Electrically-triggered microactuator powered by aluminium-nickel nanofilm

Abstract

The disclosure relates, in various embodiments, to devices, articles, and methods for jetting an active pharmaceutical ingredient into a patient using an electrically-triggered microactuator powered by a reactive material such as an aluminium-nickel nanofilm.

Description

[0001] WGS M0925.71050WG00 MIT 25827 - 1 -

[0002] ELECTRICALLY-TRIGGERED MICROACTUATOR POWERED BY ALUMINIUM-NICKEL NANOFILM

[0003] RELATED APPLICATIONS

[0004] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 63 / 703,891, filed October 4, 2024, and entitled “ELECTRICALLY- TRIGGERED MICRO ACTUATOR POWERED BY ALUMINIUM-NICKEL NANOFILM,” and to U.S. Provisional Application No. 63 / 764,550, filed February 27, 2025, and entitled “ELECTRICALLY-TRIGGERED MICROACTUATOR POWERED BY ALUMINIUM-NICKEL NANOFILM,” both of which are incorporated herein by reference in their entirety for all purposes.

[0005] GOVERNMENT SPONSORSHIP

[0006] This invention was made with government support under D24AC00040-00 by the Advanced Research Projects Agency for Health. The government has certain rights in the invention

[0007] TECHNICAL FIELD

[0008] Ingestible devices, medical devices, actuators, pyrotechnic initiators, and drug delivery, are generally described.

[0009] BACKGROUND

[0010] Studies have repeatedly demonstrated patients’ preferences for oral drug delivery over injection. However, many pharmaceuticals and other ingestibles, e.g. biologies, are challenging to deliver orally, which can be due to large molecule size and / or breakdown due to gastric fluid. Ingestible devices have been developed for oral delivery. Some have involved injection into the stomach wall of various therapeutics, including adalimumab and insulin. However, typical devices of this type rely on passive actuation mechanisms, e.g., pH-triggered or humidity-triggered dissolution. There is a need for controllable, and on-demand drug delivery.

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[0012] SUMMARY

[0013] Some aspects of the present disclosure provide a single-cycle, linear actuator and an accompanying electrical triggering mechanism for applications including drug delivery for ingestible devices. A Joule heating element (made of either graphite, nichrome, or tantalum) is powered by a single micro Li-ion battery. The Joule heating element provides a thermal impulse to a trigger piece of aluminum-nickel nanofilm. This trigger piece ignites and releases thermal energy. This thermal energy in turn ignites additional pieces of aluminum-nickel nanofilm. The combined thermal energy heats a vessel of ethanol, providing vapor pressure. This vapor pressure causes a fracture in a thin aluminum burst plate, which is designed to fracture in the center and at the desired pressure. The release in pressure pushes a piston with high force output. This force output in sufficient to eject a liquid therapeutic agent as a high velocity jet and inject the liquid into porcine gastric mucosa.

[0014] The subject matter of the present disclosure involves, in some cases, interrelated products, alternative solutions to a particular problem, and / or a plurality of different uses of one or more systems and / or articles.

[0015] In one aspect, a device configured for administration to a subject is provided. According to some embodiments, the device comprises: a reservoir configured to contain an active pharmaceutical ingredient, an outlet associated with the reservoir, and an article configured to generate jet actuation of the active pharmaceutical ingredient through the outlet using heat emitted during a mass-preserving chemical reaction of the article.

[0016] In another aspect, a device configured for administration to a subject is provided. In some embodiments, the device comprises a reservoir configured to contain an active pharmaceutical ingredient, an outlet associated with the reservoir, a power supply, an electric heater operatively coupled to the power supply, and an article configured to generate jet actuation of the active pharmaceutical ingredient by undergoing a chemical reaction triggered by actuation of the electric heater.

[0017] In yet another aspect, a linear actuator for ingestible devices is provided. In some embodiments, the linear actuator has the capacity to deliver at least 200 pl of a liquid

[0018] #14417616vl WGS M0925.71050WG00 MIT 25827 - 3 - therapeutic (including biologies such as mRNA and monoclonal antibodies) past the gastric wall and into the underlying mucosa for absorption into the bloodstream.

[0019] In still another aspect, a method is provided. According to some embodiments, the method comprises: administering to a subject, a device comprising an article configured to generate jet actuation of the active pharmaceutical ingredient through the outlet using heat emitted during a mass-preserving chemical reaction of the article.

[0020] Other advantages and novel features of the present disclosure will become apparent from the following detailed description of various non-limiting embodiments of the disclosure when considered in conjunction with the accompanying figures. In cases where the present specification and a document incorporated by reference include conflicting and / or inconsistent disclosure, the present specification shall control.

[0021] BRIEF DESCRIPTION OF THE DRAWINGS

[0022] 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:

[0023] FIG. 1 is a perspective view of a drug delivery device according to one illustrative embodiment;

[0024] FIG. 2 is a cross sectional view of a drug delivery device according to one illustrative embodiment;

[0025] FIG. 3 is a cross sectional view of a valve of a drug delivery device according to one illustrative embodiment;

[0026] FIG. 4 shows a CAD model of ingestible device, inside view, according to some embodiments;

[0027] FIG. 5 shows CAD model of ingestible device, outside view (180 degrees rotated from model in FIG. 4), according to some embodiments;

[0028] #14417616vl WGS M0925.71050WG00 MIT 25827 - 4 -

[0029] FIG. 6 shows a CAD model zoomed in view on nozzle (sealed with beeswax that can be melted by the Joule heater), according to some embodiments;

[0030] FIG. 7 shows a CAD model of ingestible device, exploded view, according to some embodiments;

[0031] FIG. 8 provides a non-limiting exploded perspective illustration of an alternative device, according to some embodiments;

[0032] FIG. 9 is a cross-sectional schematic illustration of an article in a chamber comprising a solvent, according to some embodiments;

[0033] FIG. 10 shows a thermal simulation of nichrome Joule heating element, according to some embodiments;

[0034] FIG. 11 shows a thermal simulation of nichrome Joule heating below a trigger piece of aluminium-nickel nanofilm, according to some embodiments;

[0035] FIG. 12 shows CAD model of nichrome Joule heater with nanofilm trigger piece, according to some embodiments;

[0036] FIGS. 13A-13E show an assembly process of nichrome Joule heater with nanofilm trigger piece. FIG. 13A shows wires connected to Joule heater on base. FIG. 13B shows an addition of thermally-conductive and electrically-insulating paste and nanofilm trigger piece. FIG. 13C shows an addition of more nano film pieces. FIG. 13D shows an addition of plastic housing and epoxy to create seal. FIG. 13E shows a completed assembly with fifth digit for scale, according to some embodiments;

[0037] FIG. 14 shows the design of a linear actuator for drug delivery, according to some embodiments;

[0038] FIG. 15 shows the design of an electrical triggering mechanism that facilitates the ignition of the aluminum- nickel nanofilm, according to some embodiments;

[0039] FIG. 16 shows a linear actuator attached to a drug reservoir that is loaded with water, according to some embodiments;

[0040] FIG. 17 shows an ex vivo result using the linear actuator for drug delivery via jetting into porcine gastric mucosa, according to some embodiments;

[0041] FIG. 18 shows a characterization of a linear actuator’s force output when it is used to eject a liquid jet, according to some embodiments;

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[0044] FIG. 19 presents a calibration curve of a non-limiting load cell with the linear region, according to some embodiments;

[0045] FIG. 20A presents a non-limiting schematic cross-sectional illustration of a device, according to some embodiments;

[0046] FIG. 20B presents a side view photograph of the device schematically illustrated in FIG. 20A, according to some embodiments;

[0047] FIG. 21A presents a photograph of a non-limiting trigger and article for a device, according to some embodiments;

[0048] FIG. 21B presents the impact of the sparker on the unshielded Arduino and the associated circuits, which shows the applied force versus time according to some embodiments;

[0049] FIG. 22 presents a non-limiting schematic cross-section of the experimental setup for measuring linear actuation using a non-limiting article, according to some embodiments;

[0050] FIG. 23 presents a non-limiting photograph of the experimental setup of FIG. 22, according to some embodiments;

[0051] FIG. 24 presents pressure measured in a variety of non-limiting chambers (pressure vessels) as a function of pressure vessel size, according to some embodiments;

[0052] FIG. 25 presents a cross-sectional schematic illustration of a pressure vessel and top cap assembly, according to some embodiments;

[0053] FIG. 26 provides a photograph of an article comprising a necked trigger piece configured so that the neck of the trigger piece can pass through the top of a pressure vessel, according to some embodiments;

[0054] FIGS. 27A-27C provide photographs illustrating a non-limiting method of venting of the pressure vessel through the trigger piece, according to some embodiments;

[0055] FIG. 28 presents displacement and time data recorded from a piston of a nonlimiting device, according to some embodiments;

[0056] FIG. 29 presents piston velocity vs. time data recorded from a piston of a nonlimiting device, according to some embodiments;

[0057] FIG. 30 presents piston pressure vs. time data recorded from a piston of a nonlimiting device, according to some embodiments;

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[0060] FIG. 31 presents ethanol pressure vs. ethanol density recorded from a piston of a non-limiting device, according to some embodiments;

[0061] FIG. 32 presents a superposition of the data of FIG. 31 onto a phase diagram for ethanol, according to some embodiments;

[0062] FIGS. 33A-33E present high-speed photography of assembled triggering mechanism, according to some embodiments;

[0063] FIGS 34A-34B present in vitro delivery of mRNA lipid nanoparticles (LNPs) showing that an exemplary device can deliver LNPs with 75% ± 9% transfection efficiency, according to some embodiments;

[0064] FIG 35 presents delivery of model drugs comprising viscous oils or suspensions showing that an exemplary device could be used to deliver viscous drug formulations with high concentrations, according to some embodiments;

[0065] FIG. 36A presents a photograph of an assembled, nonlimiting, prototype device, according to some embodiments;

[0066] FIG. 36B presents a photograph of a disassembled, nonlimiting, prototype device, according to some embodiments;

[0067] FIGS. 37A-37B present photographs of a non-limiting device during delivery, according to some embodiments;

[0068] FIGS. 38A-38B present theoretical and empirical data for the pressure at which burst plate fractures to initiate drug delivery, according to some embodiments;

[0069] FIG. 39A provides a non-limiting schematic flow-chart that illustrates the flowchart illustrates the functional layout of the benchtop jetting system, according to some embodiments;

[0070] FIG. 39B shows these features in a schematic cross-section of the benchtop jetting system used for experiments, according to some embodiments;

[0071] FIG. 40 shows a non-limiting schematic cross-section of an exemplary device, according to some embodiments;

[0072] FIG. 41 shows a non-limiting schematic cross-section of an exemplary actuator, according to some embodiments;

[0073] FIG. 42A shows an exploded perspective schematic illustration of a heater assembly;

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[0077] FIG. 42B shows a side view schematic illustration of a joule heater, according to some embodiments;

[0078] FIG. 43 shows a final piston design, according to some embodiments;

[0079] FIG. 44 shows a non-limiting cross-sectional schematic diagram of a drug chamber, according to some embodiments;

[0080] FIG. 45A shows a cross-sectional schematic illustration of a heater assembly, according to some embodiments;

[0081] FIG. 45B shows a side view schematic illustration of a joule heater, according to some embodiments;

[0082] FIG. 46 provides a schematic illustration of a closed-loop drug delivery operation, according to some embodiments;

[0083] FIG. 47 shows a non-limiting cross-sectional schematic illustration of a device, according to some embodiments;

[0084] FIGS. 48A-48C show the electrical schematic for mucosa contact detection, jetting direction, and nanofoil activation, according to some embodiments;

[0085] FIG. 49 shows a perspective, schematic illustration of a housing, according to some embodiments;

[0086] FIGS. 50A-50B show a non-limiting device during a test, according to some embodiments;

[0087] FIG. 51 shows the results of a non-limiting benchtop apparatus jet test, according to some embodiments;

[0088] FIGS. 52A-52B show the results of a non-limiting benchtop apparatus jet test, according to some embodiments;

[0089] FIGS. 53A-53B show various timepoints of an article ignition, according to some embodiments;

[0090] FIG. 54A shows simulation results for various burst plate geometries, according to some embodiments;

[0091] FIG. 54B shows a representative ruptured burst plate, according to some embodiments;

[0092] FIG. 55 shows a device with beeswax sealing various nozzles, according to some embodiments;

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[0095] FIGS. 56A-56D show melting of beeswax using an exemplary device at various timepoints, according to some embodiments;

[0096] FIG. 57 shows the difference in recoil behavior of non-limiting devices with and without weight balancing, according to some embodiments;

[0097] FIG. 58 shows non-limiting jetting force measurements of various devices, according to some embodiments;

[0098] FIGS. 59A-59B show the results of dye jetting, according to some embodiments;

[0099] FIG. 60 shows the non-limiting pharmacokinetics of EPO delivery in swine, according to some embodiments; and

[0100] FIGS. 61A-61B show non-limiting jetting force measurements of various devices, according to some embodiments.

[0101] DETAILED DESCRIPTION

[0102] Devices, articles, systems, and methods for on-demand, jet actuated drug delivery are generally described. Jet actuation can, in some embodiments, be advantageous for delivery of drugs past gastric mucosa. The disclosure relates, in some embodiments, to improved methods for jet actuation — in particular, to the use of controlled, byproduct- free ignition to trigger jet actuation without use of pressurized fuel. The improvements provided herein can, in at least some embodiments, provide improved jet strength without compromising the safety of a patient.

[0103] In particular, in some embodiments the disclosure relates to the use of an article configured to generate heat without losing mass. To provide a particular, non-limiting example, the article may be a metallic article configured to generate heat via intermetallic formation and mixing entropy. The heat may then be used to pressurize a device and trigger jet actuation, thereby powering trans-mucosal drug delivery. It should, of course, be understood that this description is given purely by way of example, and that other configurations, uses and advantages are described below in greater detail.

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[0105] No ingestible device is capable of controllable, on-demand drug delivery from an onboard power source. The device described herein represents the next generation of ingestible devices that would allow closed-loop drug delivery that is able to confirm an injection event. The linear actuator is able to convert a small input of electrical energy from a coin-cell battery into a high output of mechanical energy that is capable of injecting liquid therapeutics as a jet directly into gastric mucosa past the gastric wall. The device described herein is the first to leverage reactive aluminium-nickel nanofilms as an energy source for mechanical actuation. These nanofilms are traditionally used as sacrificial heat sources for soldering and electrical fabrication.

[0106] The mechanism described herein has been tested ex vivo with swine gastric tissue, demonstrating successful drug delivery and maintaining structural integrity while not damaging the tissue.

[0107] In one aspect, articles suitable for delivering active pharmaceutical ingredients to subjects are provided. Articles described herein, for example, may have one or more of the following: 1) a design that is ingestible through a capsule; 2) a structure capable of short or long gastric residence; and / or 3) a configuration allowing closed-loop sensing to result in jet actuation, or other drug delivery mechanism, delivered into the GI tract.

[0108] In some embodiments, the article has a particular configuration including a particular size and / or shape such that the article can be administered to a subject (e.g., orally). In some embodiments, the article 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 article adopts a shape and / or size configured for retention (e.g., gastric residence). In some embodiments, the article 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 article 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 article are optimized for safe transient retention of all or a portion of the article in an internal cavity such as the gastric cavity for durations greater than 24 hours, including up to about one year.

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[0111] 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 including, for example, radiation and / or chemical sensing); maintain activity / stability of such therapeutic, diagnostic, and / or enhancement agents in a hostile environment such as the gastric environment for an extended duration; maintain safety with low to no potential for gastric or intestinal obstruction and / or perforation; and / or degrade / dissolve / disassociate into one or more forms configured for passing through a gastrointestinal tract. In certain embodiments, the articles 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, articles, and methods described herein are compatible with subjects, including, but not limited to, humans and non-human animals.

