System and method for liquid injection

Abstract

To provide a self-righting article such as self-righting capsules.SOLUTION: A self-righting article includes: a self-actuating component which includes a spring and a support material maintaining the spring in a compressed state, where the support material is configured to be at least partially degraded in a biological fluid; a chamber containing a liquid active pharmaceutical agent; and a tissue interfacing component which is dynamically linked to the self-actuating component and includes an inlet, an outlet, and a channel in fluid communication with the inlet and the outlet. The chamber is in fluid communication with the inlet when the self-actuating component is started. When the self-righting article is supported at least partially by the tissue of a subject, the self-righting article allows the tissue interfacing component to release at least a part of the active pharmaceutical product into the tissue.SELECTED DRAWING: Figure 40A-40E

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 62 / 799,882, entitled “SYSTEMS AND METHODS FOR LIQUID INJECTION,” filed February 1, 2019, which is hereby incorporated by reference in its entirety for all purposes.

[0002] The present invention relates generally to self-healing systems and related components, such as self-actuating articles including self-actuating needles and / or self-actuating biopsy punches, and components having relatively high loadings of active pharmaceutical ingredients (APIs). [Background technology]

[0003] The gastrointestinal tract offers great opportunities to diagnose and treat patients. The development of smart administration systems and articles that enable this has shown substantial growth over the past decade. One of the most important challenges in maximizing delivery and interaction with the mucosa is ensuring juxtaposition of the article and / or medication system with the digestive mucosa. Previous attempts to do this have included the introduction of mucoadhesives, as well as texturing one side of a double-sided system. Orally ingested drugs generally diffuse through the gastrointestinal tissue wall to enter the bloodstream. A typical ingested tablet or article releases their cargo randomly into the gastrointestinal tract, allowing the cargo to migrate to the tissue wall by convection and diffusion. However, many biological drugs, such as insulin, even when housed in a solid formulation, are unable to travel in the liquids in the gastrointestinal tract because they are degraded, for example, by enzymes.

[0004] In addition, many pharmaceutical drug formulations on the market require administration by injection, including many vaccines, RNA, and peptides. Injections traditionally involve the use of a liquid formulation that is passed through a hollow needle and enters the body intravenously or intramuscularly.

[0005] Thus, there is a need for improved systems, articles, and methods. Summary of the Invention

[0006] The present invention relates generally to self-healing articles, such as self-healing capsules.

[0007] In one aspect, a self-healing article is provided. In some embodiments, the self-healing article includes a first portion, a second portion adjacent the first portion having a different average density than the first portion, and a hollow portion, wherein the self-healing article is constructed and arranged to be encapsulated in no more than 000 capsules.

[0008] In some embodiments, the self-healing article is configured to potentially be encapsulated in 000 capsules or less, although the self-healing article does not necessarily have to be encapsulated in such capsules. In embodiments in which the self-healing article is administered, such as by ingesting the self-healing article, the self-healing article may thus be administered without encapsulation.

[0009] In some embodiments, a self-healing article includes a first portion, a second portion adjacent the first portion having a different average density than the first portion, and a tissue-interface component associated with the self-healing article, wherein the ratio of the average density of the first material to the average density of the second material is greater than or equal to 2.5: 1. In some embodiments, the ratio of the average density of the second material to the average density of the first material is greater than or equal to 2.5: 1.

[0010] In some embodiments, the self-healing article is configured to remain in place within a subject's body and has a resistance of 1 g / cm 3and wherein the article comprises at least a first portion having an average density greater than 0.09*10^-4 Nm, the longitudinal axis perpendicular to the tissue engaging surface of the article being configured to maintain an orientation no greater than 20 degrees from vertical when subjected to an externally applied torque of no greater than 0.09*10^-4 Nm and at least one retention mechanism associated with the self-healing article.

[0011] In some embodiments, the self-healing article is configured for administration to a location within a subject and has a density of 1 g / cm 3 the self-healing article has a self-healing time of 0.05 seconds or less from 90 degrees in water, at least two tissue interface components including tissue contacting portions configured to contact tissue, each tissue contacting portion including a conductive portion configured to be in electrical communication with tissue and an insulating portion configured not to be in electrical communication with tissue, and a power source in electrical communication with the at least two tissue interface components.

[0012] In another aspect, a self-actuating article is provided. In some embodiments, the article includes a shell, a spring at least partially encapsulated within the shell, a support material associated with the spring, the support material adapted to maintain at least a portion of the spring under a compressive strain of at least 5% under ambient conditions, and a tissue interface component associated with the spring.

[0013] In some embodiments, the article is configured to be retained at a location within a subject's body and includes an outer shell, a spring at least partially encapsulated by the outer shell, the spring maintained in an at least partially compressed state by a support material under a compressive strain of at least 5%, and at least one retention mechanism operably coupled to the spring.

[0014] In some embodiments, the article is configured to be administered at a location within a subject's body and includes an outer shell, a spring at least partially encapsulated by the outer shell, the spring maintained in an at least partially compressed state by a support material under a compressive strain of at least 5%, at least two tissue interface components including tissue contacting portions configured to contact tissue, each tissue contacting portion including a conductive portion configured to be in electrical communication with the tissue and an insulating portion configured not to be in electrical communication with the tissue, and a power source in electrical communication with the at least two tissue interface components.

[0015] In another aspect, a self-healing article is provided. In some embodiments, the article includes a first portion having a mass, a second portion having a mass different from the mass of the first portion, a self-actuating component including a spring and a support material adapted to maintain the spring in at least a partially compressed state, the support material configured to at least partially degrade in a biological fluid, a tissue interface component associated with an active pharmaceutical agent and operably coupled to the self-actuating component, and a tissue engaging surface configured to contact a surface of tissue within a subject's body, the self-healing article being configured as a monostatic body due to the center of gravity of the self-healing article and the shape of the self-healing article, and when the self-healing article is at least partially supported by the tissue of the subject, the self-healing article is oriented in a direction that allows the tissue interface component to release at least a portion of the active pharmaceutical agent into the tissue.

[0016] In some embodiments, the article is configured such that upon said at least partial degradation of the support material, the spring expands to release said portion of the active pharmaceutical agent into the tissue, hi some embodiments, the expansion of the spring forces the pharmaceutical agent into the tissue.

[0017] In some embodiments, the first portion comprises a first material and the second portion comprises a second material, and the first and second materials are different, In some embodiments, the first portion comprises a first material and the second portion comprises a second material, and the first and second materials are the same.

[0018] In some embodiments, the self-healing article has a viscosity of 1 g / cm 3 has an average density greater than

[0019] In some embodiments, the first material and / or the second material is selected from the group consisting of polymers, ceramics, metals, metal alloys, and combinations thereof.

[0020] In some embodiments, the metal is selected from the group consisting of stainless steel, iron-carbon alloy, Field's metal, Wolfram, molybdenum, gold, zinc, iron, and titanium. In some embodiments, the ceramic is selected from the group consisting of hydroxyapatite, aluminum oxide, calcium oxide, tricalcium phosphate, zirconium oxide, silicates, and silicon dioxide. In some embodiments, the polymer is selected from the group consisting of polycaprolactone, polylactic acid, polyethylene glycol, polypropylene, polyethylene, polycarbonate, polystyrene, polyetheretherketone, acrylonitrile-butadiene styrene, amorphous polyetherimide, and polyvinyl alcohol.

[0021] In some embodiments, the spring comprises a spring constant in the range of 100 N / m to 1500 N / m.

[0022] In some embodiments, the support material is configured as a plug, the plug being operably coupled to the tissue interface component, and the plug being exposed to an exterior of the self-healing article through a hole in the tissue engaging surface.

[0023] In some embodiments, a self-healing article is provided, wherein a spring is positioned in a space enclosed by a first portion, and a tissue interface component is configured as a projectile extending substantially along a major axis of the self-healing article, the tissue interface component is operably coupled to the spring at one end and to a plug at the other end, the plug being positioned in the space enclosed by a second portion, and the second portion is configured to prevent the spring, in an at least partially compressed state, from pushing the plug through the tissue interface component and out of the hole in the tissue engagement surface.

[0024] In some embodiments, the tissue interface component is configured to pierce the plug upon activation of the spring.

[0025] In some embodiments, the support material is configured in the shape of a planar structure having a major plane and is operably coupled to the spring, the major plane of the planar structure being perpendicular to a major axis of the spring. In some embodiments, the support material includes a first surface along the major plane and having a first total surface area, the support material includes a second surface parallel to the first surface along the major plane and having a second total surface area different from the first total surface area, the first surface includes one or more cavities, and the first total surface area is greater than the second total surface area.

[0026] In some embodiments, the support material is configured within the self-healing article such that biological fluid entering the self-healing article contacts the first surface to initiate at least partial degradation of the support material, and the one or more cavities are configured for controlled collapse of the support material following at least partial degradation of the support material.

[0027] In some embodiments, the spring is positioned in a space enclosed by the first portion, the support material is positioned between the first portion and the second portion, the support material includes a hole through which the tissue interface component extends substantially along a major axis of the self-healing article, the tissue interface component is configured in the shape of a projectile such that one end of the projectile is operably coupled to the spring and the other end of the projectile is positioned proximate to the hole in the tissue engaging surface such that a distance exists between the projectile and the hole, and the tissue engaging surface is on the second portion.

[0028] In some embodiments, the one or more cavities surround holes in the support material.

[0029] In some embodiments, the support material is configured in the shape of a disk.

[0030] In some embodiments, the support material is selected from the group consisting of sugars, sugar derivatives, starches, sugar alcohols, maltose, isomalt, calcium carbonate, zinc, sodium chloride, polymers, and combinations thereof.

[0031] In some embodiments, the self-healing article includes one or more vents configured to fluidly communicate the self-actuating component with an external environment. In some embodiments, the one or more vents are located in the first portion. In some embodiments, the one or more vents are covered by a coating.

[0032] In some embodiments, the biological fluid is gastric fluid.

[0033] In some embodiments, the self-healing article includes a self-actuating component including a spring and a support material adapted to maintain the spring in an at least partially compressed state, the support material being configured to at least partially degrade in a biological fluid; a chamber containing a liquid active pharmaceutical agent; and a tissue interface component operably coupled to the self-actuating component, the tissue interface component including an inlet, an outlet, and channels fluidly connected to the inlet and the outlet.

[0034] In some embodiments, the chamber is configured to be in fluid communication with the inlet upon activation of the self-actuating component.

[0035] In some embodiments, the self-healing article is at least partially supported by the tissue of a subject, and the self-healing article is oriented in an orientation that allows the tissue interface component to release at least a portion of the active pharmaceutical agent into the tissue.

[0036] In some embodiments, the self-healing article includes a plug associated with the tissue interface component, the tissue interface component configured to pierce the plug upon activation of the self-actuation component.

[0037] Those skilled in the art will appreciate based on the teachings herein that in some embodiments, a self-activating component may be triggered to activate at a desired time (e.g., upon exposure to a fluid after a particular length of time and / or a particular set of physiological conditions).

[0038] In some embodiments, the tissue interface component is dissolvable or retractable.

[0039] In some embodiments, the self-healing article has a viscosity of 1 g / cm 3 has an average density greater than

[0040] In some embodiments, the support material is configured as a plug, the plug being operably coupled to the tissue interface component.

[0041] In some embodiments, the tissue interface component is configured as a projectile that extends substantially along a major axis of the self-healing article.

[0042] In some embodiments, the support material is configured within the self-healing article such that a biological fluid entering the self-healing article contacts the first surface and initiates at least partial degradation of the support material. In some embodiments, the support material is selected from the group consisting of sugars, sugar derivatives, starches, sugar alcohols, maltose, isomalt, calcium carbonate, zinc, sodium chloride, polymers, and combinations thereof.

[0043] In some embodiments, the self-healing article includes one or more vents configured to place the self-actuating component in fluid communication with the external environment.

[0044] In some embodiments, the one or more vents are covered by a coating.

[0045] In some embodiments, the article includes a component configured to retract the tissue interface component.

[0046] In some embodiments, the article includes a tissue-interfacing component capable of piercing tissue, and such component is multi-layered with an inner layer of a water-sensitive material.

[0047] In some embodiments, the water-sensitive material comprises gelatin.

[0048] In some embodiments, the tissue interface component includes an outer layer that is impermeable to aqueous fluids such that following triggering, an inner layer of the tissue interface component is exposed to the fluid in the chamber, mechanically weakening at least a portion of the tissue interface component following needle passage of the fluid.

[0049] In some embodiments, the article includes a tissue interfacing component configured to retract upon contact with a plug of self-healing element, thereby exposing an aqueous inner layer on both sides upon piercing the tissue.

[0050] In some embodiments, an article includes an outer shell having an outer shape including a circular cross-section, the outer shell defining a first axis; an actuation mechanism including a self-actuating component including a first spring component; a support material adapted to maintain the first spring component in an at least partially compressed state, the support material configured to at least partially degrade in a biological fluid; a chamber disposed within the outer shell, the chamber including a liquid active pharmaceutical agent; and a tissue interface component disposed relative to the outer shell and configured to transport liquid from the chamber to a portion of tissue of a lumen wall at a location within the subject's body, wherein the article is self-healing having a geometric center and a center of gravity, the center of gravity being offset from the geometric center in a first direction along the first axis.

[0051] In some embodiments, when the article is supported by tissue of the lumen wall while oriented such that the center of gravity is laterally offset from the geometric center, the article is subjected to an externally applied torque due to gravitational action to orient the article with the first axis oriented along the direction of gravity such that the tissue interface component interacts with tissue at a location within the subject's body, and the actuation mechanism acts on the liquid active pharmaceutical agent such that upon at least partial degradation of the support material, the tissue interface component releases at least a portion of the liquid active pharmaceutical agent into the tissue at the location within the subject's body.

[0052] In some embodiments, the liquid active pharmaceutical agent and chamber are constructed and arranged such that when the article is oriented with the first axis oriented along the direction of gravity and the tissue interface component is interacting with tissue, the center of gravity of the liquid is disposed below the geometric center relative to the surface of the tissue.

[0053] In some embodiments, the liquid active pharmaceutical agent and chamber are constructed and arranged such that when the article is oriented with the first axis oriented along the direction of the force and the tissue interface component is interacting with tissue, the center of gravity of the liquid is disposed closer to the surface of the tissue than the geometric center of the article.

[0054] In some embodiments, the chamber includes a movable wall, the movable wall configured to expel the liquid active pharmaceutical agent from the chamber.

[0055] In some embodiments, the chamber includes a cylindrical wall and the movable wall of the chamber includes a plunger in slidable engagement with the cylindrical wall.

[0056] In some embodiments, the tissue interface component is operably coupled to the self-actuating component, and the tissue interface component includes an inlet, an outlet, and a channel fluidly connected to the inlet and the outlet.

[0057] In some embodiments, the channel is configured to be in fluid communication with a chamber containing the liquid active pharmaceutical ingredient upon activation of the activation mechanism.

[0058] In some embodiments, the tissue interface component forms or includes an infusion needle operably coupled to a first spring component, wherein upon at least partial disintegration of the support material, the first spring component is operable from a first configuration to a second configuration, and when the first spring component is in the first configuration, the infusion needle is retained within the article, and the infusion needle is configured to be advanced from the article into the lumen wall by movement of the first spring component from the first configuration to the second configuration.

[0059] In some embodiments, the infusion needle extends through the chamber when the first spring is in the first configuration and / or when the first spring is in the second configuration.

[0060] In some embodiments, the injection needle includes a tissue-piercing end, a second end portion opposite the tissue-piercing end, and a sidewall extending between the tissue-piercing end and the second end portion, the sidewall including a side hole disposed such that fluid communication is established between the chamber and the tissue-piercing end of the injection needle when the first spring component is in the second configuration.

[0061] In some embodiments, when the first spring component is in the first configuration, the side hole is positioned outside of the chamber containing the liquid active pharmaceutical agent.

[0062] In some embodiments, the chamber further includes an end wall disposed opposite the movable wall, the end wall including a pierceable seal, and when the first spring component is in the first configuration, the tissue-penetrating end of the injection needle is embedded in the pierceable seal, and when the first spring component is in the second configuration, the injection needle pierces the pierceable seal.

[0063] In some embodiments, the actuation mechanism includes a second spring component releasably held in a compressed state, the second spring component configured to be released from the compressed state to drive the movable wall to expel the liquid active pharmaceutical agent from the chamber when the first spring component moves from the first configuration to the second configuration.

[0064] In some embodiments, the first spring component is disposed coaxially with the second spring component, such as radially within the second spring component, with at least partial axial overlap between the first spring component and the second spring component.

[0065] In some embodiments, the actuation assembly includes a third spring component releasably held in a compressed state, the third spring component configured to release upon expulsion of all or a predetermined portion of the expulsible liquid active pharmaceutical agent from the chamber, and release of the third spring component retracts the injection needle relative to the article housing.

[0066] In some embodiments, the third spring component is disposed coaxially with the first spring component, such as radially within the first spring component, with at least partial axial overlap between the third spring component and the first spring component.

[0067] In some embodiments, the tissue interface component is at least partially soluble or softens after actuation / penetration.

[0068] In some embodiments, the tissue interface component includes a jet injection component, and the first spring component is configured to expel the liquid active pharmaceutical agent through the jet injection component at a permeation rate that enables the liquid active pharmaceutical agent to permeate into the gastric submucosa of the luminal wall.

[0069] Other advantages and novel features of the present invention will become apparent from the following detailed description of various non-limiting embodiments of the invention when considered in conjunction with the accompanying figures. In the event that the present specification and any documents incorporated by reference include conflicting and / or inconsistent disclosure, the present specification shall control. [Brief description of the drawings]

[0070] Non-limiting embodiments of the present invention are described by way of example with reference to the accompanying drawings, which are schematic and are not intended to be drawn to scale, in which each identical or nearly identical component illustrated is typically represented by a single numeral. For clarity, not every component is labeled in every drawing, nor is every component of each embodiment of the present invention shown unless an illustrative diagram is necessary to enable a person skilled in the art to understand the invention. [Figure 1] 1 is a schematic diagram of a self-healing system, according to one set of embodiments. [Diagram 2] 1 is a cross-sectional schematic diagram of an exemplary self-healing system, according to one set of embodiments. [Diagram 3] FIG. 1 is a schematic illustration of management of a self-healing system, according to one set of embodiments. [Figure 4] 1 is a schematic diagram of an exemplary self-healing article, according to one set of embodiments. [Diagram 5] 1 is a cross-sectional schematic diagram of an exemplary self-healing system, according to one set of embodiments. [Figure 6] 1A-1D are cross-sectional schematic diagrams of an exemplary self-actuating component, according to one set of embodiments. [Figure 7] 1 is a cross-sectional schematic diagram of an exemplary self-healing system, according to one set of embodiments. [Figure 8] 1 is a schematic illustration of a support material according to one set of embodiments. [Figure 9] 1 is a schematic illustration of a support material according to one set of embodiments. [Figure 10] 1 is a schematic diagram of a self-healing system, according to one set of embodiments. [Figure 11] 1 is a cross-sectional schematic diagram of an exemplary self-healing system, according to one set of embodiments. [Figure 12] 1 is a plot of an exemplary self-healing shape graph, according to one set of embodiments. [Figure 13]1 is a photograph of an exemplary self-healing article inside a 000 capsule, according to one set of embodiments. [Figure 14] 1 is a plot of self-healing article kinetics from computer model (prediction) recovery testing according to one set of embodiments. [Figure 15] 1 is a plot of self-healing article speed of recovery by high speed camera analysis (poly), according to one set of embodiments. [Figure 16] 1 is a plot of self-healing article speed of recovery by high speed camera analysis (poly), according to one set of embodiments. [Figure 17] 1 is a photograph of an exemplary self-healing article according to one set of embodiments. [Figure 18] 1 is a series of x-ray images of an exemplary self-healing article at 0 degree, 45 degree, and 90 degree orientations compared to a control (washer) according to one set of embodiments. [Figure 19] 1 is an exemplary series of x-rays of self-healing articles in a pig's GI according to one set of embodiments. [Figure 20] 1 is an endoscopic examination of an exemplary self-healing article in the GI tract of a pig, according to one set of embodiments. [Figure 21] 1 is a plot of the percentage of articles recovered according to one set of embodiments. [Figure 22] 1 is a plot of maximum slope versus shape according to one set of embodiments. [Figure 23] 1 is a photograph of a maximum tilt test fixture according to one set of embodiments. [Figure 24] 1 is a photograph of an exemplary self-healing article including an air / water vent according to one set of embodiments. [Diagram 25] 1 is a photograph of an exemplary self-healing article including a magnetic portion attached to a magnetic object, according to one set of embodiments. [Figure 26] 1A-1C are schematic illustrations of a self-actuated article according to one set of embodiments. [Figure 27]1 is a schematic diagram of an exemplary self-actuated article according to one set of embodiments, a photograph of the article in vivo, and a photograph of the article compared to an uncompressed spring according to one set of embodiments. [Figure 28] 1 is a plot of force versus displacement for various spring constants according to one set of embodiments. [Figure 29] 1 is a plot of diameter versus time for sugar dissolution according to one set of embodiments. [Diagram 30] 1 is a plot of spring actuation time versus diameter according to one set of embodiments. [Diagram 31] Photographs and diagrams of an exemplary tissue interface component (eg, a biopsy punch) associated with a spring, according to one set of embodiments. [Diagram 32] 1 is a histology of a needle inserted from a spring-related article into tissue in vitro to reach the muscularis layer of stomach tissue, according to one set of embodiments. [Diagram 33] FIG. 1 is a schematic illustration of a tissue interface component, according to one set of embodiments. [Fig. 34A-34E] 1 is a schematic illustration of an exemplary assembly process for a system, according to one set of embodiments. [Diagram 35] 1 is a schematic illustration of an exemplary system, according to one set of embodiments. [Diagram 36] 1 is a plot of velocity versus distance (eg, gap size) between a tissue interface component and a tissue engaging surface, according to one set of embodiments. [Figure 37] 13 illustrates computational results from a self-oriented shape optimization of an exemplary system, according to one set of embodiments. [Figure 38] 1 is a cross-sectional schematic diagram of an exemplary self-healing system, according to one set of embodiments. [Figure 39A] 1 is a cross-sectional schematic illustration of an exemplary system according to one set of embodiments. [Figure 39B] 1 is a cross-sectional schematic illustration of an exemplary system according to one set of embodiments. [Figure 39C]1 is a cross-sectional schematic illustration of an exemplary system according to one set of embodiments. [Figure 39D] 1 is a cross-sectional schematic illustration of an exemplary system according to one set of embodiments. [Figure 39E] 39B is an enlarged view of a portion of the schematic diagram illustrated in FIG. 39A, according to one set of embodiments. [Fig. 40A-40E] According to one set of embodiments, A) an orally administered liquid-injected self-orienting millimeter-scale actuator (L-SOMA) is shown to deliver a formulation of an active pharmaceutical ingredient into the gastric submucosa. The system first orients towards the tissue wall. Then, the hydration-based actuator is actuated and a compression spring pushes the 32G needle into the gastric submucosa. After needle insertion, a second spring injects the drug payload. Finally, the encapsulation separates and is expelled. (B) Micro-CT scan of the L-SOMA system before actuation. (C) CAD design of the L-SOMA. (D) Timeline of the L-SOMA after ingestion. After the hydration-based actuator dissolves, the needle spring expands and inserts the needle. The needle plunger then triggers the dosing spring to expand and deliver the liquid formulation. (E) L-SOMA capsule prototype; [Fig. 41A-41N]High speed photographs at 5000 fps showing the L-SOMA with and without (A) side holes for injecting dye into 0.3% agarose gel according to one set of embodiments. The side holes allow liquid to exit through the needle into the target area. (C) An exemplary L-SOMA timeline in the stomach. (D) MicroCT images of the L-SOMA operating and injecting contrast agent into ex vivo porcine gastric tissue. (E) Controlled injection of 170 μL of contrast agent at different insertion depths into ex vivo porcine gastric tissue. The average thickness of the tissue samples was 7.0±1.3 mm. Insertion of either 3 mm or 4 mm into the tissue allowed the needle tip to reach the gastric mucosa layer. An injection depth of 4.5 mm allowed the needle tip to reach the gastric submucosa. Further insertion into the tissue targeted either the gastric submucosa or the muscularis layer. (F) Top and (G) side views of 80 μL of contrast agent depot injected by the L-SOMA capsule at a needle insertion length of 4.5 mm. (H) Microtome images of retained porcine gastric tissue before and (I) after injection in the L-SOMA demonstrating that the depot is injected into the submucosa. (J) Plot representing the percentage of contrast agent remaining in the tissue after injection. Values ​​were calculated using 3D reconstruction of Micro-CT images. (K and L) Force required to inject the depot into ex vivo porcine gastric tissue at a given needle insertion depth. (Error = SD; 4 mm n = 11; 4.5 mm n = 9; 5 mm n = 18). (M and N) Force required to displace a given plunger volume while attempting to inject contrast agent into ex vivo porcine gastric tissue using needles with a 10° backgrind and a >50° backgrind. In experiments with background needles >50°, no dye was deposited in the tissue as measured by MicroCT imaging analysis, and instead volumetric displacement was induced by compression of the plunger parts (error = SD; 10° n = 20; >50° n = 5) (**P < 0.01; ****P < 0.0001); [Diagram 42] 1 illustrates the actuation of a liquid underwater by an exemplary system according to one set of embodiments. [Diagram 43]1 illustrates the actuation of a liquid underwater by an exemplary system according to one set of embodiments. [Diagram 44] 1 illustrates an exemplary tissue interface component, according to one set of embodiments. [Fig. 45A-45J] 45A-45C show histology of pigs after administration of L-SOMA capsules according to one set of embodiments. (FIGS. 45A-45C) Histology of ex vivo pig stomachs after LSOMA insulin injection using (FIG. 45A) hematoxylin and eosin staining, (FIG. 45B) immunohistochemical staining for smooth muscle actin, or (FIG. 45D) immunohistochemical staining for insulin. (FIGS. 45D-45E) Histology of in vivo pig stomachs after administration of L-SOMA in green dye using (FIG. 45D) hematoxylin and eosin staining, or (FIG. 45E) immunohistochemical staining for smooth muscle actin. (FIGS. 45F-45J) Magnified histology images corresponding to the boxed sections of images FIG. 45A-45E, respectively (A-E: scale bar=1 mm, F-J: scale bar=250 μm). [Figures 46A-46C] 1 shows ex vivo histology of dogs from LSOMA injection according to one set of embodiments. Histology of ex vivo dog stomach after LSOMA insulin injection using (A) hematoxylin and eosin staining, (B) immunohistochemical staining for insulin, (C) or immunohistochemical staining for smooth muscle actin. Scale bar = 1 mm; [Fig. 47A-47N]1 shows in vivo oral delivery of monoclonal antibodies, peptides, and small molecule drugs in pigs according to one set of embodiments. (A) Plasma human insulin, and (B) glucose levels after administration of an L-SOMA capsule containing 1 mg recombinant human insulin (n=8). Negative control for plasma glucose is L-SOMA delivery of 4 mg inactivated GLP-1 analog (n=4 animal replicates). (C-D) Plasma levels of inactivated GLP-1 analog after administration of L-SOMA containing 4 mg inactivated GLP-1 analog (n=9). Pig anesthetized only during L-SOMA administration (0.25 hours) and pigs anesthetized 2 hours after administration are graphed. (E) Plasma human insulin, and (F) glucose levels after subcutaneous administration of 1 mg recombinant human insulin (n=3). (G-H) Plasma levels of inactivated GLP-1 analog after subcutaneous administration of 4 mg inactivated GLP-1 analog (n=3). (I) Serum levels of adalimumab after administration of an L-SOMA capsule containing 4 mg of adalimumab (n=3). (J) Plasma levels of epinephrine and (K) associated heart rate change after administration of an L-SOMA capsule containing 0.24 mg of epinephrine (n=3). The negative control for heart rate change is endoscopic gavage administration containing 0.24 mg of epinephrine (n=3). (L) Serum adalimumab levels after subcutaneous administration of 4 mg of adalimumab (n=3). (M) Plasma epinephrine levels and (N) associated heart rate change after intramuscular administration of 0.24 mg of epinephrine (n=3). For heart rate change data, time 0 corresponds to the time of device actuation or infusion. For all other data, time 0 corresponds to the time of device administration. Solid black lines represent the mean blood glucose or heart rate change for a given treatment group. All other lines represent treatments of different animals or the same animals, treated at least 3 weeks apart. [Figure 48]Shown is the injection test mechanism setup according to one set of embodiments. (Top) Computer-aided design of the custom actuation mechanism used to insert the needle a controlled distance and inject a precise amount of fluid. (Bottom) Experimental setup for controlled injection study. As the texture analyzer depresses the plunger, liquid is injected into the underlying porcine stomach tissue. [Figure 49] 1 shows blood glucose changes in pigs following 0.24 mg epinephrine injection according to one set of embodiments. The thin lines represent individual pig profiles and the thick lines represent average values. [Figure 50] 4 shows in vivo bovine histology following L-SOMA epinephrine injection according to one set of embodiments. Hematoxylin and eosin stained histology of a porcine stomach following L-SOMA injection. The L-SOMA device was injected into the fundus or corpus. [Figure 51]

[0023] Figure 1 shows the pharmacokinetics of epinephrine and adalimumab administered by gavage according to one set of embodiments. Dissolved adalimumab (4 mg) or epinephrine (0.24 mg) was administered into the lumen of a pig stomach via an endoscope (n=3 animal replicates). [Figure 52] 1 shows L-SOMA needle retraction according to one set of embodiments. A device designed to retract the needle after injection. [Fig. 53A-53B] Illustrates liquid formulation stability according to one set of embodiments.Human insulin (HI) and semaglutide (Sema) formulations were placed inside either L-SOMA or glass vial devices and exposed to 40°C and 75% relative humidity environment for 2 weeks.Then, (a) purity loss and (b) high molecular weight protein (HMWP) formation were measured.(Error=SD, n=3 device replicates, **P<0.01, ***P<0.001). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0071] overview Generally, a self-healing article, such as a self-healing capsule for administration to a subject, is provided. In some embodiments, the self-healing article may be configured such that the article can orient itself relative to a surface (e.g., the surface of a tissue of a subject). The self-healing article described herein may include one or more tissue-engaging surfaces configured to engage (e.g., interface with, inject into, retain) a surface (e.g., the surface of a tissue of a subject). For example, the self-healing article may be placed in any orientation proximate to a surface, and the self-healing article (re)orients itself such that the tissue-engaging surface contacts (e.g., directly contacts) the surface. In some embodiments, the self-healing article may have, for example, a particular shape and / or density (or mass) distribution that enables the self-healing behavior of the article. In some such embodiments, a capsule containing the self-healing article may be administered to a subject (e.g., for delivery of the self-healing article to a location within the subject's body, such as the digestive tract). In some embodiments, the self-healing article may include a tissue-interfacing component and / or a pharmaceutical agent (e.g., for delivery of an active pharmaceutical agent to a location within the subject's body). In some cases, the self-healing article may be configured to release one or more tissue interface components when tissue contacts a tissue-engaging surface of the article. In some cases, the tissue interface component is associated with a self-actuating component. For example, the self-healing article may include a self-actuating component configured to release the tissue interface component from the self-healing article upon exposure to a fluid. In some cases, the tissue interface component may include and / or be associated with a medicinal agent (e.g., for delivery to a location within the subject's body).

