG. 30D. FIG. 3 ID shows the dissolution and biosorption of the batteries, RF devices, and capsule electronics. FIG. 30E depicts a schematic illustration of the Mg-MoO3 battery and

[0520] #14443731vl the device architecture. The bioresorbable batteries permit capsule electronics for advanced healthcare applications.

[0521] Two different sizes were used to facilitate capsule electronics as shown in FIG. 3 IB. FIG. 3 IE demonstrates the schematic illustration of the bioresorbable battery. Circular batteries can fit into a 000 capsule size and for large area battery for advanced capsule electronics. Specifically, an active, bioresorbable magnesium (Mg) alloy AZ31 (Mg96A13Znl) foil serves as the anode, and bioresorbable molybdenum trioxide (MoOs) paper composite serves as the cathode for both battery types. Bio-ionic liquid based gel electrolyte (FIG. 3 IE). After encapsulation with natural waxes, the batteries can withstand the GI conditions and permit capsule devices for electroceuticals and ingestible electronics (FIG. 3 IF).

[0522] Design of the bioresorbable battery for ingestible electronics

[0523] The components of the batteries are illustrated in FIG. 3 ID. Mg alloy is selected as an anode due to its lowest standard electrode potential among other anodes such as Zn and possesses high volumetric energy density along with relatively low cost. Coupling Mg anodes with low power cathodes can generate open circuit voltages such as Mg-Mo (0.75 V), Mg-Fe (0.45 V). Therefore, high power cathodes from MoO3 is an excellent pair of choice to employ high energy, ingestible cell designs.

[0524] Earlier demonstrations of Mg- MoO3 batteries possessed operation voltages of 1.6 V using large particles of cathode binders. These yield thicker electrodes with delamination problem from the current collectors. Cellulose nanofibrils are excellent choice of cathode binders, permits thin electrodes, precise loading of active materials in the electroactive composites and porous electrodes. In this study, CNF was used as a binder to design the battery cathode for utilizing bioresorbable batteries, where it can degrade and dissolve in the bodily fluids and turn to glucose chains under the enzymatic reaction. The cathode formulation consists of 7:1:1 MoO3 cellulose nanofibril based binder, Activated carbon, respectively.

[0525] To improve the device performance, a bio IL is synthesized by melting CHC12 and DL lactic acid at 1 : 1 mole ration and incorporated into gelatin based gel electrolyte Adding gel electrolyte onto paper based cathode formed a robust structure and the full cell assembly performed adding the Mg alloy cathode on to of the gel electrolyte. Finally batteries are encapsulated dip coating the entire device into beeswax.

[0526] All materials, including the battery systems, the electrodes, the conductive pastes and the packaging materials, are biodegradable. Complete or partial bioresorption of the capsule

[0527] #14443731vl components eliminates the need for surgical extraction after a period of ingestion, (anode, 250- pm-thick Mg alloy; cathode, 200-pm-thick MoO3 composite on a 5-pm-thick Mo, and 300-pm- thick beeswax encapsulation) in simulated gastric fluid (pH 1.2) at 75 °C. For instance, Mg and Mo undergo hydrolysis to form oxides. Magnesium and Molybdenum react with water (Mg+2H2O Mg (OH)2+H2, (MO +4H2O -^MOO4’2+ 8H++ 6e").

[0528] Bioresorbable Mg battery performance and stability - Device retention

[0529] FIGS. 31A-31J show battery dimensions, design features and electrochemical performance with in vivo retention study. FIG. 31A shows 000 size and large area capsule battery device dimensions and optical images of two different sized battery systems. FIG. 31A shows the optical images of the encapsulated and each battery size. First, investigated the electrochemical performance of the circular 000 battery (R 7.5 mm). The open circuit voltage is around 1.8 V. The battery also outperforms the commercial ingestible form factor Zn (1.4V) and AgO2(1.55 V) batteries. FIG. 31B are plots of discharge behaviors of 000-size battery, FIG. 31C shows plots of discharge behaviors of large area capsule size battery at different current densities. FIG. 3 IB displays the discharge characteristics of the battery at different current densities and 000 battery has a capacity of 2 mAh at 0.05 mA / cm2. 000 batteries can be miniaturized into form factors that can fit into a standard 00 or 000 commercial capsules. FIG. 31C shows the discharging behavior for the large area battery. The large area battery has an operation voltage of 1.84V with a capacity of 3.5 mAh.