[0112] According to some embodiments, the disclosure relates to devices comprising linear jet actuators configured to direct a jet formed during actuation into a patient. For example, the disclosure may relate to the direction of a jet comprising an active pharmaceutical ingredient (e.g., a therapeutic) to a patient. The device may include a reservoir for the active pharmaceutical ingredient. The reservoir may be fluidically connected to an outlet (e.g., a nozzle) configured for the discharge of the active pharmaceutical ingredient upon actuation by a linear actuator. The linear actuator may be a piston, for example, configured to eject the active pharmaceutical ingredient by being compressed into (or against) the reservoir of the active pharmaceutical ingredient.

[0113] In some embodiments, actuation of the linear actuator is triggered, at least in part, by the use of an article to heat a solvent (e.g., a volatile solvent). For example, the article may be configured to heat the solvent via a chemical reaction of the article. In some embodiments, the chemical reaction of the article does not produce toxic, gaseous, or

[0114] #14417616vl WGS M0925.71050WG00 MIT 25827 - 11 - soluble byproducts. In some embodiments, the device comprises a power supply. The power supply may be configured to initiate the reaction of the article, in some embodiments. For example, the power supply may be configured to initiate the reaction of the article and / or the volatilization of the solvent via a heater (e.g., a Joule heater) powered by the power supply. In some embodiments, the heater acts as an initiator for a more powerful, heat-generating reaction of the article. Suitable articles, devices, and device components are described in greater detail below.

[0115] FIGS. 1-3 present non-limiting schematic illustrations of a device 100, according to some embodiments. FIG. 1 provides a perspective schematic illustration of device 100 comprising housing 101 and outlets 102 (represented as nozzles) configured to permit the jetting of an active pharmaceutical ingredient, according to some embodiments. FIG. 2 provides a cross-sectional schematic illustration of device 100, illustrating how the device operates, according to some embodiments. The device comprises chamber 112 configured to contain a volatile solvent and an article. The article may be configured to volatilize the solvent by heating it, compressing a linear actuator 113 against a reservoir 114 that can contain an active pharmaceutical ingredient (API). Nozzles 102 are separated from reservoir 114 via valves 110 (presented as burst plates, which are configured to burst as the active pharmaceutical ingredient is compressed against the burst plates by the linear actuator). Once the valve(s) open, the openings become fluidically connected to the reservoir, allowing the active pharmaceutical ingredient to jet through the nozzles (e.g., towards a tissue of a patient, not shown).

[0116] In some embodiments, linear actuator 113 may be slidably disposed within the housing of the device such that the linear actuator is disposed between the potential chamber and the reservoir. The reservoir 114 holds the dose of the API until the article is triggered to displace the linear actuator into the reservoir, or otherwise applies a force to eject the API from the reservoir 114 through one or more of the outlets 102 in selective fluid communication with the reservoir through the associated valves. In some instances, it may be desirable to isolate the API within the reservoir from an exterior environment surrounding the device. In such an embodiment, the reservoir 114 may include a metallic or otherwise non-fluid permeable barrier or lining (not illustrated).

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[0118] The barrier or lining may be hermetically sealed by a metallic binding process, such as hot welding, mechanical compression, cold bonding, soldering, electrochemical bonding or other suitable bonding method.

[0119] In some embodiments, the device 100 may include a printed circuit board (PCB) 108 to facilitate electronic communication between the electrical components of the device 100. For example, as shown in FIG. 2, PCB 108 may be electronically connected to a sensor 104, a processor 106, and / or a heater configured to heat an article (not shown). Thus, in some embodiments the sensor 104 and the heater may connected with processor 106 through the PCB. A power source 122 may also be connected to PCB 108. Thus, processor 106 may be able to selectively operate various components of the device using power provided by power source 122. The power supply may be configured to trigger reaction of the article via electrical connection to a heater contacting the article (e.g., via the PCB). Of course, power source 122, sensor 104 and processor 106 need not be disposed on the PCB 108, as these components may be operatively connecting in any suitable manner.

[0120] As noted above, a device 100 may include a plurality of valves 110 that are configured to selectively permit or prevent fluid communication between a reservoir 114 and one or more associated outlets 102 of the device. Specifically, the plurality of valves 110 may be in an initially closed state to prevent the flow of an API through the outlets prior to one or more of the valves being opened. In the open state, the reservoir is in fluid communication with the outlet associated with the one or more open valves, and the API contained in the reservoir 114 may flow through the drug delivery device 100 via the one or more open outlets 102. In some instances, each valve of the plurality of valves 110 may be located along a flow path fluidly connected to either an individual outlet or a plurality of outlets 102. Thus, the drug delivery device 100 may control which outlet, or outlets, of the plurality of outlets 102 dispense API from the reservoir 114.

[0121] One example of a valve that may be used with a drug delivery device is a burst plate. As pressure is applied to the membrane by the pressurized API, the pressurized API may burst the burst plate. In some embodiments, the specific plate to burst may be selected (e.g., by selectively weakening or heating a burst plate intended to burst first, or

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[0124] - 13 - by reinforcing burst plates which should remain intact) in order to achieve selective dispensation of the API through a selected opening. In some embodiments, the burst plate can be selectively weakened using a heater. For example, the burst plate can be selectively weakened using a heater designed to soften the burst plate. The heater can be controlled, in some embodiments, using the processor.

[0125] As previously noted, in some embodiments, a drug delivery device 100 may be configured such that the one or more outlets 102 of a device that are opened using the above described valves 110 may be oriented in a desired direction based at least in part on a sensed input. FIG. 3 shows the cross-section of FIG. 2 as it might rest in a location internal to a patient. As shown, the device may be configured to selectively allow actuation of nozzles oriented towards the patient (e.g., towards tissue 118 of the patient) so that the API is being jetted into the underlying tissue 118 of an anatomical structure of the subject, such as the submucosal tissue or other tissue of a portion of the gastrointestinal tract of a subject. Thus, in some embodiments a device provided herein may deliver an API past the gastric wall, e.g., past the underlying mucosa of the gastric wall for absorption into the bloodstream.

[0126] Specifically, processor 106 opened a selected valve 136 corresponding to the outlet 138, while keeping the remaining valves of the plurality of valves 110 closed, allowing the API from reservoir 114 to jet out of outlet 138 due to the force applied by the linear actuator. Such an arrangement may be desirable due to it being more likely that tissue is underlying the device in a direction parallel to gravity which may help avoid jetting the API into the intraluminal space within the GI tract away from the mucosa. The bold arrow labeled “g” indicates the direction of local gravity, the primary force dictating the resting configuration of the device, according to some embodiments.

[0127] FIGS. 4-7 provide additional, non-limiting schematic illustrations of a nonlimiting device, according to some embodiments. FIG. 4 shows a CAD model of ingestible device, inside view, according to some embodiments. FIG. 5 shows CAD model of ingestible device, outside view (180 degrees rotated from model in FIG. 4). FIG. 6 shows a CAD model zoomed in view on nozzle. The nozzle includes a heater, shown, configured to soften a burst plate of the nozzle (e.g., to soften a beeswax burst

[0128] #14417616vl WGS M0925.71050WG00 MIT 25827 - 14 - plate). FIG. 7 shows a CAD model of ingestible device, exploded view, according to some embodiments.

[0129] FIG. 8 provides a non-limiting exploded perspective illustration of an alternative device, according to some embodiments.

[0130] According to some embodiments, articles for heat generation are provided. An article may be configured to generate jet actuation of the active pharmaceutical ingredient by generating heat. The article may generate heat during a chemical reaction of the article. The heat generating chemical reaction of the article may be a masspreserving chemical reaction, which may be advantageous because it ensures that the article does not emit potentially toxic byproducts. For example, according to some embodiments, the mass-preserving chemical reaction is formation of an intermetallic and the heat produced is both entropy-generated and enthalpy-generated. As another example, in some embodiments the mass-preserving chemical reaction is a mixing reaction, and the heat produced is the heat of mixing entropy. In some embodiments, the chemical reaction is not mass-preserving. For example, in some embodiments the chemical reaction is a decomposition reaction, possibly via a catalyst, resulting in the production of gas.

[0131] The reaction of the article may be triggered by the device. For example, the reaction of the article may be triggered by an external heat source (e.g., an electrically powered heater or a secondary reaction). The external heat source may act as an initiator for the reaction of the article. In some embodiments, the reaction of the article is triggered by an external power source. For example, in some embodiments, the reaction of the article is triggered by Joule heating of the article itself, e.g., in order to exploit the resistivity of the article to heat the article. The reaction of the article may be self- sustaining (e.g., because progression of the reaction in one location may generate sufficient heat to initiate the reaction at another location of the article).

[0132] The article may be designed to generate sufficient heat to volatilize a solvent. For example, in some embodiments, the article may be configured, to heat a suitable mass of the solvent in the chamber (e.g., 200 pL of ethanol) to a suitable temperature (e.g., greater than or equal to 500 K). In some embodiments, the article is configured to generate heat in an amount (in units of thermal energy per mass of the article) of greater

[0133] #14417616vl WGS M0925.71050WG00 MIT 25827 - 15 - than or equal to 2 J / g, greater than or equal to 4 J / g, greater than or equal to 6 J / g, greater than or equal to 8 J / g, greater than or equal to 10 J / g, greater than or equal to 12 J / g, greater than or equal to 14 J / g, greater than or equal to 16 J / g, or greater than or equal to 18 J / g. In some embodiments, the article is configured to generate heat in an amount of less than or equal to 20 J / g, less than or equal to 18 J / g, less than or equal to 16 J / g, less than or equal to 14 J / g, less than or equal to 12 J / g, less than or equal to 10 J / g, less than or equal to 8 J / g, less than or equal to 6 J / g, or less than or equal to 4 J / g. Combinations of these ranges are also possible (e.g., greater than or equal to 2 J / g and less than or equal to 20 J / g, or greater than or equal to 5 J / g and less than or equal to 10 J / g). Other ranges, both higher and lower than those described above, are also possible, as the disclosure is not so limited.

[0134] In some embodiments, the reaction of the article uses a metallic reactants. For example, the reaction of the article may be a solid- solution forming reaction, in some embodiments. In some embodiments, the reaction of the article is an intermetallic- forming reaction.

[0135] The article may be formed from a plurality of metals (e.g., a plurality of metal reactants). For example, the article may comprise metallic aluminum (e.g., pure aluminum or an aluminum alloy) and / or metallic nickel (e.g., pure nickel or a nickel alloy), and / or titanium (e.g., pure titanium or a titanium alloy), and / or palladium (e.g., metallic palladium or a palladium alloy), and / or silicon (e.g., amorphous silicon), and / or boron. For example, in some embodiments, the article comprises pure aluminum and pure nickel. In some embodiments, the article comprises pure aluminum and pure titanium. In some embodiments, the article comprises pure titanium and amorphous silica. In some embodiments, the article comprises pure titanium with boron. And in some embodiments, the article comprises pure aluminum and pure titanium.

[0136] In some embodiments, the article comprises a first metal and a second metal in a configuration suitable for facilitating the reaction of the first metal with the second metal. For example, in some embodiments the article is a multilayered article. The article may comprise one or more layers of a first metal and one or more layers of a second metal. The layers may be laminated. In some embodiments, at least some of the layers of the first metal are alternated with at least some of the layers of the second

[0137] #14417616vl WGS M0925.71050WG00 MIT 25827 - 16 - metal, e.g., in the form of an alternating metallic bilayer of the first metal and the second metal.

[0138] The term “layer” generally refers to an arrangement of material that, when the material is laid flat, has a thickness dimension, a depth dimension that is perpendicular to the thickness dimension, and a width dimension that is perpendicular to both the thickness dimension and the depth dimension, where the lengths of each of the depth dimension and the width dimension are at least 3 times the length of the thickness dimension. In some embodiments, the length of the depth dimension of the layer is at least 5 times, at least 10 times, at least 25 times, at least 50 times, at least 100 times, at least 500 times, or at least 1000 times the length of the thickness dimension of the layer. In some embodiments, the length of the width dimension of the layer is at least 5 times, at least 10 times, at least 25 times, at least 50 times, at least 100 times, at least 500 times, or at least 1000 times the length of the thickness dimension of the layer. The width and depth dimensions of a layer define its major surfaces.

[0139] The article may have any of a variety of suitable thicknesses (in the direction of the thicknesses of the layers of the nanolaminate). In some embodiments, the article has a thickness of greater than or equal to 20 microns, greater than or equal to 25 microns, greater than or equal to 30 microns, greater than or equal to 35 microns, greater than or equal to 40 microns, greater than or equal to 45 microns, greater than or equal to 50 microns, greater than or equal to 55 microns, greater than or equal to 60 microns, greater than or equal to 65 microns, greater than or equal to 70 microns, greater than or equal to 75 microns, greater than or equal to 80 microns, greater than or equal to 85 microns, greater than or equal to 90 microns, or greater than or equal to 95 microns. In some embodiments, the article has a thickness of less than or equal to 100 microns, less than or equal to 95 microns, less than or equal to 90 microns, less than or equal to 85 microns, less than or equal to 80 microns, less than or equal to 75 microns, less than or equal to 70 microns, less than or equal to 65 microns, less than or equal to 60 microns, less than or equal to 55 microns, less than or equal to 50 microns, less than or equal to 45 microns, less than or equal to 40 microns, less than or equal to 35 microns, less than or equal to 30 microns, or less than or equal to 25 microns. Combinations of these ranges are also possible (e.g., greater than or equal to 20 microns and less than or equal to 100 microns,

[0140] #14417616vl WGS M0925.71050WG00 MIT 25827 - 17 - greater than or equal to 30 microns and less than or equal to 70 microns, or greater than or equal to 40 microns and less than or equal to 60 microns). Other ranges, both higher and lower than those described above, are also possible, as the disclosure is not so limited.

[0141] The article may include a first metal and a second metal in any of a variety of suitable ratios. In some embodiments, the article comprises a first metal (e.g., aluminum) and a second metal (e.g., nickel) in a molar ratio of greater than or equal to 40:60, greater than or equal to 45:55, greater than or equal to 50:50, or greater than or equal to 55:45. In some embodiments, the article comprises a first metal (e.g., aluminum) and a second metal (e.g., nickel) in a molar ratio of less than or equal to 60:40, less than or equal to 55:45, less than or equal to 50:50, or less than or equal to 45:55. Combinations of these ranges are also possible (e.g., greater than or equal to 40:60 and less than or equal to 60:40, or greater than or equal to 45:55 and less than or equal to 55:45). Other ranges, both higher and lower than those described above, are also possible, as the disclosure is not so limited.

[0142] The article may comprise any of a variety of suitable numbers of metal layers, depending on the embodiment. In some embodiments, an article comprises greater than or equal to 2 metal layers, greater than or equal to 5 metal layers, greater than or equal to 10 layers, greater than or equal to 20 layers, greater than or equal to 30 layers, greater than or equal to 40 layers, greater than or equal to 50 layers, greater than or equal to 60 layers, greater than or equal to 70 layers, greater than or equal to 80 layers, or greater than or equal to 90 layers. In some embodiments, an article comprises less than or equal to 100 layers, less than or equal to 90 layers, less than or equal to 80 layers, less than or equal to 70 layers, less than or equal to 60 layers, less than or equal to 50 layers, less than or equal to 40 layers, less than or equal to 30 layers, less than or equal to 20 layers, or less than or equal to 10 layers. Combinations of these ranges are also possible (e.g., greater than or equal to 0 layers and less than or equal to 100 layers, or greater than or equal to 2 layers and less than or equal to 20 layers). Other ranges, both higher and lower than those described above, are also possible, as the disclosure is not so limited.