[0072] The self-healing articles described herein may be useful, for example, as a general platform for delivering a wide variety of pharmaceuticals that are otherwise typically delivered by injection directly to tissue due to degradation in the digestive tract. In some cases, the self-healing articles may be configured to deliver pharmaceuticals to a subject at a desired location and / or at a desired time and / or for a desired period of time. In some embodiments, the self-healing articles described herein may be used to, for example, deliver sensors and / or perform biopsies without the need for endoscopy. In certain embodiments, the self-healing articles described herein may be used to retain one or more articles on the surface of tissue, for example, in the digestive tract. In some cases, the self-healing articles described herein may be used to provide electrical stimulation directly to tissue.

[0073] Advantageously, in some embodiments, the self-healing articles and / or self-actuating components described herein can be useful as a general platform for the delivery of a wide variety of pharmaceuticals (e.g., APIs) that are typically delivered by injection directly to tissues due to degradation in the digestive tract. For example, the self-healing article can localize itself to the tissue wall in a specific orientation (e.g., allowing the loaded drug to avoid passing through the digestive fluids for a long time before diffusing into the bloodstream). The article can, in some cases, serve as a platform to allow the absorption of drugs that are currently degraded by enzymes in the digestive tract with higher bioavailability. In addition, the article can allow mechanical and electrical mechanisms, such as needle plungers, clasps, sensors, etc., to act directly at and / or within the tissue wall. Thus, in certain embodiments, the article can serve as a vehicle for the delivery of electronic devices or other articles into the digestive tract.

[0074] In some embodiments, the tissue interface component (e.g., associated with a self-actuating component) may include a relatively high loading of active pharmaceutical ingredient (e.g., drug). For example, in certain embodiments, the tissue interface component includes a solid therapeutic agent (e.g., a solid API) and, optionally, a support material (e.g., a binder such as a polymer) such that the solid therapeutic agent is present in the component in a relatively high amount (e.g., 80% by weight or more) relative to the total weight of the tissue interface component. Such tissue interface components may be useful for delivery of API doses (e.g., to a subject). Advantageously, in some embodiments, the reduction in the volume required to deliver the required API dose compared to liquid formulations allows the creation of solid needle delivery systems for a wide variety of drugs in a variety of locations / tissues (e.g., tongue, digestive mucosal tissue, skin) and / or reduces and / or eliminates the application of external forces to inject drug solutions through the small opening of the needle.

[0075] In some embodiments, the article does not include a solid therapeutic agent (e.g., the article includes a liquid therapeutic agent). In some cases, a physiologically relevant dose may be present in a single tissue interface component (e.g., having a relatively high API loading).

[0076] In an exemplary embodiment, the self-healing article may include a tissue interface component and a self-actuating component (including, for example, a spring and / or a support material) associated with the tissue interface component.

[0077] As illustrated in FIG. 1, in some embodiments, the system 100 (e.g., a self-healing article) includes a tissue-engaging surface 150. Although the embodiments described herein refer to a single tissue interface surface, in some embodiments, there may be two or more tissue interface surfaces. In certain embodiments, the self-healing article may be designed and configured such that the tissue-engaging surface contacts a surface (e.g., a surface of tissue at a location within the subject's body, such as a surface of the subject's stomach). In some embodiments, the system 100 self-heals (e.g., orients without the need for or use of an external force applied to the self-healing article) such that the tissue-engaging surface 150 contacts the surface. In certain embodiments, the self-healing article is configured such that an axis essentially perpendicular to the tissue-engaging surface preferentially aligns parallel to the direction of gravity. As described in more detail herein, the self-healing article may be configured such that an axis essentially perpendicular to the tissue-engaging surface can maintain an orientation of 20 degrees or less from perpendicular under an externally applied torque. In some embodiments, the self-healing article is configured such that the tissue-interface component has its longest longitudinal axis oriented within 15 degrees from perpendicular upon self-healing.

[0078] Without wishing to be bound by theory, a self-healing article may be designed to self-heal as a result of a distribution of density (and / or mass) within the self-healing article. For example, in some embodiments, the system 100 (e.g., a self-healing article) includes a first portion 110 and a second portion 115, where the first portion and the second portion have different densities and / or different masses. The different densities / masses of the self-healing article are described in more detail herein. In certain embodiments, the self-healing article may have a particular shape that enables the self-healing behavior. For example, as illustrated in FIG. 1, the system 100 includes a monostatic shape (e.g., a mono-monostatic shape, a rubber-bock shape) as shown by the exterior surface 170 of the system 100. The term "monostatic" as used herein is given its ordinary meaning in the art and generally refers to a three-dimensional shape that has a single stable rest position (e.g., an equilibrium point). The term "mono-monostatic" as used herein is given its ordinary meaning in the art and generally refers to a three-dimensional shape that has a single stable rest position and a single unstable rest position. By way of example, and without wishing to be bound by theory, a sphere with a center of gravity shifted from the geometric center is generally considered a mono-monostatic shape. The term "rubber bock" as used herein is given its ordinary meaning in the art and generally refers to a convex three-dimensional shape that, when rested on a flat surface, has a single stable equilibrium point (or orientation) and a single unstable equilibrium point (or orientation). For example, and without wishing to be bound by theory, when a rubber bock type shape is rested on a surface in any orientation other than the shape's single stable orientation, the shape tends to reorient to the rubber bock type shape's single stable orientation. Such shapes are described in more detail below.

[0079] 2 shows a cross-sectional illustration of an exemplary system 102. In some embodiments, the system 102 includes a self-actuating component 120. The self-actuating component 120 can be configured to release a tissue interface component 130 associated with the self-actuating component 120 from the system 102, for example, upon exposure to a particular fluid. For example, in some cases, the self-actuating component 120 includes a spring 125 such that upon actuation of the self-actuating component, the spring 125 expands to push the tissue interface component 130 out of the system 102 through the hole 140 (associated with the tissue engaging surface 150). In some cases, the spring 125 includes a support material 160 that maintains the spring 125 under compression (e.g., under a compressive strain of at least 5%). In some cases, upon exposure of the support material 160 and / or the spring 125 to a fluid, the spring may be configured to release at least 10% (e.g., at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, including any percentage therein) of the spring's stored compression energy (e.g., such that the tissue interface component 130 is released). In some embodiments, the spring is associated with the support material (e.g., in direct contact with and at least partially encapsulated by the support material).

[0080] In some embodiments, the hole (e.g., hole 140 in FIG. 2) may include a fluid gate (e.g., plug, coating, barrier). In some cases, the fluid gate may prevent fluid (e.g., fluid outside the system) from entering the system at the hole until a desired time. In certain embodiments, the fluid gate includes a barrier material. Non-limiting examples of suitable barrier materials include polycaprolactone foil, thermoplastic elastomers, cellulose, and silicone. The barrier material may include one or more hydrophobic materials. In certain embodiments, the barrier material may include one or more hydrophilic materials (e.g., sugar, PEG). Possible manufacturing methods for these coatings include spray coating, dip coating, wrapping, deposition, or other manufacturing methods. One skilled in the art would be able to select suitable hydrophobic and hydrophilic materials as barrier materials based on the teachings herein.

[0081] In certain embodiments, the tissue interface component 130 includes an active pharmaceutical agent. In some embodiments, the active pharmaceutical agent may be present in the tissue interface component in relatively high amounts (e.g., 10% or more, 80% or more, or 90% or more by weight API, based on the total weight of the tissue interface component). The self-healing articles described herein may, in some cases, be administered to a subject, for example, such that a pharmaceutical agent is delivered to the subject. For example, in some cases, the article may be administered to a subject and the pharmaceutical agent is released from the article at a location within the subject's body. Administration of the article and release of the pharmaceutical agent are described in more detail herein.

[0082] In some embodiments, the tissue interface component can be configured to facilitate the transfer of an active pharmaceutical agent (e.g., a liquid active pharmaceutical agent) from a chamber of the self-healing article into tissue of a subject (e.g., at a location within the subject's body). For example, as illustrated in FIG. 38, a system 109 includes a self-actuating component 120 including a spring 125 such that upon actuation of the self-actuating component, the spring 125 expands to push the tissue interface component 130 out of the system 109 through a hole 140 (associated with a tissue engaging surface 150). In some cases, the spring 125 includes a support material 160 that maintains the spring 125 under compression (e.g., under a compressive strain of at least 5%). In some embodiments, a system 190 includes a tissue interface component 130 associated with the spring 125 and a chamber 117. In some embodiments, the chamber 117 includes an active pharmaceutical agent (e.g., a liquid active pharmaceutical agent). In some embodiments, upon activation of the self-actuating component 120, the tissue interface component facilitates fluid communication between the chamber 117 and an environment external to the system 109 and / or the tissue in contact with the tissue engagement surface 150.

[0083] In some embodiments, the tissue interface component includes an inlet in fluid communication with an outlet of the tissue interface component. For example, in some embodiments, the tissue interface component (e.g., a needle such as a hollow needle) includes an inlet, an outlet, and a fluid channel in fluid communication with the inlet and the outlet. For example, as shown in FIG. 38, the system 109 includes a tissue interface component 130 including an inlet 132 and an outlet 134 in fluid communication with the inlet 132. Upon activation of the self-actuation component 120, the inlet 132 can come into fluid communication with a fluid chamber 117 (e.g., containing an active pharmaceutical agent and / or liquid). In some embodiments, the fluid communication between the inlet 132 and the fluid chamber 117 facilitates the flow of fluid from the fluid chamber 117 through the tissue interface component 130 such that the fluid exits the outlet 134. In some embodiments, the outlet 134 can interface with a surface of a tissue of interest such that liquid is infused into the tissue. In some embodiments, the hole 140 may include a plug (eg, a septum) such that upon activation of the self-actuating component 120, the tissue interface component 130 penetrates the plug-in hole 140.

[0084] The channels of the tissue interface component need not be within the body of the tissue interface component, but in some embodiments may be channels disposed on a surface of the tissue interface component (e.g., configured to facilitate flow of fluid in the fluid chamber to the tissue of the subject upon activation of the self-activating component). In some embodiments, the fluid channels are disposed within the tissue interface component.

[0085] In some embodiments, the tissue interface component can include a first end configured to penetrate tissue (e.g., a tissue penetrating end) and a second end portion opposite the first end portion. In some embodiments, the tissue interface component includes a sidewall extending between the first end portion and the second end portion.

[0086] In some embodiments, the sidewall includes a hole. For example, referring again to FIG. 38, tissue interface component 130 has a first end portion that includes an outlet 134 and a hole 132 in a sidewall of tissue interface component 130. Hole 132, in some cases, may be configured such that when in fluid communication with chamber 117, fluid disposed within chamber 117 can enter hole 132 and be in fluid communication with outlet 134.

[0087] In some cases, when the first spring component is in the first configuration, the side hole can be positioned outside of the chamber containing the liquid active pharmaceutical agent, hi some embodiments, when the spring is in the second configuration, the hole can be positioned adjacent to the chamber.

[0088] In some embodiments, the tissue interface component 130 does not include holes 132. In some embodiments, the tissue interface component may include a channel in a sidewall of the tissue interface component. The channel may have any suitable shape. For example, the shape may be any suitable cross-sectional shape, including circular, elliptical, triangular, irregular, trapezoidal, square, rectangular, or the like. One of ordinary skill in the art would be able to select the dimensions and / or shape of the channel based on the teachings herein.

[0089] The geometry and considerations of the tissue interfacing components are described in more detail below.

[0090] In some embodiments, after a certain period of time following activation of the self-actuating component, the tissue interface component may be configured to mechanically weaken, degrade, and / or dissolve. For example, at least a portion of the tissue interface component may include a material (e.g., gelatin) that mechanically weakens, degrades, and / or dissolves in the presence of biological fluids.

[0091] In some embodiments, the tissue interface component is configured to retract after a certain period of time following activation of the self-actuating component. In some embodiments, the first spring component is operable from a first configuration to a second configuration upon at least partial degradation of the support material, and when the first spring component is in the first configuration, the infusion needle is retained within the article. In some embodiments, the tissue interface component is configured to advance from the article into tissue of the subject (e.g., a lumen wall, etc.). For example, movement of the spring from the first configuration to the second configuration such that the tissue interface component contacts and / or penetrates tissue adjacent to the article.

[0092] In some embodiments, the tissue interface component extends through the chamber when the first spring is in the first configuration and / or when the first spring is in the second configuration.

[0093] In some embodiments, the tissue interface component may be retracted from the second configuration to the third configuration by actuation of a spring such that the tissue interface component no longer interfaces with tissue adjacent to the article.

[0094] The distance traveled by the tissue interface component, the shape of the tissue interface component, the length of the tissue interface component, and / or the angle of the outlet surface of the tissue interface component may be adjusted to facilitate the flow of fluids including active pharmaceutical agents as described herein.

[0095] In some embodiments, the self-actuating component may include a second support material configured to activate a second stage of the self-actuating component configured to interface with, for example, the fluid chamber, hi some embodiments, the self-actuating component may facilitate exit of the fluid from the fluid chamber into the inlet of the tissue interface component (e.g., by applying pressure to the fluid chamber).

[0096] In some embodiments, the fluid chamber (e.g., chamber 117 of FIG. 38) may be fluidly isolated, for example, until activation of the self-actuation component. In some embodiments, upon activation of the self-actuation component, the fluid chamber may be in fluid communication with at least a portion of the tissue interface component (e.g., an inlet of the tissue interface component).

[0097] In some embodiments, the chamber includes a movable wall. For example, in some embodiments, the movable wall can be configured to expel the liquid active pharmaceutical agent from the chamber. In some embodiments, the chamber includes a chamber wall (e.g., having a cross-sectional shape that is cylindrical, square, etc.). In some embodiments, the movable wall of the chamber includes a plunger slidably engaged with the chamber wall. In some embodiments, the chamber includes an end wall portion disposed opposite the movable wall. In some embodiments, the end wall includes a pierceable seal. In some embodiments, when the first spring component assumes the first configuration, the tissue-piercing end of the tissue interface component is embedded in the pierceable seal. In some embodiments, when the first spring component assumes the second configuration, the tissue interface component pierces the pierceable seal.

[0098] In some embodiments, the tissue interface component includes an injection needle.

[0099] In some embodiments, the actuation mechanism (e.g., a self-actuating component as described herein) includes a second spring component releasably held in a compressed state. In some embodiments, the second spring component is configured to release from the compressed state when the first spring component moves from the first configuration to the second configuration. For example, the first spring component moving from the first configuration to the second configuration may, in some cases, actuate a movable wall to expel the liquid active pharmaceutical agent from the chamber.

[0100] In some embodiments, the first spring component is coaxially disposed with the second spring component, such as radially within the second spring component (see FIG. 52). In some embodiments, the first spring component is coaxially disposed with the second spring component with at least partial axial overlap between the first and second spring components.

[0101] In some embodiments, the actuation mechanism includes a third spring component releasably held in a compressed state. In some embodiments, the third spring component is configured to release when all or a predetermined portion of the expellable liquid active pharmaceutical agent has been expelled from the chamber. In some embodiments, this release of the third spring component causes the tissue interface component to retract relative to the outer shell of the article (e.g., such that the tissue interface component is contained within the article).

[0102] In some embodiments, the third spring component is coaxially disposed with the first spring component, such as radially within the first spring component, hi some embodiments, the third spring component is coaxially disposed with the first spring component with at least partial axial overlap between the third spring component and the first spring component.

[0103] In some embodiments, as described in more detail below, the tissue interface component is at least partially soluble and / or mechanically softens after actuation / penetration.

[0104] In certain embodiments, the tissue interface component includes a jet injection component (e.g., for liquid jet injection using a high velocity stream into the tissue of a subject). In an exemplary embodiment, the jet injection component includes a chamber including a polymer portion. In certain embodiments, the polymer portion may include an acid (e.g., a weak acid) and / or a base. In some cases, a fluid (e.g., gastric fluids) may enter the chamber such that the fluid reacts with the acid and / or base to form a gas. In some cases, the chamber may include a coating (e.g., dissolves so that the fluid does not contact the polymer portion below the coating). In another exemplary embodiment, the jet injection component includes a plunger / piston (e.g., actuated by a spring associated with the plunger / piston) such that material is rapidly expelled from the system.

[0105] In some embodiments, the first spring component is configured to expel the liquid active pharmaceutical agent through the jet injection component at a permeation rate such that the liquid active pharmaceutical agent permeates at least a portion of tissue at a location within the subject's body (e.g., the gastric submucosa of the luminal wall).

[0106] In some embodiments, the articles / systems described herein are administered to a subject (e.g., orally). In certain embodiments, the systems may be administered orally, rectally, vaginally, nasally, or urethrally. In certain embodiments, upon reaching a location within the subject's body (e.g., the digestive tract), the spring stretches and / or at least a portion of the support material degrades such that the tissue interface component interfaces (e.g., contacts, penetrates) with tissue located within the subject's body. In some embodiments, the location within the subject's body is the colon, duodenum, ileum, jejunum, stomach, or esophagus. In some embodiments, the location within the subject's body includes a lumen (e.g., having a lumen wall). As described above and herein, in some embodiments, the active pharmaceutical ingredient may be released during and / or after penetration of a tissue located within the subject's body. For example, the articles and / or systems described herein may be suitable for ingestion into a lumen of a subject (e.g., for delivery of an active pharmaceutical agent in a lumen). Such a lumen may, in some cases, have a luminal wall associated with it (eg, such that an active pharmaceutical agent is infused / delivered to the luminal wall).

[0107] By way of example, and not wishing to be limited by such an exemplary set of embodiments, the system may be administered orally to a subject, where in some cases the system travels to the subject's stomach, sinks to the lower part of the subject's stomach, and the system self-heals such that a tissue-engaging surface of the system contacts stomach tissue (e.g., the system is at least partially supported by stomach tissue). For example, as illustrated diagrammatically in FIG. 3, an exemplary system 100 may be administered to a subject (e.g., orally) such that the system 100 enters the subject's digestive system 198. The system 100 may travel through the digestive system 198 until it reaches the subject's stomach 199 (system 100a). In some embodiments, the system 100 may sink to the lower part of the stomach 199 (system 100b) such that the system 100 contacts a surface of the stomach 199. In certain embodiments, system 100 self-heals such that tissue engaging surface 150 of system 100 contacts the surface of stomach 199 (system 100c), and system 100 self-actuates such that tissue interface component 130 interfaces with tissue at a location within the subject's body (e.g., surface 199 of the stomach). While Figure 3 illustrates the interface of the tissue interface component with the surface of stomach 199, one of ordinary skill in the art will understand based on the teachings herein that the tissue interface component may contact one or more layers beneath the surface of the stomach (or elsewhere within the subject's body), including, for example, the mucosal layer, the submucosal layer, and / or the muscle tissue layer(s).

[0108] In some cases, as described herein, the self-healing of system 100 may be driven by gravity (e.g., acting on the center of gravity of system 100). After a desired period of time, in some embodiments, system 100 disengages (e.g., tissue interface component 130 dissolves and / or releases) and exits stomach 199 (system 100d). The above description is not meant to be limiting, and one of ordinary skill in the art will appreciate that other interactions between the system and the subject's digestive system are possible, as described herein. In some embodiments, system 100 is a monostatic body, as described in more detail below.

[0109] In an exemplary embodiment, a self-healing article (or system) as described herein includes an outer shell having an outer shape including a circular cross-section, the outer shell defining a first axis, an actuation mechanism including a self-actuating component including a first spring component and a support material adapted to maintain the first spring component in an at least partially compressed state, the support material being configured to at least partially degrade in a biological fluid, and a chamber disposed within the outer shell, the chamber including a liquid active pharmaceutical agent. In some embodiments, a tissue interface component is disposed relative to the outer shell and configured to transport liquid from the chamber to a portion of tissue of a lumen wall at a location within the subject's body; The article is self-healing having a geometric center and a center of gravity, the center of gravity being offset from the geometric center in a first direction along a first axis.

[0110] The following description provides various embodiments of the self-healing, self-actuating, and relatively high API loaded components of the systems described herein.

[0111] self-healing As discussed above, in some embodiments, the self-healing article may include two or more portions having different average densities, such that the self-healing article may orient itself substantially perpendicular to a surface (e.g., a surface substantially perpendicular to the force of gravity, a surface of a tissue, such as the wall of the digestive tract). In some cases, the self-healing article may have a particular shape that enables the self-healing behavior of the article, for example. In some embodiments, the self-healing article may be disposed (e.g., encapsulated) within a capsule. In certain embodiments, the self-healing article is not provided in a capsule. In some embodiments, a capsule containing the self-healing article may be administered to a subject (e.g., for delivery of the self-healing article to a location within the subject's body, such as the digestive tract). In some embodiments, the self-healing article and / or capsule may include a pharmaceutical agent (e.g., for delivery of an active pharmaceutical agent to a location within the subject's body).

[0112] The self-healing articles described herein can be useful, for example, as a general platform for delivering a wide variety of pharmaceutical ingredients that are otherwise typically delivered by injection directly to tissues due to degradation in the digestive tract. In some embodiments, the self-healing articles described herein can be used, for example, to deliver sensors and / or perform biopsies without the need for endoscopy.

[0113] Advantageously, the self-healing article may be able to localize itself to the tissue wall in a particular orientation (e.g., allowing the loaded drug to avoid passing through the gastrointestinal fluids for a long time before diffusing into the bloodstream). As described herein, the article may in some cases serve as a platform to allow drugs currently degraded by enzymes in the gastrointestinal tract to be absorbed with higher bioavailability. In addition, the article may allow mechanical and electrical mechanisms, such as needle plungers, clasps, sensors, etc., to operate directly at and / or within the tissue wall. Thus, in certain embodiments, the article may serve as a vehicle for delivering electronic devices or other items into the gastrointestinal tract.

[0114] In some embodiments, the self-healing article may have a particular cross-sectional shape. In certain embodiments, the shape may be any suitable cross-sectional shape, including circular, elliptical, triangular, irregular, trapezoidal, square, or rectangular, etc. In certain embodiments, the self-healing article may be non-spherical. In some embodiments, the self-healing article may be monostatic and / or have only one stable point (e.g., the self-healing article may stably maintain a particular orientation in only one given direction). In an exemplary embodiment, the self-healing article has a rubber bock shape and / or includes a rubber bock shaped component. A self-healing article having a rubber bock shape may self-heal to a particular orientation without additional force upon displacement from the particular orientation. In some cases, the self-healing article may self-heal in a fluid (e.g., a liquid with a relatively low viscosity, a liquid with a relatively high viscosity). Advantageously, the shape is such that the self-healing article is described as predictably and quickly orienting the self-healing article while minimizing movement caused by forces inside the digestive tract. In some cases, at least a surface of the self-healing article comprises a flat surface. For example, as illustrated in Figures 1 and 2, in some embodiments, the tissue-engaging surface 150 can be flat.

[0115] Referring again to FIG. 1 , in some embodiments, the self-healing article includes a first portion 110 and a second portion 115 adjacent to the first portion 110 that have a different average density than the first portion and / or a different mass than the first portion. For example, in some embodiments, the self-healing article includes a first portion and a second portion adjacent to the first portion that have different average densities in the first portion. For example, the first portion can have a first average density and the second portion can have a second average density that is different from the first average density. In some embodiments, the ratio of the average density of the first portion to the average density of the second portion can be greater than 1:1, 2:1 or more, 2.5:1 or more, 3:1 or more, 3.5:1 or more, 4:1 or more, 4.5:1 or more, 5:1 or more, 5.5:1 or more, 5.5:1 or more, 6:1 or more, 6.5:1 or more, 7:1 or more, 8:1 or more, 9:1 or more, or 10:1 or more. In certain embodiments, the ratio of the average density of the first portion to the average density of the second portion can be 15:1 or less, 10:1 or less, 9:1 or less, 8:1 or less, 7:1 or less, 6.5:1 or less, 6:1 or less, 5.5:1 or less, 5:1 or less, 4.5:1 or less, 4:1 or less, 3.5:1 or less, 3:1 or less, 2.5:1 or less, 2:1 or less, or 1.5:1 or less. Combinations of the above-mentioned ranges are possible (e.g., 1:1 or more and 15:1 or less). Other ranges are also possible. Without wishing to be bound by theory, having a first portion and a second portion with different average densities can result in the auto-recovering article substantially maintaining a particular orientation(s) relative to a surface (e.g., the wall of the digestive tract).

[0116] In some embodiments, the ratio of the average density of the second portion to the average density of the first portion can be greater than 1:1, 2:1 or more, 2.5:1 or more, 3:1 or more, 3.5:1 or more, 4:1 or more, 4.5:1 or more, 5:1 or more, 5.5:1 or more, 5.5:1 or more, 6:1 or more, 6.5:1 or more, 7:1 or more, 8:1 or more, 9:1 or more, or 10:1 or more. In certain embodiments, the ratio of the average density of the second portion to the average density of the first portion can be 15:1 or less, 10:1 or less, 9:1 or less, 8:1 or less, 7:1 or less, 6.5:1 or less, 6:1 or less, 5.5:1 or less, 5:1 or less, 4.5:1 or less, 4:1 or less, 3.5:1 or less, 3:1 or less, 2.5:1 or less, 2:1 or less, or 1.5:1 or less. Combinations of the above-mentioned ranges are possible (eg, greater than or equal to 1:1 and less than or equal to 15:1). Other ranges are also possible.

[0117] In certain embodiments, a self-healing article includes a first portion and a second portion adjacent to the first portion having a different mass than the first portion. For example, the first portion can have a first mass and the second portion can have a second mass different from the first mass. In some embodiments, the ratio of the mass of the first portion to the mass of the second portion can be greater than 1:1, 2:1 or more, 2.5:1 or more, 3:1 or more, 3.5:1 or more, 4:1 or more, 4.5:1 or more, 5:1 or more, 5.5:1 or more, 5.5:1 or more, 6:1 or more, 6.5:1 or more, 7:1 or more, 8:1 or more, 9:1 or more, or 10:1 or more. In certain embodiments, the ratio of the mass of the first portion to the mass of the second portion can be 15:1 or less, 10:1 or less, 9:1 or less, 8:1 or less, 7:1 or less, 6.5:1 or less, 6:1 or less, 5.5:1 or less, 5:1 or less, 4.5:1 or less, 4:1 or less, 3.5:1 or less, 3:1 or less, 2.5:1 or less, 2:1 or less, or 1.5:1 or less. Combinations of the above-mentioned ranges are possible (e.g., 1:1 or more and 15:1 or less). Other ranges are also possible. Without wishing to be bound by theory, having a first portion and a second portion with different masses in the self-recovering article can result in the self-recovering article substantially maintaining a particular orientation(s) relative to a surface (e.g., the wall of the digestive tract).