[0530] To demonstrate battery stability, conducted both SGF immersion and retention test in vivo swine models. Stomach properties, humidity etc. Immersing the batteries in SGF gives information of the battery performance when it is completely make a contact with bodily fluids, here in this case GI related fluids. Functioning devices in vivo is a critical technological step for safe and green ingestible electronics. To achieve this goal and demonstrate the robustness of the proposed technology, conducted retention tests. Batteries placed with biodegradable capsules and encapsulated with beeswax. The devices are measured before and after the retention day of interest. Two methods used in providing retention capability. An arm shaped capsule with a flexible core for the retention study of 000 batteries was used and for the large area batteries anchored the batteries using Endoclip to the stomach wall to maintain a stable environment.

[0531] FIG. 3 ID is a schematic diagram of in vivo retention study that investigates the battery capacities after days of retention in swine stomach. Effect of in vivo retention on the battery capacity encapsulated in different capsule forms. Retention study conducted using different

[0532] #14443731vl capsule types for different battery types. Arm-shaped capsules are for 000-size batteries and 3D printed capsules for large area batteries which can be anchored to the stomach wall using endoclip. FIG. 3 IE are X-Ray images of arm-shape capsule loaded with batteries at day 0 and the retention day 3. FIG. 3 IF is an Endoscopic image visualizing the position of the capsule loaded with three 000-size batteries for investigation of retention. FIG. 31G shows change in the energy density and open circuit potential for the 000-size batteries in SGF and in vivo retention days spent in the stomach. FIG. 31H is an X-Ray image of 3D printed capsule loaded with large area capsule batteries at day 0 and FIG. 311 shows the retention day 3. FIG. 31 J shows the effect of retention on the energy density and open circuit potential for the large area batteries in SGF and in vivo retention days spent in the stomach.

[0533] FIG. 3 ID shows, for both battery types, that the number of samples on each retention day and SGF immersion test were maintained for n=3 devices. X-Ray images show the devices in swine stomach using an arm shaped capsule, where the metal parts of the battery are visible and showing the stable retention on day 3. FIG. 3 IE displays the Energy Density and the voltage of the 000 batteries on the days of retention. The voltage decreases from 1.8V to 1.6 V on day 1 and 1.2 V on day 3. Capacity of the batteries decreased from 3.5 mAh to 0.4 mAh at the end of Day 3 retention

[0534] FIG. 3 IF displays the Energy Density and the voltage of the 000 batteries on the days of retention. Same trends observed for the large area batteries. The voltage decreases from 1.8V to 1.6 V on day 1 and 1.2 V on day 3. Capacity of the batteries decreased from 3.5 mAh to 0.4 mAh at the end of Day 3 retention.

[0535] The performance of the batteries in simulated gastric fluid also demonstrated the robustness of batteries. Open circuit voltage tests for hours long and continuous discharging of the devices fully immersed in SGD reveals that until the wax encapsulation dissolves the batteries are performing well however the capacity decays after average of 48 hours.

[0536] The key performance characteristics, a radar plot was given. The operation voltage (1.84 V), the areal capacity (9.8 mA h cm 2), the areal energy density (17.7 mW h cm 2), the areal power density (0.7 mW cm 2), the volumetric energy density (93.0 mW h cm 3), and the volumetric power density (3.8 mW cm 3) are all significantly higher than those of alternatives.

[0537] The degradation of the ingestible batteries in simulated gastric fluid at 37 °C was demonstrated using shaking at 25 rpm agitation, mimicking the stomach move.