[0143] In some embodiments, it is advantageous for the article to have a relatively low thermal conductivity, e.g., to ensure that heat remains localized long enough to keep the

[0144] #14417616vl WGS M0925.71050WG00 MIT 25827 - 18 - reaction of the article self-sustaining. The article may have any of a variety of suitable thermal conductivities. In some embodiments, the article has a thermal conductivity of greater than or equal to 20 W / m-K, greater than or equal to 25 W / m-K, greater than or equal to 30 W / m-K, greater than or equal to 35 W / m-K, greater than or equal to 40 W / m- K, greater than or equal to 45 W / m-K, greater than or equal to 50 W / m-K, greater than or equal to 55 W / m-K, greater than or equal to 60 W / m-K, greater than or equal to 65 W / m- K, greater than or equal to 70 W / m-K, or greater than or equal to 75 W / m-K. In some embodiments, the article has a thermal conductivity less than or equal to 80 W / m-K, less than or equal to 75 W / m-K, less than or equal to 70 W / m-K, less than or equal to 65 W / m-K, less than or equal to 60 W / m-K, less than or equal to 55 W / m-K, less than or equal to 50 W / m-K, less than or equal to 45 W / m-K, less than or equal to 40 W / m-K, less than or equal to 35 W / m-K, less than or equal to 30 W / m-K, or less than or equal to 25 W / m-K. Combinations of these ranges are also possible (e.g., greater than or equal to 20 W / m-K and less than or equal to 80 W / m-K, or greater than or equal to 30 W / m-K and less than or equal to 50 W / m-K). Other ranges, both higher and lower than those described above, are also possible, as the disclosure is not so limited. A configuration comprising alternating metallic layers may be advantageous for promoting the reaction of the two metals together, for example, by ensuring that atoms of the first metal can rapidly diffuse to reach atoms of the second metal when heated. Without wishing to be bound by any particular theory, it may be advantageous to use metallic nanolayers for this purpose (e.g., alternated metallic nanolayers that form a metallic nanolaminate), again because nanolayers may place atoms of the first metal in close proximity to atoms of the second metal in at least some embodiments.

[0145] FIG. 9 provides a non-limiting schematic cross-section of an article 903 comprising a first metal (black layers) and a second metal (white layers), wherein the article is configured to heat a solvent 905 in a chamber 901. As shown, the reaction of article 903 destroys the nanolamination by mixing the two metals (to form a solid solution or an intermetallic, for example), volatilizing some of solvent 905 and / or causing thermal expansion of solvent 905 (as indicated by the reduced solvent level in chamber 901) and increasing the pressure of the chamber (as indicated by the change from initial pressure P to new pressure P+AP. It should, of course, be understood that

[0146] #14417616vl WGS M0925.71050WG00 MIT 25827

[0147] - 19 - the change in pressure may be used, in some embodiments, to drive a linear actuator (e.g., a piston) as shown in FIG. 2. The reaction exemplified in FIG. 9 is masspreserving, since the metal-metal reaction does not produce byproducts that the article can shed.

[0148] It should, of course, be understood that where additional heat is desired, more than one article may be used. For example, a plurality of articles may be used to actuate the jet, in some embodiments. E.g., in some embodiments, at least 5, at least 10, or at least 20 articles may be used, as the disclosure is not so limited.

[0149] In addition to the article, a device may include any of a variety of suitable additional components. For example, in some embodiments, the device comprises a power supply.

[0150] Any of a variety of suitable power supplies may be used, and the power supply may be configured to perform any of a variety of suitable functions. For example, in some embodiments, the power supply is a battery. The battery may have any of a variety of battery chemistries known to those of ordinary skill, as the disclosure is not so limited. For example, the battery may be a lithium-ion battery. The battery may be relatively small (e.g., may have a form factor suitable for use in a pill- or capsule-sized device). For example, in some embodiments, the battery is a coin cell battery or a microbattery.

[0151] The battery may provide power to one or more device components. For example, the battery can power a sensor, an on-board processor, and / or a heater of the device, according to some embodiments. In some embodiments, use of the battery to power a heater may be particularly advantageous.

[0152] According to some embodiments, the device comprises a heater. The heater may be configured for Joule heating. For example, in some embodiments, the heater is a nichrome heater. Of course, it should be understood that in some embodiments the device does not comprise a heater, e.g., where the resistance of the article is used to generate heat by passing current through the article.

[0153] The heater may be configured for any of a variety of suitable power dissipations. For example, the heater may be configured for a power input of 100-400 mW, according to some embodiments. In some embodiments, a heater and / or an article is configured for a power input of greater than or equal to 100 mW, greater than or equal to 150 mW,

[0154] #14417616vl WGS M0925.71050WG00 MIT 25827 - 20 - greater than or equal to 200 mW, greater than or equal to 250 mW, greater than or equal to 300 mW, or greater than or equal to 350 mW. In some embodiments, a heater and / or an article is configured for a power input of less than or equal to 400 mW, less than or equal to 350 mW, less than or equal to 300 mW, less than or equal to 250 mW, less than or equal to 200 mW, or less than or equal to 150 mW. Combinations of these ranges are also possible (e.g., greater than or equal to 100 mW and less than or equal to 400 mW, or greater than or equal to 150 mW and less than or equal to 350 mW). Other ranges, both higher and lower than those described above, are also possible, as the disclosure is not so limited. It should, of course, be understood that the device may be configured to supply one of the foregoing powers to the heater and / or the article.

[0155] FIG. 10 provides a non-limiting, schematic top-view illustration of a heater suitable for heating an article, according to some embodiments. Further, FIG. 10 shows a thermal simulation of the heater (also sometimes referred to herein as a heating element), according to some embodiments. As shown in FIG. 10, in some embodiments, the heater comprises a serpentine heating element configured to concentrate current within a narrower area, thereby increasing heat concentration at the element during use of the heater. The heating element may be made from any of a variety of suitable materials.

[0156] FIG. 11 shows the heater of FIG. 10, superimposed on an article (schematically exemplified as a nanolaminated foil (a “nanofoil”) to illustrate heating of the article by the heater. FIG. 12 shows a non-limiting perspective schematic illustration of the nichrome Joule heater with the nanofilm trigger piece, according to some embodiments.

[0157] In some aspects, the disclosure relates to methods of making the devices described herein. FIGS. 13A-13E show an assembly process of nichrome Joule heater with a nanolaminated foil, according to some embodiments.

[0158] The heater may, in some embodiments, be configured to heat the article via direct contact with the article. However, in some embodiments the joule heater does not directly contact the article. In some embodiments, for example, it may be advantageous for the device to comprise a thermal paste configured for relatively high thermal conductivity (e.g., the paste may be a thermal conductor) and relatively high electrical

[0159] #14417616vl WGS M0925.71050WG00 MIT 25827 - 21 - resistance (e.g., the paste may be an electrical insulator). The paste may convey heat from the heater to the article (e.g., to initiate reaction of the article).

[0160] In some embodiments, the device does not comprise a heater. For example, in some embodiments, the device is configured to heat the article using, e.g., the electrical resistance of the article. According to some embodiments, the article is Joule heated. For example, in some embodiments, the device is configured to pass a current through the article, e.g., to resistively heat the article to a temperature that initiates its chemical reaction. The resistive heating of the article may initiate the reaction of the article in much the same way that the resistive heating of a Joule heater may be used to initiate the reaction of the article. In some embodiments, the article has comparatively lower electrical resistance than a Joule heater, meaning that dissipation of thermal energy during Joule heating is less efficient. However, the use of the article as a heater may, advantageously, simplify design, manufacturing, and / or assembly of the device, and may thus provide engineering advantages outweighing these inefficiencies. Whether a Joule heater or direct Joule heating of the article is used, suitable components (e.g., electrical leads electrically connecting the heater and / or the article to the power supply) may also be included in the article.

[0161] The chamber configured to contain the solvent and / or the article(s) may be suitably designed to contain the solvent and / or the articles. For example, the chamber may be a pressure vessel. The chamber may be configured to retain a suitable solvent volume in addition to the articles, and the chamber size and / or solvent volume may be chosen in order to ensure that a linear actuator connected thereto is capable of jetting an active pharmaceutical ingredient with a sufficient flow rate and / or pressure. Likewise, the chamber may be configured to retain the solvent and / or the articles even at the high temperatures that may be produced during triggering of the article, depending on the embodiment.

[0162] The walls of the chamber may be made from any of a variety of materials suitable for use with the pressures and temperatures of the device. For example, the walls may comprise steel (e.g., stainless steel), titanium, or brass, depending on the embodiment. The walls may be configured to withstand the pressure and the temperature of the volatilized solvent and / or the articles inside the chamber.

[0163] #14417616vl WGS M0925.71050WG00 MIT 25827 - 22 -

[0164] At least a portion of a boundary of the chamber may be formed by a linear actuator. Any of a variety of linear actuators may be used. For example, the linear actuator may be a piston, according to some embodiments. The linear actuator may be configured to be actuated by a change in the pressure of the chamber (e.g., of the sort that may be induced by volatilization of the solvent therein). In some embodiments, the linear actuator is configured to slide on one or more O-rings (e.g., rubber O-rings), though of course other linear actuators and indeed other pistons are also possible.

[0165] The linear actuator may be configured to pressurize a reservoir for an active pharmaceutical ingredient. For example, a linear actuator may form at least a portion of the boundary of the reservoir, or else may be configured to compress at least a portion of the boundary of the reservoir (e.g., by compressing a flexible or foldable wall of the reservoir to reduce the volume of the reservoir). In some embodiments, pressure of the linear actuator on the reservoir is configured to eject the active pharmaceutical ingredient (e.g., the therapeutic) from an opening of the device (e.g., a nozzle of the device).

[0166] The reservoir may be of any of a variety of suitable types. For example, in some embodiments, the reservoir is configured to hold a liquid-state active pharmaceutical ingredient. However, it should, of course, be understood that other active pharmaceutical ingredients can also be stored in and / or jetted from the reservoir. Thus, the active pharmaceutical ingredient could be a solid powder or an alginated-coated cell therapeutic, to provide a few non-limiting examples. The reservoir may, like the chamber, have walls suitable for containing the pressure of the reservoir. Such walls may be advantageous for facilitating the directed flow of mass through burst plates and towards openings of the device.

[0167] The reservoir may have any of a variety of suitable geometries, and may be configured to retain an active pharmaceutical ingredient. Although the reservoir may be configured to retain the active pharmaceutical ingredient, this is not a requirement of all reservoirs. In some embodiments, the reservoir does not comprise an active pharmaceutical ingredient. For example, the reservoir may be empty, as the disclosure is not so limited.

[0168] At least a portion of the boundary of the reservoir may be formed by one or more burst plates (e.g., as illustrated in FIG. 2). The burst plate may be comparatively thin

[0169] #14417616vl WGS M0925.71050WG00 MIT 25827 - 23 -

[0170] (e.g., relative to the walls of the reservoir). In some embodiments, a burst plate is configured to rupture when the chamber reaches a desired pressure. For example, the materials, thickness, and lateral dimension of the burst plate may be chosen to ensure that the burst plate fails when subjected to a target pressure. Any of a variety of suitable materials may be used to form the burst plate. For example, in some embodiments, the burst plate comprises aluminum and / or stainless steel.

[0171] The chamber may (e.g., upon rupture of a burst plate) be fluidically connected to one or more openings (e.g., nozzles). In some embodiments, the openings are always open. However, in some embodiments, at least some openings may be selectively sealed (e.g., using valves) so that a jet only passes through selectively opened openings. Thus, in some embodiments the device may be configured to selectively jet an active pharmaceutical ingredient in a desired direction (e.g., towards a patient) without jetting the pharmaceutical ingredient in another direction.

[0172] The opening(s) may have an appropriate size. For example, an opening may have a maximum transverse dimension (e.g., a diameter) of about 0.4 mm. In some embodiments, the opening may be sized to jet the active pharmaceutical ingredient at any of a variety of desired initial velocities. For example, in some embodiments, the initial velocity of a pharmaceutical ingredient leaving an opening in situ within a subject is greater than or equal to 100 m / s (e.g., is about 130 m / s).

[0173] Openings (e.g., nozzles) may be integrated openings connected to the same reservoir of an active pharmaceutical ingredient. It should, of course, be appreciated that multiple reservoirs and / or multiple linear actuators could also be used, depending on the embodiment, as the disclosure does not require the openings to be integrated with the same reservoir. In some embodiments, the device is configured for selective drug delivery in a desired direction, e.g., by jetting the active pharmaceutical ingredient only through nozzles with a desired orientation within the patient. For example, the device may be configured to jet the pharmaceutical ingredient towards gastric tissue.

[0174] In some embodiments, the device is configured to determine the position and / or orientation of 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.

[0175] #14417616vl WGS M0925.71050WG00 MIT 25827 - 24 -

[0176] Non-limiting examples of suitable sensors for use with the structures and methods described herein include light sensors (e.g., light-reflectance sensors with or without LEDs), impedance sensors (e.g., resistive or capacitive impedance sensors) 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), radiation sensors, chemical toxin sensors, and environmental sensors (e.g., pH, biologic concentration, chemical concentration).

[0177] 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.

[0178] 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 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

[0179] #14417616vl WGS M0925.71050WG00 MIT 25827 - 25 - those cores may constitute a processor. Though, a processor may be implemented using circuitry in any suitable format.

[0180] 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.

[0181] 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.

[0182] 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 enabling 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 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.

[0183] 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

[0184] #14417616vl WGS M0925.71050WG00 MIT 25827 - 26 - also may be compiled as executable machine language code or intermediate code that is executed on a framework or virtual machine.

[0185] 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., device 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.

[0186] 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 distributed in a modular fashion amongst a number of different computers or processors to implement various aspects of the present disclosure.

[0187] Computer-executable instructions may be in many forms, such as program modules, executed by one or more computers or other devices. Generally, program

[0188] #14417616vl WGS M0925.71050WG00 MIT 25827 - 27 - 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.

[0189] 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.

[0190] 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.

[0191] Any of a variety of solvents may be used for pressure generation in the context of a device provided herein. It should generally be understood that the term “solvent” here does not necessarily connote the presence of a solvent — rather, the solvent could be a pure organic solvent such as ethanol. The solvent may be volatile (e.g., easily capable of forming a gas or supercritical fluid), in some embodiments. In some embodiment, the solvent is safe for use in the human body. For example, the use of ethanol may be relatively advantageous, since ethanol may be metabolized by the body with comparative safety (relative to other organic solvents).

[0192] The active pharmaceutical ingredient may have a solid form (e.g., may be or may be comprised by a solid powder). The active pharmaceutical ingredient may have a liquid form. The active pharmaceutical ingredient may have the form of a suspension, with solid particulates in a dispersion medium. For example, the active pharmaceutical composition may comprise a dissolved active pharmaceutical ingredient. In some embodiments, the therapeutic is gel-coated (e.g., an alginate-coated therapeutic).

[0193] 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

[0194] #14417616vl WGS M0925.71050WG00 MIT 25827 - 28 - 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 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). In some embodiments, the API is a biologic. In some embodiments, the API is a monoclonal antibody. In some embodiments, the API is mRNA (e.g., mRNA contained within lipid nanoparticles).

[0195] 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.)