[0118] In some embodiments, the ratio of the mass of the second portion to the mass of the first portion can be greater than 1:1, 2:1 or more, 2.5:1 or more, 3:1 or more, 3.5:1 or more, 4:1 or more, 4.5:1 or more, 5:1 or more, 5.5:1 or more, 5.5:1 or more, 6:1 or more, 6.5:1 or more, 7:1 or more, 8:1 or more, 9:1 or more, or 10:1 or more. In certain embodiments, the ratio of the mass of the second portion to the mass of the first portion can be 15:1 or less, 10:1 or less, 9:1 or less, 8:1 or less, 7:1 or less, 6.5:1 or less, 6:1 or less, 5.5:1 or less, 5:1 or less, 4.5:1 or less, 4:1 or less, 3.5:1 or less, 3:1 or less, 2.5:1 or less, 2:1 or less, or 1.5:1 or less. Combinations of the above-mentioned ranges are possible (eg, greater than or equal to 1:1 and less than or equal to 15:1). Other ranges are also possible.

[0119] 4, system 100 can include a first portion 110 and a second portion 120 adjacent to first portion 110. As used herein, when a portion is referred to as "adjacent" another portion, the portion can be directly adjacent (e.g., in contact with) the portion or there may be one or more intervening components (e.g., liquids, hollow portions). A portion "directly adjacent" another portion means that there are no intervening component(s).

[0120] For example, referring back to Figure 1, first portion 110 may occupy a first volume of the self-healing article having a first average density and / or mass, and second portion 115 may occupy the remaining volume of the self-healing article having a second average density and / or mass. In certain embodiments, referring back to Figure 4, first portion 110 may occupy a first volume of the self-healing article, second portion 115 may occupy a second volume of the self-healing article, and third portion 130 may be hollow and / or may include one or more (additional) components.

[0121] In some embodiments, the first portion occupies 1 vol% or more, 5 vol% or more, 10 vol% or more, 20 vol% or more, 25 vol% or more, 30 vol% or more, 40 vol% or more, 45 vol% or more, 50 vol% or more, 55 vol% or more, 60 vol% or more, 65 vol% or more, 70 vol% or more, 75 vol% or more, 80 vol% or more, 90 vol% or more, or 95 vol% or more of the total volume of the self-healing article. In certain embodiments, the first portion occupies 99 vol% or less, 95 vol% or less, 90 vol% or less, 80 vol% or less, 75 vol% or less, 70 vol% or less, 60 vol% or less, 55 vol% or less, 50 vol% or less, 45 vol% or less, 40 vol% or less, 30 vol% or less, 25 vol% or less, 20 vol% or less, 10 vol% or less, or 5 vol% or less of the total volume of the self-healing article. Combinations of the above-mentioned ranges are also possible (eg, greater than or equal to 1% and less than or equal to 99% by volume, greater than or equal to 40% and less than or equal to 60% by volume; other ranges are also possible.

[0122] In certain embodiments, the second portion occupies 1 vol% or more, 5 vol% or more, 10 vol% or more, 20 vol% or more, 25 vol% or more, 30 vol% or more, 40 vol% or more, 45 vol% or more, 50 vol% or more, 55 vol% or more, 60 vol% or more, 65 vol% or more, 70 vol% or more, 75 vol% or more, 80 vol% or more, 90 vol% or more, or 95 vol% or more, based on the total volume of the auto-recovering article. In some embodiments, the second portion occupies 99 vol% or less, 95 vol% or less, 90 vol% or less, 80 vol% or less, 75 vol% or less, 70 vol% or less, 60 vol% or less, 55 vol% or less, 50 vol% or less, 45 vol% or less, 40 vol% or less, 30 vol% or less, 25 vol% or less, 20 vol% or less, 10 vol% or less, or 5 vol% or less, based on the total volume of the auto-recovering article. Combinations of the above-mentioned ranges are also possible (eg, greater than or equal to 1% and less than or equal to 99% by volume, greater than or equal to 40% and less than or equal to 60% by volume; other ranges are also possible.

[0123] In some embodiments, the third portion (e.g., the hollow portion) occupies 1 vol% or more, 5 vol% or more, 10 vol% or more, 20 vol% or more, 25 vol% or more, 30 vol% or more, 40 vol% or more, 45 vol% or more, 50 vol% or more, 55 vol% or more, 60 vol% or more, 65 vol% or more, 70 vol% or more, 75 vol% or more, 80 vol% or more, 90 vol% or more, or 95 vol% or more of the total volume of the self-healing article. In certain embodiments, the third portion occupies 99 vol% or less, 95 vol% or less, 90 vol% or less, 80 vol% or less, 75 vol% or less, 70 vol% or less, 60 vol% or less, 55 vol% or less, 50 vol% or less, 45 vol% or less, 40 vol% or less, 30 vol% or less, 25 vol% or less, 20 vol% or less, 10 vol% or less, or 5 vol% or less of the total volume of the self-healing article. Combinations of the above-mentioned ranges are also possible (eg, greater than or equal to 1% and less than or equal to 99% by volume, greater than or equal to 40% and less than or equal to 60% by volume; other ranges are also possible.

[0124] In some embodiments, the self-healing article can include any suitable ratio of a first volume occupied by a first portion to a second volume occupied by a second portion. In certain embodiments, the ratio of the first volume to the second volume is 1:100 or more, 1:50 or more, 1:25 or more, 1:10 or more, 1:8 or more, 1:6 or more, 1:4 or more, 1:3 or more, 1:2 or more, 1:1.5 or more, 1:1.1 or more, 1:1 or more, 1.1:1 or more, 1.5:1 or more, 2:1 or more, 3:1 or more, 4:1 or more, 6:1 or more, 8:1 or more, 10:1 or more, 25:1 or more, or 50:1 or more. In certain embodiments, the ratio of the first volume to the second volume is 100:1 or less, 50:1 or less, 25:1 or less, 10:1 or less, 8:1 or less, 6:1 or less, 4:1 or less, 2:1 or less, 1.5:1 or less, 1.1:1 or less, 1:1 or less, 1:1.1 or less, 1:1.5 or less, 1:2 or less, 1:4 or less, 1:6 or less, 1:8 or less, 1:10 or less, 1:25 or less, or 1:50 or less. Combinations of the above-mentioned ranges are also possible (e.g., 1:100 or more and 100:1 or less, 1:10 or more and 10:1 or less, 1:2 or more and 2:1 or less). Other ranges are also possible. Other volume ratios are also possible. While not wishing to be bound by theory, in some embodiments, the ratio of a first volume occupied by a first portion to a second volume occupied by a second portion can be selected such that the center of gravity of the self-healing article has a single local minimum.

[0125] In some embodiments, the self-healing article is configured to be administered directly to a subject (e.g., without encapsulation in a capsule). In certain embodiments, the self-healing article is configured and arranged to be encapsulated in a capsule having a shell (e.g., exterior surface 170 of FIG. 4 includes a shell). In some such embodiments, referring now to FIG. 4, the self-healing article may include a third portion 130 (e.g., a hollow portion). In certain embodiments, a tissue interface component and / or an active pharmaceutical ingredient may be disposed within the hollow portion.

[0126] In some embodiments, the capsule is 000 capsules or less (e.g., the capsule has a shape or size as described in the USP, including, but not limited to, 000 capsules, 00 capsules, 0 capsules, 1 capsule, 2 capsules, 3 capsules, 4 capsules, or 5 capsules). In certain embodiments, the capsule at least partially encapsulates the first and second portions of the self-healing article. In some embodiments, multiple devices can be placed inside the capsule.

[0127] In some embodiments, the self-healing article may be configured to potentially be encapsulated in up to 10,000 capsules, although the self-healing article need not necessarily be encapsulated in such capsules. Thus, in embodiments in which the self-healing article is administered, such as by ingesting the self-healing article, the self-healing article may be administered without encapsulation.

[0128] In certain embodiments, the self-healing article may include a coating on at least a portion of the exterior surface of the self-healing article. In certain embodiments, a system (e.g., a system including a self-healing article) includes a coating (e.g., a film disposed on at least a surface of the system). In some embodiments, the coating may be applied as an aqueous or organic solvent-based polymer system, a fat, and / or a wax. In certain embodiments, the coating includes one or more of a polymer, a plasticizer, a colorant, a solvent, a fat, and a wax. Non-limiting examples of suitable fats and / or waxes include beeswax, carnauba wax, cetyl alcohol, and cetostearyl alcohol.

[0129] Non-limiting examples of polymers suitable for coating include cellulosics (e.g., hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxyethyl cellulose phthalate, ethyl cellulose, cellulose acetate phthalate, cellulose acetate trimellitate), vinyls (e.g., poly(vinylpyrrolidone), poly(vinyl alcohol), poly(vinyl alcohol), poly(vinylpyrrolidone)-poly(vinyl acetate) copolymers, poly(vinyl alcohol)-poly(ethylene glycol) copolymers, poly(vinyl acetate phthalate), glycols (e.g., poly(ethylene glycol)), acrylics (e.g., aminoalkyl methacrylate copolymers), other carbohydrates (e.g., maltodextrin, polydextrose), and combinations thereof.

[0130] Non-limiting examples of suitable colorants include natural pigments (e.g., riboflavin, beta carotene, carmine lake), inorganic pigments (e.g., titanium dioxide, iron oxide), water soluble dyes (FD&C Yellow #5, FD&C Blue #2), FD&C Lake (FD&C Yellow #5 Lake, FD&C Blue #2 Lake), and D&C Lake (D&C Yellow #10 Lake, D&C Red #30 Lake).

[0131] Non-limiting examples of suitable plasticizers include polyhydric alcohols (e.g., propylene glycol, glycerol, polyethylene glycol), acetates (e.g., triacetin, triethyl citrate, acetyltriethyl citrate), phthalates (e.g., diethyl phthalate), glycerides (e.g., acylated monoglycerides), and oils (e.g., castor oil, mineral oil).

[0132] The polymers, plasticizers, colorants, solvents, fats, and / or waxes may be combined in any suitable amounts to form the coating. The coating may be applied in any suitable manner, including, for example, dip coating and / or spraying. Other methods of depositing the coating are also possible.

[0133] In some embodiments, the tissue interface component is associated with a self-healing article. Non-limiting examples of tissue interface components include needles (e.g., stainless steel needles, needles containing an API), biopsy punches, microneedles (e.g., microneedles containing an API), projectiles, and the like.

[0134] In some embodiments, the tissue interface component includes a spring-actuated component. Such tissue interface components are generally described in co-pending International Patent Application No. WO2018 / 213600, entitled "SELF-RIGHTING SYSTEMS AND RELATED COMPONENTS AND METHODS," filed May 17, 2018, the entirety of which is incorporated herein by reference. For example, a self-healing article including a tissue interface component (e.g., a needle) may be administered to a subject such that the self-healing article is oriented at a location within the subject's body such that the tissue interface component pierces tissue adjacent to the location within the subject's body. In some such corrections, and active pharmaceutical ingredients associated with the self-healing article may be released into and / or adjacent to the tissue. In some embodiments, the tissue interface component may penetrate the tissue. In some embodiments, the tissue is penetrated with a force of 1 mN or more and 20,000 mN or less (eg, 10 mN or more and 20 mN or less, 10 mN or more and 100 mN or less, 100 mN or more and 20,000 mN or less, 5,000 mN or more and 20,000 mN or less).

[0135] In certain embodiments, the tissue interface component may be oriented within the self-healing article such that upon administration to a subject, the tissue interface component is aligned substantially perpendicular (e.g., within 15° of perpendicular) with a tissue (e.g., digestive mucosal tissue) within the subject's body. In some embodiments, the tissue interface component may be disposed within a hollow portion of the self-healing device such that the tissue interface component is released from the self-healing device along the longitudinal axis of the hollow portion. For example, referring again to FIG. 2, the self-healing article may have a longest longitudinal axis 180 aligned within 15 degrees of perpendicular to the tissue engaging surface 150. In certain embodiments, the longest longitudinal axis 180 is parallel to the major axis of the tissue interface component 130. In some embodiments, the tissue interface component 130 is released (e.g., upon activation of the self-actuating component 120 and / or the spring 125), which causes the spring 125 to expand along the longitudinal axis 180 and / or the tissue interface component to move parallel to the direction of the longitudinal axis 180. In some such embodiments, the tissue interface component may exit aperture 140 and enter the subject's tissue in a direction substantially parallel to longitudinal axis 180. However, in other embodiments, the tissue interface component is not aligned substantially orthogonally with the tissue within the subject's body.

[0136] In some embodiments, the self-healing article has its longest longitudinal axis oriented within 15 degrees or less, 10 degrees or less, 5 degrees or less, 2 degrees or less, or 1 degree or less from vertical when self-healing. In certain embodiments, the self-healing article has its longest longitudinal axis oriented within 0.1 degrees or more, 1 degree or more, 2 degrees or more, 5 degrees or more, or 10 degrees or more. Combinations of the above-mentioned ranges are also possible (e.g., 0.1 degrees or more and 15 degrees or less). Other ranges are also possible.

[0137] In certain embodiments, the tissue interface component has its longest longitudinal axis oriented within 15 degrees or less, 10 degrees or less, 5 degrees or less, 2 degrees or less, or 1 degree or less from vertical when self-healing. In some embodiments, the tissue interface component has its longest longitudinal axis oriented within 0.1 degrees or more, 1 degree or more, 2 degrees or more, 5 degrees or more, or 10 degrees or more. Combinations of the above-mentioned ranges are also possible (e.g., 0.1 degrees or more and 15 degrees or less). Other ranges are also possible.

[0138] In some embodiments, the hollow portion may be cylindrical in shape. Other shapes are also possible.

[0139] In an exemplary embodiment, the tissue interface component includes multiple microneedles. In another exemplary embodiment, the tissue interface component includes a single needle. In yet another exemplary embodiment, the tissue interface component includes a biopsy component (e.g., a biopsy jaw). In some cases, the tissue interface component may include a retention mechanism (e.g., hooks, mucoadhesives). The tissue interface component is described in more detail below.

[0140] As discussed above, in some embodiments, the first portion includes a first material having a first average density. In some embodiments, the first material and / or the second material may be selected to impart a particular mass and / or density to the first portion and / or the second portion.

[0141] In some embodiments, the average density of the first portion is 2 g / mL or less, 1.8 g / mL or less, 1.6 g / mL or less, 1.4 g / mL or less, 1.2 g / mL or less, 1 g / mL or less, 0.8 g / mL or less, 0.6 g / mL or less, 0.4 g / mL or less, 0.2 g / mL or less, 0.1 g / mL or less, 0.05 g / mL or less, or 0.02 g / mL or less. In certain monuments, the first portion has an average density of 0.01 g / mL or more, 0.02 g / mL or more, 0.05 g / mL or more, 0.1 g / mL or more, 0.2 g / mL or more, 0.4 g / mL or more, 0.6 g / mL or more, 0.8 g / mL or more, 1 g / mL or more, 1.2 g / mL or more, 1.4 g / mL or more, 1.6 g / mL or more, or 1.8 g / mL or more. Combinations of the above-mentioned ranges are also possible (e.g., greater than or equal to 0.01 g / mL and less than or equal to 2 g / mL, greater than or equal to 0.6 g / mL and less than or equal to 2 g / mL). Other ranges are also possible.

[0142] In certain embodiments, the second portion includes a second material having a second average density (e.g., different from the first average density). In some embodiments, the average density of the second portion (e.g., and / or the second material) is 20 g / mL or less, 18 g / mL or less, 16 g / mL or less, 14 g / mL or less, 12 g / mL or less, 10 g / mL or less, 8 g / mL or less, 6 g / mL or less, 4 g / mL or less, or 3 g / L or less. In certain embodiments, the average density of the second portion is 2 g / mL or more, 3 g / mL or more, 4 g / mL or more, 6 g / mL or more, 8 g / mL or more, 10 g / mL or more, 12 g / mL or more, 14 g / mL or more, 16 g / mL or more, or 18 g / mL or more. Combinations of the above-mentioned ranges are also possible (e.g., 2 g / mL or more and 20 g / mL or less). Other ranges are also possible. In some embodiments, the second portion may have one or more of the ranges of average density described above in connection with the first portion (e.g., greater than or equal to 0.6 g / mL and less than or equal to 2 g / mL) and is different from the average density of the first portion.

[0143] The first and second portions may be selected to have any suitable mass. In some embodiments, the first portion may have a total mass (e.g., including all components in the first portion) of 20 mg or more, 50 mg or more, 75 mg or more, 100 mg or more, 200 mg or more, 300 mg or more, 400 mg or more, 500 mg or more, 750 mg or more, 1 g or more, 1.5 g or more, 2 g or more, 3 g or more, 4 g or more, 5 g or more, 7 g or more, 10 g or more, 15 g or more, including any mass between 20 mg and 15 g. In certain embodiments, the first portion may have a total mass of 15 g or less, 10 g or less, 7 g or less, 5 g or less, 4 g or less, 3 g or less, 2 g or less, 1.5 g or less, 1 g or less, 750 mg or less, 500 mg or less, 400 mg or less, 300 mg or less, 200 mg or less, 100 mg or less, 75 mg or less, 50 mg or less, 20 mg or less, including any mass between 15 g and 20 mg. Combinations of the above-mentioned ranges are also possible (e.g., 50 mg or more and 4 g or less, 50 mg or more and 15 g or less). In some embodiments, the first portion or the second portion has a mass in the range of 20 mg or more and 1 g or less. In some embodiments, the first portion or the second portion has a mass in the range of 300 mg or more and 12 g or less. In some embodiments, the first or second portion has a mass in the range of 100 mg or more and 250 mg or less. In some embodiments, the first or second portion has a mass in the range of 20 mg or more and 15 g or less. In some embodiments, the first or second portion has a mass in the range of 1.5 or more and 6.5 g or less. Other ranges are also possible.

[0144] In certain embodiments, the second portion may have a total mass (e.g., including all components in the second portion) of 50 mg or more, 75 mg or more, 100 mg or more, 200 mg or more, 400 mg or more, 500 mg or more, 750 mg or more, 1 g or more, 1.5 g or more, 2 g or more, 3 g or more, 4 g or more, 5 g or more, 7 g or more, or 10 g or more. In certain embodiments, the second portion may have a total mass of 15 g or less, 10 g or less, 7 g or less, 5 g or less, 4 g or less, 3 g or less, 2 g or less, 1.5 g or less, 1 g or less, 750 mg or less, 500 mg or less, 400 mg or less, 200 mg or less, 100 mg or less, or 75 mg or less. Combinations of the above-mentioned ranges are also possible (e.g., 50 mg or more and 4 g or less, 50 mg or more and 15 g or less). Other ranges are also possible.

[0145] In some embodiments, the first material and / or the second material are selected from the group consisting of polymers, ceramics, metals, and combinations thereof (e.g., metal-filled polymers). In some cases, the first material and / or the second material may be biocompatible. In some cases, the metal may be selected from the group consisting of stainless steel, iron-carbon alloys, Field's metal, Wolfram, molybdenum, gold, zinc, iron, and titanium.

[0146] In some embodiments, the ceramic may be selected from the group consisting of hydroxyapatite, aluminum oxide, calcium oxide, tricalcium phosphate, silicates, silicon dioxide, and zirconium oxide.

[0147] In certain embodiments, the polymer may be selected from the group consisting of polycaprolactone, polylactic acid, polyethylene glycol, polypropylene, polyethylene, polycarbonate, polystyrene, and polyetheretherketone, acrylonitrile-butadiene styrene, amorphous polyetherimide, and polyvinyl alcohol.

[0148] In an exemplary embodiment, the first material comprises a metal and the second material comprises a polymer.

[0149] A self-healing article generally has a geometric center (e.g., a center of geometric volume). In some embodiments, a self-healing article has a geometric center and a center of gravity, the center of gravity being offset from the geometric center in a first direction along a first axis. In some embodiments, when the article is supported by a tissue of a subject (e.g., a lumen wall) while oriented such that the center of gravity is laterally offset from the geometric center, the article is subjected to an externally applied torque due to gravitational action, which orients the article with the first axis oriented along the direction of gravity. In some such embodiments, the tissue-engaging surface interacts with tissue at a location within the subject (e.g., such that the tissue-interfacing component may interface with tissue).

[0150] In certain embodiments, the density, mass, and / or volume of the first and / or second portions can be selected such that the self-healing article exhibits self-healing behavior. For example, in some embodiments, the center of gravity of the self-healing article can be offset from the geometric center from the vertical such that the center of gravity is offset laterally from the geometric center such that an article suspended via an axis passing through the geometric center is configured to maintain an orientation of 20 degrees or less from the vertical when subjected to an externally applied torque of 0.09*10^-4 Nm or less.

[0151] In some embodiments, the self-recovering article maintains an orientation of 20° or less from the vertical when subjected to an externally applied torque of 0.09*10^-4 Nm or less. In certain embodiments, the self-recovering article maintains an orientation of 15° or less, 12° or less, 10° or less, 8° or less, 6° or less, 4° or less, or 2° or less from the vertical when subjected to an externally applied torque of 0.09*10^-4 Nm or less. In some embodiments, the self-recovering article maintains an orientation of 1° or more, 2° or more, 4° or more, 6° or more, 8° or more, 10° or more, 12° or more, or 15° or more from the vertical when subjected to an externally applied torque of 0.09*10^-4 Nm or less. Combinations of the above-mentioned ranges are also possible (e.g., 20° or less and 1° or more). Other ranges are also possible.

[0152] In some embodiments, a self-healing article may be characterized as having a particular self-healing time from 90° in a particular fluid. The self-healing time may be determined by placing the self-healing article at 90° in a particular fluid and allowing the self-healing article to return to a particular orientation otherwise maintained by the self-healing article in the absence of fluid (e.g., an orientation that corresponds to a stable equilibrium point (or orientation) of the article).

[0153] In certain embodiments, the fluid is oil. In some such embodiments, the self-healing article has a self-healing time from 90° in oil of 0.15 seconds or less, 0.1 seconds or less, 0.05 seconds or less, or 0.02 seconds or less. In certain embodiments, the self-healing article has a self-healing time from 90° in oil of 0.01 seconds or more, 0.02 seconds or more, 0.05 seconds or more, 0.1 seconds or more, or 0.12 seconds or more. Combinations of the above-mentioned ranges are also possible (e.g., 0.15 seconds or less and 0.01 seconds or more). Other ranges are also possible. The self-healing time in oil is determined by fully immersing the system / article.

[0154] In some embodiments, the fluid is gastric fluid. In some such embodiments, the self-healing article has a self-healing time from 90° in gastric fluid of 0.06 seconds or less, 0.05 seconds or less, 0.04 seconds or less, 0.03 seconds or less, or 0.02 seconds or less. In certain embodiments, the self-healing article has a self-healing time from 90° in gastric fluid of 0.005 seconds or more, 0.01 seconds or more, 0.02 seconds or more, 0.03 seconds or more, 0.04 seconds or more, or 0.05 seconds or more. Combinations of the above-mentioned ranges are also possible (e.g., 0.06 seconds or less and 0.005 seconds or more). Other ranges are also possible. The self-healing time in gastric fluid is determined by fully immersing the system / article.

[0155] In certain embodiments, the fluid is mucus. In some such embodiments, the self-healing article has a self-healing time from 90° in mucus of 0.05 seconds or less, 0.04 seconds or less, 0.03 seconds or less, or 0.02 seconds or less. In certain embodiments, the self-healing article has a self-healing time from 90° in mucus of 0.005 seconds or more, 0.01 seconds or more, 0.02 seconds or more, 0.03 seconds or more, 0.04 seconds or more, or 0.045 seconds or more. Combinations of the above-mentioned ranges are also possible (e.g., 0.05 seconds or less and 0.005 seconds or more). Other ranges are also possible. The self-healing time in mucus is determined by fully immersing the system / article.

[0156] In some embodiments, the fluid is water. In some such embodiments, the self-healing article has a self-healing time from 90° in water of 0.05 seconds or less, 0.04 seconds or less, 0.03 seconds or less, or 0.02 seconds or less. In certain embodiments, the self-healing article has a self-healing time from 90° in water of 0.005 seconds or more, 0.01 seconds or more, 0.02 seconds or more, 0.03 seconds or more, 0.04 seconds or more, or 0.045 seconds or more. Combinations of the above-mentioned ranges are also possible (e.g., 0.05 seconds or less and 0.005 seconds or more). Other ranges are also possible. The self-healing time in water is determined by fully immersing the system / article.

[0157] In some embodiments, the self-healing article includes one or more vents (e.g., to allow air and / or fluid flow through the self-healing article). In some embodiments, the self-healing article includes one or more (e.g., two or more, three or more, four or more) vents associated with at least a portion (e.g., first portion, second portion) of the self-healing article. In some such embodiments, the vents may allow fluid (e.g., gastric fluids) to enter at least a portion of the self-healing article, such that, for example, the self-actuating component and / or spring are exposed to the fluid (e.g., the self-actuating component and / or spring are actuated). For example, referring again to FIG. 2, the system 102 includes a vent 190 associated with at least a portion (e.g., first portion 110) of the self-healing article. In some cases, the vent(s) 190 may be in fluid communication with the self-actuating component 120, the support material 160, and / or the spring 125. Although the vents are depicted herein as being associated with a first portion of the self-healing article, in some embodiments, a person of ordinary skill in the art based on the teachings herein will understand that one or more vents can be associated with a second portion of the self-healing article.

[0158] In some embodiments, one or more vents (e.g., vent 190 in FIG. 2) may include a fluid gate (e.g., a plug, coating, barrier). In some cases, the fluid gate may prevent fluid (e.g., fluid outside the system) from entering the system at the vent until a desired time. In certain embodiments, the fluid gate includes a barrier material. Non-limiting examples of suitable barrier materials include polycaprolactone foil, thermoplastic elastomers, silicones, cellulosics (e.g., hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxyethyl cellulose phthalate, ethyl cellulose, cellulose acetate phthalate, cellulose acetate trimellitate), vinyls (e.g., poly(vinylpyrrolidone), poly(vinyl alcohol), poly(vinyl alcohol), poly(vinylpyrrolidone)-poly(vinyl acetate) copolymer, poly(vinyl alcohol)-poly(ethylene glycol) copolymer, poly(vinyl acetate phthalate), glycols (e.g., For example, poly(ethylene glycol)), acrylics (e.g., aminoalkyl methacrylate copolymers), other carbohydrates (e.g., maltodextrin, polydextrose), and combinations thereof. The barrier material may include one or more hydrophilic materials. The barrier material may include one or more hydrophobic materials. One of ordinary skill in the art would be able to select a suitable hydrophilic or hydrophobic material as the barrier material based on the teachings herein. In certain embodiments, at least one of the one or more vents (e.g., at least one, at least two, all of the vents) does not include a fluid gate (e.g., the vent is open).

[0159] In certain embodiments, the auto-recovery article does not include a vent.

[0160] In some embodiments, the self-healing article may have a particular large cross-sectional dimension. In some embodiments, the largest cross-sectional dimension of the self-healing article is 2.0 cm or less, 1.8 cm or less, 1.6 cm or less, 1.4 cm or less, 1.2 cm or less, 1.1 cm or less, 1 cm or less, 0.8 cm or less, 0.6 cm or less, 0.4 cm or less, or 0.2 cm or less, including any dimension less than 2.0 cm (e.g., 0.1 cm, 0.3 cm, 0.5 cm...1.7 cm, etc.). In certain embodiments, the largest cross-sectional dimension of the self-healing article is 0.1 cm or more, 0.2 cm or more, 0.4 cm or more, 0.6 cm or more, 0.8 cm or more, 1 cm or more, 1.2 cm or more, 1.4 cm or more, 1.6 cm or more, 1.8 cm or more, including any dimension greater than 0.1 cm and less than 2.0 cm (e.g., 0.3 cm, 0.5 cm...1.7 cm, 1.9 cm, etc.). Combinations of the above-mentioned ranges are also possible (eg, less than or equal to 2 cm and more than or equal to 0.1 cm, less than or equal to 1.1 cm and more than or equal to 0.1 cm). Other ranges are also possible.

[0161] In some embodiments, the self-healing article can be administered (e.g., orally) to a subject. In some such embodiments, the self-healing article can include one or more active pharmaceutical ingredients. In certain embodiments, the active pharmaceutical ingredients are released at a location within the subject's body (e.g., in the digestive tract).

[0162] In certain embodiments, one or more sensors may be associated with the self-healing article. For example, in some cases, one or more sensors may be used to determine the location of the self-healing article (e.g., a location within a subject's body) and / or trigger the actuation of one or more tissue interface components associated with the self-healing article. Non-limiting examples of suitable sensors include pH, gas, light, GPS, Bluetooth, orientation, proximity, heat, fluid, etc.