[0538] Ingestible electronics applications

[0539] #14443731vl This bioresorbable platform can address a wide range of ingestible electronics scenarios and target GI organs, including the stomach, esophagus and small intestine due to the ingestible form factor. The performance of the 000 capsule battery can support the applications of the low power electronics applications. Supplying 20-50 uA currents at 1.5 V permits ingestible electronics that consumes low power.

[0540] RFID based wireless sensor monitoring or ingestible device tracking is crucial for... Introducing completely bioresorbable RFID tags are challenging but a few attempts demonstrated. One downside of the technology is that passive RFID tags require reader antennas close to device of interest. Battery assisted RFID permits long distance. In the event of ingestion, the bioresorbable RFID device can be visible from the external reader with a change in the RSSI intensity, confirming the ingestion. RFID tags can be loaded with information regarding serial numbers, manufacture date, sensory component and any other relevant information. Once the device is placed in the esophagus, it is possible to record the change in the RSSI and RFID tag can be dissolved in the stomach and all device components can be degraded or absorbed in the body (FIG. 31 A). Unlike the passive RFID, in the battery assisted configuration signal is sent from an RFID reader and received by the RFID tag within a long distance, where the signal backscattered to the reader.

[0541] FIG. 32A shows the concept of bioresorbable battery assisted RFID technology with details of platform components. The device consists of molybdenum-based RFID antenna, RFID chip, bioresorbable circular battery and interconnects (FIG. 32C). The electrical connection between the molybdenum antenna and RFID chip is maintained by Mo wire and conductive wax. The entire battery assisted RFID tag can be incorporated into a 000-gelatin capsule and overall size permits safe passage through the GI tract (FIG. 32D). This Mo based BA-RFID tag resonates at a frequency of 915 MHz. Simulations (CST Microwave Studio) were performed using different scenarios. The volume of the entire package is 1.37 cm3, which leaves 76% for payload or drug of interest.

[0542] The Received Singal Strength Indicator (RSSI) for the RFID tag was monitored over a distance from 20 cm to 4 m (FIG. 32E). FIG. 32E depicts the increase in the read range of the bioresorbable RFID tag. Measured read range is consistent and RSSI values range between 35- 50 dBm for long communication range, indicating that the RFID tag has sufficient performance for continuous reading. Battery assisted technology shows the steps.

[0543] First, administered the shielded 000 size capsules into the stomach. To acquire tag properties in live animals, the same measurement setup is maintained. FIG. 32F shows the RSSI

[0544] #14443731vl data recorded from known tag ID, showing dB level of the different devices operating in the esophagus. Before administration, the BA-RFID tags exhibit 50 dB from Im distance from the reader. Once placed in esophagus, the RSSI shifts towards 60 dB, showing the change of the medium. The X-Ray image of the capsule in the swine esophagus is shown in FIG. 32G.

[0545] FIG. 32H demonstrates a series of images that show the process of dissolution of a tag during immersion in SGF at 37°C. The molybdenum antenna and the battery disintegrate into smaller pieces and fragments in a week, while the entire device degrades over several weeks. The dissolved components can be absorbed by the GI tract and the remaining part, RFID IC, may be excreted during the digestion process. This long-range communication system may record the ingestion event, permits electronic medication adherence and leads to a digital health application.

[0546] FIGS. 32A-32J shows bioresorbable battery powered ingestible electronics demonstration. FI. 32A is a schematic representation of fully degradable battery assisted RFID tag application. FIG. 32B shows components and materials for battery assisted RFID tag device. FIGS. 32C and 32D are optical images of the BA-RFID tag before administration. The device can fit in a 000-size gelatin capsule. FIG. 32E shows antenna RF behavior (Sn) of the Mo based paper-clip antenna. FIG. 32F is a schematic illustration of battery assisted RFID tag application measuring from a long range. FIG. 32G shows RSSI and frequency of a RFID tag measured over 4m distance. FIG. 32H shows in vivo demonstration of the RFID tags for measuring the medication adherence. FIG. 321 shows RSSI recorded in three different live swine. Change in the RSSI gives information for the medication taken, which permitted the healthcare professional to assess the medication adherence. FIG. 32J shows an X-Ray image of the BARFID tag delivered in the esophagus. Zoomed in inset images clearly indicates the bioresorbable battery and the RFID antenna. FIG. 32K shows the optical images of dissolution for BA-RFID tag in SGF at 37 °C.