[0196] #14417616vl WGS M0925.71050WG00 MIT 25827 - 29 -

[0197] (the “Orange Book"). Examples of drugs approved for human use are listed by the FDA under 21 C.F.R. §§ 330.5, 331 through 361, and 440 through 460, incorporated herein by reference; drugs for veterinary use are listed by the FDA under 21 C.F.R. §§ 500 through 589, incorporated herein by reference. In certain embodiments, the therapeutic agent is a small molecule. Exemplary classes of therapeutic agents include, but are not limited to, analgesics, anti-analgesics, anti-inflammatory drugs, antipyretics, antidepressants, antiepileptics, antipsychotic agents, neuroprotective agents, anti-proliferatives, such as anti-cancer agents, antihistamines, antimigraine drugs, hormones, prostaglandins, antimicrobials (including antibiotics, antifungals, antivirals, antiparasitics), antimuscarinics, anxioltyics, bacteriostatics, immunosuppressant agents, sedatives, hypnotics, antipsychotics, bronchodilators, anti-asthma drugs, cardiovascular drugs, anesthetics, anti-coagulants, inhibitors of an enzyme, steroidal agents, steroidal or nonsteroidal anti-inflammatory agents, corticosteroids, dopaminergics, electrolytes, gastrointestinal drugs, muscle relaxants, nutritional agents, vitamins, parasympathomimetics, stimulants, anorectics and anti-narcoleptics. Nutraceuticals can also be incorporated into the drug delivery article. These may be vitamins, supplements such as calcium or biotin, or natural ingredients such as plant extracts or phytohormones.

[0198] 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).

[0199] 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.

[0200] In certain embodiments, the therapeutic agent is present in the article in an amount greater than or equal to 1 gram, greater than or equal to 2 grams, greater than or

[0201] #14417616vl WGS M0925.71050WG00 MIT 25827 - 30 - 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 article 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. 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.

[0202] In some embodiments, the articles 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 article 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).

[0203] In certain embodiments, the therapeutic agent is present in the article at a concentration such that, upon release from the article, the therapeutic agent elicits a therapeutic response.

[0204] In some embodiments, a subject may demonstrate health benefits, e.g., upon administration of the article (e.g., treatment for radiation exposure, treatment for chemical toxin exposure).

[0205] #14417616vl WGS M0925.71050WG00 MIT 25827 - 31 -

[0206] 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; com 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.

[0207] 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.

[0208] 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

[0209] #14417616vl WGS M0925.71050WG00 MIT 25827 - 32 - compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0210] In some embodiments, the article may be configured to adjust various parameters based on physiological and / or external metrics. For example, in some embodiments, the article is configured to adjust the rate and / or amount of a pharmaceutical agent released from the article (e.g., stored within one or more reservoirs associated with the article) 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 article. In some embodiments, the article adjusts the rate and / or amount of a pharmaceutical agent released from the article in response to an input from the user and / or a signal from the sensor. In some embodiments, the article 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 article.

[0211] A device provided herein may have any of a variety of suitable form factors. For example, the device may have the form factor of a cylinder or pill. In some embodiments, the device has a suitable diameter for oral administration. For example, the device may have a diameter of less than or equal to 10 mm. In some embodiments, the pill has a suitable height for oral administration. For example, the pill may have a height of less than or equal to 21 mm.

[0212] The following examples are intended to illustrate certain embodiments of the present disclosure, but do not exemplify the full scope of the disclosure.

[0213] EXAMPLE 1

[0214] Presented herein is an electrically-triggered, single-use linear actuator with high power density. The power density is an order of magnitude higher than what is achievable by conventional solenoids and motors with similar form factors.

[0215] FIG. 14 shows the design of a linear actuator for drug delivery described herein. The green chamber shows the location of the ignition mechanism, which holds the Joule heating element. The blue chamber shows the location of the ignitable aluminium-nickel

[0216] #14417616vl WGS M0925.71050WG00 MIT 25827 - 33 - nanofilm and the ethanol. When the ethanol heats up, it fractures a thin aluminium burst plate in the center. The pressure is released and pushes on the orange piston which slides on rubber O-rings. This orange piston creates the linear motion. In summary, the device converts a small impulse of electrical energy from a coin-cell battery to a high amount of thermal energy via the aluminium-nickel nanofilm, which is then converted to mechanical energy in the piston.

[0217] FIG. 15 shows a design of the electrical triggering mechanism that triggers the ignition of the aluminium-nickel nanofilm. A miniature Joule heating meander is laser cut from graphite, nichrome, or tantalum. This meander is placed on a small piece of laser cut aluminium-nickel nanofilm, which has the shape of a needle protruding from a rectangle. In between the Joule heating element and the nanofilm is a thin thermal paste that is thermally conductive but electrically insulating. This allows the successful ignition of the aluminium-nickel nanofilm.

[0218] EXAMPLE 2

[0219] The actuator described herein can be incorporated into an ingestible device for oral drug delivery via injection into the gastric mucosa. FIG. 16 shows the device attached to a drug reservoir that is loaded with water. The drug reservoir is attached to a nozzle that is 0.4mm in diameter. High-speed photography demonstrates that the device delivers 150 pl of a liquid therapeutic with an initial velocity of 130 m / s.

[0220] FIG. 17 shows the ex vivo result using the linear actuator for drug delivery via jetting into porcine gastric mucosa. The mucosa was harvested directly after euthanasia. 150 pl methylene blue dye was loaded into the device. Visually, the entirely of the dye was deposited beneath the gastric wall and into the underlying mucosa. An incision into the tissue confirmed that the dye was successful deposited into the mucosa.

[0221] FIG. 18 shows the characterization of the linear actuator’s force output when it is used to eject a liquid jet. This characterization was performed with 150 pl of water loaded into the device. The results shows that a peak force of -0.8N was achieved. The results also show that injection was completed in -0.03 seconds.

[0222] EXAMPLE 3

[0223] #14417616vl WGS M0925.71050WG00 MIT 25827 - 34 -

[0224] This example describes manufacture and testing of non-limiting devices. Pressure vessels of varying size were 3D printed on a Formlabs Form 3 or a Stratasys printer.

[0225] The pressure vessel shape was chosen as being approximately cylindrical in order to minimize differences in the amount of Al-Ni nano-laminate per unit volume of liquid between pressure vessel sizes. The volume of the pressure vessel was changed by varying the height of the pressure vessel.

[0226] A TE Connectivity FX29 load cell was used to measure the force generated in the pressure vessel. This load cell allowed the measurement of the pressure vessel without changing the volume of the vessel. The load cell measured force with near zero displacement. The load cell was mechanically connected to the pressure vessel via a piston with a diameter of approximately seven millimeters. The load cell was connected to an Arduino for data collection via an amplification circuit. The calibration curve of the load cell with the linear region shown can be seen in FIG. 19.

[0227] The pressure in the pressure vessel applied force to the piston head and transferred the force to the load cell; a known piston head area allowed pressure determination on the inside of the pressure vessel by dividing applied force by the piston area head. The device construction is presented in the non-limiting schematic crosssection illustrated in FIG. 20A and photographed in FIG. 20B.

[0228] The test device also comprised a top cap to house an Al-Ni article. The Al-Ni article was a nano-laminated foil extending from the top of the pressure vessel and into the electrodes of a sparker, which was used to initiate the reaction thus propagating the reaction and inputting thermal energy into the pressure vessel. The trigger, without the top cap installed can be seen in FIG. 21A. Because the sparker uses a large AC voltage to produce the spark to initiate the Al-Ni reaction, the amplification circuit and the Arduino data collection device were kept in an electrostatic discharge (ESD) bag to prevent electromagnetic interference. The impact of the sparker on the unshielded Arduino and the associated circuits are presented in FIG. 21B, which shows the applied force versus time.

[0229] The tested pressure vessel sizes are shown in Table 1. The radius of all approximately cylindrical pressure vessels was 7mm.

[0230] #14417616vl WGS M0925.71050WG00

[0231] MIT 25827 - 35 -

[0232] Table 1: Tested IPA chamber sizes

[0233] The Al-Ni nano-laminate foil was cut into rectangular pieces such that the width of the rectangle was approximately equal to the diameter of the cylindrical pressure vessel and the length was approximately equal to the height of the pressure vessel. The parameters used to cut the reactive nano-layered foil with a LPKF R4 laser cutting machine are presented in Table 2.

[0234] Table 2: Laser Parameters to Cut Al-Ni

[0235] Once the pressure vessel was printed and the Al-Ni reactive foil was cut, the process pressure vessel preparation and testing were performed as follows:

[0236] 1. Threads were applied to the bottom of the pressure vessel with a tap; thread brass cylinder onto threads on bottom of pressure vessel

[0237] 2. With appropriate O-ring lubrication, the piston was inserted into the open end of the cylinder. The piston head was seated onto bottom of the pressure vessel. The piston extended from the bottom of the cylinder.

[0238] 3. The end of the cylinder opposite from the pressure vessel was threaded onto the load cell housing such that the exposed end of the piston made contact with the load cell. To verify positive contact, the Arduino output was read and the cylinder was threaded until deflection was seen in load cell readout.

[0239] #14417616vl WGS M0925.71050WG00 MIT 25827 - 36 -

[0240] 4. Through the top of the pressure vessel, the pressure vessel was filled with a volatile liquid (isopropyl alcohol, IPA) with a syringe.

[0241] 5. Air bubbles were removed. The device was placed in a desiccator and vacuum was used to remove air bubbles from the pressure vessel through the opening in the top of the pressure vessel.

[0242] 6. The Al-Ni nano-laminate foil was added to the pressure vessel (10 pieces) with one trigger piece extending from the pressure vessel (for a total of 11 pieces) far enough to be impacted by a sparker mechanism in the top cap.

[0243] 7. A UV cure glue, was caulked around the trigger piece of reactive nanolaminate foil to seal the pressure vessel. The glue was cured with a UV light.

[0244] 8. The top cap was fastened and aligned such that the trigger piece of foil was between the electrodes of the sparker, onto the pressure vessel with five nuts and five bolts.

[0245] 9. The expected starting output was verified on Arduino.

[0246] 10. The exothermic reaction of the Al-Ni foil was initiated with the sparker; record data.

[0247] EXAMPLE 4

[0248] This example demonstrates how, and to what extent, the forces through the piston stroke cycle could be associated to an ethanol phase change diagram. The mass of the system was assumed to be conserved, water was assumed to be incompressible, and displacements in the assembly materials from pressure were ignored for the purposes of prediction. Based on a prediction that the system would pass through the liquid-vapor region rather than behave as a supercritical fluid, the piston was expected to have constant pressure through the stroke length, but experimental observation was used to gain insight to the effects of thermodynamic and other inefficiencies. The pressure vessel design of Example 3 was used to model the behavior of the pressure vessel prior to burst plate shim failure. In order to characterize the work output, the piston was allowed to move within a clear piston 3D printed with an internal diameter of 6.32 mm and used in place of the brass cylinder so that the position of the piston could be recorded. To allow the piston to move, it was not used to mechanically join the pressure

[0249] #14417616vl WGS M0925.71050WG00

[0250] MIT 25827

[0251] - 37 - vessel to the load cell to ensure that the volume of the pressure vessel did not change. The piston’s position was recorded through the stroke length with a Phantom VEO-E 340L high speed camera. A nozzle of diameter 0.4 mm was fixed to end of the cylinder opposite the pressure vessel. The pressure vessel, was loaded with ethanol and the cylinder was loaded with water with the piston separating the pressure vessel from the water loaded cylinder. An aluminum burst plate shim with a thickness of 0.002 inches was installed between the pressure vessel and the piston to ensure the pressure vessel pressurized as intended in the desired end state device. The high-speed camera was used to record the position and time of the piston at a 50-frame interval. The position and time data were used to calculate the pressure on the piston using fluid dynamics. The equation used to estimate the pressure applied to the piston came from rearranging Bernoulli’s equation as presented in Equation (1): where, because of conservation of mass and considering water as incompressible, it could be assumed that: where, m is the mass flow rate of fluid, therefore where A is the cross-sectional area, and, again because of conservation of mass and incompressibility assumptions, it can be said Vcyimder could be determined from the piston position data recorded on the high-speed camera. FIG. 22 presents a non-limiting schematic cross-section of the experimental setup. FIG. 23 presents a non-limiting photograph of the experimental setup. Two pressure vessel sizes were used: 0.18 mL of ethanol and 0.165 mL of ethanol (not including the volume of nano-laminate foil).

[0252] The work output experiment was performed by using the following steps:

[0253] 1. Threads were applied to the bottom of the pressure vessel with a tap.

[0254] #14417616vl WGS M0925.71050WG00 MIT 25827 - 38 -

[0255] 2. The Al-Ni nano-laminate foil was loaded into the top pressure vessel (10 pieces) with one trigger piece extending from the pressure vessel (for a total of 11 total pieces) far enough to be impacted by the sparker ignition mechanism.

[0256] 3. UV cure glue was used to seal the top of pressure vessel leaving the smallest possible penetration to accommodate the trigger and allow the nano-laminate reaction to enter the pressure vessel. The glue was cured with a UV light.

[0257] 4. Ethanol was loaded in through the bottom of the pressure vessel. Loading the volatile liquid in through the bottom of the bottom of the pressure vessel helped minimize the formation of bubbles in the pressure vessel and avoided the need to vacuum remove bubbles.

[0258] 5. With appropriate O-ring lubrication, insert the piston into the cylinder. A small gauge needle was placed between the O-ring and the side of the piston wall to vents air past the piston and prevent air bubbles from getting trapped between the piston and the burst plate shim and the pressure vessel.

[0259] 6. The burst plate shim was installed.

[0260] 7. The clear cylinder with the piston was installed onto the pressure vessel. The piston was seated onto the burst plate / pressure vessel. The needle was removed to form seal between the piston and cylinder wall.

[0261] 8. The cylinder was loaded with water. The cylinder was checked to ensure it was full and bubble-free.

[0262] 9. The nozzle was screwed on the clear cylinder at the end opposite the pressure vessel. As the threads of the nozzle displaced water from the inner volume of the cylinder, it was confirmed that water vented from the nozzle tip to verify there was no air in the nozzle.

[0263] 10. An arc lighter was used to ignite nano-laminate foil. Piston travel was recorded with high-speed camera.

[0264] The data collected in order to experimentally model pressure of the pressure vessel as a function of pressure vessel size are presented in FIG. 24. Based on the theoretical model used to qualitatively understand the behavior of the pressure vessel

[0265] #14417616vl WGS M0925.71050WG00 MIT 25827 - 39 - prior to piston movement, the pressure was expected to be constant across all pressure vessel sizes. However, the measured pressure data shows not only a deviation from the theoretical predictions, but a large standard deviation between different trials of the same size. These results emphasize the importance of precise design in devices such as those described herein. In particular, the variability in the results seems at least partially attributable to the formation of bubbles, which could have affected the thermodynamic behavior of the fluid in the pressure vessel.

[0266] In order to mitigate the impact of bubbles in the pressure vessel, the pressure vessel was placed in a desiccator to vacuum remove the bubbles after the pressure vessel was loaded with volatile fluid but before the nano-laminate foil was installed. Even though the volume of air bubbles in the pressure vessel depends on stochastic factors, the size and number of bubbles was, through observation, determined to be largely independent from the pressure vessel size.

[0267] Because the proportional effect of bubbles may, in some cases, be larger for bubbles in a comparatively smaller pressure vessel, the focus of vacuum removal experimentation was on the smallest pressure vessel sizes. The results of vacuum removing the bubbles are represented by the square data points presented in FIG. 24. Vacuum desiccation likely helped mitigate the effect of bubbles, but loading the nanolaminate foil after vacuum desiccation appears to have reintroduced air to the pressure vessels in at least some cases.