[0163] In some cases, one or more of the first portion and / or the second portion may be magnetic.

[0164] In an exemplary embodiment, the self-healing article is ingestible. According to certain embodiments, the ingestible self-healing article includes a first portion having an average density, a second portion having an average density different from the average density of the first portion, and a payload portion for carrying an agent for release into the body of a subject ingesting the article. In certain embodiments, the self-healing article has a density of less than 1 g / cm 3 The self-healing article includes at least a first portion having an average density of greater than 1.001 mm. According to certain embodiments, the ratio of the average density of the first portion to the average density of the second portion is 2.5:1 or greater. In certain exemplary embodiments, the self-healing article includes a first portion including a first material having a first average density and a second portion including a second material having a second average density different from the first average density. In certain embodiments, the self-healing article includes a first material, a second material different from the first material, and an active pharmaceutical agent associated with the self-healing article. According to some embodiments, the ratio of the average density of the first material to the average density of the second material is 2.5:1 or greater. In some embodiments, the self-healing article has a maximum cross-sectional dimension of less than or equal to 1.1 cm.

[0165] In certain embodiments, the article has a geometric center and a center of gravity offset from the geometric center such that the center of gravity is offset laterally from the geometric center such that an article suspended via an axis passing through the geometric center experiences an externally applied torque of 0.09*10^-4 Nm or less about the axis due to gravity. According to some embodiments, the self-healing article is configured to be encapsulated in a capsule of 000 or less. In other embodiments, the self-healing article is not encapsulated. In certain embodiments, the self-healing article includes a tissue-interfacing component associated with the self-healing article. Some exemplary embodiments relate to an axis essentially perpendicular to the tissue-engaging surface of the self-healing article configured to maintain an orientation of 20 degrees or less from the vertical when subjected to an externally applied torque of 0.09*10^-4 Nm or less. According to some embodiments, the self-healing article has a most stable, lowest potential energy physical configuration and a self-healing time in water of 0.05 seconds or less from a 90 degree offset in any orientation from the most stable configuration. According to certain embodiments, the self-healing article has a blockage rate of 1% or less (eg, 0.5% or less, 0.1% or less).

[0166] Certain exemplary embodiments relate to a method of delivering a pharmaceutical agent to a location within a subject. According to some embodiments, the method includes administering to a subject a capsule including an outer shell and a self-healing article, and orienting the self-healing article at the location within the subject such that the tissue interface component pierces tissue adjacent to the location within the subject.

[0167] Tissue retention In some embodiments, the article (e.g., a self-healing article) may be configured to retain at a location within a subject's body (e.g., tissue at a location within a subject's body). As described above, in some embodiments, the self-healing article may include one or more tissue-interfacing components including one or more retention features (e.g., hooks, mucoadhesives). Hooks are described in more detail below. Mucoadhesives are described in more detail below. In an exemplary embodiment, the self-healing article may have a longitudinal axis perpendicular to the tissue-engaging surface of the article, in some cases configured to maintain an orientation of 20 degrees or less from the vertical when subjected to an externally applied torque of 0.09*10^-4 Nm or less and at least one retention feature associated with the self-healing article. In another exemplary embodiment, the article may include a spring associated with (e.g., in direct contact with and at least partially encapsulated by) a support material (e.g., such that the spring is maintained in an at least partially compressed state by the support material under a compressive strain of at least 5%) and at least one retention feature operably coupled to the spring. The springs and support materials are described in more detail below. Other embodiments are also possible that include at least one retaining mechanism associated with the self-healing article and / or the self-actuating component.

[0168] In some embodiments, the retaining mechanism includes a hook (e.g., a hook-shaped needle). For example, as illustrated in FIG. 5, the system 104 includes a first portion 110 and a second portion 115. In certain embodiments, a tissue engaging surface 150 is associated with the second portion 115. In some cases, the system 104 may include a tissue interface component 130 that includes a retaining mechanism 135. In some embodiments, the retaining mechanism 135 may be a hook. In certain embodiments, the retaining mechanism 135 may be disposed internally within the system 104 and released (e.g., via holes 140) under a desired set of conditions (e.g., at a particular location within the subject's body). In certain embodiments not depicted in FIG. 5, the hook 135 may be disposed on an exterior surface of the system 104.

[0169] 6, in certain embodiments, the system 106 includes a retaining mechanism 135 associated with a self-actuating component 120 (e.g., including a spring 125 and / or a support material 160). In certain embodiments, upon exposure to fluid (e.g., gastric fluids) and / or under a particular set of conditions (e.g., physiological conditions of the digestive tract, such as in the stomach), the self-actuating component is actuated to insert the retaining mechanism into tissue located within the subject's body.

[0170] In some embodiments, the retaining feature (and / or article including the retaining feature) is configured to be retained at a location within a subject's body. For example, in some embodiments, the retaining feature engages a surface (e.g., a surface of tissue) at a location within the subject's body to be retained at the location.

[0171] Advantageously, a system including one or more retention mechanisms described herein may be inserted onto the surface of tissue at a location within a subject's body and may maintain contact with the tissue under relatively high applied forces and / or relatively high changes in orientation (e.g., by compressive forces exerted by the digestive tract and / or under high flow rates within the digestive tract). In some embodiments, the systems described herein do not substantially block an opening within the digestive tract (e.g., within the pylorus), e.g., regulating flow and allowing for longer contact times. In certain embodiments, natural refilling of the walls of the digestive tract may permit the desired disengagement and / or expulsion of the systems described herein without the need for surgical and / or endoscopic retrieval.

[0172] For example, in some embodiments, the retention mechanism may be inserted into the surface of tissue at a location within the subject's body and may maintain contact with the tissue (e.g., the system remains retained) under a change in the orientation of the system of 1 degree or more, 2 degrees or more, 5 degrees or more, 10 degrees or more, 15 degrees or more, 20 degrees or more, 25 degrees or more, 30 degrees or more, 45 degrees or more, 60 degrees or more, 75 degrees or more, or 85 degrees or more. In certain embodiments, the system may remain retained under a change in the orientation of the system of 90 degrees or less, 85 degrees or less, 75 degrees or less, 60 degrees or less, 45 degrees or less, 30 degrees or less, 25 degrees or less, 20 degrees or less, 15 degrees or less, 10 degrees or less, 5 degrees or less, or 2 degrees or less. Combinations of the above-mentioned ranges are also possible (e.g., 1 degree or more and 90 degrees or less, 1 degree or more and 45 degrees or less, 2 degrees or more and 30 degrees or less). Other ranges are also possible.

[0173] In certain embodiments, the system (e.g., including the retaining features) is configured to be retained at a location within a subject's body under a normal retention force of 0.002 N or more, 0.004 N or more, 0.006 N or more, 0.008 N or more, 0.01 N or more, 0.012 N or more, 0.014 N or more, 0.016 N or more, 0.018 N or more, 0.02 N or more, 0.025 N or more, 0.03 N or more, 0.04 N or more, 0.05 N or more, 0.1 N or more, 0.15 N or more, 0.2 N or more, 0.25 N or more, 0.3 N or more, 0.35 N or more, 0.4 N or more, 0.5 N or more, 0.6 N or more, 0.7 N or more, 0.8 N or more, or 0.9 N or more, applied in the normal direction per retaining feature. In some embodiments, the system has a normal retention force of 1 N or less, 0.9 N or less, 0.8 N or less, 0.7 N or less, 0.6 N or less, 0.5 N or less, 0.4 N or less, 0.35 N or less, 0.3 N or less, 0.25 N or less, 0.2 N or less, 0.15 N or less, 0.1 N or less, 0.05 N or less, 0.04 N or less, 0.03 N or less, 0.025 N or less, 0.02 N or less, 0.018 N or less, 0.016 N or less, 0.014 N or less, 0.012 N or less, 0.01 N or less, 0.008 N or less, 0.006 or less, or 0.004 N or less, applied in the normal direction per retaining feature. Combinations of the above mentioned ranges are also possible (e.g., 0.002N or more and 1N or less, 0.02N or more and 0.08N or less, 0.1N or more and 1N or less). Other ranges are also possible. The normal retention force as described herein can be determined by inserting the retaining mechanism of the system into a tissue surface (e.g., ex vivo pig stomach) to a penetration depth of at least 0.9 mm and then pulling the system in a direction perpendicular to the tissue surface until the system detaches from the tissue. The maximum force before the system is removed is the normal retention force.

[0174] In some embodiments, the system (e.g., including the retaining features) is configured to be retained at a location within a subject's body under an orthogonal retention force of 0.002 N or more, 0.004 N or more, 0.006 N or more, 0.008 N or more, 0.01 N or more, 0.012 N or more, 0.014 N or more, 0.016 N or more, 0.018 N or more, 0.02 N or more, 0.025 N or more, 0.03 N or more, 0.04 N or more, 0.05 N or more, 0.1 N or more, 0.15 N or more, 0.2 N or more, 0.25 N or more, 0.3 N or more, 0.35 N or more, 0.4 N or more, 0.5 N or more, 0.6 N or more, 0.7 N or more, 0.8 N or more, or 0.9 N or more, applied in a normal direction per retaining feature. In some embodiments, the system has an orthogonal retention force of 1 N or less, 0.9 N or less, 0.8 N or less, 0.7 N or less, 0.6 N or less, 0.5 N or less, 0.4 N or less, 0.35 N or less, 0.3 N or less, 0.25 N or less, 0.2 N or less, 0.15 N or less, 0.1 N or less, 0.05 N or less, 0.04 N or less, 0.03 N or less, 0.025 N or less, 0.02 N or less, 0.018 N or less, 0.016 N or less, 0.014 N or less, 0.012 N or less, 0.01 N or less, 0.008 N or less, 0.006 or less, or 0.004 N or less, applied in the normal direction per retaining feature. Combinations of the above mentioned ranges are also possible (e.g., 0.002N or more and 1N or less, 0.02N or more and 0.08N or less, 0.1N or more and 1N or less). Other ranges are also possible. The orthogonal retention force as described herein can be determined by inserting the retaining mechanism of the system into the surface of tissue (e.g., ex vivo pig stomach) to a penetration depth of at least 0.9 mm and then applying a force to the system in a direction parallel to the surface of the tissue until the system detaches from the tissue (see, e.g., FIG. 64). The maximum force before the system is removed is the orthogonal retention force.

[0175] In some embodiments, the system is configured to remain anchored to a surface of tissue located within a subject's body under an orientation change of 30 degrees or less and an applied (e.g., normal, orthogonal) force of 1 N or less.

[0176] In some embodiments, the system includes two or more retention features. In some cases, the system may include a single self-healing article that includes two or more retention features. In certain embodiments, the system includes two or more self-healing articles, each including one or more retention features. In certain embodiments, the force required to remove a retention feature (e.g., normal retention force, orthogonal retention force) may be increased by increasing the number of retention features associated with the system. Without wishing to be bound by theory, the spacing between retention features may be related to the retention force (e.g., normal retention force, orthogonal retention force) of the system.

[0177] In some embodiments, the system may have an average spacing between retention features of 0.1 mm or more, 0.2 mm or more, 0.3 mm or more, 0.4 mm or more, 0.5 mm or more, 0.6 mm or more, 0.7 mm or more, 0.8 mm or more, 0.9 mm or more, 1 mm or more, 1.2 mm or more, 1.4 mm or more, 1.5 mm or more, 1.6 mm or more, 1.8 mm or more, or 2 mm or more. In certain embodiments, the system may have an average spacing between retention features of 2.5 mm or less, 2 mm or less, 1.8 mm or less, 1.6 mm or less, 1.4 mm or less, 1.2 mm or less, 1 mm or less, 0.9 mm or less, 0.8 mm or less, 0.7 mm or less, 0.6 mm or less, 0.5 mm or less, 0.4 mm or less, 0.3 mm or less, or 0.2 mm or less. Combinations of the above-mentioned ranges are also possible (e.g., 0.1 mm or more and 2.5 mm or less, 1 mm or more and 1.5 mm or less). Other ranges are also possible.

[0178] The retention feature may have any suitable size and / or shape. For example, in some embodiments, the maximum dimension (e.g., length) of the tissue interface component including the retention feature may be 1 cm or less, 0.8 cm or less, 0.6 cm or less, 0.5 cm or less, 0.4 cm or less, 0.3 cm or less, 0.25 cm or less, 0.23 cm or less, or 0.2 cm or less. In certain embodiments, the maximum dimension (e.g., length) of the tissue interface component including the retention feature may be 0.15 cm or more, 0.2 cm or more, 0.23 cm or more, 0.25 cm or more, 0.3 cm or more, 0.4 cm or more, 0.5 cm or more, 0.6 cm or more, or 0.8 cm or more. Combinations of the above-mentioned ranges are also possible (e.g., 0.2 cm or more and 1 cm or less, 0.15 cm or more and 1 cm or less). Other ranges are also possible.

[0179] In some embodiments, the retention feature has a particular retention length. By way of example, for a retention feature that includes a hook, the retention length corresponds to the maximum cross-sectional dimension of the bent length of the hook (e.g., the diameter of the hook not including the unbent portion). In certain embodiments, the retention length is 10 microns or more, 20 microns or more, 23 microns or more, 25 microns or more, 30 microns or more, 34 microns or more, 35 microns or more, 40 microns or more, 50 microns or more, 60 microns or more, 70 microns or more, 80 microns or more, 90 microns or more, 100 microns or more, 120 microns or more, 140 microns or more, 160 microns or more, 180 microns or more, 200 microns or more, or 225 microns or more. In certain embodiments, the fastener length is 250 microns or less, 225 microns or less, 200 microns or less, 180 microns or less, 160 microns or less, 140 microns or less, 120 microns or less, 100 microns or less, 90 microns or less, 80 microns or less, 70 microns or less, 60 microns or less, 50 microns or less, 40 microns or less, 30 microns or less, or 20 microns or less. Combinations of the above-mentioned ranges are also possible (e.g., 10 microns or more and 250 microns or less). Other ranges are also possible.

[0180] In some cases, the retention feature may be configured to have an optimal penetration depth (e.g., the depth to which the retention feature is disposed below the surface of the tissue located within the subject's body). In some embodiments, the retention feature has a penetration depth of 0.5 mm or more, 0.6 mm or more, 0.7 mm or more, 0.8 mm or more, 0.9 mm or more, 1 mm or more, 1.2 mm or more, 1.4 mm or more, 1.5 mm or more, 1.7 mm or more, 1.9 mm or more, 2 mm or more, 2.2 mm or more, 2.4 mm or more, 2.5 mm or more, 3 mm or more, 3.5 mm or more, 4 mm or more, 4.5 mm or more, or 5 mm or more. In certain embodiments, the retaining mechanism has a penetration depth of 6 mm or less, 5 mm or less, 4.5 mm or less, 4 mm or less, 3.5 mm or less, 3 mm or less, 2.5 mm or less, 2.4 mm or less, 2.2 mm or less, 2 mm or less, 1.9 mm or less, 1.7 mm or less, 1.5 mm or less, 1.4 mm or less, 1.2 mm or less, 1 mm or less, 0.9 mm or less, 0.8 mm or less, 0.7 mm or less, or 0.6 mm or less. Combinations of the above-mentioned ranges are also possible (e.g., 0.5 mm or more and 6 mm or less, 0.9 mm or more and 2.5 mm or less). Other ranges are also possible. Without wishing to be bound by theory, the tissue displacement may be greater than or equal to the penetration depth of the retaining mechanism. By way of example only, in a particular set of embodiments, the retaining mechanism may displace tissue up to 14 mm to achieve a penetration depth of, for example, up to 4 mm.

[0181] Advantageously, the system including the retention mechanism described herein can be retained for a relatively long period of time under physiological conditions and fluid flow (e.g., exposed to a fluid flowing at approximately 0.1 m / sec). For example, in some embodiments, the system including the retention mechanism is retained on the surface of tissue located inside the subject's body for 1 hour or more, 2 hours or more, 4 hours or more, 8 hours or more, 12 hours or more, 24 hours or more, 2 days or more, 3 days or more, 5 days or more, 7 days or more, or 10 days or more. In certain embodiments, the system is retained for 14 days or less, 10 days or less, 7 days or less, 5 days or less, 3 days or less, 2 days or less, 24 hours or less, 12 hours or less, 8 hours or less, 4 hours or less, or 2 hours or less. Combinations of the above-mentioned ranges are also possible (e.g., 1 hour or more and 14 days or less). Other ranges are also possible. In some cases, the retention mechanism can be configured to be retained for a relatively very long period of time under physiological conditions and fluid flow. For example, in certain embodiments, the retention mechanism can be retained on the surface of the tissue location in the subject's body for 1 month or more, 2 months or more, 3 months or more, 6 months or more, or 1 year or more. In some embodiments, the retention mechanism can be retained on the surface of the tissue location in the subject's body for 2 years or less, 1 year or less, 6 months or less, 3 months or less, or 2 months or less. Combinations of the above-mentioned ranges are also possible (e.g., 1 hour or more and 2 years or less, 1 month or more and 2 years or less). Other ranges are also possible.

[0182] The retention mechanisms described herein may include any suitable material. In some embodiments, the retention mechanism material is relatively non-degradable. In certain embodiments, the retention mechanism may be configured to degrade within a certain period of time. In some embodiments, the retention mechanism is configured to degrade within one or more of the time ranges described above in a retained state. For example, in some embodiments, the retention mechanism is configured to degrade (e.g., such that the system is no longer retained in place within the subject's body) in 1 hour or more, 2 hours or more, 4 hours or more, 8 hours or more, 12 hours or more, 24 hours or more, 2 days or more, 3 days or more, 5 days or more, 7 days or more, or 10 days or more. In certain embodiments, the retention mechanism is configured to degrade in 14 days or less, 10 days or less, 7 days or less, 5 days or less, 3 days or less, 2 days or less, 24 hours or less, 12 hours or less, 8 hours or less, 4 hours or less, or 2 hours or less. Combinations of the above-mentioned ranges are also possible (e.g., 1 hour or more and 14 days or less). Other ranges are also possible. In some cases, the retention mechanism may be configured to degrade (e.g., so that the system is no longer held in place within the subject's body) in 1 month or more, 2 months or more, 3 months or more, 6 months or more, or 1 year or more. In some embodiments, the retention mechanism may degrade in 2 years or less, 1 year or less, 6 months or less, 3 months or less, or 2 months or less. Combinations of the above-mentioned ranges are also possible (e.g., 1 hour or more and 2 years or less, 1 month or more and 2 years or less). Other ranges are also possible.

[0183] In some cases, the retaining mechanism may include a conductive material, as described below.

[0184] Electrical stimulation In some embodiments, the systems, articles, and methods described herein may be useful for providing electrical stimulation at a location within a subject's body. Advantageously, the systems described herein may be administered orally (e.g., in a capsule) to provide temporary electrical stimulation to the digestive tract, as compared to conventional methods, including, for example, endoscopic placement and / or electrical device mounting. In some embodiments, the systems include one or more retention mechanisms, at least one of which includes a conductive portion (e.g., for electrical communication with tissue at a location within the subject's body). Such systems may be useful, for example, for iontophoresis (e.g., introducing an API into tissue within the subject's body during application of a local current). In certain embodiments in which the systems described herein are configured for iontophoresis, the systems may include a first tissue interface component (e.g., contained within a first self-healing article) that includes a conductive tip, and a second tissue interface component (e.g., contained within a second self-healing article) that is configured to contact but not penetrate tissue (e.g., a blunt cylinder). In some embodiments, one or more electrodes may be in electrical communication with the first tissue interface component and / or the second tissue interface component.

[0185] In some embodiments, the system (e.g., a self-healing system) includes two or more tissue interface components. In certain embodiments, each of the tissue interface components includes a tissue contacting portion configured to contact tissue. In some cases, the tissue contacting portion may be electrically conductive. In certain embodiments, the tissue contacting portion may be electrically insulating.

[0186] In some embodiments, the tissue contacting portion includes a first conductive portion and a second insulative portion, In some such embodiments, the conductive portion may be configured to be in electrical communication with tissue and the insulative portion may be configured not to be in electrical communication with tissue.

[0187] Without wishing to be bound by theory, in some embodiments, the length of the insulating portion may be configured to prevent electrical communication with a particular layer of tissue (e.g., for stomach muscle stimulation, the length may correspond to the outer muscular layer (e.g., 2-4 mm); for SI mucosa, the length may be, for example, 0.1-1 mm. In some cases, the insulating portion may be configured to prevent gastrointestinal fluids and / or mucosal coating of the tissue from contacting the conductive portion (e.g., without wishing to be bound by theory, gastrointestinal fluids and mucosal coatings are generally conductive and thus, in some cases, may prevent electrical stimulation from reaching the underlying tissue). The tissue contacting portion may include any suitable ratio of conductive portion to insulating portion. For example, in some embodiments, the conductive portion may be 0.1% or more of the total surface area of ​​the tissue contacting portion of the tissue interface component. The conductive portion is present in the tissue contacting portion in an amount of 0.5% or more, 1% or more, 2% or more, 5% or more, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, or 90% or more. In certain embodiments, the conductive portion is present in the tissue contacting portion in an amount of 100% or less, 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, 5% or less, 2% or less, 1% or less, or 0.5% or less of the total surface area of ​​the tissue contacting portion of the tissue interface component. Combinations of the above-mentioned ranges are also possible (e.g., 0.1% or more and 100% or less, 10% or more and 100% or less, 30% or more and 90% or less). Other ranges are also possible. In some embodiments, the tip of the tissue contacting portion is conductive and the remainder of the tissue contacting portion is insulating.

[0188] In certain embodiments, the insulating portion is present in the tissue contacting portion in an amount of 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, or 90% or more of the total surface area of ​​the tissue contacting portion of the tissue interface component. In certain embodiments, the insulating portion is present in the tissue contacting portion in an amount of 100% or less, 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, or 20% or less of the total surface area of ​​the tissue contacting portion of the tissue interface component. Combinations of the above-mentioned ranges are also possible (e.g., 10% or more and 100% or less, 30% or more and 90% or less). Other ranges are also possible.

[0189] In some embodiments, the system includes a self-healing article as described herein and at least one tissue interface component, each including a tissue contacting portion configured to contact tissue associated with each tissue interface component. In certain embodiments, the system includes two or more self-healing articles as described herein, each including at least one tissue interface component, each including a tissue contacting portion configured to contact tissue. For example, in an exemplary set of embodiments, a single self-healing article may be administered to a subject, the self-healing article including two or more tissue interface components, where a power source may be placed in electrical communication with the two or more tissue interface components such that an electric current may be applied to tissue in direct contact with the tissue contacting portion of the tissue interface component. In another exemplary set of embodiments, two (or more) self-healing articles, each including at least one tissue interface component, may be administered to a subject, where a power source may be placed in electrical communication with the self-healing article, such that such an economy applies to tissue in direct contact with the tissue contacting portion of each tissue interface component from each self-healing article. Other combinations are also possible. One of ordinary skill in the art will know, based on the teachings herein, how to select a combination of self-healing articles, tissue interface components, and tissue contacting portions.

[0190] As described herein, in some embodiments, a system including a self-healing and / or self-actuating article may be administered to a subject, where the system includes at least one tissue interface component (e.g., a self-lighting and / or self-actuating article) disposed within the article. The system may be administered such that at least one interface component is released from the article and / or inserted into tissue at a location within the subject's body. In certain embodiments, an electrical current may be applied (e.g., generated by a power source intelligently in communication with the tissue interface components) such that the current travels across two or more tissue interface components. In some such embodiments, the tissue interface components are not in electrical communication with the tissue.

[0191] The conductive portion may comprise any suitably conductive material. Non-limiting examples of suitable electronically conductive materials include conductive polymers, silver, copper, gold, stainless steel, platinum, zinc, and steel. Other conductive materials are also possible.

[0192] The insulating portion may comprise any suitable electrically insulating material. Non-limiting examples of suitable insulating materials include polymers such as parylene, polycaprolactone, and polyethylene. Other insulating materials are also possible.

[0193] The conductive and / or insulating material may in some cases be provided as a coating on the tissue interface component. In certain embodiments, the tissue contacting portion may include a bulk material that includes the conductive and / or insulating material.

[0194] In some embodiments, the current applied (e.g., across the tissue contacting portion to electrically stimulate the tissue) can be 0.001 milliamps or more, 0.01 milliamps or more, 0.1 milliamps or more, 0.5 milliamps or more, 1 milliamps or more, 5 milliamps or more, 10 milliamps or more, 50 milliamps or more, 100 milliamps or more, or 250 milliamps or more. In certain embodiments, the current applied can be 500 milliamps or less, 250 milliamps or less, 100 milliamps or less, 50 milliamps or less, 10 milliamps or less, 5 milliamps or less, 1 milliamps or less, 0.5 milliamps or less, 0.1 milliamps or less, or 0.01 milliamps or less. Combinations of the above-mentioned ranges are also possible (e.g., 0.001 milliamps or more and 500 milliamps or less, 0.1 milliamps or more and 10 milliamps or less). Other ranges are also possible. The electrical current may be applied using any suitable means, including, for example, an external power source (eg, a battery).

[0195] In certain embodiments, the system is configured to be maintained in place within a subject's body under a force of 0.1 N or more (e.g., 0.6 N or more) and / or a change in orientation of 30 degrees or more, as described above.

[0196] self-actuated For example, self-actuating articles are generally provided that include self-actuating tissue interface components such as self-actuating needles, self-actuating retaining mechanisms, and / or self-actuating biopsy punches. Advantageously, in some embodiments, the self-actuating articles described herein may be useful as a general platform for delivering a wide variety of pharmaceuticals that are typically delivered by injection directly to tissue due to degradation in the digestive tract. The self-actuating articles described herein may also be used to deliver sensors, electrical stimulation, retaining systems, and / or perform biopsies to tissue without the need for endoscopy. In some embodiments, the article includes a spring (e.g., a coil spring, a wave spring, a Belleville washer, a beam, a membrane, a material with specific mechanical recovery properties). Those skilled in the art will appreciate that the term spring is not intended to be limited to coil springs, but generally encompasses any reversibly compressed material / component where, after releasing an applied compressive force on the material / component, the material / component substantially returns to its uncompressed length under ambient conditions (e.g., within 40%, within 50%, within 60%, within 70%, within 80%, within 90%, within 95%, or any percentage in between, of the length of the material / component before compression).

[0197] In certain embodiments, the term spring of a self-actuating article may be provided as or may further include an expanding component. Those skilled in the art will appreciate that the term elongating component includes reversibly compressible and irreversibly compressible materials, and is a component that expands in at least one direction (e.g., along the length of the expanding component) upon stimulation and / or release of a constraint on the expanding component. In some embodiments, the expanding component includes a gas composition (e.g., a mixture of baking soda and vinegar) for expanding the gas volume expanding component.

[0198] In some embodiments, the spring and / or expansion component may expand in at least one direction via thermal expansion, swelling (e.g., due to fluid absorption), a gas-driven process, a pneumatic process, a hydraulic process, an electric motor, a magnetic mechanism, a torsion spring mechanism, a chemical gas generator, and / or an autocatalytic reaction. In an exemplary set of embodiments, the spring and / or expansion component may expand in at least one direction upon exposure of the spring and / or expansion component to a fluid (e.g., gastrointestinal fluids).

[0199] In some cases, the spring and / or expanding component may be activated (e.g., stretched in at least one direction and returned to the component's uncompressed length) by any suitable activation mechanism. Non-limiting examples of suitable activation mechanisms include release of pressure differential, electrical timer, light sensor, color sensor, enzyme sensor, capacitance, magnetism, activation by applied stress (e.g., shape memory material), external activation (e.g., applied magnetic field, applied light, reaction with gastrointestinal fluids such as gastric acid), and combinations thereof. In an exemplary set of embodiments, the spring and / or expanding component is activated by interaction (e.g., reaction) with gastrointestinal fluids.

[0200] In some cases, the actuation mechanism displaces the tissue interface component by a particular distance (e.g., 10 mm or less, 8 mm or less, 6 mm or less, 4 mm or less, 2 mm or less) and / or with a particular force (e.g., 0.1 N or more, 0.3 N or more, 0.5 N or more, 1 N or more, 1.5 N or more).

[0201] As illustrated in Figure 26, in some embodiments, article 100 includes a spring 110 and a support material 120 associated with (e.g., operatively coupled to) spring 110. In certain embodiments, support material 120 maintains the spring under compressive strain under a first set of conditions (e.g., under ambient conditions (e.g., room temperature, atmospheric pressure, and relative humidity)). In some embodiments, the support material at least partially releases the spring from the compressive strain (e.g., at least a portion of the support material degrades) under a second set of conditions that is different from the first set of conditions. For example, in some embodiments, the second set of conditions includes physiological conditions (e.g., at or about 37°C in a physiological fluid such as gastric fluid).