[0547] Electroceutical therapy delivery using bioresorbable capsule electronics

[0548] Gastric electrical stimulation (GES) is an established gastrointestinal electroceutical method to treat gastroparesis. These stimulation methods are utilizing subcutaneously implanted and the electrode implantation is invasive, where the probes are placed to the gastric serosal surface. To tackle this challenge capsule based, ingestible electrostimulation device development is crucial. These systems are designed to be excreted after stimulation and do not provide tissue anchoring for a better electroceutical delivery to the thick GI mucosa. The degradation of

[0549] #14443731vl electrodes after stimulation offers great advantages, non-invasiveness, bioabsorption due to the degradation.

[0550] Gastric electric stimulation devices have shown in promise in modulating hormone secretions within the gastrointestinal tract, offering therapeutic benefits for motility disorders like gastroparesis.

[0551] FIGS. 33A-33K shows a bioresorbable battery powered electroceutical capsule. FIG. 33A is a conceptual schematic of gastric electrical stimulation for regulating hunger hormone ghrelin. FIG. 33B depicts a schematic representation (i) and optical micrograph (ii) of degradable capsule system with capsule open and closed forms (iii), as shown in FIG. 33C. FIG. 33D are schematics of ingestible form factor stimulation PCB. Inset shows the optical image of the PCB waveform of the output signal. FIG. 33E shows discharging at 1.5 mA performance of 2 biodegradable batteries in series. Inset shows the output voltage of the PCB, powered using 2 batteries in series. FIG. 33F provides a schematic representation of in vivo GES application using fully degradable capsule electroceutical system. FIG. 33G is an endoscope photograph showing a biodegradable capsule in swine gastric antrum. FIG. 33H is an X-Ray image of the degradable capsule in swine stomach. FIG. 331 are H&E stains of biopsied stomach mucosa before and after electrical stimulation at the stimulation site. FIG. 33J show the change in plasma ghrelin concentration over time after delivery of bioresorbable battery powered stimulation capsule and sham. FIG. 33K show optical images of dissolution for biodegradable GES capsule in SGF at 37C.

[0552] Battery assisted technology shows the concept of an ingestible biodegradable system for GES FIG. 33A. The GES capsule is composed of two main parts, the capsule which houses the electronics (biodegradable battery, and PCB) and the surface electrode which delivers electrical stimulation FIG. 33B. The flexible electrode consists of a PLA substrate, molybdenum foil electrode, and PCL encapsulation fabricated using laser ablation and hot-press techniques. Molybdenum is used in the electrode due to its lower impedance compared to other bioresorbable metals. The Molybdenum microelectrodes result in a low impedance of 19.0 ±8.4 at 14 Hz and 8.7+5.3 at 1 kHz in SGF. Additionally, there is negligible difference in impedance of the microelectrode before and after stimulation.

[0553] The electrode is connected to the PCB using an FFC connector. The PCB is powered by biodegradable batteries, which serve as a transient power source for the device. The electrical connections between the battery and the PCB are formed using molybdenum wire and conductive wax to be biodegradable within the body (FIG. 33B). The closed form of the capsule

[0554] #14443731vl fits in the restrictions FDA-approved capsule dimensions (000 capsule, 26 mm in length and 9.5 mm in diameter) (FIG. 33C).

[0555] The electrical stimulation PCB utilizes a magnetic switch, power management for optimizing the GES signal power consumption, signal generation comparators, passive components, and voltage to current converter (FIG. 33D). The overall output of this PCB is square wave voltage (0.3ms pulse, Frequency 14Hz, Amplitude: 0.5 mA), which is the FDA approved protocol, and this capsule electronics configuration can maintain the stimulation continuously for 1 hour with a single biodegradable battery and 3 hours with two in series configuration. FIG. 33E shows the discharging performance of two batteries in series at 1.5 mA discharge current.