[0268] Another device design was also tested to measure pressure generated from a nano-laminate reaction. In this design, to measure the pressure generated from the heat input from a nano-laminate reaction, a penetration in the top of the pressure vessel was used to load the pressure vessel with liquid, nano-laminate foil, and the nano-laminate foil trigger. Even though UV cure glue was used to caulk around the edges of the nanolaminate foil trigger to seal the pressure vessel, the trigger still included a large penetration. When ignition of the nano-laminate foil occurred, the reaction deformed the shape of the trigger leaving an opening in the top of the pressure vessel that vented the pressure vessel into the top cap component of the assembly. A diagram of the pressure vessel and top cap assembly cross sections can be seen in FIG. 25.

[0269] #14417616vl WGS M0925.71050WG00

[0270] MIT 25827

[0271] - 40 -

[0272] In order to address the size of the penetration, the nano-laminate foil trigger was redesigned to neck down between the external portion used for an external initiation of the reaction and the interior of the pressure vessel. The necked trigger piece is shown in FIG. 26, where the neck passed through the top of the pressure vessel, and the hole through which the interior pieces of nano-laminate foil were loaded was sealed with UV cure glue. The necked trigger helped to transfer an externally initiated reaction to the interior of the pressure vessel through a very small penetration. The use of a small penetration restricted flow through the penetration sufficiently to facilitate a pressure measurement.

[0273] The results of the pressure test are indicated in FIG. 24, superimposed on data already discussed above and indicated in the figure by the dots labeled "UV Glue Seal." The "UV Glue Seal" samples, like the “Vaccum removal of bubbles” samples discussed above, were placed into the vacuum desiccator to remove bubbles prior to nano-laminate foil installation. An advantage of the small neck size was the ability to assemble the test device without breaking the trigger foil. Venting of the pressure vessel through the trigger piece penetration was still visually observed as in FIGS. 27A-27C. But, the venting affected the larger of the two tested sizes less

[0274] Pressure vessel sizes of 0.18mL and 0.165mL of ethanol were tested in two trials each. The non-limiting piston displacement and time data recorded from the high-speed camera are shown in FIG. 28, while FIGS. 29-32 show piston velocity vs. time (FIG. 29), piston pressure vs. time (FIG. 30), ethanol pressure vs. ethanol density (FIG. 31, and the superposition of ethanol pressure vs. ethanol density onto the ethanol phase diagram, according to some embodiments. Of note, the liquid vapor mixture was visible in the cylinder indicating the ethanol is not combusting.

[0275] Based on the experimental design and theoretical model for this process, the isothermal phase change of ethanol was expected to apply a constant pressure to the piston. Therefore, the position versus time data was expected to be linear. The data was nearly linear (FIG. 28), but there was a clear, visible acceleration at the beginning and deceleration towards the end of the piston stroke. In all four tests, the piston traveled through the entirety of the available stroke length in roughly the same amount of time. All four tests appear to be similar to each other within experimental error when

[0276] #14417616vl WGS M0925.71050WG00 MIT 25827 - 41 - considering uncontrolled stochastic effects like resolution of assembly components, venting of ethanol through the trigger penetration in the pressure vessel, effectiveness of lubrication in the cylinder, leakage between the cylinder and the pressure vessel, etc.

[0277] The calculated velocity of the piston can be seen in FIG. 29. Even though the velocity was visually predicted to be approximately constant based on the position data, a drop in velocity can be observed. The velocity of the piston is directly related to the applied pressure and was used to calculate the pressure applied to the piston; the pressure as a function of time is shown FIG. 30. The shape of the graphs indicates that the largest drop in pressure occurred in the first 50 ms of time and in the first 15 mm of piston travel. This steep drop in pressure near the beginning of piston travel may indicate the pressure change experienced as the ethanol state transitioned from a super-heated liquid to a liquid-vapor system.

[0278] The calculated ethanol pressure is presented in FIG. 31; the experimental results superimposed on the phase change diagram can be seen in FIG. 32. The mass of the ethanol within the pressure vessel was assumed to be conserved in order to calculate the ethanol density. However, as noted above, at least some of the ethanol may have vented from the pressure vessel. The venting of ethanol to the atmosphere may have artificially inflated the density values reported in FIGS. 31 and 32, with the result that the reported densities may underestimate the true ethanol density. Put differently, the lines used to represent experimental pressure as a function of density would, in an experiment where mass was conserved, be elongated to the left, shifted to the left, or both. Nevertheless, with the available information, it is reasonable to presume that the phase change processes are the dominant pressure effect, and that the system travels between the 500K and 550K isotherms along the liquid-vapor saturation line. These examples demonstrate that the devices and, in particular, the nanolayered articles used for heat generation, were successful methods of pressurizing ethanol in the device to trigger the spray of material through a nozzle of the device.

[0279] EXAMPLE 5

[0280] This example demonstrates assembly and testing of a non-limiting device, according to some embodiments.

[0281] #14417616vl WGS M0925.71050WG00 MIT 25827 - 42 -

[0282] FIGS. 33A-33E present high-speed photography of assembled triggering mechanism and article, according to some embodiments. The photographs were taken by using a high speed camera to image the full ignitions mechanism, exactly as it would occur in a device. Ignition was triggered via a current supplied by a DC power supply, and FIGS. 33A-33E show frames selected from a 1000 fps video to show stages of the triggering, from initial spread (FIG. 33B) of the ignition, to full ignition which saturated the camera and so the mechanism couldn’t be seen (FIG. 33C), to the article post ignition, which appeared as a shriveled intermetallic compound. The experiment was done in air.

[0283] FIGS 34A-34B present in vitro delivery of mRNA lipid nanoparticles (LNPs) showing that an exemplary device can deliver LNPs with 75% ± 9% transfection efficiency, according to some embodiments. Modern-like mRNA were formulated into lipid nanoparticles in solution then concentrated with an amicon filter. In the figures, "control" means the LNPs were not used in the device, "chamber" means the LNPs in solution were loaded into the device and then taken out, "jet" means the LNPs in solution were jetted into glass vials. After treatment the LNPs transfected Caco2 cells, and the transfection efficiency was measured the next day on a plate reader. The results show that jetting caused about a 20% loss in the transfection efficacy of the LNPs. Three replicates were done.

[0284] PIG 35 presents delivery of model drugs comprising viscous oils or suspensions showing that an exemplary device could be used to deliver viscous drug formulations with high concentrations, according to some embodiments. The model drugs were jetted with a benchtop pneumatic setup that modeled the device. The results show that viscous suspensions of high concentration drugs (liquid in liquid or solid in liquid) could be jetted with comparable jetting force to water, illustrating that the device is capable of delivering such formulations to a subject.

[0285] PIG. 36A presents a photograph of an assembled, nonlimiting, prototype device, according to some embodiments.

[0286] PIG. 36B presents a photograph of a disassembled, nonlimiting, prototype device, according to some embodiments.

[0287] #14417616vl WGS M0925.71050WG00 MIT 25827 - 43 -

[0288] FIGS. 37A-37B present photographs of a non-limiting device during delivery, according to some embodiments.

[0289] FIGS. 38A-38B present theoretical and empirical data for the pressure at which an aluminum burst plate fractures to initiate drug delivery, according to some embodiments. Theoretical calculations of the pressure at which the aluminium burst plate would break and release based on the mechanics of a thin plate, simulations of the same were conducted in Ansys Mechanical. Empirical results were collected by exerting different pressures in a pneumatic system until the Al burst plate broke on the bench, and recording the break pressure, assuming negligible inelastic deformation in the burst plate during the experiment.

[0290] The results described in FIGS. 33A-38B illustrate that the devices provided herein can be assembled and used for drug delivery.

[0291] EXAMPLE 6

[0292] This example demonstrates the manufacture and testing of an article configured to generate jet actuation of the active pharmaceutical ingredient through the outlet using heat emitted during a mass-preserving chemical reaction.

[0293] Methods

[0294] Benchtop Jetting Apparatus

[0295] To experimentally evaluate jetting dynamics and their impact on biologies delivery, a benchtop jetting apparatus was developed. This platform served as a simplified, modular analog to the capsule system, offering greater control over individual jetting parameters and facilitating systematic testing of jet behavior, device components, and formulation stability under varied conditions. The benchtop jetting apparatus was used to address the following research questions and use cases: quantification of shear force impact on mRNA transfection efficiency, as a function of nozzle diameter and inlet pressure leakage testing of capsule components without requiring full assembly or activation of the heater, measurement of burst pressure thresholds for rupture plates, and the velocity of the jet.

[0296] #14417616vl WGS M0925.71050WG00

[0297] MIT 25827

[0298] - 44 -

[0299] The benchtop jetting apparatus was designed and built using a combination of commercially available components, 3D-printed parts, and one custom-machined element fabricated on a lathe. Power was provided by a pressurized air tank, with an adjustable pressure regulator to control the output pressure. This pressure acted on a primary piston, which was held in place by a quick-release valve, allowing for instantaneous pressure delivery when triggered. The triggering mechanism comprised a spring-actuated housing that, when pushed back, released ball bearings positioned on an inclined plane. This released the piston, which in turn drove the device piston forward. The device piston and air piston were mounted by the custom machined part. The resulting motion ejected fluid — either drug solution or water for testing purposes — through the nozzle. The difference in bore diameters between the air piston and the drug piston introduced a pressure scaling factor, assuming constant net force, given by:

[0300] To characterize jetting performance, the output force was measured using a Kistler 9215A force transducer placed downstream of the nozzle. FIG. 39A provides a non-limiting schematic flow-chart that illustrates the flowchart illustrates the functional layout of the benchtop jetting system. As shown in FIG. 39A, an air tank flows air through a regulator to an air piston connected to a quick release valve. The quick release valve, in turn, drives a piston of the jetting apparatus (“Device piston”), providing force to a nozzle and a force transducer. FIG. 39B shows these features in a schematic cross-section of the benchtop jetting system used for experiments.

[0301] LNP-mRNA Formulation - Jetting Characterization

[0302] The effect of jetting on the structural integrity and functional efficacy of lipid nanoparticles (LNPs) encapsulating mRNA was tested using a Moderna-like composition containing C14-PEG lipid in an in-vitro experiment. During jetting, the formulation was subjected to shear forces, which may compromise nanoparticle integrity and consequently reduce transfection efficiency.

[0303] To assess these effects, two separate experiments were conducted: one using a benchtop jetting apparatus with two different nozzle diameters and the other

[0304] #14417616vl WGS M0925.71050WG00 MIT 25827 - 45 - utilizing the developed capsule. The complete experiments span three days, covering nanoparticle formulation, cell plating, jetting, and transfection analysis. The following section outlines the full protocol,

[0305] The non-limiting protocol for LNP-mRNA formulation, synthetization, jetting, and readout follow:

[0306] Day 1 : Cell Plating and LNP-mRNA Preparation

[0307] Cell Plating:

[0308] Plate Caco-2 cells in a white 96-well plate at a density of 30,000 cells per well. Prepare one 96-well plate.

[0309] Allow the cells to adhere and grow overnight. On Day 2, cells should be elongated and approximately 70% confluent.

[0310] LNP-mRNA Preparation:

[0311] 1. Dilute 187.5 L of firefly luciferase mRNA stock solution (1 mg / mL) with 3562.5 L of 10 mM citrate buffer to achieve a final concentration of 0.05 mg / mL in a total volume of 3750 L.

[0312] 2. Prepare the lipid mixture according to the formulation in Table 3.

[0313] Table 3: Lipid composition and volumes used for the LNP formulation.

[0314] Mix 1250 L of the prepared lipid solution with the 3750 L mRNA solution (0.05 mg / mL).

[0315] Lipid Molar Ratio Weight Ratio Concentration (E / L) Volume ( L)

[0316] SM102 50 0.57 10 300.0

[0317] DSPC 10 0.13 10 66.75

[0318] Cholesterol 38.5 0.24 10 125.78

[0319] C14-PEG-PE 1.5 0.06 10 34.11

[0320] Ethanol - - - 1061

[0321] 3. Pipette up and down 20-30 times, vortex for 30 seconds, then place on ice to promote nanoparticle self-assembly.

[0322] 4. The resulting LNP-mRNA mixture has a final concentration of 0.0375 mg / mL and total volume of 5000 L.

[0323] #14417616vl WGS M0925.71050WG00 MIT 25827 - 46 -

[0324] 5. Place the formulation into dialysis cassettes and dialyze overnight at 4 C against phosphate-buffered saline (PBS) to remove ethanol and citrate buffer.

[0325] Day 2: Concentration, Jetting, and Transfection

[0326] Concentration of Formulations:

[0327] Following dialysis, take 3000 L of the LNP-mRNA formulation and concentrate using an Amicon spin filter (max speed, 20 minutes, 4 C) to yield a 2x solution (final volume: 1500L, concentration: 0.075 mg / mL).

[0328] Retain the remaining 2000 L as a lx working solution (concentration: 0.0375 mg / mL).

[0329] Jetting Experiments:

[0330] The following two jetting experiments were conducted in two separate studies, whereas the capsule experiment was conducted twice:

[0331] Benchtop jetting apparatus Jetting Experiment Due to location constraints, the benchtop jetting system could not be moved to the LNP- mRNA synthesis site. Therefore, the LNP-mRNA formulations were transported to the jetting site.

[0332] Transfer both lx and 2x LNP-mRNA samples on ice to the jetting site. Reserve 30 L from each concentration for RBG assay and control at the synthesis location.

[0333] Jet samples using two nozzle diameters (0.4 mm and 0.6 mm) and applying pressure configurations representative of drug depot delivery, as well as lower pressure conditions. Pressure settings were tuned by adjusting the pressure regulator on the air tank and measuring the actual jet force on a force transducer.

[0334] After jetting, promptly return all samples on ice to the synthesis site for downstream processing.

[0335] #14417616vl WGS M0925.71050WG00 MIT 25827 - 47 -

[0336] Capsule Jetting Experiment The capsule device was portable and could be operated directly at the LNP synthesis site, allowing for immediate jetting without transport of the LNP-mRNA formulations.

[0337] Wash the capsule device with RNA-free water 2-3 times before each replicate. Initially treat the system with a small amount of RNaseZAP, followed by 10 rinses with RNA-free water.

[0338] Clean collection vials in the same manner with RNaseZAP and extensive rinsing.

[0339] Jetting:

[0340] Load 200 L of each formulation (lx and 2x) into the cooled capsule (on ice) and initiate jetting. The burst plate configuration used was a thickness of 0.002” and a diameter of 2.3 mm, selected to align with the desired delivery pressure range. Further details are provided below.

[0341] Transfection Procedure:

[0342] Change the media in each well to 80 L of fresh complete media. For the lx concentration, dilute the jetted LNP-mRNA by mixing 14 L of sample with 196 L of complete media, yielding a final mRNA concentration of 0.0025 mg / mL in 210 L.

[0343] For the 2x concentration, dilute by mixing 7 L of the sample with 7 L of lx PBS and 175 L of complete media (same final concentration and volume as above).

[0344] Add 20 L (containing 50 ng of mRNA) of the final LNP-mRNA formulation to each well already containing 80 L of media, resulting in a final concentration of 0.0005 mg / mL in 100 L.

[0345] Day 3: Measuring Transfection Efficiency

[0346] If using a new Steady-Glofi kit, thaw the assay buffer to room temperature. Add the buffer to the lyophilized Steady-Gio substrate and mix until completely dissolved. Aliquot into 10 mL tubes. For this experiment, a total of 60 mL of reagent was used.

[0347] #14417616vl WGS M0925.71050WG00 MIT 25827 - 48 -

[0348] If using pre-prepared Steady-Gio reagent, thaw 60 mL at 25 °C and protect from light during thawing.