[0202] In some cases, the spring 110 may be adjacent (e.g., directly adjacent) to the support material 120. As used herein, when a component is referred to as "adjacent" to another component, the component may be directly adjacent (e.g., in contact with) the component, and there may be one or more intervening components. A component "directly adjacent" to another component means that there are no intervening component(s). In some cases, the spring may be at least partially embedded within the support material. In certain embodiments, the spring is coated with the support material.

[0203] In certain embodiments, referring again to FIG. 26, the article 100 includes a shell 170 (e.g., such that the spring 110 is at least partially encapsulated within the shell 170). In some cases, the support material can be a coating. In some embodiments, the support material is a biodegradable coating. In certain embodiments, the coating can have any suitable thickness. For example, the thickness of the coating can be 3 mm or more, 4 mm or more, or 5 mm or more. In certain embodiments, the thickness of the coating can be 6 mm or less, 5 mm or less, or 4 mm or less. Combinations of the above-mentioned ranges are also possible (e.g., 3 mm or more and 6 mm or less). In certain embodiments, the biodegradable coating at least partially degrades under physiological conditions. In some cases, the support material can be a brittle material. Non-limiting examples of suitable support materials include sugars and / or polymers (e.g., polyethylene glycol, polyvinylpyrrolidinone, polyvinyl alcohol).

[0204] The support material may have any suitable cross-sectional dimension. In some embodiments, the average cross-sectional dimension of the support material may be 0.1 mm or more, 0.5 mm or more, 1 mm or more, 1 mm or more, 2 mm or more, 3 mm or more, 4 mm or more, or 5 mm or more. In certain embodiments, the average cross-sectional dimension of the support material is 10 mm or less, 6 mm or less, 5 mm or less, 4 mm or less, 3 mm or less, 2 mm or less, 1 mm or less, or 0.5 mm or less. Combinations of the above-mentioned ranges are also possible (e.g., 0.1 mm or more to 10 mm or less). Other ranges are also possible.

[0205] In some embodiments, the support material, spring, and / or expansion component comprise one or more materials configured to dissolve (e.g., in an acidic environment, in water, in a basic environment, in a pH neutral environment), melt at physiological temperatures (e.g., 37° C.), change stiffness (e.g., in response to a change in temperature, in response to fluid absorption), thermally expand, and / or change shape (e.g., in response to fluid absorption, by contraction, by leakage).

[0206] supporting material In some embodiments, the support material is located at a distal end of the spring (eg, at the end opposite from the end of the spring associated with the tissue interface component).

[0207] For example, as illustrated in FIG. 7 , system 108 includes spring 125 associated with support material 160 that maintains spring 125 under compression (e.g., under a compressive strain of at least 5%). In some embodiments, support material 160 may be in the form of a disk positioned at a distal end of spring 125. In certain embodiments, spring 125 may be in direct contact with support material 160 (e.g., disk). In some cases, one or more additional layers and / or components may be positioned between spring 125 and disk 160. In some embodiments, spring 125 may be at least partially embedded in support material 160 (e.g., disk).

[0208] In certain embodiments, the support material includes a plug configured to keep the spring under compression, e.g., until the support material dissolves. As used herein, the term "plug" is given its ordinary meaning in the art and generally refers to a component configured to occlude. In an exemplary set of embodiments, the article includes a shell and a support material associated with at least a portion of the shell. In certain embodiments, upon exposure of the shell and support material to fluids (e.g., gastrointestinal fluids), the support material detaches and the spring directly adjacent the support material releases at least a portion of the spring's stored energy (e.g., such that the tissue interface component is released from the article).

[0209] In some cases, the support material can be in the form of a disk (e.g., includes sugar). For example, the support material can be a disk having an axis perpendicular to the major plane of the disk, where the axis perpendicular to the major plane of the disk is perpendicular to the major axis of the spring, such that the support material maintains the spring in a compressed state. The disk can be disposed within the article, for example, such that a fluid can interact with the support material, causing it to dissolve and release the spring.

[0210] Other configurations of the support material are also possible.

[0211] Advantageously, the configuration and / or materials used for the support material may allow for tuning of the dissolution of the support material. In some cases, the dissolution of the support material may be tuned so that the tissue interface component is released from the article at a desired location and / or at a desired time. In certain embodiments, the geometry of the support material (e.g., shape, ratio of first surface area to second surface area) may be designed and configured such that the retention force / strength (e.g., for a spring) may be tuned.

[0212] The support material (e.g., disc) may comprise any suitable material. Non-limiting examples of suitable materials include sugars and sugar derivatives (e.g., sugar alcohols such as isomalt, sugar mixtures such as taffy), starch, calcium carbonate, zinc, sodium chloride, and / or polymers (e.g., polyethylene glycol, polyvinylpyrrolidinone, polyvinyl alcohol, polyethylene oxide, diethylpyrocarbonate, hydrogels). Other materials are also possible. Without wishing to be bound by theory, the support material may be selected to be relatively brittle (e.g., so that the spring is released upon dissolution of the support material).

[0213] The support material may include any suitable shape. In some embodiments, the support material has a cylindrical shape, an elliptical shape, a spherical shape, a section of a sphere, a conical shape, a tapered shape (e.g., a tapered disk, such as a section of a cone), a triangular shape, a rectangular shape, a prismatic shape, a star shape, and combinations thereof. In certain embodiments, the support material has a disk shape (e.g., a tapered disk shape). Other shapes are also possible.

[0214] In certain embodiments, the support material may be configured to have a particular architecture that provides a desirable dissolution profile. For example, in some embodiments, the support material may be configured to enhance the dissolution profile, have a controlled disintegration mode (e.g., breaking into small pieces in relatively predictable locations), and / or provide structural integrity to the support material.

[0215] In the exemplary embodiment illustrated in FIG. 8, the support material 300 includes pores 310 and one or more cavities 320. Without wishing to be bound by theory, the cavities of the support material may be useful to control surface area (e.g., exposed to a fluid prior to dissolution) and / or provide locations for controlled mechanical disintegration after at least partial dissolution of the support material (e.g., after exposure to a body of fluid). For example, the support material may include any suitable number of pores (e.g., 1 or more, 2 or more, 3 or more, 4 or more, 5 or more pores) and / or any suitable number of cavities (e.g., 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more cavities) such that the mechanical disintegration of the support material (e.g., upon exposure to a fluid such as gastrointestinal fluid) may be controlled (e.g., to occur within a specific time period, such as less than 10 minutes after exposure to the fluid).

[0216] 8 depicts multiple cavities, other configurations are also possible. In some embodiments, the support material includes one or more cavities, one or more rings, and / or one or more holes. The cavities, rings, and / or holes may have any suitable shape.

[0217] In some embodiments, the support material can have a first surface having a first total surface area and a second surface having a second total surface area different from the first total surface area. For example, as shown in Figure 9, the support material 300 includes a first side 330 having a first surface and a second side 340 (e.g., opposite the first side 330) having a second surface. In some embodiments, the first surface has a total surface area that is equal to or greater than the total surface area of ​​the second surface.

[0218] FIG. 10 illustrates an exemplary system 302 that includes a support material 300 that includes a number of cavities 320 and is associated with a spring 325 .

[0219] In some embodiments, the first surface has a first total surface area that is 0.1 times or more, 0.2 times or more, 0.3 times or more, 0.4 times or more, 0.5 times or more, 0.6 times or more, 0.7 times or more, 0.8 times or more, 0.9 times or more, 1 times or more, 1.1 times or more, 1.2 times or more, 1.25 times or more, 1.3 times or more, 1.35 times or more, 1.4 times or more, 1.45 times or more, 1.5 times or more, 1.55 times or more, 1.6 times or more, 1.65 times or more, 1.7 times or more, 1.75 times or more, 1.8 times or more, 1.9 times or more, or 2 times or more the total surface area of ​​the second surface. In certain embodiments, the first total surface area is 2.5 times or less, 2 times or less, 1.9 times or less, 1.8 times or less, 1.75 times or less, 1.7 times or less, 1.65 times or less, 1.6 times or less, 1.55 times or less, 1.5 times or less, 1.45 times or less, 1.4 times or less, 1.35 times or less, 1.3 times or less, 1.25 times or less, 1.1 times or less, 1 times or less, 0.9 times or less, 0.8 times or less, 0.7 times or less, 0.6 times or less, 0.5 times or less, 0.4 times or less, 0.3 times or less, or 0.2 times or less than the second total surface area. Combinations of the above-mentioned ranges are also possible (e.g., 0.1 to 2.5, 1 to 2.5, 1.4 to 1.6). Other ranges are also possible. Those skilled in the art will understand that the total surface area described herein generally refers to the geometric surface area of ​​a comparable smooth surface, regardless of local microscale and nanoscale roughness. Advantageously, such a ratio of the total surface area of ​​the first surface to the total surface area of ​​the second surface can increase the strength of resistance to mechanical collapse by the force exerted by the adjacent spring, and / or control the dissolution / disintegration time of the support material upon exposure to fluids such as gastrointestinal fluids (e.g., exposure of a surface having a larger surface area compared to other surfaces).

[0220] In some embodiments, the roughness (e.g., microscale roughness, nanoscale roughness) and / or texture of one or more surfaces (e.g., first surface, second surface) of the support material may be increased or decreased (e.g., to alter the dissolution time of the support material).

[0221] In some embodiments, the support material has desirable mechanical properties (e.g., such that the spring recovers at least a portion of its uncompressed length relatively quickly.) For example, in certain embodiments, the support material may have a critical stress of 0.01 N or more, 0.1 N or more, 0.5 N or more, 1 N or more, 2 N or more, 3 N or more, 5 N or more, 7 N or more, 10 N or more, 15 N or more, 20 N or more, 25 N or more, 30 N or more, 35 N or more, 40 N or more, 45 N or more, 50 N or more, or 60 N or more, including critical stress values ​​therebetween. In certain embodiments, the support material may have a critical stress of 70N or less, 60N or less, 50N or less, 45N or less, 40N or less, 35N or less, 30N or less, 25N or less, 20N or less, 15N or less, 10N or less, 7N or less, 5N or less, 3N or less, 2N or less, 1N or less, 0.5N or less, or 0.1N or less, including critical stress values ​​in between. Combinations of the above-mentioned ranges are also possible (e.g., 10N or more to 70N or less, 30N or more to 45N or less). Other ranges are also possible. The critical stress is generally the maximum force (e.g., applied by an adjacent spring) that the support material can withstand before a crack occurs, and the critical stress TIFF2025028862000002.tif11170, Here, σ cis the critical stress applied by the spring, γ is the surface energy of the material, E is the Young's modulus of the material, and a is the surface area perpendicular to the applied stress. In some embodiments, the support material may have a characteristic dissolution time. In certain embodiments, the characteristic dissolution time of the support material is 10 minutes or less, 9 minutes or less, 8 minutes or less, 7 minutes or less, 6 minutes or less, 5 minutes or less, 4 minutes or less, 3 minutes or less, or 2 minutes or less. In some embodiments, the characteristic dissolution time of the support material is 1 minute or more, 2 minutes or more, 3 minutes or more, 4 minutes or more, 5 minutes or more, 6 minutes or more, 7 minutes or more, 8 minutes or more, or 9 minutes or more. Combinations of the above-mentioned ranges are also possible (e.g., 1 minute or more and 10 minutes or less). Other ranges are also possible. The characteristic dissolution time is determined as the time at which the support material begins to propagate cracks after exposure to gastrointestinal fluids.

[0222] *Spring In some embodiments, the support material maintains at least a portion of the spring under a compressive strain of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% under the first set of conditions. In certain embodiments, the support material maintains at least a portion of the spring under a compressive strain of no more than 90%, no more than 80%, no more than 70%, no more than 60%, no more than 50%, no more than 40%, no more than 30%, no more than 25%, no more than 20%, no more than 15%, or no more than 10% under the first set of conditions.

[0223] In certain embodiments, the spring restores (e.g., within less than 10 minutes, less than 5 minutes, less than 1 minute, less than 30 seconds, less than 10 seconds, less than 5 seconds, less than 1 second, less than 0.1 seconds, less than 0.01 seconds) to a length that is 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more (including any percentage between 10% and 99%) of the length of the spring before the application of compressive strain (e.g., by a supporting material) and / or without compressive strain (e.g., uncompressed spring length). In some embodiments, the spring restores to a length that is 100% or less, 99% or less, 98% or less, 95% or less, 90% or less, 85% or less, 80% or less, 75% or less, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, or 20% or less of the length of the spring prior to application of the compressive strain and / or without the compressive strain, including any percentage between 20% and 100%. Advantageously, the use of a spring and support material as described herein may enable release of a tissue interface component (e.g., a needle) associated with (e.g., operably coupled to) the spring, for example, such that the tissue interface component contacts and / or penetrates tissue adjacent to the article. In an illustrative example, in some embodiments, a needle associated with the spring is administered to a subject, such that upon degradation of the support material, the spring restores and the needle is forced into tissue adjacent to the article such that the needle penetrates the tissue (e.g., a digestive mucosal layer). In some such embodiments, the active pharmaceutical ingredient may be delivered into the tissue by the tissue interface component. For example, in some embodiments, the article includes the active pharmaceutical ingredient such that upon release of the spring at the location within the subject's body, the active pharmaceutical ingredient is released (e.g., into tissue proximate to the location within the subject's body). In other embodiments, a biopsy may be performed (e.g., by a tissue interface component such as a biopsy device) upon release of the spring by the support material. Referring again to FIG. 26, in some embodiments, the article 100 includes a tissue interface component 115 associated with the spring 110.The tissue interfacing components (eg, needles, hooks, high API loaded components) are described in more detail herein.

[0224] In certain embodiments, the tissue interface component comprises a needle, a patch or an array of needles (eg, a microneedle), a biopsy component, a hook, a mucoadhesive patch, or a combination thereof.

[0225] In some embodiments, the spring comprises a resilient material, hi certain embodiments, the spring comprises a material selected from the group consisting of Nitinol, a metal, a polymer, and combinations thereof.

[0226] In certain embodiments, the spring may have a particular spring constant. For example, in some embodiments, the spring constant of the spring may include 100 N / m or more, 150 N / m or more, 200 N / m or more, 250 N / m or more, 300 N / m or more, 350 N / m or more, 400 N / m or more, 450 N / m or more, 500 N / m or more, 600 N / m or more, 700 N / m or more, 800 N / m or more, 900 N / m or more, 1000 N / m or more, 1100 N / m or more, 1200 N / m or more, 1300 N / m or more, 1400 N / m or more, 1500 N / m or less, 1800 N / m or less, or 2000 N / m or more, including any spring constants between these values. In certain embodiments, the spring constant of the spring may include 2200N / m or less, 2000N / m or less, 1800N / m or less, 1500N / m or less, 1400N / m or less, 1300N / m or less, 1200N / m or less, 1100N / m or less, 1000N / m or less, 900N / m or less, 800N / m or less, 700N / m or less, 600N / m or less, 500N / m or less, 450N / m or less, 400N / m or less, 350N / m or less, 300N / m or less, 250N / m or less, 200N / m or less, or 150N / m or less, and any spring constant between these values. Combinations of the above-mentioned ranges are also possible (eg, ≧100 N / m to ≦500 N / m, ≧100 N / m to ≦1500 N / m). Other ranges are also possible.

[0227] In some embodiments, the spring is compressed (e.g., by a supporting material) by 1 mm or more, 2 mm or more, 3 mm or more, 4 mm or more, 5 mm or more, 6 mm or more, 7 mm or more, 8 mm or more, 9 mm or more, 10 mm or more, 12 mm or more, or 15 mm or more along the longitudinal axis of the spring, as compared to the uncompressed length of the spring. In certain embodiments, the spring is compressed by 20 mm or less, 15 mm or less, 12 mm or less, 10 mm or less, 9 mm or less, 8 mm or less, 7 mm or less, 6 mm or less, 5 mm or less, 4 mm or less, 3 mm or less, or 2 mm or less along the longitudinal axis of the spring, as compared to the uncompressed length of the spring. Combinations of the above-mentioned ranges are also possible (e.g., 1 mm or more to 5 mm or less, 5 mm or more to 10 mm or less). Other ranges are also possible.

[0228] In certain embodiments, the spring is configured to release a desired amount of the spring's stored compressive energy (e.g., upon exposure of the support material to a fluid, such as gastrointestinal fluids). For example, the spring and / or support material may be exposed to a fluid, and upon at least partial dissolution of the support material, the spring at least partially releases the stored compressive energy, e.g., to displace a tissue interface component operably coupled to the spring (e.g., to release the compressive energy into tissue located within the subject's body). For example, in some embodiments, the spring is configured to release at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% of the spring's stored compressive energy, including any percentages between these values. In certain embodiments, the spring is configured to release (e.g., upon exposure of the support material to fluids such as gastrointestinal fluids) at least 90% of the spring's stored compression energy, at least 92% of the spring's stored compression energy, at least 94% of the spring's stored compression energy, at least 96% of the spring's stored compression energy, at least 98% of the spring's stored compression energy, or at least 99% of the spring's stored compression energy, including any percentages between these values. In certain embodiments, the spring is configured to release no more than 100% of the spring's stored compression energy, less than 99% of the spring's stored compression energy, less than 98% of the stored compression energy, less than 96% of the spring's stored compression energy, less than 94% of the spring's stored compression energy, less than 92% of the spring's stored compression energy, or less than 91% of the spring's stored compression energy. In some embodiments, the spring is configured to release no more than 90%, no more than 80%, no more than 70%, no more than 60%, no more than 50%, no more than 40%, no more than 30%, or no more than 20% of the spring's stored compressive energy (e.g., upon exposure of the support material to fluids such as gastrointestinal fluids), including percentages between these values.Combinations of the above-mentioned ranges are also possible (e.g., at least 92% and less than 98% of the stored compression energy of the spring, at least 94% and less than 96%, at least 10% and less than or equal to 99% of the stored compression energy of the spring). Other ranges are also possible.

[0229] In some embodiments, the spring is configured to release the stored compression energy of the spring within any suitable time of exposure of the support material to the fluid and / or mechanical collapse (e.g., cracking, fracturing) of the support material. For example, in some embodiments, the spring is configured to release the stored compression energy of the spring (e.g., at least 10% of the stored compression energy) within less than 5 milliseconds, less than 4 milliseconds, less than 3 milliseconds, less than 2 milliseconds, less than 1 millisecond, less than 0.5 milliseconds, or less than 0.2 milliseconds of mechanical failure of the support material. In certain embodiments, the spring is configured to release the stored compression energy of the spring within more than 0.1 milliseconds, more than 0.2 milliseconds, more than 0.5 milliseconds, more than 1 millisecond, more than 2 milliseconds, more than 3 milliseconds, or more than 4 milliseconds of mechanical failure of the support material. Combinations of the above-mentioned ranges are also possible (e.g., less than 5 milliseconds and more than 1 millisecond, less than 2 milliseconds and more than 0.1 millisecond). Other ranges are also possible.

[0230] In certain embodiments, the spring is configured to release the stored compression energy of the spring as described herein (e.g., at least 10% of the stored compression energy) within less than 10 minutes, less than 9 minutes, less than 7 minutes, less than 5 minutes, less than 3 minutes, or less than 1 minute, including any time between these values, after exposing the support material to the fluid. In some embodiments, the spring is configured to release the stored compression energy of the spring within more than 30 seconds, more than 1 minute, more than 3 minutes, more than 5 minutes, more than 7 minutes, or more than 9 minutes, including any time between these values. Combinations of the above-mentioned ranges (e.g., within less than 10 minutes and more than 30 seconds, less than 7 minutes and more than 5 minutes). Other ranges are also possible.

[0231] Any combination of the above mentioned ranges is also possible. For example, in certain embodiments, the spring is configured to release at least 10% (e.g., at least 90%) of the stored compression energy of the spring within 10 minutes of exposing the support material to the fluid. In certain embodiments, the spring is configured to release at least 10% (e.g., at least 90%) of the stored compression energy of the spring within 30 seconds of exposing the support material to the fluid. In some embodiments, the spring is configured to release no more than 100% of the stored compression energy of the spring within 10 minutes of exposing the support material to the fluid. In certain embodiments, the spring is configured to release no more than 100% of the stored compression energy of the spring within 30 seconds of exposing the support material to the fluid.

[0232] In certain embodiments, the spring is configured to release at least 10% (e.g., at least 90%) of the stored compressive energy of the spring within 5 milliseconds of the mechanical collapse of the support material. In certain embodiments, the spring is configured to release at least 10% (e.g., at least 90%) of the stored compressive energy of the spring within 0.1 milliseconds of the mechanical collapse of the support material. In some embodiments, the spring is configured to release no more than 100% of the stored compressive energy of the spring within 5 milliseconds of the mechanical collapse of the support material. In certain embodiments, the spring is configured to release no more than 100% of the stored compressive energy of the spring within 0.1 milliseconds of the mechanical collapse of the support material.

[0233] The spring may have any suitable cross-sectional dimension. In some embodiments, the maximum cross-sectional dimension of the (uncompressed) spring is 1 mm or more, 2 mm or more, 3 mm or more, 4 mm or more, or 5 mm or more. In certain embodiments, the maximum cross-sectional dimension of the (uncompressed) spring is 10 mm or less, 6 mm or less, 5 mm or less, 4 mm or less, 3 mm or less, or 2 mm or less. Combinations of the above-mentioned ranges are also possible (e.g., 1 mm or more and 10 mm or less). Other ranges are also possible.

[0234] In some embodiments, the article is administered to the subject (e.g., orally). In certain embodiments, the article may be administered orally, rectally, vaginally, nasally, or urethrally. In certain embodiments, upon reaching a location within the subject's body (e.g., the digestive tract), at least a portion of the support material degrades such that the spring extends and / or the tissue interface component interfaces (e.g., contacts, penetrates) with tissue located within the subject's body. In some embodiments, the location within the subject's body is the colon, duodenum, ileum, jejunum, stomach, or esophagus. In certain embodiments, the location within the subject's body is in the buccal cavity, venous system (e.g., arteries), respiratory system (e.g., lungs), renal system, urinary system, or digestive system. As described above and herein, in some embodiments, the active pharmaceutical ingredient is released during and / or after penetration of tissue located within the subject's body.

[0235] In some embodiments, the tissue interface component comprises a needle and the tissue is penetrated with a force of 1 to 100 mN (e.g., 10 to 20 mN). In certain embodiments, the tissue interface component comprises a plurality of microneedles and the tissue is penetrated with a force of 100 to 10 N (e.g., 1 to 2 N, 100 to 6 N).

[0236] In some cases, the article, as described herein, may be oriented such that the longitudinal axis of the tissue interface component is perpendicular (e.g., within 10% or less, 5% or less, or 1% or less of 90°) to the tissue located proximate to the article. In some embodiments, the self-actuating article (e.g., including a tissue interface component) described herein may be associated with one or more self-healing articles. Non-limiting examples of suitable self-healing articles are generally described in co-pending International Patent Application No. WO2018 / 213600, entitled "SELF-RIGHTING SYSTEMS AND RELATED COMPONENTS AND METHODS," filed May 17, 2018, the entirety of which is incorporated herein by reference.

[0237] In an exemplary embodiment, the article includes a shell, a spring at least partially encapsulated within the shell, a support material associated with the spring adapted to maintain at least a portion of the spring under a compressive strain of at least 5% under ambient conditions, and a tissue interface component operably coupled to the spring. In certain embodiments, the article includes a tissue interface component and a spring associated with the tissue interface component, the spring being maintained at least partially compressed by the support material under a compressive strain of at least 5%. According to certain embodiments, the spring is configured to release at least 10% (e.g., at least 90%) of the stored compressive energy of the spring within 0.1 milliseconds of mechanical collapse of the support material. According to certain embodiments, the article compresses a pharmaceutical agent associated with the tissue interface component. In some embodiments, the article includes a self-healing article associated with the tissue interface component.

[0238] Needle Distance and Speed In some embodiments, as illustrated in FIG. 11, a self-healing system, such as the exemplary system 300, includes a tissue interface component 330 proximate an aperture 340 of a tissue engaging surface 350. For example, referring back to FIG. 2, the self-actuating component 120 includes a spring 125 that expands upon actuation of the self-actuating component to push the tissue interface component 130 out of the system 102 through the aperture 140 (associated with the tissue engaging surface 150). Referring back to FIG. 11, in some embodiments, a tip end 335 of the tissue interface component 330 may be positioned such that the end 335 has a particular distance 310 d from the tissue engaging surface. Without wishing to be bound by theory, the greater the distance d between the tip end of the tissue interface component and the tissue engaging surface, the greater the speed at which the tissue interface component passes through the tissue engaging surface (e.g., into the tissue of a subject located within the subject's body). For example, the tissue interface component may accelerate over the distance d traveled. Advantageously, the distance d may be selected such that, for example, upon activation of the self-actuating component and / or engagement of the tissue interface component with the surface of the tissue, the system remains in contact with the tissue (e.g., does not bounce off the tissue).

[0239] In some embodiments, the system is configured such that the tissue interface component has a velocity upon impact with the tissue of the subject of 0.1 m / sec or greater, 0.2 m / sec or greater, 0.5 m / sec or greater, 1 m / sec or greater, 1.5 m / sec or greater, 2 m / sec or greater, 5 m / sec or greater, 10 m / sec or greater, 12 m / sec or greater, 15 m / sec or greater, 20 m / sec or greater, 25 m / sec or greater, 50 m / sec or greater, 60 m / sec or greater, 70 m / sec or greater, 75 m / sec or greater, 80 m / sec or greater, 90 m / sec or greater, 100 m / sec or greater, 120 m / sec or greater, or 150 m / sec or greater, including any velocity therebetween (e.g., the velocity of the tip of the tissue interface component as it passes through the tissue contact surface). In certain embodiments, the tissue interface component has a velocity upon impact with the tissue of interest of 200 m / s or less, 150 m / s or less, 120 m / s or less, 100 m / s or less, 90 m / s or less, 80 m / s or less, 75 m / s or less, 70 m / s or less, 60 m / s or less, 50 m / s or less, 25 m / s or less, 20 m / s or less, 15 m / s or less, 12 m / s or less, 10 m / s or less, 5 m / s or less, 2 m / s or less, 1.5 m / s or less, 1 m / s or less, 0.5 m / s or less, or 0.2 m / s or less, including any velocity between these values. Combinations of the above-mentioned ranges are also possible (e.g., 0.1 m / s or more and 80 m / s or less, 0.1 m / s or more and 25 m / s or less, 20 m / s or more and 80 m / s or less). Other ranges are also possible.

[0240] In some embodiments, the tip of the tissue interface component (e.g., prior to engaging with the tissue of interest) is positioned 0 mm or more, 0.1 mm or more, 0.2 mm or more, 0.5 mm or more, 1.0 mm or more, 1.5 mm or more, 2.0 mm or more, or 2.5 mm or more from the tissue engaging surface, including any distance between these values. In certain embodiments, the tip of the tissue interface component is positioned 3.0 mm or less, 2.5 mm or less, 2.0 mm or less, 1.5 mm or less, 1.0 mm or less, 0.5 mm or less, 0.2 mm or less, or 0.1 mm or less from the tissue engaging surface, including any distance between these values. Combinations of the above-mentioned ranges are also possible (e.g., 0 mm or more and 3 mm or less, 0.1 mm or more and 3.0 mm or less). Other ranges are also possible.

[0241] Plugs and Vents In some embodiments, the system may include one or more vents (e.g., such that at least a portion of the system is in fluid communication with the external environment). For example, referring back to FIG. 2, the system 102 includes at least one vent 190, such that, for example, the self-actuating component 120 is in fluid communication with the external environment. In certain embodiments, fluid outside the system 102 enters through the vent(s) 190 and contacts the self-actuating component 102, the support material 160, and / or the spring 125 (e.g., such that the spring extends).

[0242] In certain embodiments, at least a portion of the system may be fluidically isolated from the external environment. For example, referring back to FIG. 2, in some cases, the hole 140 and / or the vent(s) 190 may include a fluid gate, as described herein. The fluid gate, in certain embodiments, prevents fluid from contacting one or more internal components of the system (e.g., tissue interface components, self-actuating components) until a desired time and / or location. In some embodiments, each fluid gate may be the same or different. For example, the fluid gate associated with the hole 140 may dissolve under a first set of conditions and / or rate, and the fluid gate associated with the vent(s) 190 may dissolve under a second set of conditions and / or rate that is different from the first set of conditions and / or rate. In an exemplary embodiment, the fluid gate associated with the hole 140 may include a hydrophobic material, and the fluid gate associated with the vent 190 may include a soluble material. Other combinations are also possible.

[0243] In some cases, the fluid gate may be a plug. In some cases, the fluid gate may prevent fluid (e.g., fluid outside the system) from entering the system at the hole and / or vent(s) until a desired time. In certain embodiments, the fluid gate includes a barrier material. Non-limiting examples of suitable barrier materials include polycaprolactone foil, thermoplastic elastomers, cellulose, and silicone. The barrier material may include one or more hydrophobic materials. One skilled in the art would be able to select a suitable hydrophobic material as the barrier material based on the teachings herein.