[0556] To validate the capsule as an electroceutical technology, the platform is tested in vivo. Porcine models were selected due to the similarity of their GI tract size to that of humans. The GES capsule is capable of regulating hormones and delivering electroceutical therapy in large animal model (FIG. 33F). First, administered the capsule into the stomach. Endoscopy image reveals the position of the electrode and the capsule in the stomach (FIG. 33G). Endoscopic images were taken to assess the position of the the capsule and the electrode for electroceutical therapy. The capsule is placed into the stomach of each swine using endoscopy and confirmed with X-Ray radiography (FIG. 33H).

[0557] After administration, to initiate electrostimulation through stomach, further evaluated the increase trend of the plasma ghrelin levels, the “hunger hormone” in the blood. To further validate the stimulation effect of the capsule, plasma ghrelin levels were monitored for a 70-min period using the device is delivering an active 20 minutes of stimulation. During the electrical stimulation, the plasma ghrelin levels of the swine is increased by 80% after 20 min of electrostimulation (FIG. 33J). Plasma ghrelin levels continued to increase for the first 10-30 minutes and dropped after the capsule was removed.

[0558] For histological analysis, hematoxylin and eosin (H&E)-stained sections of stimulation site, stomach during the stimulation show no discernible immune reactions related to stimulation site using the Mo electrode (FIG. 331).

[0559] FIG. 33K demonstrates a series of images that show the process of dissolution of a device during immersion in SGF at 37°C. To understand the dissolution, tested the degradability of the capsule and its component layers in vitro at physiological temperature (37 °C) in SGF then later in the accelerated dissolution test (75°C, corresponds 15x of 37°C). The components

[0560] #14443731vl parts disintegrated into pieces in 24 hours. The substrate PLA is a biodegradable commercial polymer that dissolves in water, upon swelling.

[0561] Conclusion

[0562] This study presents a significant advancement in the field of bioresorbable electronics through the development and in vivo demonstration of Mg-MoOs paper batteries as a reliable power source for ingestible devices. By permitting functionalities such as device tracking, intrabody communication, and electroceutical therapy, the bioresorbable battery technology supports a new generation of fully degradable, capsule-based systems. The successful integration and performance of these batteries in applications tested swine models highlight their translational potential, offering a promising route toward clinical implementation. Overall, the work not only validates the practicality of bioresorbable power sources in complex gastrointestinal applications but also establishes a foundational platform for future bioelectronic devices aimed at minimally invasive, intelligent health monitoring and therapeutic delivery.

[0563] Experimental Section

[0564] Reagent and Materials

[0565] MoO3, PBS, glycerol, gelatin, and beeswax were purchased from Sigma- Aldrich. Magnesium alloy, AZ31 (250 pm), molybdenum foil (15 and 25 pm), PLA (50 pm), Cellulose acetate (35 pm) substrates were purchased from Goodfellow Corporation. Choline chloride and DL-Lactic Acid were purchased from Thermoscientific. Carbon Black was purchased from MSE Supplies. W particles (0.5 pm Strem Chemicals) and Molybdenum wire (100 pm, California Fine Wire Company) were used for bioresorbable conductive interconnect. Cellulose Nanofibrils (1.27 wt%) was provided from University of Maine. DI water was used as solvent in all ink preparations.

[0566] Ink Preparation

[0567] Cathode Fabrication: The cathode was prepared by mixing 10 grams of 0.5wt% percent cellulose nanofibers in water, 0.35 grams of molybdenum trioxide, 0.25 grams of glycerol, and 0.10 grams of activated carbon. Next, the mixture blended for five minutes to remove large chunks. Then the slurry is homogenized at 2000 RPM using a speed mixer (Flacktek) for 3 minutes. Next, the cathode slurry is poured into a petri dish and left to dry for approximately 16 hours at 42°C. Eastly, once solidified, the cathode is laser cut into the shape of the desired battery. The small batteries are cut into 7.5 mm diameter circles, and the large batteries are 8 x 24 mm.