[0349] Allow all cell plates to equilibrate at 25 °C to match the reagent temperature. Add 100 L of Steady-Gio reagent directly to each well.

[0350] Incubate the plate at 25 °C protected from light for 5 minutes to allow signal development.

[0351] Measure bioluminescence with a microplate reader

[0352] Encapsulation Efficiency

[0353] Beyond transfection efficiency, the encapsulation efficiency of LNPs plays a crucial role in determining the overall delivery performance of the formulation. Encapsulation efficiency quantifies the fraction of mRNA that was successfully enclosed within LNPs, protecting it from degradation and ensuring targeted delivery. It was expressed as follows:

[0354] To evaluate encapsulation, LNP samples were dialyzed overnight against lx PBS (pH 7.2), free of calcium, magnesium, RNase, and DNase. Unencapsulated (free) mRNA was quantified by incubating the LNP solution with RiboGreen reagent at 37 °C for 3 minutes on a lateral shaker. Lor total mRNA quantification, the LNPs were lysed using a buffer comprising 5% Triton X in Tris-EDTA with 5 mg / mL heparin, followed by a 10- minute incubation under the same conditions. The lysate was then treated with RiboGreen, and fluorescence intensity was recorded using a microplate reader at an excitation / emission wavelength of 485 / 515 nm.

[0355] Device Development

[0356] Device Overview

[0357] The device comprised four main sub-components: the actuator, the drug chamber, the electronics module, and the weight balancing element. In summary, the device operates as follows: The device can jet in one of three directions. When mucosa contact

[0358] #14417616vl WGS M0925.71050WG00

[0359] MIT 25827 - 49 - is detected at any outlet by the onboard sensors, the microprocessor selects the jetting direction and activates the actuator. An overview of the device design, along with the fully assembled capsule, is shown in FIG. 40.

[0360] Device Assembly

[0361] The device was assembled as follows:

[0362] 1. Subcomponent Preparation: Independently, the actuator, drug chamber, and electronics were assembled.

[0363] 2. Mechanical Integration: The actuator was screwed into the drug chamber using a thread sealant to ensure a secure and leak-proof connection.

[0364] 3. Electrical Connections: The actuator wires and the beeswax joule heater leads were soldered to the designated terminals on the PCB.

[0365] 4. Chamber Loading: The drug chamber was filled with ethanol using a syringe and the inlet was sealed with UV-curable adhesive to prevent leakage.

[0366] 5. Power Connection: The battery was connected to the electronics to activate the system.

[0367] 6. Final Assembly: The electronics housing was bonded to the drug chamber using a biocompatible adhesive, completing the capsule assembly.

[0368] Actuator

[0369] Overview

[0370] A thermally activated gaseous actuator was developed by vaporizing ethanol through heat supplied by a self-propagating chemical reaction, requiring no prepressurization. An overview of the sub-components of the actuator is shown in FIG. 41. The actuation process comprised four steps:

[0371] 1. Heat Release: Heat release through self-sustaining exothermic reaction of reactive multilayer foil (nanofoil) was activated, producing an intermetallic compound.

[0372] 2. Pressure Build-Up: Ethanol contained in a sealed chamber was heated, resulting in vaporization and pressure accumulation.

[0373] 3. Burst Plate Rupture: Once a critical pressure threshold was reached, a thin metallic burst plate ruptured to initiate flow.

[0374] 4. Piston Displacement: The released pressure drove a piston forward, which in turn forced the liquid drug through the nozzle.

[0375] #14417616vl WGS M0925.71050WG00 MIT 25827 - 50 -

[0376] Heat Generation

[0377] A nanofoil configured to undergo a mass-preserving chemical reaction was selected as the heating source. The nanofoil was a highly reactive, multilayered material comprising alternating nanoscale layers of aluminum and nickel. When a localized heat source raised the temperature of a small region to its ignition point, the layers underwent a rapid exothermic reaction. This reaction propagated across the foil, releasing a significant amount of thermal energy in a very short time. These properties made the nanofoil particularly suitable for applications requiring localized, high-energy heat bursts, such as microscale jet actuation. The nanofoil was precisely patterned using laser cutting, facilitating custom geometries. 40 ,um- thick nanofoil was used, as the available alternative 60 urn thickness ignited during laser cutting.

[0378] The activation of reactive multilayer films started the self-propagating reaction, which was triggered when a critical energy threshold in relation to the heat loss was exceeded. At low ignition temperatures, conduction and convection dominated the heat loss mechanisms, leading to the ignition criterion:

[0379] Two distinct methods for initiating the reaction in the nanofoil were evaluated: direct Joule heating of the nanofoil and external heating via an adjacent resistive element. Joule heating involved passing an electrical current through a conductive material, generating heat due to the material’s electrical resistance. Direct Joule heating involved passing current directly through the nanofoil, where the generated heat is governed by its intrinsic electrical resistance. As this approach used relatively high input energy, it was employed in the development of a benchtop heater triggered by an external power supply.

[0380] Alternatively, external heating allowed the use of high-resistance materials as heating elements placed in close proximity to the nanofoil. This configuration achieved higher temperatures at lower currents, thereby reducing power consumption. However, it introduced additional challenges in the assembly process, particularly in achieving

[0381] #14417616vl WGS M0925.71050WG00 MIT 25827 - 51 - reliable thermal contact and precise alignment between the heating element and the nanofoil.

[0382] Benchtop Nanofoil Heater

[0383] The benchtop heater comprised several components designed to improve ignition reliability and thermal energy release. Activation was achieved through Joule heating of a nanofoil trigger piece, which featured a locally thinned cross-section to increase its electrical resistance and concentrate heat generation in a confined region. This localized heating reduces thermal losses to adjacent nanofoil components and ensures reliable ignition. The two ends of the trigger piece were electrically connected to ground and high voltage, respectively, facilitating current flow through the narrowed section for activation. In addition to the trigger element, larger bulk nanofoil pieces were integrated to increase the total thermal energy released during activation. One-half of the trigger piece was in direct contact with the bulk pieces, facilitating it to initiate all bulk layers. The other half was electrically insulated by a small Kapton film to prevent shortcircuiting. The other face of the bulk pieces were free for better heat transfer into the ethanol discussed in the next section. All components were securely assembled using plastic screws, ensuring reliable contact and structural integrity, even when the heater is operated in a volatile liquid environment.

[0384] The assembly was based on the sequential stacking of individual subcomponents. The benchtop nanofoil trigger element was iteratively designed to ensure reliable and consistent activation. Varied parameters included the width and length of the reduced cross-sectional region. A critical design constraint was the ability to trigger the foil using a power supply delivering up to 3.2 A, based on safety considerations and the available setup for the in-vivo study.

[0385] Initial ignition tests were conducted in air, chosen for its low thermal conductivity, followed by tests in water, which provided a more thermally demanding and safer environment compared to ethanol. In the final step, the complete heater assembly — including all bulk structural components — was assembled and successfully ignited underwater.

[0386] #14417616vl WGS M0925.71050WG00 MIT 25827 - 52 -

[0387] Capsule nanofoil Heater

[0388] The nanofoil heater was similar to the benchtop version, with the main difference being the use of an external Joule heater made from nichrome, which has a higher electrical resistivity. It was fabricated via lasercutting where a 40 m nichrome sheet was glued onto a lasercutting substrate and cured for 24 h while clamped with a hydraulic press. As a result, the nanofoil trigger piece was designed with a thin cross-section that was placed onto the external heater, submerged in thermal paste. The thermal paste served to ensure effective thermal contact while preventing direct electrical contact, which could short-circuit the heater elements and reduce heat generation. The entire heater assembly was then covered by a 3D-printed air bubble to protect it from ethanol exposure.

[0389] The bulk nanofoil pieces were placed directly onto the trigger piece, and the entire assembly was securely held together using UV-curing adhesive. This adhesive was applied while all the nanofoil components were clamped together to ensure proper alignment and bonding. An exploded view, along with the fully assembled heater, is shown in FIGS. 42A-42B.

[0390] Experimental Verification

[0391] For the developed capsule nanofoil heater developed, the activation of the nanofoil trigger element using the battery and transistor for device operation was experimentally verified. A dedicated test board was used to connect the heater to the battery through the transistor. To simplify the setup and eliminate the need for microcontroller integration during testing, the transistor was manually triggered. This approach facilitated straightforward validation of the heater activation under controlled conditions.

[0392] Pressure Generation

[0393] Pressure to jet out the drug volume was generated through vaporizing ethanol with the heat of the nanofoil. Since heat transfer was a transient process, the pressure buildup was temporarily contained until a sufficient level was reached to achieve the desired peak actuation force. This containment was achieved using a thin aluminum burst plate engineered to rupture at a specific pressure threshold.

[0394] #14417616vl WGS M0925.71050WG00 MIT 25827 - 53 -

[0395] The actuator held 10 g of nanofoil and 250 pL of ethanol were used to generate the vapor pressure for jetting. According to the datasheet, 10 g of nanofoil released approximately 66 J of heat. Assuming a constant specific heat capacity for ethanol at 20 °C (2.44J7g °C) and steady-state conditions, this energy was sufficient to heat 60 pL of ethanol to 224 °C. At this temperature, ethanol reached a vapor pressure of approximately 50 bar, a pressure previously reported to be sufficient for drug depot delivery. The drug chamber was filled completely with ethanol to prevent premature expansion prior to rupture. This configuration served as an initial design. Jetting performance was further tuned by either adding more nanofoil if too low jet forces were achieved or by tuning the burst plate parameters and accounting for potential inefficiencies, such as incomplete energy transfer or premature rupture before the maximal internal pressure was achieved.

[0396] In addition to vapor pressure, thermal expansion of the liquid contributed to pressure buildup during heating. In a perfectly rigid, sealed chamber, the incompressibility of the liquid caused even small thermal expansions to lead to significant pressure increases before burst plate rupture. Although the stainless steel actuator housing were considered rigid, the face seal was more compliant, and the burst plate underwent slight deformation during pressurization, resulting in an increase in chamber volume.

[0397] However, the pressure contribution from thermal expansion did not affect piston actuation after burst plate rupture as it was negligible compared to that generated by ethanol vaporization. Since the burst plate configuration was experimentally tuned to achieve the desired jetting profile, distinguishing between pressure contributions from thermal expansion and vaporization was not necessary.

[0398] Rupture of Burst Plate

[0399] Burst Plate The burst plate was a thin metal plate positioned atop a rigid burst plate holder, which featured a circular orifice defining the effective rupture diameter. The rupture pressure was tuned by adjusting either the plate thickness or the orifice diameter. Aluminum was selected as the burst plate material due to its favorable ductility and consistent rupture behavior. The ethanol chamber was sealed via a face seal positioned

[0400] #14417616vl WGS M0925.71050WG00 MIT 25827 - 54 - between the burst plate and the actuator housing. This design facilitated simple fabrication — requiring only laser cutting — and allowed easy customization of rupture pressure.

[0401] Piston Design

[0402] The piston serves to transfer pressure from the vaporized ethanol onto the drug volume while isolating it from the ethanol vapor and preventing ethanol leakage through the nozzles once jetting was completed. To boost drug capacity, the piston thickness was reduced, while ensuring sufficient mechanical stability and resistance to rotation. Although a thickness-to-diameter ratio greater than one was typically recommended for linear guidance according to Saint- Venant’s principle, this was not feasible due to drug volume constraints. Instead, a compact design employing two O-rings without a center gland was implemented. The O-ring glands were dimensioned for 15% compression and 80% volume fill to ensure effective sealing without excessive friction. To facilitate piston retrieval post-actuation, an internal M2x0.25 blind-hole thread was incorporated, allowing bolt attachment for retraction. To reduce dead volume for vapor expansion, the thread cavity was pre-filled with beeswax, which was melted prior to piston removal. The final piston design is illustrated in FIG. 43.

[0403] The assembly of the actuator is summarized in the following steps:

[0404] 1. Kapton Insulation: A layer of Kapton film was placed in the ethanol chamber and secured using UV-curing adhesive.

[0405] 2. Nanofoil Heater Preparation: The nanofoil heater was assembled and positioned

[0406] 3. Wire Placement: The heater wires were inserted through the designated feedthrough hole in the ethanol chamber.

[0407] 4. Burst Plate: The face seal, burst plate, and burst plate holder were placed, in that order, to ensure pressure containment and controlled rupture.

[0408] Drug Chamber

[0409] Overview

[0410] The design of the drug chamber was relatively simple, consisting of a chamber made to hold the drug volume and a nozzle to serve as the jetting outlet. A beeswax heater was positioned at each nozzle to control the direction of jetting. The components

[0411] #14417616vl WGS M0925.71050WG00 MIT 25827 - 55 - were fabricated from brass, chosen for its favorable machinability. An overview of the drug chamber design is illustrated in FIG. 44.

[0412] Nozzle Design

[0413] The nozzle featured a straight outlet section for jet formation, preceded by a converging chamfer to reduce frictional losses and turbulence. A 30 chamfer angle was selected to lower shear stresses compared to no chamfer while keeping practical manufacturing considerations. Specifically, this angle allowed for sufficient wall thickness near the threaded interface while maintaining a compact inner nozzle diameter. A smaller nozzle base diameter was desirable, as it facilitates the piston to seal as close as possible to the nozzle seat. Additionally, the more gradual transition provided by the chamfer reduces abrupt changes in flow direction, reducing boundary layer separation and promoting a more stable, laminar flow profile. An external M20.25 thread was incorporated to securely fasten the nozzle to the drug chamber. The nozzle was machined in accordance with ISO 2768 Fine tolerances, with a surface finish of Ra 0.8 m to achieve smoother flow. The inner wall of the drug chamber was also machined to the same specifications to improve sealing characteristics and reduce friction.

[0414] Nozzle Selection Mechanism

[0415] A nozzle selection strategy based on Joule heating of beeswax was developed. Each nozzle was sealed by a heater element covered with beeswax positioned above the outlet. Activation of the heater melts the beeswax, thereby opening the nozzle. Beeswax was selected The beeswax heater was designed with the same resistance as the capsule nanofoil activation heater. However, unlike the nanofoil system, this approach took only a 30-40 C temperature increase to melt the beeswax, although a larger mass must be heated. Each Joule heater was connected to a transistor on the PCB, allowing the microprocessor to individually control nozzle opening. An overview of the system design, including the Joule heater, is provided in FIGS. 45A-45B.

[0416] Experimental Verification

[0417] #14417616vl WGS M0925.71050WG00 MIT 25827 - 56 -

[0418] A proof-of-concept validation was conducted to assess the feasibility of the proposed nozzle selection mechanism. The method relied on two primary criteria: (1) consistent sealing of undesired nozzles using beeswax, and (2) reliable melting of the beeswax seal using the onboard battery-powered heating system. For the clogging test, beeswax was manually applied to the outlet of each nozzle and allowed to form an adhesive seal. This test was conducted using a benchtop jetting prototype with six nozzles, which was mechanically equivalent to the three-nozzle configuration of the final device. To evaluate the melting performance, the integrated nanofoil-based Joule heater was used. Since the heater and the battery output circuits were designed with matched resistances, the thermal power delivered in both configurations was equivalent. These experiments verified both the sealing capability and melting behavior of the beeswax similar to operational conditions.

[0419] The following steps were performed to assemble the device.

[0420] 1. Nozzles were screwed into the thread sealing of the drug chamber

[0421] 2. The beeswax heater was mounted onto the nozzles with UV-curable adhesive

[0422] 3. The beeswax was gently pressed onto the heater surface.