[0244] In some embodiments, the fluid gate may include a soluble material (e.g., the fluid gate dissolves to allow fluid to enter the system at a desired time and / or location within the subject's body). Non-limiting examples of suitable soluble materials include sugars and polyvinyl alcohol.

[0245] In certain embodiments, the fluid gate may comprise a substantially non-soluble material (e.g., the material does not dissolve under physiological conditions in the gastrointestinal environment, e.g., in less than 7 days, less than 3 days, less than 24 hours). In some such embodiments, the non-soluble material may have suitable mechanical properties such that, upon release from the system, the tissue interface component is able to penetrate at least a portion of the non-soluble material.

[0246] Referring now to FIG. 35, in some embodiments, a fluid gate may be present in the hole 140 such that the tissue interface component is not in fluid communication with the external environment (eg, until dissolution / removal of the plug).

[0247] Fluidically separated compartments The systems described herein may, in some cases, include two or more fluidly separated components. For example, in some embodiments, two or more portions of a system may not be in fluid communication.

[0248] Referring again to FIG. 2, in some embodiments, the first portion 110 and the second portion 115 are not in fluid communication. In certain embodiments, the self-actuation component 120 may be fluidly isolated (e.g., not in fluid communication) from the tissue interface component 130. Advantageously, having two or more fluidly isolated components may, in some cases, permit dissolution and / or actuation of one component without dissolution and / or activation of another component. By way of example, in an exemplary embodiment, the tissue interface component 130 may be fluidly isolated from the self-actuation component 120 such that upon exposure of the self-actuation component 120 to a fluid, the self-actuation component 120 is actuated (e.g., the spring 125 expands) without exposing the tissue interface component 130 to the fluid. For example, the tissue interface component may include an API that will at least partially dissolve upon exposure to a fluid. Advantageously, preventing exposure of the tissue interface component to fluids (e.g., protecting the tissue interface component) until a desired time (e.g., after release from the system) may prevent premature dissolution of the API prior to insertion into the tissue and / or maintain the mechanical integrity of the tissue interface component.

[0249] In some embodiments, the support material (e.g., the support material associated with the spring) is configured such that at least a portion of the self-actuating component (e.g., the first surface of the support material, the spring) is not in fluid communication with the tissue interface component. That is, in some cases, the support material may act as a barrier (e.g., a fluid barrier) between the self-actuating component and the tissue interface component. For example, referring again to FIG. 7, in some embodiments, the portion 122 of the system 108 is not in fluid communication with the tissue interface component 130. In some such embodiments, the portion 122 may be exposed to a fluid such that at least a portion of the support material 160 dissolves without the tissue interface component 130 coming into contact with the fluid.

[0250] Assembly Process In some embodiments, the system may be assembled such that the self-actuating components (e.g., including the spring and support material) and the tissue interface components are associated with each other. For example, as illustrated in Figs. 34A-34E, the lower and upper portions of the system may be fixed along a 1D axis. In some embodiments, the lower portion is held in place with a hole in the center of the lower portion, and the upper portion is held in place by a hole, for example, drilled directly in the center of the upper portion. In certain embodiments, the support material may be placed on top of the lower portion, and the tissue interface components already inside the holder may be placed on top of the support material. In some cases, the spring may then be placed on top of the support material. In some cases, a registration pin may be used that may be placed through the upper portion and the spring. The upper and lower portions may be moved together, in some cases, until they snap, press fit, or screw together. Then, in some embodiments, the registration pin may be removed. Other methods of assembling the components are also possible.

[0251] High API In some embodiments, as described above and herein, the system includes a component (e.g., a tissue interface component) that includes a solid therapeutic agent (e.g., a solid API) and a second material (e.g., a supporting material for the solid API, such as a binder and / or a polymer) such that the solid therapeutic agent is present in the component in an amount of 10% or more by weight relative to the total weight of the tissue interface component. Such a tissue interface component can be useful for delivery of an API dose (e.g., to a subject). Advantageously, in some embodiments, the reduction in the volume required to deliver the required API dose compared to liquid formulations allows the creation of a solid needle delivery system for a wide variety of drugs in a variety of locations / tissues (e.g., tongue, digestive mucosal tissue, skin) and / or reduces and / or eliminates the application of external forces to inject drug solutions through the small opening of the needle. In some cases, a physiologically relevant dose can be present in a single tissue interface component (e.g., with a relatively high API loading).

[0252] In certain embodiments, the API is substantially solid (e.g., powder, compressed powder, crystalline solid, amorphous solid), i.e., a solid therapeutic agent. In some embodiments, the API may be in liquid form. In certain embodiments, the API may be.

[0253] In some embodiments, the tissue interface component comprises a needle, a biopsy component, a projectile, a plurality of microneedles, a hook, a mucoadhesive patch, or a combination thereof. In certain embodiments, as described herein and above, the tissue interface component is configured to penetrate tissue (e.g., tissue of the digestive tract, such as skin, tongue, digestive mucosal tissue, etc.). In some embodiments, the tissue is penetrated with a force of 1 mN or more and 20 mN or less (e.g., 10 mN or more and 20 mN or less, 1 mN or more and 100 mN or less, 20 mN or more and 1 N or less, 1 N or more and 20 N or less, 10 N or more and 20 N or less).

[0254] Advantageously, tissue interface components including needles with relatively high API loadings (e.g., 10% by weight or more, based on the total weight of the component) and / or multiple microneedles may significantly reduce the number of needles and / or the overall size of the microneedle array required to deliver a particular API dose, as compared to conventional microneedles (e.g., which typically include less than 10% by weight loadings and / or require thousands to tens of thousands of multiple microneedles to deliver a similar dose).

[0255] In some embodiments, the tissue interface component has a particular maximum dimension (e.g., length). In certain embodiments, the maximum dimension of the tissue interface component is 1 mm or more, 2 mm or more, 3 mm or more, 5 mm or more, 7 mm or more, 10 mm or more, 12 mm or more, 15 mm or more, 20 mm or more, 25 mm or more, 30 mm or more, or 50 mm or more. In some embodiments, the maximum dimension of the tissue interface component is 100 mm or less, 50 mm or less, 30 mm or less, 25 mm or less, 20 mm or less, 15 mm or less, 12 mm or less, 10 mm or less, 7 mm or less, 5 mm or less, 3 mm or less, or 2 mm or less. Combinations of the above-mentioned ranges are also possible.

[0256] In certain embodiments, the tissue interface component has an average cross-sectional dimension (e.g., diameter) of 0.25 mm or more, 0.5 mm or more, 0.6 mm or more, 0.7 mm or more, 0.8 mm or more, 0.9 mm or more, 1 mm or more, 1.1 mm or more, 1.2 mm or more, 1.3 mm or more, 1.4 mm or more, 1.5 mm or more, 1.7 mm or more, 1.9 mm or more, 2.5 mm or more, 3.0 mm or more, 4.0 mm or more, or 5.0 mm or more. In some embodiments, the tissue interface component has an average cross-sectional dimension of 6.0 mm or less, 5.0 mm or less, 4.0 mm or less, 3.0 mm or less, 2.5 mm or less, 1.9 mm or less, 1.7 mm or less, 1.5 mm or less, 1.4 mm or less, 1.3 mm or less, 1.2 mm or less, 1.1 mm or less, 1.0 mm or less, 0.9 mm or less, 0.8 mm or less, 0.7 mm or less, 0.6 or less, or 0.5 mm or less. Combinations of the above-mentioned ranges are also possible (eg, greater than or equal to 0.5 mm and less than or equal to 2.0 mm). Other ranges are also possible.

[0257] In some embodiments, the tissue interface component may include a plurality of microneedles, in some such embodiments, the plurality of microneedles may have a particular base maximum cross-sectional dimension (e.g., base diameter), a particular height, and / or a particular spacing.

[0258] In some embodiments, the average diameter of the base of the plurality of microneedles is 100 microns or more, 150 microns or more, 200 microns or more, 250 microns or more, 300 microns or more, 350 microns or more, 400 microns or more, or 450 microns or more. In certain embodiments, the average diameter of the base of the plurality of microneedles is 500 microns or less, 450 microns or less, 400 microns or less, 350 microns or less, 300 microns or less, 250 microns or less, 200 microns or less, or 150 microns or less. Combinations of the above-mentioned ranges are also possible (e.g., 100 microns or more and 500 microns or less). Other ranges are also possible.

[0259] In certain embodiments, the average height of the plurality of microneedles is 0.1 mm or more, 0.2 mm or more, 0.5 mm or more, 0.7 mm or more, 1 mm or more, 1.2 mm or more, 1.5 mm or more, or 2 mm or more. In some embodiments, the average height of the plurality of microneedles is 2.5 mm or less, 2 mm or less, 1.5 mm or less, 1.2 mm or less, 1 mm or less, 0.7 mm or less, 0.5 mm or less, or 0.2 mm or less. Combinations of the above-mentioned ranges are also possible (e.g., 0.1 mm or more and 2.5 mm or less). Other ranges are also possible.

[0260] In some cases, the average spacing of the microneedles (e.g., the spacing between adjacent microneedles of the plurality of microneedles) may be 100 microns or more, 200 microns or more, 300 microns or more, 400 microns or more, 500 microns or more, 600 microns or more, 700 microns or more, 800 microns or more, 900 microns or more, 1000 microns or more, 1100 microns or more, 1200 microns or more, 1300 microns or more, or 1400 microns or more. In certain embodiments, the average spacing of the microneedles is 1500 microns or less, 1400 microns or less, 1300 microns or less, 1200 microns or less, 1100 microns or less, 1000 microns or less, 900 microns or less, 800 microns or less, 700 microns or less, 600 microns or less, 500 microns or less, 400 microns or less, 300 microns or less, or 200 microns or less. Combinations of the above-mentioned ranges are also possible (e.g., 100 microns or more and 1500 microns or less). Other ranges are also possible.

[0261] Advantageously, in some embodiments, the tissue interface component (e.g., needle) dissolves relatively quickly, reducing and / or eliminating the risk of secondary penetration by the component at undesired locations. In some embodiments, the maximum cross-sectional dimension (e.g., length) of the component is designed to be delivered to any organ targeted by the component to prevent pain and / or undesired perforation of the gastrointestinal tract.

[0262] In some embodiments, the tissue interface component includes a base portion and a tip portion. For example, as illustrated in FIG. 33, tissue interface component 100 includes a base portion 110 and a tip portion 115. In some embodiments, the base portion and / or the tip portion include a mucoadhesive material. Non-limiting examples of suitable mucoadhesive materials include polymers such as poly(vinyl alcohol), hydroxylated methacrylates, and poly(methacrylic acid), polyacrylates (e.g., polyacrylic acid, thiolated poly(acrylic acid), Carbopol®), cyanoacrylates, sodium carboxymethylcellulose, hyaluronic acid, hydroxypropylcellulose, polycarbophil, chitosan, mucin, alginates, xanthan gum, gellan, poloxamer, cellulose acetophthalate, methylcellulose, hydroxyethylcellulose, poly(amidoamine) dendrimers, poly(dimethylsiloxane), poly(vinylpyrrolidone), polycarbophil, combinations thereof, and copolymers thereof.

[0263] In some embodiments, the base portion and / or tip portion include a solid therapeutic agent (e.g., an API) and a second material (if present) such that the solid therapeutic agent is present in the tissue interface component in an amount of 10% or more by weight based on the total weight of the tissue interface component. In certain embodiments, the solid therapeutic agent is present in the tissue interface component in an amount of 10% or more by weight, 20% or more by weight, 30% or more by weight, 40% or more by weight, 50% or more by weight, 60% or more by weight, 70% or more by weight, 80% or more by weight, 90% or more by weight, 95% or more by weight, 98% or more by weight, or 99.1% or more by weight based on the total weight of the tissue interface component. In some embodiments, the solid therapeutic agent is present in the tissue interface component in an amount of 100% or less, 99% or less, 98% or less, 95% or less, 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, or 20% or less by weight, based on the total weight of the tissue interface component. Combinations of the above-mentioned ranges are also possible (e.g., 10% or more and 100% or less, 80% or more and 100% or less). Other ranges are also possible. In an exemplary set of embodiments, the solid therapeutic agent is present in the tissue interface component in an amount of 80% or more and 100% or less by weight, based on the total weight of the tissue interface component.

[0264] In certain embodiments, the solid therapeutic agent is present in the base portion in an amount of 0% or more, 5% or more, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 95% or more, 98% or more, or 99% or more by weight, based on the total weight of the base portion. In some embodiments, the solid therapeutic agent is present in the base portion in an amount of 100% or less, 99% or less, 98% or less, 95% or less, 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, or 5% or less by weight, based on the total weight of the base portion. Combinations of the above-mentioned ranges are also possible (e.g., greater than or equal to 10% and less than or equal to 100% by weight, greater than or equal to 80% and less than or equal to 100% by weight). Other ranges are also possible. In an exemplary embodiment, the base portion includes substantially only the solid therapeutic agent.

[0265] In certain embodiments, the solid therapeutic agent is present in the tip in an amount of 0% or more, 5% or more, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 95% or more, 98% or more, or 99% or more by weight, based on the total weight of the tip. In some embodiments, the solid therapeutic agent is present in the tip in an amount of 100% or less, 99% or less, 98% or less, 95% or less, 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, or 5% or less by weight, based on the total weight of the tip. Combinations of the above-mentioned ranges are also possible (e.g., 10% or more and 100% or less, 80% or more and 100% or less). Other ranges are also possible. In an exemplary embodiment, the tip includes substantially only a solid therapeutic agent. In another exemplary embodiment, the tip includes substantially no solid therapeutic agent.

[0266] In certain embodiments, the tissue interface component comprises 10% or more (eg, 80% or more) by weight of a solid form therapeutic agent based on the total weight of the tissue interface component, regardless of the configuration of the base portion and / or tip portion.

[0267] In some embodiments, the tissue interface component comprises 0.1 mg or more, 0.5 mg or more, 0.8 mg or more, 1 mg or more, 1.5 mg or more, 2 mg or more, 2.5 mg or more, 3 mg or more, 4 mg or more, 5 mg or more, 7 mg or more, 9 mg or more of a therapeutic agent (e.g., a solid therapeutic agent). In certain embodiments, the tissue interface component comprises 10 mg or less, 9 mg or less, 7 mg or less, 5 mg or less, 4 mg or less, 3 mg or less, 2.5 mg or less, 2 mg or less, 1.5 mg or less, 1 mg or less, 0.8 mg or less, 0.5 mg or less, or 0.2 mg or less of a therapeutic agent. Combinations of the above-mentioned ranges are also possible (e.g., 0.1 mg and up to 10 mg or less). Other ranges are also possible.

[0268] In certain embodiments, at least a portion of the solid therapeutic agent (e.g., API) is associated with the base portion and / or one or more tips of the tissue interface component. For example, in some embodiments, the solid therapeutic agent and the second material (if present) are substantially uniformly distributed throughout the tissue interface component (e.g., throughout the base portion and / or tips). In some cases, the solid therapeutic agent may be a coating (e.g., disposed on at least a portion of the tip(s)) such that the tissue interface component includes 10% or more by weight of the solid therapeutic agent relative to the total weight of the tissue interface component.

[0269] In some embodiments, the tissue interface component may include an additional coating. In some embodiments, the additional coating may include a material configured to slow down the dissolution time relative to dissolution of the tissue interface component without the additional coating, for example. Non-limiting examples of suitable additional coating materials include Zn, Al, Mg, polymers (e.g., enteric polymers, polycaprolactone, parylene, hypromellose, polyethylene glycol), and combinations thereof. Other additional coating materials are also possible. In some embodiments, the additional coating may be configured to release the solid therapeutic agent over a specific time period. For example, in some embodiments, the additional coating is configured to release the solid therapeutic agent in 6 months or less, 3 months or less, 1 month or less, 2 weeks or less, 1 week or less, 4 days or less, 2 days or less, 1 day or less, 12 hours or less, 6 hours or less, 3 hours or less, 1 hour or less, 30 minutes or less, 15 minutes or less, 10 minutes or less, 5 minutes or less, or 2 minutes or less (e.g., upon exposure of the additional coating to fluids such as gastric fluids). In certain embodiments, the additional coating is configured to release the solid therapeutic agent in 1 minute or more, 2 minutes or more, 5 minutes or more, 10 minutes or more, 15 minutes or more, 30 minutes or more, 1 hour or more, 3 hours or more, 6 hours or more, 12 hours or more, 1 day or more, 2 days or more, 4 days or more, 1 week or more, 2 weeks or more, 1 month or more, or 3 months or more. Combinations of the above-mentioned ranges are also possible (e.g., 1 minute or more and 1 day or less, 1 day or more and 2 weeks or less, 1 week or more and 6 months or less). Other ranges are also possible.

[0270] In certain embodiments, the tissue interface component comprises a plurality of microneedles that contain the solid therapeutic agent and the second material, if present.

[0271] In some embodiments, at least a portion of the solid therapeutic agent is present on at least a surface of the tip. In certain embodiments, at least a portion of the second material is present on at least a surface of the tip.

[0272] The tissue interface components described herein may be formed using any suitable method. In some embodiments, the tissue interface component is formed by providing a solid therapeutic agent and a second material (if present) and centrifuging and / or compressing the solid therapeutic agent and the second material together using a pressure of at least 1 MPa to form the tissue interface component. In some embodiments, the second material (if present) and the solid therapeutic agent are heated to form the tissue interface component.

[0273] In some embodiments, the tissue interface component is formed using a pressure of at least 1 MPa, at least 2 MPa, at least 3 MPa, at least 5 MPa, at least 7 MPa, at least 10 MPa, at least 12 MPa, at least 15 MPa, at least 20 MPa, at least 25 MPa, at least 30 MPa, at least 40 MPa, at least 50 MPa, at least 75 MPa, at least 150 MPa, at least 300 MPa, at least 600 MPa, at least 900 MPa, at least 1 GPa, or at least 1.2 GPa. In some embodiments, the tissue interface component is formed using a pressure of 1.4 GPa or less, 1.2 GPa or less, 1 GPa or less, 900 MPa or less, 600 MPa or less, 300 MPa or less, 150 MPa or less, 100 MPa or less, 75 MPa or less, 50 MPa or less, 40 MPa or less, 30 MPa or less, 25 MPa or less, 20 MPa or less, 15 MPa or less, 12 MPa or less, 10 MPa or less, 7 MPa or less, 5 MPa or less, 3 MPa or less, or 2 MPa or less. Combinations of the above-mentioned ranges are also possible (e.g., at least 1 MPa and at most 100 MPa, and at least 20 MPa and at most 100 MPa, at least 100 MPa and at most 1.4 GPa). Other ranges are also possible.

[0274] In certain embodiments, the tissue interface component may be formed at a particular temperature. For example, in some embodiments, the tissue interface component is formed at a temperature of 50° C. or more, 60° C. or more, 70° C. or more, 80° C. or more, 90° C. or more, 100° C. or more, or 120° C. or more. In some embodiments, the tissue interface component is formed at a temperature of 150° C. or less, 130° C. or less, 120° C. or less, 110° C. or less, 100° C. or less, 90° C. or less, 80° C. or less, 70° C. or less, or 60° C. or less. Combinations of the above-mentioned ranges are also possible (e.g., 50° C. or more and 130° C. or less). Other temperatures and ranges are also possible.

[0275] Advantageously, the tissue interface component may have desirable mechanical properties (e.g., Young's modulus) so that, for example, the tissue interface component may suitably pierce tissue of the gastrointestinal tract. In some embodiments, the Young's modulus of the tissue interface component is 100 MPa or more (e.g., 125 MPa or more, 150 MPa or more, 175 MPa or more, 200 MPa or more, 250 MPa or more, 300 MPa or more, or 350 MPa or more). In certain embodiments, the tissue interface component has a Young's modulus of 400 MPa or less, 350 MPa or less, 300 MPa or less, 250 MPa or less, 200 MPa or less, 175 MPa or less, 150 MPa or less, or 125 MPa or less. Combinations of the above-mentioned ranges are also possible (e.g., 100 MPa or more and 250 MPa or less, 100 MPa or more and 400 MPa or less). Other ranges are also possible.

[0276] In some cases, the tissue interface component may be configured to penetrate a particular depth into human gastrointestinal mucosal tissue with a particular force. For example, the tissue interface component may be configured to penetrate 1 mm or more (e.g., 2 mm or more, 3 mm or more, or 4 mm or more) with a force of 20 N or less (e.g., 10 N or less, 5 N or less, 1 N or less, 500 mN or less, 100 mN or less, 50 mN or less, 20 mN or less, 15 mN or less, 10 mN or less, 5 mN or less).

[0277] As described above and herein, the tissue interface component can be configured to have a particular velocity upon penetration, for example, into human gastrointestinal mucosal tissue.

[0278] In some embodiments, the second material comprises a polymerizable monomer and / or polymer. In certain embodiments, the second material is biodegradable. Non-limiting examples of materials suitable for the second material include polyethylene glycol, polyvinylpyrrolidone, polylactic acid, polysaccharides (e.g., maltose, lactose, starch, cellulose), acacia, methylcellulose, gelatin, tragacanth, clay, HPMC, stearic acid, sodium stearate, magnesium stearate, talc, polyethylene glycol, mineral oil, preservatives (e.g., phenol, paraben, cetrimide), antioxidants (e.g., gallic acid, tocopherol), derivatives thereof, and combinations thereof.

[0279] In some embodiments, the tissue interface component comprises a coating that has a yield strength of 50 MPa or greater (eg, 60 MPa or greater, 70 MPa or greater, or 80 MPa or greater).

[0280] In some embodiments, the coating may be comprised of a thin film metal, ceramic, or diamond-like coating (DLC). In some embodiments, the tissue interface component does not include a coating.

[0281] In some embodiments, the coating may be composed of an erodible material (e.g., iron, zinc, aluminum, or alloys) such that the coating disintegrates upon contact with a physiological environment to present the therapeutic agent, hi certain embodiments, the coating may include a polymer, such as parylene, as described herein.

[0282] In some cases, the tissue interface component may be configured to deliver a specific amount of active pharmaceutical agent per square centimeter of the subject's tissue. For example, in some embodiments, the tissue interface component is configured to deliver 0.01 μg or more, 0.05 μg or more, 0.1 μg or more, 0.2 μg or more, 0.5 μg or more, 0.7 μg or more, 1 μg or more, 2 μg or more, 5 μg or more, or 10 μg or more of pharmaceutical agent per square centimeter of the subject's tissue proximate the location of the tissue interface component penetration. In certain embodiments, the tissue interface component is configured to deliver 20 μg or less, 5 μg or less, 2 μg or less, 1 μg or less, 0.7 μg or less, 0.5 μg or less, 0.2 μg or less, 0.1 μg or less, or 0.05 μg or less of pharmaceutical agent per square centimeter of tissue. Combinations of the above-mentioned ranges are also possible (e.g., 1 μg or more and 20 μg or less). In some embodiments, the tissue interface component is configured to deliver 1 μg or more of agent per square centimeter of tissue of the subject over any suitable period of time (e.g., 0.1 seconds or more, 0.5 seconds or more, 1 second or more, 5 seconds or more, 30 seconds or more, 1 minute or more, 5 minutes or more, 10 minutes or more, 30 minutes or more, 1 hour or more, 4 hours or more, 24 hours or more, 48 hours or more, 72 hours or more, 96 hours or more, 120 hours or more, 144 hours or more, 168 hours or more).

[0283] In certain embodiments, the tissue interface component includes a binder (e.g., in some cases, the second material is a binder). Non-limiting examples of suitable binders include sugars such as sorbitol and sucrose, gelatin, polymers such as polyvinyl alcohol (PVA), polyethylene glycol (PEG), polycaprolactone (PCL), and polyvinylpyrrolidone (PVP), and polymers that include ethanol or other class 3 organic solvents (e.g., acetic acid, heptane, acetone, formic acid, isobutyl acetate, etc.).

[0284] In exemplary embodiments, the article comprises 80% or more by weight of a solid active pharmaceutical agent based on the total weight of the article. In certain embodiments, the article comprises 1 mg or more of an active pharmaceutical agent. According to some embodiments, the pharmaceutical agent is selected from the group consisting of bacteriophage, DNA, mRNA, insulin, human growth hormone, monoclonal antibody, adalimumab, epinephrine, and ondansetron. In certain exemplary embodiments, the active pharmaceutical agent is poured into a mold to form the article. In some embodiments, the mold is centrifuged. According to certain embodiments, the article further comprises a binder. In certain embodiments, the binder comprises a sugar, such as sorbitol or sucrose, a polymer, such as gelatin, PVA, PEG, PCL, PVA, or PVP, and / or ethanol. According to certain embodiments, the article has a Young's modulus of elasticity of 100 MPa or more. In some embodiments, the article is configured to penetrate at least 1 mm into human gastrointestinal mucosal tissue with a force of 20 mN or less. According to certain embodiments, the article is configured to deliver at least 1 mg of pharmaceutical agent per square centimeter of tissue of a subject and / or the article comprises 1 mg or more of active pharmaceutical agent per square centimeter.

[0285] Certain exemplary embodiments relate to a method of forming an article, the method comprising: introducing into a mold a composition comprising greater than 80% by weight of a solid pharmaceutical agent based on the total weight of the composition; and applying a pressure of 1 MPa or greater to the composition and heating the composition to a temperature of at least 70° C. for at least 1 minute. As used herein, the term “active pharmaceutical ingredient” (also referred to as “drug” or “therapeutic agent”) refers to an agent administered to a subject to treat a disease, disorder, or other clinically recognized abnormality, or for prophylactic purposes, that has a clinically significant effect on the subject's body to treat and / or prevent a disease, disorder, or abnormality.

[0286] Drugs According to some embodiments, the compositions and methods described herein are compatible with one or more therapeutic, diagnostic, and / or enhancing agents, such as drugs, nutrients, microorganisms, in vivo sensors, and tracers. In some embodiments, the active agent is a therapeutic agent, a nutritional supplement, a preventative agent, or a diagnostic agent. Although much of the specification describes the use of therapeutic agents, other agents listed herein are also possible.

[0287] In some embodiments, the agent may be in powder form. In some embodiments, the agent may be in solid form. In some embodiments, the agent may be in liquid form.

[0288] In some embodiments, the system includes a chamber (eg, a reservoir) configured to contain an active pharmaceutical agent (or a liquid containing an active pharmaceutical agent).

[0289] Agents can include, but are not limited to, any synthetic or naturally occurring biologically active compound or composition of matter that, upon administration to a subject (e.g., a human or non-human animal), induces a desired pharmacological, immunogenic, and / or physiological effect by local and / or systemic action. For example, useful or potentially useful within the context of certain embodiments are compounds or chemicals traditionally considered to be drugs, vaccines, and biopharmaceuticals, with certain such agents being used for the medical or veterinary treatment, prevention, diagnosis, and / or mitigation of disease or illness (e.g., HMG-like inhibitors such as rosuvastatin, co-A reductase inhibitors (statins), nonsteroidal anti-inflammatory drugs such as meloxicam, selective serotonin reuptake inhibitors such as escitalopram, blood thinners such as clopidogrel, steroids such as prednisone, antipsychotics such as aripiprazole and risperidone, analgesics such as buprenorphine, antagonists such as naloxone, montelukast, and memantine, cardiac glycosides such as digoxin, alpha blockers such as tamsulosin, cholesterol absorption inhibitors such as ezetimibe, metabolites such as corticosterone, antihistamines such as loratadine and cetirizine, opioids such as loperamide, proton pump inhibitors such as omeprazole, entecavir, dolutegravir, rilpivirine, and cabotegravir; antibiotics such as doxycycline, ciprofloxacin, azithromycin, antimalarials, and synthroid / levothyroxine); substance abuse treatment (e.g., methadone and varenicline); family planning (e.g., hormonal contraceptives); 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).