[0568] #14443731vl Electrolyte preparation: Synthesis of a ChCl / DLLA-based ionic liquid is prepared mixing choline chloride and DL-Lactic acid at 65 °C in molar ratio of 1:1. 1g gelatin and 1g glycerol in 7 ml PBS, is placed in an oven for half an hour at 70°C and then mixed for 3 hours. Next, 1g of ionic liquid is added to the mixture, and it is mixed using a hot plate at 65 °C for one hour.

[0569] Electrochemical Characterizations

[0570] Three-electrode cell and two-electrode configuration electrochemical measurements were performed for battery and electrode characterizations. Open circuit potential, galvanostatic discharge test, Electrochemical impedance spectroscopy (EIS) of the devices were performed by using an electrochemical potentiostat (PalmSens4, Netherlands) with a two-electrode setup. Molybdenum based electrodes were characterized using standard three-electrode electrolytic cell. The Mo electrode served as the working electrode, the platinum wire as the counter electrode, the Ag / AgCl (3M KC1, ItalSens) electrode as the reference electrode, and SGF or SIF was employed as the electrolyte. Impedance spectroscopy was conducted between 0.1 Hz and 100 kHz with an input of a 10 mV sinusoidal voltage.

[0571] 3D Printing

[0572] SLA 3D printer Formlabs, Form 3 was used for the printing of flexible molds, capsule body and cap parts. For 3D printing of biodegradable capsule and holders FDM-based 3D printer, Bambu Lab XI, USA is used.

[0573] Battery Fabrication and Assembly

[0574] First, 25 pm molybdenum foil and 250 pm AZ-31 magnesium alloy sheets are laser-cut into either 9 x 24 mm rectangles or 7.5 mm diameter circles using the U4 LPKF laser system, depending on whether a large or small battery is being fabricated. These components serve as the current collector and anode, respectively. Battery molds are 3D printed using a Formlabs Form 3 printer with Flexible Resin. To prevent adhesion, the mold surfaces are coated with a thin layer of soybean oil. The Mo foil is then placed into the mold, followed by lamination of the MoOs paper cathode. A gel electrolyte is subsequently drop-cast onto the cathode, and the AZ31 anode is positioned on top. After allowing the assembly to sit and set overnight, the batteries are carefully removed from the flexible molds. Finally, the assembled batteries are encapsulated by dipping them in melted beeswax.

[0575] Capsule Electronics Assembly

[0576] #14443731vl Stimulation PCB: Schematic diagrams and the board layouts for the ingestible stimulation platform were designed using Altium. The components include 0201 footprint passive components (capacitors, resistors), a Reed switch (MK24-B-3-OE), two comparators for pulse generation (TLV2691), a DC-DC boost converter (TPS61299), and an op-amp for current conversion (MAX40006ANT).

[0577] The capsule was printed using PLA on a BambuLabs 3D printer. Inside the capsule two batteries and a PCB were placed. Electrical connections between the anode and cathode of the batteries and the PCB were created using conductive wax (W / Beeswax). The output from the stimulation PCB was connected to the encapsulated electrode using an FFC connector that protruded from an opening at the top of the capsule. The top and bottom of the capsule were bonded using PCL, and the entire assembly was encapsulated in beeswax for added protection.

[0578] Retention Capsule Design

[0579] The flexible star-shape capsule base and core were printed using TPU filament on a BambuLabs 3D printer. The solid arms were printed using Formlabs Form 3. The arms connected to the body of the capsule, inserting the arms to openings and formed a stable connection using UV curable epoxy (Loctite 4305).