[0423] 4. The assembled drug chamber was placed in an oven at 60 °C until the beeswax was lightly melted (inspect visually)

[0424] Electronics

[0425] Concept - Closed Loop Drug Delivery

[0426] Closed-loop drug delivery was achieved by integrating on-board electronics and a battery into the capsule system. It was achieved through three light-emitting diodes (LED) - photodiode pairs, which exploited the light-reflective properties of the mucosal surface to detect tissue contact in real time. This feedback mechanism allowed the system to initiate drug delivery only upon confirmed contact, enhancing both the reduction of failure modes and repeatability. The decision-making process for this closed-loop operation is illustrated in the flowchart of FIG. 46 and an overview of the PCB, battery, and its housing is seen in FIG. 47.

[0427] #14417616vl WGS M0925.71050WG00 MIT 25827 - 57 -

[0428] Mucosa Contact Detection

[0429] Mucosal contact detection in this system was based on Photoplethysmography. The optical properties of gastric mucosa are used to determine contact or no contact. Therefore, a LED was positioned adjacent to a photodiode. The LED emits light, whose reflection was then measured by the photodiode. When the LED and photodiode are in contact with the gastric mucosa, the reflection of light was increased, resulting in a higher intensity signal compared to non-contact conditions and shining into the lumen. By defining an appropriate signal threshold, the system can distinguish between mucosal contact and noncontact conditions, facilitating closed-loop control of the jetting process.

[0430] To determine threshold values for nozzle selection, an in-vivo study was conducted using a simplified tethered device. The device, equipped with three 650nm LEDs and corresponding photodiodes, was inserted into a swine via endoscopy. It was oriented to establish contact with the mucosa under various configurations. For each configuration, all LEDs were activated simultaneously, and photodiode measurements were recorded over a 10-second interval.

[0431] Printed. Circuit Board

[0432] The printed circuit board (PCB) was responsible for controlling the sensing components, processing measurement data, and executing the decision logic for jetting direction and timing. It acted as the central interface between the sensor array and the actuator system. The PCB comprised a sensor board, which integrated three LEDs and their corresponding photodiodes, and a microprocessor board, which houses the microprocessor and transistors for switching the nozzle heaters and activating the actuator. When a transistor was switched on, it created a direct connection between the corresponding component and the battery, supplying the power.

[0433] The electrical schematic for mucosa contact detection, jetting direction, and nanofoil activation is shown in FIGS. 48A-48C.

[0434] Housing

[0435] #14417616vl WGS M0925.71050WG00 MIT 25827 - 58 -

[0436] The housing of the electronics was designed to accommodate the PCB, battery, and weight-balancing component. It featured three double windows, each aligned with one of the nozzles, to facilitate light emission and detection by the LEDs and photodiodes. Additionally, the 3D-printed PLA housing was resistant to gastric fluids.

[0437] The design of the electronics housing is illustrated in FIG. 49.

[0438] Assembly was completed by the following steps:

[0439] 1. LED / Photodiode windows were sealed with plastic film and UV-curable adhesive

[0440] 2. The battery was placed on top of weight-balancing insert

[0441] 3. The PCB was placed on top of battery while ensuring alignment of each LED / Photodiode with its window

[0442] Weight Balance

[0443] During the jetting process, the capsule experiences a counterforce and a torque due to the jet delivering the drug.

[0444] To mitigate these effects, a tungsten insert was used to adjust the mass distribution, compensating for the heavier actuator relative to the electronics. Tungsten was chosen for its low specific volume and its bio-compatibility. By increasing the capsule’s mass, the effect of both recoil and torque were decreased, improving stability and the efficiency of drug delivery.

[0445] The tungsten insert was manufactured from tungsten powder, which was compressed into the base of the electronics housing. Mass was added until the center of mass was aligned with the nozzle. The insert was then fixed in place using a UV-curable adhesive.

[0446] To assess the effect of recoil during jetting, first, a reference experiment was performed using the capsule without any weight balancing. The capsule was mounted vertically on a holder with the active nozzle oriented downward, while the other two nozzles were sealed. Jetting was initiated, and the resulting motion was recorded using a high-speed camera.

[0447] #14417616vl WGS M0925.71050WG00 MIT 25827 - 59 -

[0448] In a follow-up experiment, the standard electronics housing was replaced with a weighted version. This modification aligned the center of mass with the active nozzle and added extra mass to the system. The jetting experiment was then repeated.

[0449] Drug Depot

[0450] The goal of the proposed capsule was to reliably form a drug depot by generating sufficient jetting force without causing tissue perforation or significant drug loss. For the proposed device two main criteria must be fulfilled: (1) identifying a burst plate configuration that generates the force profile, and (2) verifying the successful formation of a depot without perforation. Generally delivering enough force to achieve mucosal penetration with a capsule-size device was much more difficult than the risk of fullthickness perforation. Based on related work the system should reach a peak force of at least 0.65N. The force profiles for different burst configurations were recorded using a force transducer (Kistler 9215A). During testing, the capsule was mounted rigidly above the transducer with the active nozzle aligned vertically downward and the remaining nozzles sealed as seen in FIGS. 50A-50B.

[0451] Following the evaluation of jetting force profiles, the optimal burst plate configuration was selected for an ex-vivo study using gastric swine tissue to verify drug depot. Two visualization methods were employed to confirm the formation and location of the drug depot. The first method used a 1% methylene blue solution as the jetted payload, facilitating visual confirmation of depot formation through direct inspection of tissue after the experiment. The second method involved micro-computed tomography uCT) using a radiopaque marker (lohexol) instead of dye. / CT was a high-resolution imaging modality suitable for visualizing soft tissue penetration and distribution of the marker. In both setups, the capsule was oriented with its open nozzle facing downward onto the tissue and lightly clamped from above to ensure proper contact and limit movement during jetting. The setup was shown in FIGS. 50A-50B.

[0452] In-vivo Pharmacokinetic Study

[0453] A first investigation into the pharmacokinetics of the proposed delivery device was also performend. The jetting of two devices with the delivery of Recombinant

[0454] #14417616vl WGS M0925.71050WG00 MIT 25827 - 60 - human EPO protein (GenScript) was characterized in an in-vivo swine model, with all procedures conducted in accordance with protocols approved by the Committee on Animal Care at the Massachusetts Institute of Technology. Swine were selected due to the anatomical similarity of their gastrointestinal tract to that of humans, as well as their established utility in evaluating Gl-targeted medical devices.

[0455] Sensor-based measurements of both healthy and ischemic small intestines were performed under general anesthesia in terminal (non- survival) experiments. Animals were fasted overnight prior to the procedure. Anesthesia was induced using Telazolfl(5mg / kg; tiletamine / zolazepam) and xylazine (2mg / kg), followed by endotracheal intubation and maintenance on 1-3% isoflurane in oxygen. Animals were placed in dorsal recumbency on a heated surgical table to maintain core body temperature.

[0456] Vital signs — including heart rate, respiratory rate, end-tidal CO2, oxygen saturation (SpO2), noninvasive blood pressure, and body temperature — were continuously monitored throughout the procedure. Intravenous fluids were administered to maintain proper hydration. Local subcutaneous anesthesia was provided using either lidocaine or bupivacaine prior to making surgical incisions. Access to the stomach was achieved via midline laparotomy, a surgical technique involving a vertical incision through the abdominal wall to expose the abdominal cavity.

[0457] The jetting devices used in the study employed the most effective burst plate configuration identified in prior ex-vivo experiments. To ensure correct targeting, the capsule was mounted in a custom-designed device holder and oriented directly against the stomach wall. To isolate the effect of a single nozzle, two of the three nozzles were occluded with adhesive. The benchtop nanofoil heater was chosen for its 100% reliability.

[0458] Recombinant human EPO protein (GenScript) at a concentration of 1.2 mg / mL was used as the test drug, selected for its stability, ease of handling, and straightforward quantification. The drug was loaded into the delivery device immediately prior to injection. To assess the effect of drug delivery, blood samples were collected at the following time points: -1, -0.5, 0, 0.25, 0.5, 0.75, 1, 2, and 3 hours relative to administration. At each time point, 4 mL of blood was drawn via IV into serum collection tubes, followed by a 1 mL heparin flush. Samples were allowed to clot at room

[0459] #14417616vl WGS M0925.71050WG00 MIT 25827 - 61 - temperature for 30 minutes, then centrifuged at 4 C for 10 minutes at 4000 rpm. The supernatant was collected by pipette and aliquoted into seven replicate Micronic tubes for AlphaLISA analysis. In this method, EPO was quantified via luminescence generated by proximity-based binding of donor and acceptor beads to the target protein.

[0460] Results

[0461] LNP-mRNA Formulation - Jetting Characterization

[0462] The benchtop jetting apparatus jetting experiment showed high variability in transfection efficiency across different handling conditions, making it difficult to isolate the specific impact of jetting pressure. No consistent trend suggested that lower jetting forces result in higher transfection efficiency. When comparing high-pressure jetted samples to those stored at the synthesis site, transfection efficiency ranged from 26.2% to 51.8%. In contrast, when compared to samples that were also transported prior to jetting, transfection efficiency increased (50.4% to 119.7%), and was even higher compared to low-pressure jetted samples (83.6% to 182.7%). The corresponding jetting force ranges and values are provided in Table 4 and Table 5, respectively.

[0463] As the high-pressure jetted samples actually demonstrated higher transfection efficiency than those jetted at low pressure, jetting pressure itself likely did not significantly reduce transfection efficiency. However, the drop for both was already significant compared to the samples left on the synthesis site and the dominant factor appears to be sample handling and manipulation — particularly during transport and device loading rather than the jetting itself in this experiment. A full comparison, including sample variability, is presented in FIG. 51.

[0464] Table 4: Summary of applied jetting forces across different conditions for benchtop jetting apparatus jetting experiment and pipette for reference.

[0465] Force Range Description

[0466] 0.58 - 1.15 N High pressure jetting forces (comparable to jetting forces for drug depot)

[0467] #14417616vl WGS M0925.71050WG00

[0468] MIT 25827

[0469] - 62 -

[0470] 0.16 - 0.33 N Low pressure jetting forces (lowest stable pressure range on benchtop device)

[0471] 0.05 N Approximate force of a 200L pipette outlet

[0472] Table 5: Comparison of high-pressure nozzle conditions against stored, transported, and low-pressure conditions.

[0473] Condition Stored (%) Transported (%) Low Pressure (%)

[0474] High Pressure 0.4 mm lx 51.8 119.7 165.0

[0475] High Pressure 0.4 mm 2x 40.7 50.4 169.2

[0476] High Pressure 0.6 mm lx 26.2 60.6 83.6

[0477] High Pressure 0.6 mm 2x 44.0 54.4 182.7

[0478] Capsule Jetting Experiment

[0479] In the capsule jetting experiment an average transfection efficiency of 74% - 9% at 2x concentration was achieved. The results are summarized in FIGS. 52A-52B.

[0480] In the first experiment, one out of two capsules functioned properly and achieved 80% efficiency. In the second experiment, both capsules operated successfully, achieving 62% and 81% efficiency, respectively. The variability in delivery was primarily attributed to mechanical differences in the capsule devices rather than formulation instability, as control wells demonstrated consistent transfection and loading across all replicates.

[0481] Encapsulation Efficiency

[0482] Encapsulation efficiency was measured for the second capsule jetting experiment, as summarized in Table 6. Based on these values and the observed transfection efficiencies, a delivery volume of 250 L would result in an mRNA dose of approximately 3.97 g and 4.25 g for each of the respective capsules at a IX concentration.

[0483] These doses fall within the range of those used in currently approved mRNA- based therapeutics, such as those developed by Modema or Pfizer. The dosage was further increased by either increasing the delivery volume or formulating and evaluating higher-concentration LNP-mRNA formulations.

[0484] #14417616vl WGS M0925.71050WG00

[0485] MIT 25827 - 63 -

[0486] Table 6: Encapsulation efficiency and mRNA concentration for different LNP formulations used in the capsule jetting experiment.

[0487] Encapsulation Efficiency (%) Concentration ( g / mL)

[0488] Device 1 84.68 30.32

[0489] Device 2 78.02 26.92

[0490] Chamber 93.82 45.81

[0491] Control 82.11 27.79

[0492] Device Development

[0493] Heat Generation

[0494] A trigger geometry was selected to have a 0.1 mm width and 2 mm length for the reduced cross-sectional region of the nanofoil trigger piece. This configuration facilitated reliable manual assembly of the full benchtop nanofoil heater without frequent damage to the trigger piece and it ignited instantaneously upon power delivery in both air and water, as shown in FIGS. 53A-53B.

[0495] Integrating the bulk structural components did not affect the ignition behavior, as anticipated. In total, fifteen benchtop heaters were assembled and all were activated successfully. Submersion in ethanol had no observable effect on activation reliability; the longest- tested sample was submerged for one hour and still ignited successfully.

[0496] Device Development

[0497] The capsule nanofoil heater was successfully triggered using the internal battery and transistor, as shown in FIGS. 53A-53B. The activation was rapid and consistent, demonstrating that the on-board power and switching components were able to ignite the nanofoil.

[0498] In contrast to the benchtop version, which was assembled with bolts, the device heater utilized UV-curing adhesive to fix the nanofoil and bulk elements in place. This approach proved mechanically robust in air and did not interfere with ignition performance. However, when heaters were submerged in ethanol for longer than 10 minutes, adhesion reliability declined significantly. Inspection of inactivated heaters

[0499] #14417616vl WGS M0925.71050WG00 MIT 25827 - 64 - revealed that the UV adhesive had softened and could be peeled away with tweezers, indicating ethanol ingress into the heater assembly and increased heat loss.

[0500] Rupture Pressure of Burst Plate

[0501] The experimentally measured rupture pressures and corresponding FEM simulation results for various burst plate geometries are shown in FIG. 54A. As expected, thinner burst plates and smaller rupture diameters generally resulted in higher rupture pressures. The same burst plate configurations repeatably ruptured at similar rupture pressures in the experimental setup showing the repeatability of the design. No pressure differences were detectable within the resolution of the air pressure regulator (- 3 bar). A representative ruptured burst plate is shown in FIG. 54B, with rupture consistently occurring along the edge across all tested configurations.

[0502] Among the prediction methods, the FEM simulation with simply supported boundary conditions demonstrated the closest agreement with the experimental data, with an error of 5.7% ± 8.6%. The analytical model overestimated the rupture pressure by 58.3%±9.5%, while the FEM simulation with fixed boundary conditions underestimated it by 76.3%±1.5%.

[0503] Nozzle Selection Mechanism

[0504] The results demonstrate that beeswax sealing and joule heating provide a viable strategy for nozzle selection. When beeswax was applied to seal all but one nozzle, the system successfully jetted fluid solely through the unsealed nozzle, as shown in FIG. 55.

[0505] Device Development

[0506] In addition, the joule heater of the capsule nano foil heater, powered by the onboard battery, melted the beeswax on top of it. The thermal output was sufficient to initiate melting and, led to bubble formation — an indication of sufficient energy availability and localized heating which is shown in FIGS. 56A-56D.

[0507] Mucosa Detection

[0508] #14417616vl WGS M0925.71050WG00 MIT 25827 - 65 -

[0509] The measurements from the in-vivo study confirm that the LED-photodiode setup can reliably distinguish between mucosal contact and lumen within the stomach. Data was collected under three distinct configurations: one LED in contact, two LEDs in contact, and one in contact with another in close proximity to the mucosa. Based on the analog photodiode readings, a threshold analog output value of 80 was identified as a reliable discriminator between full contact and no contact.

[0510] Weight Balance

[0511] A significant difference in motion was observed between the unbalanced and weightbalanced capsules. The unbalanced capsule jumped approximately 35mm and rotated 180° during jetting. In contrast, the weight-balanced capsule — with added mass and realigned center of mass — exhibited a reduced vertical motion of only 12mm and minimal rotation. This reduction in recoil demonstrates the effectiveness of weight balancing for stabilizing the capsule during jetting. The difference in behavior is illustrated in FIG. 57.