[0290] In certain embodiments, the active substance is one or more specific therapeutic agents.As used herein, the term "therapeutic agent" or also called "drug" refers to the drug administered to a subject for treating disease, disorder or other clinically recognized abnormalities or for preventive purposes, and has a clinically significant effect on the subject's body for treating and / or preventing disease, disorder or abnormality. Lists 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 its subsequent publication, the 18th ed (2006), Mark H. Beers and Robert Berkow (eds.), Merck Publishing Group, or, in the case of animals, The Merck Veterinary Manual, 9th ed., Kahn, CA (ed.), Merck Publishing Group, 2005, and in “Approved Drug Products with Therapeutic Equivalence and The information can be found in the “Orange Book,” published in the United States Food and Drug Administration (FDA)’s “Orange Evaluations.”Examples of drugs approved for human use are listed by the FDA under 21 C.FR §§ 330.5, 331-361, and 440-460, which are incorporated herein by reference, and drugs for veterinary use are listed by the FDA under 21 C.FR §§ 500-589, which are 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 agents, anti-pyretics, antidepressants, anti-epileptics, anti-psychotics, neuroprotective agents, anti-cancer agents, anti-proliferative agents such as antihistamines, anti-migraine agents, hormones, prostaglandins, antimicrobial agents (including antibiotics, antifungals, antivirals, and antiparasitics), antimuscarinics, anti-inflammatory agents, bacteriostatic agents, immunosuppressants, sedatives, hypnotics, antipsychotics, bronchodilators, antiasthmatics, cardiovascular agents, anesthetic enzymes, anticoagulants, enzyme inhibitors, steroids, steroidal or nonsteroidal anti-inflammatory agents, corticosteroids, dopaminergic agents, electrolytes, gastrointestinal agents, muscle relaxants, nutrients, vitamins, parasympathomimetics, stimulants, appetite suppressants, and antihypnotics. Nutritional supplements can also be incorporated into the drug delivery device. These can be supplements such as vitamins, calcium or biotin, or natural ingredients such as plant extracts or plant hormones.

[0291] In some embodiments, the therapeutic agent is one or more antimalarial drugs.Exemplary antimalarial drugs include quinine, lumefantrine, chloroquine, amodiaquine, pyrimethamine, proguanil, chlorproguanil-dapsone, sulfonamides such as sulfadoxine and sulfamethoxypyridazine, mefloquine, atovaquone, primaquine, halofentrine, doxycycline, clindamycin, artemisinin, and artemisinin derivatives.In some embodiments, the antimalarial drug is artemisinin or a derivative of artemisinin.Exemplary artemisinin derivatives include artemether, dihydroartemisinin, arteether, and artesunate.In certain embodiments, the artemisinin derivative is artesunate.

[0292] In another embodiment, the therapeutic agent is an immunosuppressant. Exemplary immunosuppressants include glucocorticoids, cytosuppressants (such as alkylating agents, metabolites, and cytotoxic antibodies), antibodies (such as those directed against the T cell receptor or the Il-2 receptor), drugs acting on immunophilins (such as cyclosporine, tacrolimus, and sirolimus), and other drugs (such as interferons, opioids, TNF-binding proteins, mycophenolic acid, and other small molecules such as fingolimod).

[0293] In certain embodiments, the therapeutic agent is a hormone or a derivative of a hormone.Non-limiting examples of hormones include insulin, growth hormone (e.g., human growth hormone), vasopressin, melatonin, thyroxine, thyrotropin-releasing hormone, glycoprotein hormones (e.g., luteinizing hormone, follicle-stimulating hormone, thyroid-stimulating hormone), eicosanoids, estrogen, progestin, testosterone, estradiol, cortisol, adrenaline, and other steroids.

[0294] In some embodiments, the therapeutic agent is a small molecule drug having a molecular weight of 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, or less than about 400 daltons. In some cases, the therapeutic agent is a small molecule drug having a molecular weight of 200-400 daltons, 400-1000 daltons, or 500-2500 daltons.

[0295] In some embodiments, the therapeutic agent is insulin, a nucleic acid, a peptide, a bacteriophage, DNA, mRNA, human growth hormone, a monoclonal antibody, adalimumab, epinephrine, a GLP-1 receptor agonist, semaglutide, liraglutide, dulaglitide, exenatide, factor VIII, a small molecule drug, proglucin, a vaccine, a subunit vaccine, a recombinant vaccine, a polysaccharide vaccine, and a conjugate vaccine, a toxoid vaccine, an influenza vaccine, a single vaccine, a pre-pneumonia vaccine, an mmr vaccine, a tetanus vaccine, a hepatitis vaccine, an HIV vaccine. The active pharmaceutical agent is selected from the group consisting of Ad4-env clade C, HIV vaccine Ad4-mGag, DNA vaccine, RNA vaccine, etanercept, infliximab, filgastrim, glatiramer acetate, rituximab, bevacizumab, any molecule encapsulated in a nanoparticle, epinephrine, lysozyme, glucose-6-phosphate dehydrogenase, other enzymes, certolizumab pegol, ustekinumab, ikekizumab, golimumab, brodalumab, gucelu, ab, sesikinumab, omalizumab, TNF-alpha inhibitors, interleukin inhibitors, vedolizumab, octreotide, teriperatide, CRISPR Cas9, insulin glargine, insulin detemir, insulin lispro, insulin aspart, human insulin, antisense oligonucleotides, and ondansetron.

[0296] In an exemplary embodiment, the therapeutic agent is insulin.

[0297] In some embodiments, the tissue interface components described herein comprise more than one type of therapeutic agent.

[0298] In certain embodiments, the therapeutic agent is present in the tissue interface component at a concentration such that, upon release from the tissue interface component, the therapeutic agent elicits a therapeutic response.

[0299] In some cases, the therapeutic agent may be present at a concentration (e.g., in a microdose concentration) lower than the minimum concentration typically associated with an active therapeutic agent. For example, in some embodiments, the tissue interface component includes a relatively low dose of a first therapeutic agent (e.g., a steroid) (e.g., without wishing to be bound by theory, a low dose of a therapeutic agent such as a steroid may mediate a foreign body response(s) at a location within the subject's body (e.g., a response to contact by the tissue interface component). In some embodiments, the concentration of the therapeutic agent is a microdose of 100 μg and / or 30 nMol or less. However, in other embodiments, the therapeutic agent is not provided in a microdose, but is present in one or more of the amounts listed above.

[0300] In some embodiments, the tissue interface component includes a self-actuating tissue interface component, such as is generally described in co-pending International Patent Application No. WO2018 / 213600, entitled "SELF-RIGHTING SYSTEMS AND RELATED COMPONENTS AND METHODS," filed May 17, 2018, the entirety of which is incorporated herein by reference.

[0301] In some embodiments, the tissue interface component is administered to the subject (e.g., orally). In certain embodiments, the article may be administered orally, rectally, vaginally, nasally, or urethrally. In certain embodiments, the tissue interface component (e.g., and / or the API contained therein) is administered by contacting the skin of the subject with the component. In an exemplary embodiment, the tissue interface component (e.g., and / or the API contained therein) is administered by contacting the buccal tissue of the subject (e.g., lips, palate area, cheek, sublingual, tongue) with the component. In yet another exemplary embodiment, the tissue interface component is administered orally, and upon reaching a location within the subject's body (e.g., digestive tract such as colon, duodenum, ileum, jejunum, stomach, buccal cavity, esophagus, etc.), the tissue interface component interfaces (e.g., contacts) with the subject's tissue at the location within the subject's body and at least partially penetrates the tissue. In certain embodiments, at least a portion of the tissue interface component penetrates the subject's tissue and at least a portion of the support material and / or active pharmaceutical agent dissolves in the subject's tissue.

[0302] Advantageously, administration of a tissue interface component with a relatively high loading of API to the gastrointestinal tract may allow for more effective delivery of the API compared to traditional methods. For example, without wishing to be bound by theory, delivery of drugs to the gastrointestinal tract via injection has been shown to have higher bioavailability compared to other methods.

[0303] In some embodiments, the system includes a self-healing article (e.g., configured to localize to a location within a subject's body in a particular orientation), a self-actuation component (e.g., configured to activate under a particular set of conditions, e.g., upon exposure to fluids such as gastric fluids), a tissue interface component associated with the self-actuation component, and an API associated with the tissue interface component. In certain embodiments, the system includes a self-healing article, a self-actuation component, and a tissue interface component associated with the self-actuation component. In some embodiments, the system includes a self-actuation component and a tissue interface component associated with the self-actuation component. In certain embodiments, the system includes a self-healing article and an API associated with the self-healing article. In some embodiments, the system includes a tissue interface component and an API associated with the tissue interface component. In some embodiments, the system includes a self-actuation component, a tissue interface component associated with the self-actuation component, and an API associated with the tissue interface component. The self-healing article, the self-actuation component, the tissue interface component, and the API and related configurations are described above and herein.

[0304] definition "Subject" refers to any animal, such as a mammal (e.g., a human). Non-limiting examples of subjects include humans, non-human primates, cows, horses, pigs, sheep, goats, dogs, cats, or rodents, such as mice, rats, hamsters, birds, fish, or guinea pigs. In general, the present invention is intended for use in humans. In some embodiments, the subject may demonstrate a health benefit, for example, upon administration of the self-healing article.

[0305] As used herein, "fluid" is given its ordinary meaning, i.e., liquid or gas. A fluid cannot maintain a defined shape and will flow during an observable time frame to fill the container in which it is placed. Thus, a fluid may have any suitable viscosity that allows for flow. When more than one fluid is present, each fluid may be independently selected from among essentially any fluid (liquid, gas, etc.) by one of ordinary skill in the art. EXAMPLES

[0306] The following examples are intended to illustrate certain embodiments described herein, including certain aspects of the invention, but do not exemplify the full scope of the invention.

[0307] Example 1 - Self-healing article Self-healing articles of particular shape and / or density distributions are provided, optionally with the ability to be encapsulated in standard "000", "00", or potentially smaller or larger capsules. For example, the density and / or shape distributions can be as follows: 1. This design has only one stable point and one unstable point, so the self-healing article will always recover itself in a single configuration and orientation. 2. The design of the article has a relatively low recovery time to a stable configuration of the article from every possible orientation; 3. The design minimizes the destabilizing effects felt from forces within the gastrointestinal tract, such as fluid flow and muscular contractions, and / or 4. The design allows items of various shapes and weights to be loaded into the system through hollow gaps created at specific locations of the item.

[0308] In some cases, the article shape results from a smooth curve drawn in the two right quadrants of a Cartesian plane and rotated about the y-axis. The shape has several notable features. The shape possesses a flat bottom that is perpendicular to the y-axis and moves to a corner of high curvature and then gradually decreases in curvature as one follows the curve. The flat bottom section of the curve may help to meet the third specification of the article. Because the bottom is flat and surrounded by sharp corners, more force is required to push the article over on its side. This is similar to the way an ellipsoid will wobble when pushed, but a cube will not.

[0309] The remainder of the curve may be optimized to meet the first and second specifications using the following formula: The recovery time of the article is calculated from the angular kinematic equation. TIFF2025028862000003.tif11170 where ω is the angular velocity, t is time, and α is the angular acceleration. The angular acceleration is calculated from the torque generated by gravity and buoyancy acting on the object. where τ is the torque and I is the moment of inertia. The torque is determined from the cross product between the force vector and the distance vector, TIFF2025028862000005.tif12170In the formula, d is the distance vector from the center of gravity (in the case of gravity) or center of volume (in the case of buoyancy) to the end point of the curve tangent to the rest surface, F is the force vector in the direction of the generated force, and θ is the angle between these two vectors.

[0310] The article can, in some cases, be made of two different materials, one with high density and one with low density. The density ratio is defined such that the center of gravity of the shape is located at the origin of the coordinate system. The lower half of the plane is composed of high density material, while the upper half of the plane is composed of low density material. In order to keep the material density achievable from currently available materials, certain holes and modifications can be made to the original shapes described in the examples. These holes and modifications are also utilized to accommodate the article within the system, which are then taken into account when determining the density of the other materials.

[0311] Once the 3D shape is designed, it is possible to test the recovery time from a given direction by using the above equations. The weight and volume of the item determine the acting force that determines the torque and are set by the density of the material as well as the curve generated. The distance and angle measurements used to determine the torque are determined solely by the curve generated. The curve is generated by drawing a smooth curve through a set of points in radius coordinates with an angle coordinate set. The code then varies the distance coordinates of the points until the minimum set of recovery times is reached.

[0312] Example 2 A solid shape created by rotating a defined smooth curve around the y-axis (example: Figure 12). The shape is made of a biocompatible polymer (e.g., PCL, PLA, PEG) in all regions with positive y values, and a biocompatible ceramic (e.g., hydroxyapatite) or metal (e.g., stainless steel, field metal) in all regions with negative y values. The ratio of the densities of the two materials should be between 6:1 and 16:1. The article can be scaled to any length, but the points in Figure 12 describe an object that can fit inside a capsule (Figure 13), such as a 000 capsule.

[0313] This shape was tested for its recovery ability against ellipsoids and spheres with the same volume and similar dimensions. The article was tested with a high speed camera at 1000 FPS in several different liquids including water, oil, and gastric fluid, and on different surfaces including plastic and porcine stomach tissue. The results (Figures 14-17) showed that the article had faster recovery times overall, as well as faster recovery times at angles closer to the stable orientation. This makes the article superior to other shapes, since the article was most likely to start out close to the stable orientation of the article.

[0314] The articles were also tested for their ability to remain recovered by placing them on a tilting mixer. The mixer was set to tilt 15 degrees in each direction at 50 rpm. The sphere was tilted 18 degrees from the optimal orientation and the ellipsoid was tilted 31 degrees from the optimal orientation, yet the articles did not leave their stable orientation (Figures 18-21).

[0315] We also placed the objects in intact pig stomachs suspended in vitro using a plastic tube as an artificial esophagus and compared the number of times they landed in the correct orientation compared to a sphere made of PCL alone. Out of 60 trials for each of the objects in a water-filled, oil-filled, or empty stomach, we found that the sphere landed in the correct orientation only 25% of the time, whereas the object shaped as in Figure 12 landed in the correct orientation every time.

[0316] In addition, a similar experiment was performed in vivo. Six self-healing articles and six articles that were not self-healing but had the same shape were fed to sedated pigs via the digestive tract. The pigs were then vigorously shaken to simulate walking. After shaking the pigs were placed under an x-ray and the number of articles that remained in the correct orientation were counted. These articles were identified by placing a metal piece inside the article (Figures 22-23). ​​The self-healing articles already had a hemisphere of metal on the bottom half of the self-healing article, which appeared under the x-ray as a perfect circle when they healed and like a waning moon when they did not heal. A circular washer was placed inside the control article and was shown as a perfect circle when they self-healed or as a distorted oval when they did not self-heal. 65 / 66 self-healing orientations showed the correct orientation after shaking, while only 7 / 31 control articles showed the correct orientation.

[0317] Example 3 An object with a similar shape as described in Example 2, but with holes, vents, and slits made into the article. Such holes and slits can be used to allow fluids to enter the system or to store items within the system (FIG. 24). These slits can also be used to hollow out the article to keep the density ratio at a reasonable value that can be achieved using the available materials. For example, by hollowing out the top section of the article, a high density material can be used to fill the remaining top area, and since the only constraints on the article are the profile and center of gravity, a higher density material is allowed. When drilling holes, the article should try to remain axisymmetric or as close to axisymmetric as possible.

[0318] Such examples of these holes and slits include, but are not limited to: 1. A cylinder with a radius less than the radius of the object, centered on the y-axis. 2. A conic section centered on the y-axis, whose radius is capable of changing as the radius of the system changes. 3. A vertical linear cut of a given width from the top or bottom of the system. 4. Any other type of cut into the article that maintains the overall integrity of the system.

[0319] Example 4 An object with a shape similar to that described in Examples 2 and 3, but with a drug delivery article built into the system. The article can be a solid or hollow needle loaded with drug. The needle can be a hollow needle connected to a reservoir, or a series of needles loaded or coated with drug. Other drug delivery articles, such as patches, are possible as well.

[0320] In the example of a needle, the needle may be housed either inside or outside the system. When housed outside the system, the needle may be connected via adhesive or embedded into the mold of the article. When housed within the system, the needle may be housed within a hollowed-out hole in the article.

[0321] The needle puncture can be passively actuated from the gravity of the article. In this implementation, the weight of the article can push the needle into the tissue.

[0322] Example 5 Objects having shapes similar to those described in Examples 2-4, but with electronic devices built into the system.

[0323] By adding electronic devices to the article in combination with the fastener, the article can be used as a gastroretention mechanism for electronic devices. The sensor can access the tissue wall or the inside of the gastrointestinal tract due to the orientation of the article. For example, a pH sensor attached to the bottom of the article could read the pH of the stomach wall area or the intragastric area depending on the placement on the system.

[0324] Example 6 An object having a similar shape to those described in Examples 2-4, but with the ability to remotely attach other items to the system (FIG. 25).

[0325] By applying attractive and / or adhesive forces to the walls of the system, the patient can swallow other capsules filled with new articles or drugs and cause these capsules to clump together in the system. Such forces can be generated by magnets, adhesives, vacuum, or any number of other mechanisms.

[0326] For example, a magnet can be attached to the wall of the system as well as the wall of the electronic sensor. The patient can first swallow the self-healing system and allow it to be anchored to the tissue wall as described in Example 4. The patient can then swallow a separate capsule containing the electronic sensor. The magnetic force generated between the two articles from the magnet placed will allow the two systems to be attached. Because the self-healing system is anchored to the tissue wall, the electronic sensor can remain in the stomach even if the electronic sensor does not have gastroretentive properties. This system can allow any type of article to become gastroretentive.

[0327] Example 7 - Self-actuating article The device can be actively actuated. This can include mechanisms such as shape memory nitinol, foam elastomers, or compression springs. Compression springs can be immobilized in solid biodegradable and biocompatible polymers or sugars (e.g., sucrose, maltose), mechanisms that have been shown to function in vivo (Figure 27). These mechanisms can then be housed within hollowed-out sections of the article or on the outside of the article. Methods of retaining the device to the system product include, but are not limited to, magnets, knots, and application of adhesives.

[0328] Continuing with the spring example, to deliver a drug, it may be desirable for the needle to enter the submucosa of the GI tract, e.g., for the needle to penetrate at least 1 mm into the tissue. If the needle penetrates the tissue more than 5 mm, the patient is at risk of perforation. For this reason, the spring may be compressed 1-5 mm. Also, the amount of force required to penetrate the GI tissue is generally small, around 1-10 mN, but it may take about 100 mN of force to enter the muscular layer of the stomach between the mucosa and submucosa. In some cases, the spring will contain enough force when compressed that the spring will push the tissue with 100 mN plus a 3-10 times safety factor. This means that in some cases, the spring may have a spring constant of about 100-250 N / m (FIG. 28).

[0329] In addition, the compression spring may be wrapped in a material capable of holding such a force. The material may also be brittle, for example, so that the spring will pop out of the material at once. Brittle materials such as (crystallized) sugar generally crumble quickly when the material is subjected to a given stress. Caramelized sucrose generally breaks under a stress of 0.1 Mpa. If the compression spring exerts a force of 1 N on the sucrose coating the compression spring, the sucrose coating may be at least 3.56 mm in diameter to contain the spring. Any more caramelized sucrose added to the coating action may be used as a timing mechanism for the device (e.g., without wishing to be bound by theory, the thickness of the coating may be at least proportional to the time required to break down the coating).

[0330] Using modeling software to perform a diffusion mass transfer problem at interfacial equilibrium, it was determined that by coating the spring with 4-6 mm of sucrose, actuation could be delayed by 1-4 minutes as the sucrose coated spring dissolved in water. This was confirmed by experiment (Figures 29-30). A delay of at least 20 seconds was shown to be sufficient so that actuation would occur in the stomach and not in the mouth or esophagus.

[0331] To ensure that liquid reaches the sucrose to begin this dissolution process, vents may be added to the top and bottom of the device to allow for fluid flow. These vents may, for example, allow a way for air trapped inside to escape. These vents may also be hygroscopic to allow water to pass easily.

[0332] In some cases, the retention device will allow the system to adhere to the tissue wall of the GI tract through physical or chemical means. Such devices may include barbed or hooked needles, mucoadhesive patches, capture and closure mechanisms (FIG. 31), vacuum suction, or any number of other mechanisms. The retention device may be located at the bottom of the device to ensure that it remains facing the tissue wall.

[0333] If the retention device uses a hook, such as a hooked needle, the retention device can reach the muscular layer of tissue between the mucosal layer and the submucosa. Figure 32 shows a histology slide of a gastric tissue piece penetrated by a device penetrating the muscular layer of the subject. The penetration was made by using a sugar-coated spring, such as that described above, compressed 6 mm and having a spring constant of 210 N / m.

[0334] Calculation optimization: The optimized shape was created by performing a 2D curve optimization on the 180 degree plane of quadrants I and IV and rotating the curve around the Y axis. Figure 37 illustrates the optimized curve, as well as the vectors and methods described in this section. The optimization function varied the radius of 25 different points equiangularly spaced along the curve plotted in polar coordinates. When converted back to Cartesian coordinates, the space inside the rotated curve and below the XZ plane was filled with a high density material (7.7 g / cm 3 ), while the space above the XZ plane and inside the rotated curve was filled with low density material (1.1 g / cm 3) was set to encompass the y-axis, ...

[0335] The optimization itself utilized Newton's equations of motion to find the self-orientation time t for a given shape. TIFF2025028862000006.tif51170 where the angular acceleration α and angular velocity ω are determined based on the moment of inertia I and torque τ of the device. Gravity F acts as an external force in the model and was used to calculate the simulated torque applied to the lever arm d, defined as the distance between the center of gravity of the device and the contact point with the tissue wall.

[0336] The angular acceleration of the device in a given direction determines the orientation velocity, which varies with the torque and moment of inertia, as defined by Equation 2. The moment of inertia was calculated along with the total weight of the device by dividing the 3D space into a 50×50×50 array of equal sized blocks and assigning a density to each block and performing the summation described in Equation 4.

[0337] To calculate the torque of the device, it was necessary to determine both the direction and magnitude of the force and distance vectors according to Equation 5. The force vector was the force of gravity on the object, starting from the center of gravity and pointing in a direction perpendicular to the contact surface. The distance vector was calculated as the distance between the center of gravity and the fulcrum of the device on the contact surface. When determining the fulcrum, the larger curvature of the device was taken into account, since areas with a concave curvature will not contact the surface.

[0338] Sucrose encapsulation dissolution modeling Griffith's criteria TIFF2025028862000007.tif11170 was used to calculate the radius at which the sucrose encapsulation propagates the crack, where σ c is the critical stress applied by the spring, γ is the surface energy of the material, E is the Young's modulus of the material, and a is the surface area perpendicular to the applied stress. Since all variables in the equation remain constant except for the surface area, the dissolution rate defines the time to crack event and spring release. The COMSOL model and experimental testing are based on a spring providing a force of 1 N. The physical spring was created by cutting a purchased spring to the appropriate size.

[0339] Using COMSOL Multiphysics (Stockholm, Sweden), we mathematically modeled the dissolution of a sucrose cylinder in both stationary water and in water flowing at 0.02 m / s, similar to that of the human stomach.(37) Fick's law was used to estimate the rate of the diffusion process at the contracting boundary between sucrose and water: 5.2*10^ -10 m 2 / sec, diffusion coefficient is 6720 mol / m 3 The equilibrium concentration of sucrose in water is 7.8*10 -4 The mass transfer coefficient in m / sec (determined experimentally) was used as a parameter. The COMSOL model was run with starting sucrose cylinder diameters of 6 mm, 5 mm, and 4 mm, and the time it took for the cylinder to dissolve to a diameter of 1.7 mm was used to predict the actuation timing when a spring was present within the cylinder.

[0340] To calculate the mass transfer coefficient of sucrose in water, sucrose was caramelized at 215 °C for 15 min to create a cylindrical shape in a PDMS mold with a 6 mm diameter hole. The caramelized sucrose cylinder was placed in a 500 mL beaker of water at room temperature and the diameter of the sucrose was measured every minute. The dissolution rate was modeled and the slope of the linear fit was determined to be the mass transfer coefficient.

[0341] To test the dissolution of the sucrose coating on the springs, the sucrose-encapsulated springs were placed in a 500 mL beaker of water at room temperature and the timing of spring actuation was recorded for 4 mm, 5 mm, and 6 mm diameter sucrose springs, each with three trials.

[0342] Example 17 - Tip to tissue distance The following example demonstrates the relationship between speed and gap size (ie, the distance between the tip of the tissue interface component and the tissue engaging surface) as described herein.

[0343] Table 1 shows the relationship between starting distance from the tip and tip velocity in m / sec for various springs with different spring constants (e.g., 500N / m, 1000N / m, 1500N / m). Figure 36 shows a plot of velocity versus gap (in mm) for a particular force (6N). JPEG2025028862000008.jpg115170

[0344] Example 18 - Assembly Process 34A-34E show an exemplary process for assembling a self-healing system as described herein.

[0345] Example 20 - Delivery of molecules to the gastrointestinal tract by liquid injection This example demonstrates the use of a liquid-injected self-orienting millimeter-scale actuator (L-SOMA) for the delivery of a liquid (e.g., containing a therapeutic agent).

[0346] In this example, the L-SOMA generally includes a chamber for holding a liquid formulation before being released into the gastrointestinal tract (e.g., stomach, such as the stomach wall), a liquid tissue interface component (e.g., needle) based delivery mechanism, and a system (e.g., containing isomalt) for actuating the needle insertion and pressure mechanism.

[0347] 39A-39D illustrate various exemplary L-SOMA components and four states of compression while performing an injection.

[0348] Prior to injection, the liquid drug formulation is held and protected inside the system by a chamber with a volume of approximately 80 μL. The chamber includes three parts that together form a completely sealed internal volume: 1) the L-SOMA lower part, 2) an outer septum (such as a plug) made of silicone or TPE, and 3) a 2K molded plunger made of hard polymer and soft TPE that acts as an inner septum. In some embodiments, the plunger is made entirely of chlorobutyl rubber, bromobutyl rubber or any similar rubber, and / or isoprene or a similar polymer. In some embodiments, an SK molded plunger is used made of hard polymer and chlorobutyl rubber, bromobutyl rubber or any similar rubber, and / or isoprene or a similar polymer.

[0349] These septa generally provide a seal around the injection needle and can prevent food or liquid from passing through from the outside environment, so that, for example, enzymes in the stomach cannot reach the formulation through the septum and the drug formulation will not leak through the septum.

[0350] Needle-Based Delivery Mechanisms To deliver the liquid formulation to the tissue, a needle may be used to aid in delivery. The needle is inserted directly into the inner septum, creating a tight-fitting seal. The needle may be hollow (e.g., containing a channel), but the liquid formulation does not necessarily pass through the top of the needle. Instead, there may be a hole (e.g., an inlet) on the side of the needle. The liquid may be configured to pass through this hole and exit the beveled end. For example, a liquid chamber (e.g., a reservoir) may be placed in fluid communication with the hole upon activation of the spring, thus facilitating the transfer of fluid from the liquid chamber to the needle.

[0351] The hole is at a height above the needle such that the hole is outside the liquid chamber before activation. When the device is activated, the needle moves down, for example, 5 mm, in this example. This movement inserts the needle approximately 4.6 mm into the stomach tissue and moves the side hole into the liquid chamber to enable a flow path from the chamber to the tissue. Since the height of the needle can be adjusted, the needle penetration stroke can also be adjusted. Both values ​​can be adjusted up to 2 mm or more. The top end of the needle can be closed and used as a connection point to the actuation spring via the needle hub. Therefore, the only path for fluid to pass through the needle is from the side hole to the hole at the tip.

[0352] Dual sequential actuation mechanism The L-SOMA autonomously orients in the stomach after ingestion to align the injection mechanism of the L-SOMA with the tissue (Figures 40A-40E). The shape and density distribution of the device are inspired by the leopard tortoise, an animal that has the ability to self-orient from any configuration. The high curvature upper portion of the device coupled with the low center of gravity ensures that the device possesses only one stable orientation, defined as the angle at which the center of gravity of the device is at a local minimum. In addition, the flat lower portion of the L-SOMA stabilizes the preferred configuration of the L-SOMA, ensuring that the L-SOMA does not tip over and misfire into the lumen if the patient moves around during actuation. The robust self-healing of the shape is described in the examples above (e.g., when validating the ability of the L-SOMA to deliver solid dosage forms). After configuring the device to allow for liquid administration, the L-SOMA was retested for self-orientation 100 times in a silicone mold of simulated stomach tissue. The L-SOMA device was oriented to the preferred configuration of the L-SOMA device during every experiment in less than one second.

[0353] As soon as the L-SOMA is ingested, a hydration-based actuator plug (e.g., made from isomalt) begins to dissolve. The plug holds in place a hub connected to the infusion needle. Upon dissolving, the plug releases the hub and a compression spring expands to deliver the needle to the tissue. After a set distance, the hub is stopped by a tab on the housing of the device. This ensures that the needle is inserted the set distance into the tissue. From the experiments, it was determined that the device actuated in 4+-1 minutes after exposure to water in vitro. In vivo, the device actuated in 4+-2 minutes.

[0354] When the device inserts the needle, the needle hub immediately activates a second compression spring that delivers the loaded liquid formulation. By decoupling needle insertion from liquid injection, the device is able to inject the entire liquid dose of the device at a precise tissue depth, instead of injecting the dose as the needle passes through the tissue. High speed photography of the first prototype L-SOMA device with a 21G needle actuated in 0.3% agarose gel demonstrated that all of the liquid exits through the needle tip and no liquid exits through the substratum (Figure 41A, Figure 41B). This ensures that the liquid dose enters the tissue and is not drained above the tissue. These experiments were repeated with ex vivo porcine stomach tissue, demonstrating that the L-SOMA can insert a 30G needle into the tissue, followed by injection of contrast agent into the tissue (Figure 41D). 29G and 32G needles were also successfully demonstrated.