[0580] Dissolution Test

[0581] Immersion test, SGF preparation: SGF was prepared by dissolving 0.2% w / v NaCl in DI water and pH 1.2 was adjusted using HC1. FaSSIF preparation: FaSSIF was prepared by stirring the FaSSIF Buffer Concentrate (Biorelevant, UK), 3F powder (Biorelevant, UK), and DI water until dissolved. For RGF tests, fresh gastric fluid is collected every other 2 days and replaced in every 24 h. For RGF tests, fresh gastric fluid is collected and used for electrolyte. SGF is changed every 3 days.

[0582] RF measurements

[0583] An Impinj RAIN R700 reader along with a panel antenna (902-928 MHz, 9dBic, TE Connectivity) is employed to communicate with the BA-RFID tags. Impinj Itemtest software is used for capturing tag ID, RSSI and operation frequency.

[0584] In vivo testing

[0585] In vivo swine studies were conducted to validate and assess the performance of the device following approval from the Committee on Animal Care at the Massachusetts Institute of Technology. All procedures adhered to institutional and federal animal welfare guidelines.

[0586] #14443731vl Female Yorkshire pigs (n > 10, aged 4-8 months, weighing approximately 50-70 kg) were selected due to the close anatomical resemblance of their gastrointestinal (GI) tract to that of humans. Prior to intervention, animals were placed on a liquid diet (Ensure, Abbott Laboratories) for 24 hours, followed by an overnight fast. Animals were anesthetized before capsule placement using an intramuscular injection of midazolam (0.25 mg kg *) and dexmedetomidine (0.03 mg kg *)• Once sedated, animals were provided thermal support and ophthalmic ointment was applied to both eyes. The pigs were intubated and maintained under isoflurane (2% in oxygen) anesthesia, with continuous monitoring of vital signs. Device delivery was performed by orally administering the capsule into the stomach through an orogastric tube. Stomach localization and capsule positioning were confirmed via endoscopic imaging using a PENTAX EC-3870TLK system (160 cm length). Two primary studies were conducted. In the RFID study, capsules containing passive BA-RFID tags were positioned in the upper esophagus, and a panel antenna was placed approximately 2 m from the animal to monitor and record tag transmission events. In the electrical stimulation study, capsule deployment was followed by serial blood draws to measure ghrelin levels in response to stimulation over 20 minutes under full survival conditions.

[0587] All swine studies were approved by and performed in accordance with the Committee on Animal Care at the Massachusetts Institute of Technology. In vivo studies were performed in female Yorkshire pigs, n>10 (4-8 months, weighing -50-70 kg) due to the anatomical similarity of their GI tract to that of humans. Prior to any procedure, the animals were placed on a liquid diet (Ensure, Abbot Laboratories) for 24 h and then fasted overnight. For capsule placement, animals were anaesthetized using an intramuscular injection of midazolam 0.25 mg kg-1and dexmedetomidine 0.03 mg kg-1. Following sedation, animals were placed on thermal support and ophthalmic ointment was applied to both eyes. The animal was intubated and placed on isoflurane (2%) in oxygen and connected to a vital sign monitoring system. The capsules were delivered orally into the stomach, using an orogastric tube and imaged using PENTAX EC- 3870TLK (160 cm) to visualize the stomach. For the BA-RFID study, following tag delivery to the upper esophagus, the panel antenna is placed 2 m away from the animal to record BA-RFID tag events. For the electrical stimulation experiments, after capsule delivery and endoscopic imaging, blood is collected interval. Fully survival settings

[0588] Stimulation Electrode Fabrication

[0589] #14443731vl Molybdenum foil (15 p m, Goodfellow) was bonded to a polylactic acid (PLA) substrate using polyvinyl alcohol (PVA, lOOkDa, Sigma Aldrich) based adhesive. The LPKF ProtoLaser U4 was used to cut the electrode outline in the molybdenum layer, allowing the excess material to be peeled off. For encapsulation, the electrode-substrate assembly was positioned between two acrylic plates within a hot press set to 70 °C. Solid polycaprolactone (PCL, Mw ~ 14,000, Sigma-Aldrich) pellets were placed on top of the electrode, and the press was closed with a force of 2000 N after the PCL melted to achieve a uniform encapsulation layer approximately 20 pm thick. Finally, the encapsulation layer on top of the electrode pads were etched off using the LPKF ProtoLaser U4 laser.