[0512] Drug Depot

[0513] Jetting Force Profile

[0514] The initial peak force of the jet to achieve a drug depot was aimed to be at least 0.65 N. Two burst plate configurations have been tested. The second burst plate configuration achieved that force. An initial configuration using a 0.002” shim with a 2.4mm burst diameter reached a peak force of 0.57N — below the 0.65N threshold. A second configuration, using a 0.003” shim and a 2.6mm burst diameter, produced a peak force of 1.1N and was selected for further testing. This configuration reliably ruptured in additional experiments, confirming its consistency where no force profile data was measured. To explore the upper-performance limit of the actuator, a 0.003” shim with a 2.2mm burst diameter was tested, reaching 1.2N. However, in a repeat experiment, this configuration failed to burst, indicating reliability issues. Therefore, the 0.003”-2.6mm configuration was chosen.

[0515] #14417616vl WGS M0925.71050WG00 MIT 25827 - 66 -

[0516] Force profiles for the first two configurations are shown in FIG. 58. The raw measurement was smoothened with a band-pass filter with a cut-off frequency of 1000 Hz due to the high noise in the measurement.

[0517] Ex-vivo Tissue Study

[0518] To evaluate the capability of submucosal depot formation with the proposed device, the selected burst plate configuration was tested in gastric swine tissue. The capsule successfully created a submucosal depot using the methylene blue dye without perforating the tissue. Minimal leakage was observed, likely due to slight movement of the capsule during jetting, which was observed in high-speed video footage. Postexperiment, the tissue was dissected to verify dye deposition beneath the mucosa. Results are shown in FIGS. 59A-59B. To obtain quantitative data, the experiment was repeated using a radiopaque marker and imaged via / CT. However, due to diffusion of the marker within the whole tissue during sample transport, no conclusive results could be obtained.

[0519] In-vivo Pharmacokinetic Study

[0520] In-vivo pharmacokinetic data of the delivery of EPO was obtained in a swine model. Two devices functioned successfully during the animal study and were jetted sequentially, each loaded with 171.39 / L and a total drug weight of 205.7 ,ug. Due to limited access to animal models and time constraints, a subcutaneous reference control was not included in this experiment. The plasma concentration of EPO is shown in FIG. 60. Peak concentrations of 25.77 ng / mL were observed at 82 and 76 minutes following the first and second device deliveries, respectively, indicating delayed absorption through the gastric tissue.

[0521] Discussion

[0522] LNP-mRNA Formulation - Jetting Characterization: Benchtop jetting apparatus vs. Capsule

[0523] The capsule jetting experiments showed significantly higher transfection efficiency compared to the benchtop jetting apparatus jetting experiment of the jetted

[0524] #14417616vl WGS M0925.71050WG00 MIT 25827 - 67 - samples compared to the control at the synthesis site. The benchtop jetting apparatus experiment was conducted before the capsule jetting experiment and thus the jetting protocol was adapted accordingly.

[0525] One difference was the handling and transport of the LNP-mRNA formulation. In the benchtop jetting apparatus jetting experiment, the LNP-mRNA formulation was prepared at a different location than the conduction of the jetting experiment. In contrast, the capsule jetting experiments were done entirely at one site. As seen in FIG. 51, transport correlated with a clear drop in transfection efficiency, likely due to temperature changes and handling during transit. Another difference was the use of RNaseZap in the capsule jetting experiments, followed by rinsing with RNase-free water. This reduced contamination and better-preserved mRNA integrity, whereas the benchtop experiments did not include this step. The control which was loaded in the drug chamber in the capsule jetting experiments measured almost identical luminesce as the control one indicating that the loading of the drug did not destroy it as in the benchtop jetting apparatus jetting experiment. The capsule experiment also allowed for faster handling of the device and LNP-mRNA formulations. LNPs were jetted shortly after loading, limiting ambient exposure, and the devices were pre-cooled on ice, further limiting temperature rise.

[0526] Jetting Force: Benchtop jetting apparatus vs. Capsule

[0527] The force profiles generated by the benchtop jetting apparatus and the capsule device reveal distinct differences arising from their respective actuation mechanisms and system dynamics as shown in FIGS. 61A-61B. The benchtop jetting apparatus, driven by a compressed air tank, maintains a relatively constant pressure throughout the jetting event. In contrast, the capsule operates via gaseous expansion, which adheres to the ideal gas law — leading to a pressure drop as the gas expands within a closed volume. This behavior resulted in a more rapid force decay in the capsule’s profile, as seen in both burst plate configurations tested as shown in FIGS. 61A-61B .

[0528] In the case of the 0.002” shim with a 2.4 mm rupture diameter, the capsule reached a peak force of 0.57 N, while the benchtop jetting apparatus achieved a higher peak of 1.2 N. Similarly, for the 0.003” shim with a 2.6 mm rupture diameter, the capsule

[0529] #14417616vl WGS M0925.71050WG00

[0530] MIT 25827

[0531] - 68 - produced a peak force of 1.10 N, compared to 1.7 N from the benchtop. Notably, the benchtop measurements exhibit pronounced oscillations at the onset of actuation, which may exaggerate the apparent peak values. These high-frequency oscillations were likely due to the dynamics of the piezoelectric force transducer, which behaved as an underdamped second-order system when subjected to sudden force input — a characteristic response to impulsive loading.

[0532] Efficiency of the Actuator

[0533] The total efficiency of the actuator was evaluated by comparing the input energy of the nanofoil to the kinetic energy imparted to the liquid jet. Additionally, the theoretical jet force based on rupture pressure was compared to the force measured by the force transducer. The nanofoil initiator embedded in the device delivered between 59 J and 75 J of thermal energy upon activation. The total efficiency, / , of the device is defined as: where Ejet is the kinetic energy of the waterjet, and Einput is the thermal energy provided by the nanofoil.

[0534] The calculated jet energy and both efficiencies for the two burst plate configurations shown in FIG. 58 — are summarized in Table 7.

[0535] Table 7: Jet energy and estimated efficiency for each actuator configuration.

[0536] Metric 0.002” 2.4mm 0.003” 2.6mm

[0537] Jet Energy (J) 0.57 0.97

[0538] Rupture Pressure - Jet Force Efficiency 47.49 61.45

[0539] (%)

[0540] Potential Energy - Jet Energy Efficiency 0.76-0.97 1.29-1.64

[0541] (%)

[0542] #14417616vl WGS M0925.71050WG00 MIT 25827 - 69 -

[0543] Comparing the two efficiency metrics reveals that the efficiency between rupture pressure and jet force was significantly higher than the efficiency between the nanofoil potential energy and jet energy.

[0544] The simulations were conducted under the assumption of a constant internal temperature of 250 °C, with radial heat transfer and the outer boundary was insulated. In the first simulation, the Kapton insulation layer matched the one used in the experimental configuration with a 0.003” thickness and a 2.4mm rupture diameter. The heat transfer was simulated for a duration of 250ms, corresponding to the time until the burst was observed experimentally with the high-speed camera.

[0545] In the second simulation, all parameters were held constant except for the insulation thickness, which was doubled. By comparing the temperature profiles in the steel wall for both simulations, the effect of conductive heat losses becomes apparent. It was important to note that these simulations were conducted for comparative purposes only and do not capture all the complexities of the real system. The model was simplified to isolate the influence of insulation thickness, and the resulting trends should be interpreted qualitatively rather than as absolute predictions.

[0546] Rupture of Burst Plate

[0547] The observed discrepancies in rupture pressure and rupture behavior were most likely attributed to differences between the physical boundary conditions and those assumed in the simulations or analytical models. While the simply supported FEM simulations showed reasonable agreement with experimental rupture pressures, it was consistently observed that the burst plates ruptured along the edge of the burst diameter. In contrast, the simply supported FEM model predicted maximum shear stress at the center of the burst disk, indicating that the boundary conditions in the simulation did not fully capture the experimental setup.

[0548] Simulations assuming fully fixed boundary conditions predicted maximum shear stress along the edge were consistent with the experimental rupture location, but significantly underestimated the rupture pressure. This discrepancy may be explained by several factors. In the FEM model, the fixed boundary condition likely overestimates the

[0549] #14417616vl WGS M0925.71050WG00 MIT 25827 - 70 - actual structural stiffness at the rupture diameter, as in the physical device the plate was only held by face seal pressure and friction against the holder. It was possible that some deformation or material flow into the burst diameter area occurs under loading, effectively reducing local shear stress and leading to a higher rupture pressure than predicted by a fully clamped model. Additionally, material properties used in the FEM simulations were simplified to a bilinear stress-strain curve. The yield strength and ultimate tensile strength values were taken from general literature data.

[0550] Ex-vivo Tissue Study

[0551] A peak force of approximately 0.65 N was identified as a threshold for creating a drug depot with effective tissue deposition. In experiments, the capsule device with a peak force of 1.1 N successfully produced a qualitatively strong drug depot without perforating the tissue. Although this force significantly exceeds the 0.65 N target, it resulted in a depot with no perforation. However, a comparable burst plate configuration tested using the benchtop apparatus with similar peak forces led to tissue perforation. This indicates that not only the peak force but also the force profile and the overall energy were critical. These results underscore the need for ex-vivo tissue validation of each burst plate configuration.

[0552] Additional testing with a capsule configuration similar to the 0.002” shim and 2.4 mm rupture diameter one which produced less than 0.65 N of peak force, failed to form a depot and instead caused noticeable dispersion of the payload around the capsule.

[0553] In-vivo Pharmacokinetic Study

[0554] A comprehensive pharmacokinetic analysis of erythropoietin administration was not possible based on the initial experiment conducted. For an accurate calculation of the area under the concentration-time curve (AUC), it was necessary to record the complete concentration profile over time in further experiments. Moreover, a comparative analysis of the AUC of erythropoietin following intravenous administration in swine was used to determine bioavailability.

[0555] Erythropoietin has a relatively high molecular weight of approximately 34 kDa and therefore distributes primarily within the intravascular compartment. The total blood

[0556] #14417616vl WGS M0925.71050WG00 MIT 25827 - 71 - volume of the experimental swine was estimated based on its body weight . Based on these considerations, it was roughly extrapolated that at tmax, the time point at which the maximum plasma concentration was reached, at least approximately 125.64 g, which was 30% of the administered erythropoietin dose, should have been absorbed. Although this represents a considerable simplification, it nonetheless suggests that a relevant proportion of the administered substance was systemically available.

[0557] For comparison, a standard 0.5mL erythropoietin injection contains approximately 8.4 g of active substance. This indicates that the amount administered via the device used in the present study was several times higher than a typical injection dose.

[0558] Collectively, these results demonstrate the viability of generating jet actuation of an active pharmaceutical ingredient through the outlet using heat emitted during a masspreserving chemical reaction, and demonstrates the successful use of such actuation mechanisms in the context of devices suitable for gastrointestinal use.

[0559] While several embodiments of the present disclosure 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 disclosure. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and / or configurations will depend upon the specific application or applications for which the teachings of the present disclosure is / are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the disclosure 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 disclosure may be practiced otherwise than as specifically described and claimed. The present disclosure is directed to each individual feature, system, article, material, and / or method described herein. In addition,

[0560] #14417616vl WGS M0925.71050WG00 MIT 25827 - 72 - 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 disclosure.

[0561] 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.”

[0562] 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.

[0563] 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.

[0564] 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

[0565] #14417616vl WGS M0925.71050WG00 MIT 25827 - 73 - list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and / or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0566] As used herein, “wt%” is an abbreviation of weight percentage. As used herein, “at%” is an abbreviation of atomic percentage.

[0567] 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.

[0568] 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.

[0569] 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

[0570] #14417616vl WGS M0925.71050WG00

[0571] MIT 25827

[0572] - 74 - closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

[0573] #14417616vl

Claims

1. WGS M0925.71050WG00MIT 25827- 75 -CLAIMSWhat is claimed is:

1. A device configured for administration to a subject, the device comprising: a reservoir configured to contain an active pharmaceutical ingredient, an outlet associated with the reservoir, and an article configured to generate jet actuation of the active pharmaceutical ingredient through the outlet using heat emitted during a mass-preserving chemical reaction of the article.

2. A device configured for administration to a subject, the device comprising: a reservoir configured to contain an active pharmaceutical ingredient, an outlet associated with the reservoir, a power supply, an electric heater operatively coupled to the power supply, and an article configured to generate jet actuation of the active pharmaceutical ingredient by undergoing a chemical reaction triggered by actuation of the electric heater.

3. The device of any one of the preceding claims, wherein the article comprises metallic aluminum and metallic nickel.

4. The device of any one of the preceding claims, wherein the chemical reaction is formation of an intermetallic compound.

5. The device of any one of the preceding claims, wherein the chemical reaction is exothermic and the jet actuation is generated, at least in part, by evaporating a solvent using heat emitted by the article.

6. The device of any one of the preceding claims, wherein the products of the chemical reaction are retained by the article.#14417616vlWGS M0925.71050WG00 MIT 25827 - 76 -7. The device of any one of the preceding claims, wherein the article is a layer.

8. The device of any one of the preceding claims, wherein the article is a multilayer.

9. The device of any one of the preceding claims, wherein the article comprises a plurality of metallic bilayers.

10. The device of any one of the preceding claims, wherein the article is configured to direct a jet formed during jet actuation into a patient.

11. A linear actuator for ingestible devices with the capacity to deliver at least 200 pl of a liquid therapeutic (including biologies such as mRNA and monoclonal antibodies) past the gastric wall and into the underlying mucosa for absorption into the bloodstream.

12. The actuator according to claim 11 wherein actuation can be powered by a single micro Li-ion battery with the form factor of a coin-cell battery.

13. The actuator according to claim 11 wherein an electrical impulse from the battery in claim 2 can ignite aluminium-nickel nanofilm with 400 mW of input power via thermal conduction through an electrically-insulating and thermally-conductive paste.

14. The nanofilm according to claim 13 wherein it heats 200 pl of ethanol inside a chamber.

15. The ethanol in claim 14 wherein its pressure builds up until it bursts a thin aluminium plate.

16. The actuator according to claim 11 wherein it is fabricated with either stainless steel, brass, or titanium with sufficient strength to withstand the pressure of the ethanol as it is vaporized according to claim 15.#14417616vlWGS M0925.71050WG00 MIT 25827 - 77 -17. The aluminium or stainless steel plate in claim 15 wherein it bursts at a preset pressure in the middle, releasing pressure onto a piston.

18. The piston in claim 16 wherein it pushes linearly while sliding on rubber O-rings.

19. The piston in claim 16 wherein it can push on a liquid drug reservoir to eject the liquid out of a 0.4mm nozzle at an initial velocity of at least 130 m / s.

20. The actuator according to claim 11 wherein it can be integrated with a drug reservoir into a form factor of a cylinder or pill measuring not more than 10mm in diameter and 21mm in height.

21. The actuator according to claim 11 wherein the drug reservoir can be modified for non-liquid therapeutics such as solid powders or alginate-coated cell therapeutics.

22. The actuator according to claim 11 wherein it can be integrated with nozzles in multiple directions to facilitate drug delivery in multiple directions once ingested.

23. The actuator according to claim 11 wherein it can be integrated with mechanism for mucosal detection and mucosal engagement to perform liquid drug delivery in a desired direction.

24. A method comprising: administering to a subject, a device comprising an article configured to generate jet actuation of the active pharmaceutical ingredient through the outlet using heat emitted during a mass-preserving chemical reaction of the article.#14417616vl

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