[0590] Characterization Methods

[0591] For morphology analysis, SEM was conducted by Hitachi FlexSEM TM-1000 II (Tokyo, Japan) using low voltage imaging (3-5 kV). The rheological property of the electrode ink was measured by DHR-3 Rheometer (TA Instruments. New Castle, Delaware USA). The surface roughness and step height profiles were quantitatively analyzed by laser confocal scanning using a 3D surface profilometer (Keyence VK-X3000. Osaka, Japan). Conductivity measurements were taken by Ossila Four Point Probe System. Thickness values were measured with micrometer (Mitutoyo).

[0592] 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 were 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 / 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,

[0593] #14443731vl 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.

[0594] 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.”

[0595] 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.

[0596] 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.

[0597] 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

[0598] #14443731vl 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.

[0603] #14443731vl

Claims

1. CLAIMSWhat is claimed is:

1. A device, comprising a biodegradable RFID antenna; and a coating surrounding the biodegradable RFID antenna and configured to dissolve after placement of the device within an internal organ of a subject, wherein the coating is configured to electromagnetically shield the biodegradable RFID antenna, such that the biodegradable RFID antenna is unable to receive a signal until the coating dissolves.

2. The device of claim 1, wherein the biodegradable RFID antenna is bioresorbable.

3. The device of any one of the preceding claims, wherein the coating is configured to dissolve within 72h of placement of the device within the internal organ of a subject.

4. The device of any one of claims 2-3, wherein the device is configured to completely dissolve within the subject.

5. The device of any one of claims 1-4, wherein the coating comprises a polymer matrix and a bioresorbable metal filler disposed within the polymer matrix.

6. The device of any one of claim 5, wherein the bioresorbable metal filler comprises particles of Mo, W, Fe, Mg, Zn, and / or an alloy thereof.

7. The device of any one of claims 5-6, wherein the polymer matrix comprises a polysaccharide.

8. The device of any one of claims 1-7, wherein the biodegradable RFID antenna comprises a metal.#14443731vl9. The device of claim 8, wherein the metal of the biodegradable RFID antenna is Zn.

10. The device of any one of claims 1-9, wherein the device is disposed within a containing structure suitable for administration to the subject.

11. The device of any one of claims 1-10, further comprising a biodegradable battery.

12. The device of claim 11, wherein the device comprises an RFID tag comprising the RFID antenna.

13. The device of claim 12, wherein the biodegradable battery is configured to power the RFID tag.

14. The device of any one of claims 1-13, wherein the coating is configured to dissolve within 48h, 24h, 12h, Ih, 30 min, or 10 min of placement of the device within an internal organ of a subject.

15. A method comprising administering the device of any one of claims 1-14 to a subject and transmitting a signal from the device to a device external of the stomach and / or transmitting a signal from a device external of the stomach to the device.

16. A device as in any preceding claim, further comprising a biodegradable battery, wherein the device is configured to be retained at a location internal to the subject for at least about 24 hours.

17. The device of claim 16, comprising a Mg foil anode.

18. The device of any one of claims 16-17, comprising a MoO3 based nanopaper composite cathode.#14443731vl19. The device of claim 18, wherein the nanopaper composite comprises cellulose nanofibrils (CNF).

20. A device as in any one of claims 16-19, wherein the battery is bioresorbable.

21. The device of claim 20, wherein the battery is bioresorbable.

22. The device of any one of claims 1-21, wherein the device is configured to be completely biodegradable within less than or equal to 2 weeks of placement of the device within the internal organ of a subject.

23. A device, comprising a biodegradable RFID antenna; a biodegradable battery; and a coating surrounding the biodegradable RFID antenna and configured to dissolve after placement of the device within an internal organ of a subject, wherein the coating is configured to electromagnetically shield the biodegradable RFID antenna, such that the biodegradable RFID antenna is unable to receive a signal until the coating dissolves.#14443731vl

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