[0355] Submucosal needle penetration depth and depot creation To determine how needle penetration depth affects the delivery of the liquid dose, we performed controlled injections of contrast agent to various known depths of ex vivo pig stomach tissue and took MicroCT images of the depots created (Figure 41E). The layer of tissue targeted by a particular injection depth was confirmed by taking microtome slices of the tissue and looking for areas disturbed by the dye injection (Figure 41H and Figure 41I). We also measured the percent of liquid remaining in the tissue after administration using the volume calculator in the MicroCT software (Figure 41J). The ex vivo pig stomach measured 6.99±1.28 mm thick at the injection site, and we administered to depths of 3, 4, 4.5, 5, and 6 mm. Overall, we delivered a total volume of 170 μL of contrast agent during these controlled injection experiments. This is comparable to the maximum dose volume of 80 μL for the L-SOMA device. We found that for injection depths of 3 and 4 mm, the needle sometimes did not reach the gastric submucosa. When injected only into the mucosa, the contrast dose leaked out and only a small portion of the liquid remained inside the tissue. Insertion depths of 4.5 mm and above were found to consistently deliver the entire liquid dose to the submucosa and were not subject to leakage. At insertion depths of 5 and 6 mm, occasional injection into the muscularis layer of gastric tissue was observed. During injection into this tissue layer, the contrast produced a marbling pattern.

[0356] During these injection experiments, we measured the force required to deliver a given dose of liquid into the tissue (Figure 41K, Figure 41L). To deliver an 80 μL liquid dose through a needle inserted 4 mm into the tissue, a force of 12.1 ± 6.0 N was found to be statistically significantly greater than the force of 5.7 ± 2.7 N required to administer the same amount of liquid through a needle inserted 4.5 mm into the tissue (P = 0.009). To inject an 80 μL liquid dose through a needle inserted 5 mm into the tissue, a force of 7.6 ± 3.1 N was found to be required, which was not statistically significantly greater than the injection force found for a needle insertion depth of 4.5 mm (P = 0.12). In addition, the force of 8.0 ± 4.1 N required when administering into the muscular layer of the tissue at a needle insertion depth of 5 mm (n = 6) was not statistically significantly different from the injection force required to administer liquid throughout this depth (P = 0.8). This suggests that penetration of the muscle layer generally does not affect the force required to inject a liquid dose, and therefore does not generally limit the delivered dose volume.

[0357] Considering the experimental data on liquid administration, it was decided to design a SOMA device with a needle inserted 4.5 mm into the tissue. This insertion depth provided statistically significantly greater dose retention compared to insertion depths of 3 mm and 4 mm. Also, by choosing an insertion depth lower than 5 mm and 6 mm, tissue disturbance was reduced, thereby mitigating the possibility of other disorders. Six L-SOMA devices were actuated at this needle insertion depth, administering a total of 80 μL of contrast agent per L-SOMA. During these experiments, it was observed that a submucosal depot was created (Figures 41F-41I). In addition, during these L-SOMA injections, the entire dose was delivered into the tissue every time (Figure 41J). Further testing in an in vivo porcine stomach demonstrated that the SOMA injected the dye directly into the gastric submucosa. Immediately after administration of these dye-loaded devices, the animals were sacrificed and histology was obtained.

[0358] Figures 42 and 43 show exemplary actuation of an L-SOMA in water. As shown in Figure 42, the dye is released from the liquid compartment into a water bath in a span of 2 milliseconds after actuating the device. The dye exits through the tip of the needle. As shown in Figure 43, the dye is released from the liquid compartment into a 0.35% agarose gel in a span of 2 milliseconds after actuating the device. The dye exits through the tip of the needle.

[0359] Figure 44 shows a photograph of an exemplary needle with a hole in the side connected to a needle / spring attachment. Liquid passes through the hole in the side and exits the beveled end.

[0360] Use of long beveled needle tips Since injection force is generally related to insertion depth, needles with higher angle grinds were tested. These needles possessed smaller exit holes in the needle insertion direction, thus more precisely targeting the insertion depth. These needles were found to be unable to insert significant amounts of fluid into the tissue even with forces >50 N. The plunger was displaced by a tensile strength tester used to measure the force, but there was no contrast agent in the tissue after attempting to deliver the dose. Instead, these forces were generally attributed to compression of the rubber stopper and other materials used in the administration mechanism. From these experiments, needles with low angle grinds were selected for the L-SOMA.

[0361] Dissolvable or hydrated needles A needle inserted into tissue can be removed from the tissue and moved back into the device via a retractable mechanism, a swollen hygrogel, or the needle can lose its needle sharpness. A third spring can be used to move the needle back into the device from the needle insertion state. A soluble needle can be used to eliminate the needle. However, currently, designs use needles that contact the fluid inside the device, so in some cases it may be desirable for the needle not to dissolve from the outside. Thus, for example, the needle may include a protective coating on the outside surface of the needle. Such a coating may be a metal, such as gold, or a polymer, such as parylene. This layer may be anything from 300 nm to 5 um thick. It is desirable for a soluble needle to maintain the functionality of the needle after it has been inserted into the tissue. For example, the needle should be able to easily penetrate the tissue. In some cases, the needle may use a relatively sharp tip. The needle may also be configured to pass liquid through the inner tube. In addition, the needle may be configured to have a hole on the top section to allow liquid to enter. Some examples of materials the needles can be made from include sugars or sugar-like materials such as isomalt or sucrose, biodegradable polymers or copolymers such as PVP, PVA, Soluplus, hydrogels, gelatin, starch. The needles can be configured to dissolve from the inner tube outward. If the needles hydrate and soften, this can also eliminate the possibility of perforation by the protruding needle. If there is a soft border made around the tip of the needle, this can also prevent perforation. If the needles soften like pasta, this can also work. If the needles break into small pieces, this can also work. The needles can be made of decomposable metals so that they split. Such metals include zinc, magnesium, and iron, among others.

[0362] Work and spring force required to expel fluid In some embodiments, it has been found that a force in the range of 3-10 N is required to rapidly expel the liquid from the device. However, it is not necessary for the liquid to be rapidly expelled. As long as the force provided by the spring is greater than the force required to create a depot in the tissue, the liquid will eventually enter the tissue. The springs have been tested with as little as a maximum force of 5 N; therefore, it is envisioned that the spring force may be significantly reduced therefrom. Higher forces would also work.

[0363] Different gauge needles require different amounts of work to eject. Smaller gauge needles may require more work to force the liquid through the tubing, however any needle size will work with this device. Needles as low as 32G to as high as 18G have been tested, however higher and lower needle gauges will work.

[0364] Hole size and use of sprinkler needles A low angle grind produces larger holes that are useful. Aside from the side holes that allow liquid into the needle, in some embodiments, it has been found that the sprinkler needle does not necessarily contribute to the efficiency of injection. This may be because in some cases injection into the mucosal layer itself did not produce favorable results.

[0365] Use in various animals L-SOMA can be used in humans, but also in other animals, such as pigs, horses, and cattle.

[0366] Adding electronic devices for detection or actuation The L-SOMA can embed electronic devices such as wireless communication devices like NFC and Bluetooth inside the device, tethered to the device or outside the device. Other electronics that can be included would be batteries, wiring, microcontrollers, capacitors, resistors, etc. One use of the electronic device could be to send a message when the capsule is activated. Another could be a sensor used to measure temperature or molecules inside the stomach or inside the gastric mucosa. Another could be a triggerable activation mechanism.

[0367] In vivo testing In vivo pig experiments were performed in which L-SOMA devices were prepared loaded with either an inactivated GLP-1 receptor agonist or fast-acting insulin. L-SOMA administration experiments were compared to subcutaneous administration experiments and to administration of liquid formulations into the stomach lumen of pigs. Using an endoscope, L-SOMA devices were placed into the pig stomach and activated independently. After 2 hours, the devices were removed from the animals. Time 0 corresponds to the time the device was placed in the stomach, not the time the device was activated. The administered pigs were partially fasted, but contained a layer of gastric fluid and food approximately the same height as the L-SOMA capsule. Even with food, L-SOMA was able to deliver the drug load with similar efficacy as subcutaneous injection.

[0368] After administration, the animals were monitored for one week. The animals maintained normal behavior and feeding patterns. No bloody stools were observed. In addition, the animals were sacrificed for histology immediately after administration of L-SOMA, and no traces of tissue holes or perforations from the inserted needle were found. The above examples demonstrate the ability of the SOMA device and other ingestible devices to safely pass through the digestive tract intact after actuation, with or without a protruding needle, and without causing obstruction. Retrospective medical studies of ingested sharp objects have also demonstrated a low risk of injury associated with sharp objects less than 1 cm in length. To address the potential injury of a protruding needle, the gelatin biodegradable injection needle in the L-SOMA was tested in vitro. In addition, the L-SOMA, which has the ability to retract the needle into the device after injection, was tested in vitro. Both devices were able to inject liquid formulations and then expel the sharp object in each of these device modalities.

[0369] L-SOMA was designed to prevent or reduce the risk of gastrointestinal obstruction. The volume of the device is less than that of the OROS capsule, an FDA-approved daily oral drug delivery device that does not degrade as it passes through the gastrointestinal tract and has a 1 in 29 million obstruction rate. Several other non-degradable capsules containing metal components, such as ingestible electronic devices, have also been approved by the FDA, supporting a comparable environmental analysis of L-SOMA.

[0370] Loading of various APIs and formulations Any liquid can be loaded into L-SOMA, and any material can be put into solution and added to L-SOMA. Such solutes include water, oil, and ethanol. Such drugs include insulin, glp1 receptor agonists, monoclonal antibodies, proteins, nucleic acids, lipid nanoparticles, polymer nanoparticles, small molecule drugs such as epinephrine, etc. (such as those listed herein).

[0371] Alternative Actuation Mechanism Although a spring may be used, the L-SOMA does not necessarily have to be propelled by a spring. The L-SOMA may be actuated by a gas-producing chemical reaction or by stored pressurized gas. The L-SOMA may also be actuated by magnets, electromagnets, swellable hydrogels / polymers, etc.

[0372] Example 21 - Delivery of antibodies, peptides, and small molecules The following example details the use and design of L-SOMA, generally described in Example 20, for the delivery of molecules such as antibodies, peptides, and small molecules. Other active therapeutic agents are also possible with this exemplary article.

[0373] Oral administration provides a simple and non-invasive method for drug delivery, but generally cannot achieve the desirable pharmacokinetics realized by subcutaneous and intramuscular injection. In this example, an oral autoinjector capsule is demonstrated that can provide absorption kinetics and systemic bioavailability equivalent to parenteral administration of liquid formulations of drugs ranging in size from small molecules to monoclonal antibodies. To demonstrate the broad utility of this platform technology, capsules were administered to pigs at clinically relevant doses of four commonly injected drugs, including adalimumab, a semaglutide-like inactivated GLP-1 analog, insulin, and epinephrine.

[0374] The problem of suboptimal kinetics and limited drug dose was addressed by developing a capsule with the ability to rapidly deliver liquid depot injections of drugs ranging in size from small molecules to monoclonal antibodies directly into the gastric submucosa for immediate systemic uptake upon administration. Unlike solid drug posts, liquid formulations can generally spread throughout the submucosa. This can provide a larger surface area for systemic uptake while allowing for a larger volume of injected drug. In some cases, by targeting the stomach rather than the small intestine, the capsule can immediately deliver the capsule payload, thereby avoiding the 1-4 hour wait time typically required for gastric emptying. The 4-6 mm thick tissue of the stomach wall also generally provides a greater safety margin for injection compared to the 0.1-2 mm thick wall of the small intestine. This exemplary capsule design utilizes a self-orienting geometry that autonomously positions the device such that the injection mechanism of the device generally always points towards the tissue wall. This design helps ensure that the capsule delivers the dose directly into the tissue and avoids the enzymatic degradation that occurs in the lumen.

[0375] This exemplary liquid injection self-orienting millimeter-scale applicator (L-SOMA), a capsule with a diameter of 12 mm and a height of 15 mm, injects a subcutaneous injection needle beneath the gastric mucosa and immediately thereafter delivers up to 80 μL of liquid drug formulation into the submucosal space (FIGS. 40A-40E). By decoupling needle insertion from liquid injection, the device achieves delivery of the entire device dose to the precise tissue depth instead of expelling the dose as the needle passes through the tissue (FIGS. 41E-41J). As the plunger pushes the liquid out of the tip of the needle through the needle's side hole, two membranes seal the dose containment area and prevent leakage (see FIGS. 41A-41B). These engineering designs can help ensure that the entire liquid dose enters the tissue and prevent part or all of the dose from being expelled onto the tissue.

[0376] How needle penetration depth affects the delivery of the liquid dose was determined by performing injections of contrast agent to predefined depths in ex vivo pig stomach tissue and recording MicroCT images of the created depots (Figures 41E-N and 48). The percentage of liquid remaining in the tissue after administration was measured to a given depth, and visualization confirmed the tissue layer targeted by the injection (Figures 41H-I). During these controlled injection experiments, a volume of 170 μL of contrast agent was delivered. This was comparable to the maximum dose volume of 80 μL for the L-SOMA device. For injection depths of 3 and 4 mm, the needle behaved inconsistently, and it was observed that the needle sometimes injected dye into the mucosa and mostly leaked out of the tissue. By extending the needle insertion depth beyond 4.5 mm, the device consistently delivered the entire liquid volume into the tissue and did not suffer from leakage. At insertion depths of 4.5 mm, 5 mm, and 6 mm, injection into the outer muscular layer of the stomach tissue was occasionally seen. Guided by this data, we designed the L-SOMA device with a needle insertion depth of 4.5 mm, which reduced the risk of perforation compared to deeper injection depths while ensuring that the entire drug load was delivered to the tissue. Ex vivo experiments (Figures 41D-G) with the L-SOMA device (Figure 40E) revealed that needles of these dimensions reliably targeted the submucosa and that the device delivered the entire drug payload of these devices to the tissue. This allowed drugs with a wide range of molecular weights to be delivered through the stomach lining (Figure 1r). Histology from ex vivo experiments on pig and dog stomachs, as well as histology taken from pigs dosed in vivo with L-SOMA, demonstrated that injected fluid did not leak through the gastric mucosa or serosa, confirming that the device delivered the entire payload of the device and that the needle did not puncture the tissue (Figures 45A-45J and Figures 46A-46C).

[0377] In vivo pig experiments were performed in which a single L-SOMA device was administered to each animal loaded with 1 mg of recombinant human insulin, 4 mg of semaglutide-like inactivated GLP-1 analog, 4 mg of the monoclonal antibody adalimumab, or 0.24 mg of the small molecule epinephrine (Figures 47A-47N). L-SOMA administration was compared to subcutaneous or intramuscular administration as a positive control. Using an endoscope, we placed L-SOMA devices into the pig stomach and activated these L-SOMA devices independently. After 2 hours, the devices were removed from the animals. Plasma exposure of the drug was observed within 15 minutes after L-SOMA administration of insulin, inactivated GLP-1, or epinephrine. Adalimumab was observed in serum within 1 hour after L-SOMA administration. Insulin-treated pigs immediately suffered hypoglycemic episodes (Figure 47B,F), and epinephrine-treated pigs in both the intramuscular injection and L-SOMA experimental groups suffered rapid increases in heart rate (Figure 47K,N) and blood glucose (see Figure 49). H&E staining from epinephrine-treated pigs showed no evidence of drug-induced necrosis or adverse effects (see Figure 50). Pigs administered adalimumab or inactivated GLP-1 using either L-SOMA capsules or subcutaneous injections retained the drug in their plasma for at least 3 days after administration due to the extended half-life of the drug.

[0378] Although the treated pigs were partially fasted, some pigs contained layers of gastric juice and food in their stomachs. In these pigs, L-SOMA was able to partially displace the food layer and insert these L-SOMA needles into the tissue and still deliver the drug load. Of note, one device loaded with a GLP-1 analog actuated in the stomach, but the pig did not demonstrate systemic uptake. This may be due to the drug formulation not reaching the gastric submucosa in some cases. All other 22 L-SOMA treated pigs demonstrated systemic uptake.

[0379] Bioavailabilities in pigs were calculated from L-SOMA administration of insulin and GLP-1 analogs, and these bioavailabilities were compared to those from subcutaneous administration of the same formulations and amounts of drug. Recombinant human insulin administered with L-SOMA demonstrated a bioavailability of 48 ± 16% (SD) over the 2-hour sampling period (range = 25%-81%, n = 8). This compared to a bioavailability of 57 ± 8% (SD) in pigs administered insulin subcutaneously (range = 50.8%-66.2%, n = 3). Bioavailability of L-SOMA-administered GLP-1 analogs over the 3-day sampling period was 103 ± 42% (SD) (range = 55%-135%, n = 3) excluding L-SOMA, which showed 0% uptake after gastric actuation, and 78 ± 62% when this additional data point was included. This compared with a bioavailability of 78±4% (SD) for the subcutaneously administered GLP-1 analogue.

[0380] Insulin and GLP-1 generally have limited ability to cross the stomach lining for systemic uptake when administered without a permeation enhancer or physical permeation enhancing device. Endoscopic gavage experiments with drug loads equivalent to L-SOMA for both epinephrine and adalimumab were performed in pigs as negative controls, and negligible uptake was observed (see FIG. 51).

[0381] After administration, the animals were monitored for one week. The animals maintained normal behavior and feeding patterns. No bloody stools were observed. Retrospective medical and experimental studies in large animal models of ingested sharp objects have demonstrated a low risk of injury associated with sharp objects, generally less than 1 cm in length. Furthermore, Carr-Locke injection needles, needles of 25G and 5mm length, are routinely used by gastroenterologists during gastric endoscopy with little incidence of injury. In contrast, the L-SOMA uses a 32G needle that protrudes only 4.5mm from the device. To mitigate the problem of needle exposure in the gastrointestinal tract, the L-SOMA was designed with the ability to retract the needle into the device after injection. This technique mitigates the risk associated with sharp objects present in the L-SOMA system at the cost of adding additional complexity to the device (see Figure 52). A hollow needle to further mitigate the problem of puncture during gastrointestinal transit may also be used.

[0382] Stability studies of liquid formulations of both human insulin and semaglutide were performed and demonstrated that the purity loss and high molecular weight protein formation of formulations placed in the L-SOMA system was greater than that of formulations placed in a glass vial system after 2 weeks at 40°C and 75% relative humidity (Figures 53A-53B). In addition, the purity loss of the liquid formulations was higher than that of solid formulations we have previously reported for use in the SOMA system. Optimization of the L-SOMA containment system and the loaded liquid formulations will be required to ensure long-term stability of the loaded drugs.

[0383] In this example, we demonstrated the ability of the L-SOMA pill to deliver four different drugs with a range of molecular weights, half-lives, pharmacodynamic effects, and dose size requirements. The rapid pharmacokinetic uptake of the capsule within minutes of administration, the loading capacity of up to 4 mg of bioavailable drug, and the capacity to work with a wide range of molecules, allows the compatibility of this capsule with a new set of drugs that could not be delivered orally before. Although the ability to deliver epinephrine for anaphylaxis using L-SOMA may be hindered by throat swelling in severe cases, the capsule may still be used to deliver agents for asthma therapy or treatment of delayed anaphylaxis. In addition, the use of epinephrine in the L-SOMA device demonstrates the ability to deliver small molecule drugs. Poorly soluble small molecule drugs that demonstrate low systemic uptake may also be suitable candidates for the L-SOMA system. Although reformulation and high concentrations may be necessary to reach the required therapeutic dose for a given drug, the broad applicability of L-SOMA means that in general any liquid formulation, including small molecule or macromolecular drugs, can be loaded into the capsule. Compared to solid formulations, liquid formulations do not rely on solid state properties of the drug, such as the capacity to be compressed into a needle-like shape, thus broadening the range of molecules that can be administered via the device. L-SOMA has demonstrated the ability to load and deliver formulations encompassing both fast-acting drugs and drugs with extended half-lives, encompassing a broad range of drug modalities, via oral capsules. In doing so, L-SOMA offers a less intrusive route of administration for drugs that are otherwise limited to injectables, thereby advantageously achieving higher compliance among patients and ultimately better clinical outcomes.

[0384] While several embodiments of the invention have been described and illustrated herein, those skilled in the art will readily envision various 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 such variation and / or modification is deemed to be within the scope of the present invention. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are intended to be exemplary, and that the actual parameters, dimensions, materials, and / or configurations will depend on the particular application or applications for which the teachings of the present invention are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Thus, the foregoing embodiments have been presented by way of example only, and it will be understood that, within the scope of the appended claims and equivalents thereto, the invention may be practiced otherwise than as specifically described and claimed. The present invention is directed to each individual feature, system, article, material, kit, and / or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and / or methods is within the scope of the present invention, provided that such features, systems, articles, materials, kits, and / or methods are not mutually inconsistent.

[0385] As used herein and in the claims, the indefinite articles "a" and "an" are to be understood to mean "at least one," unless expressly stated to the contrary.

[0386] As used herein and in the claims, the phrase "and / or" 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, whether related or unrelated to those elements specifically identified, other than the elements specifically identified may optionally be present, unless expressly stated 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), and so forth.

[0387] As used herein and in the claims, "or" shall 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., including at least one, but also including a plurality, of an element or list of elements, and optionally additional unlisted items. Only terms explicitly stated to the contrary, such as "only one of" or "exactly one of," or "consisting of," when used in the claims, refer to the inclusion of exactly one element of an element or list of elements. In general, the term "or" as used herein shall only be interpreted to indicate exclusive alternatives (i.e., "one or the other, but not both") when preceded by a term 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.

[0388] As used herein and in the claims, the phrase "at least one" in connection with a list of one or more elements should be understood to mean at least one selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements, and not excluding any combination of elements in the list of elements. This definition also allows for the optional presence of elements other than those 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 A (and optionally including elements other than B), where B is absent, and optionally including more than one; in another embodiment to at least one B (and optionally including elements other than A), where A is absent, and optionally including more than one; in yet another embodiment to at least one A, optionally including more than one, and at least one B (and optionally including other elements), optionally including more than one; and so forth.

[0389] 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., meaning including but not limited to. As set forth in Section 2111.03 of the United States Patent Office Manual of Patent Examining Procedure, the transitional phrases "consisting of" and "consisting essentially of" shall be closed or semi-closed transitional phrases, respectively.

[0390] For example, terms used herein relating to the shape, orientation, alignment, and / or geometric relationships of or between one or more articles, structures, forces, fields, flows, directions / trajectories, and / or subcomponents and / or combinations thereof, and / or other tangible or intangible elements not listed above that are suitable for characterization by such terms, unless otherwise defined or indicated, shall be understood not to require absolute adherence to the mathematical definitions of such terms, but rather to indicate adherence to the mathematical definitions of such terms to the extent possible for the subject matter being characterized as would be understood by one of ordinary skill in the art most closely related to such subject matter. Examples of such terms relating to shape, orientation, and / or geometric relationships include shapes such as round, square, rubberbock, circular, rectangular, triangular, cylindrical, elliptical, (n)polygon, angular orientations such as perpendicular, orthogonal, parallel, perpendicular, horizontal, collinear, plane, coplanar, hemispherical, line, hyperbolic, parabolic, flat, curved, rectilinear, arcuate, sinusoidal, tangent. These terms include, but are not limited to, terms describing contours and / or trajectories such as square / tangent, directions such as north, south, east, west, etc., surfaces and / or bulk material properties and / or spatial / temporal resolutions and / or distributions such as smooth, reflective, transparent, transparent, opaque, rigid, impermeable, uniform (uniformly), inert, non-wettable, insoluble, stationary, unchanging, constant, homogeneous, etc., and many others that will be apparent to one of ordinary skill in the relevant art. As an example, a manufactured article described herein as being "square" need not be perfectly planar or linear and have faces or sides that intersect at exactly 90 degree angles (indeed, such articles may exist only as mathematical abstractions), but rather the shape of such an article should be interpreted as approximating a mathematically defined "square" to the extent that it is typically achievable and is achieved for the cited manufacturing techniques as would be understood by one of ordinary skill in the art or as specifically described.As another example, two or more manufactured articles described herein as being "aligned" need not be such articles having perfectly aligned faces or edges (indeed, such articles may exist only as a mathematical abstraction), but the arrangement of such articles should be construed as approximating the mathematically defined "alignment" to the extent that is typically achievable and achieved for the cited manufacturing techniques, as would be understood by one of ordinary skill in the art or as specifically described.

Claims

1. A self-healing article, comprising: a self-actuating component including a spring and a support material adapted to maintain the spring in an at least partially compressed state, the support material being configured to be at least partially degraded in a biological fluid; a chamber containing a liquid active pharmaceutical agent (or an inactive one acting as a contrast agent or cushion); a tissue interface component operably coupled to the self-actuating component, the tissue interface component including an inlet, an outlet, and a channel fluidly connected to the inlet and the outlet; the chamber is configured to be in fluid communication with the inlet upon activation of the self-actuating component; A self-healing article, wherein when the self-healing article is at least partially supported by tissue of a subject, the self-healing article orients in an orientation that enables the tissue interface component to release at least a portion of the active pharmaceutical agent into the tissue.

2. The self-healing article of claim 1 , comprising a plug associated with the tissue interface component, the tissue interface component configured to pierce the plug upon activation of the self-actuating component.

3. The self-healing article of claim 1 or 2, wherein the tissue interface component is soluble or retractable or softens after actuation / penetration.

4. The self-healing article has a viscosity of 1 g / cm ３ The self-healing article of any one of claims 1 to 3, having an average density of greater than or equal to 100%.

5. The self-healing article of any of claims 1-4, wherein the support material is configured as a plug, the plug being operably coupled to the tissue interface component.

6. The self-healing article of any of claims 1 to 5, wherein the tissue-interfacing component is configured as a projectile that extends substantially along a major axis of the self-healing article.

7. The self-healing article of any one of claims 1 to 6, wherein the support material is configured within the self-healing article such that the biological fluid entering the self-healing article contacts a first surface and initiates the at least partial decomposition of the support material.

8. 8. The self-healing article of any of claims 1 to 7, wherein the support material is selected from the group consisting of sugars, sugar derivatives, sugar alcohols, maltose, isomalt, starch, calcium carbonate, zinc, sodium chloride, polymers, and combinations thereof.

9. The self-healing article of any of claims 1 to 8, wherein the self-healing article includes one or more vents configured to place the self-actuating component in fluid communication with an external environment.

10. The self-healing article of any of claims 1-9, wherein the one or more vents are covered by a coating.

11. The self-healing article of any one of claims 1 to 10, wherein the biological fluid is gastric fluid.

12. The self-healing article of any of claims 1-11, wherein the article includes a component configured to retract the tissue-interface component.

13. The self-healing article of any of claims 1 to 12, wherein the article comprises a tissue-interfacing component capable of piercing tissue, and such component is multi-layered with an inner layer of a water-sensitive material.

14. The self-healing article of any of claims 1 to 13, wherein the water-sensitive material comprises gelatin.

15. 15. The self-healing article of any of claims 1-14, wherein the tissue interface component comprises an outer layer that is impermeable to aqueous fluids such that following triggering, an inner layer of the tissue interface component is exposed to the fluid in the chamber, mechanically weakening at least a portion of the tissue interface component following needle passage of the fluid.

16. 16. The self-healing article of any of claims 1-15, wherein the article comprises a tissue interface component configured to retract upon contact with a plug of self-healing element, thereby revealing an aqueous inner layer on both sides upon piercing tissue.

17. 1. An article suitable for ingestion into a lumen of a subject, the lumen having a lumen wall, the article comprising: a shell having a contour that includes a circular cross-section, the shell defining a first axis; an actuation mechanism including a self-actuating component including a first spring component and a support material adapted to maintain the first spring component in an at least partially compressed state, the support material being configured to at least partially degrade in a biological fluid; and a chamber disposed within the shell, the chamber containing a liquid active pharmaceutical agent; and a tissue interface component disposed relative to the shell and configured to transfer a fluid from the chamber to a portion of tissue of the lumen wall at a location within the subject's body; The article is self-healing having a geometric center and a center of gravity, the center of gravity being offset from the geometric center in a first direction along the first axis.

18. orienting the article with the first axis oriented along a direction of gravity such that, when the article is supported by tissue of the lumen wall while oriented with the center of gravity laterally offset from the geometric center, the article is subjected to an externally applied torque due to gravitational action such that the tissue interface component interacts with the tissue at a location within the subject; The article of claim 17 , wherein the actuation mechanism acts on the liquid active pharmaceutical agent such that, upon at least partial degradation of the support material, the tissue interface component releases at least a portion of the liquid active pharmaceutical agent into the tissue at the location within the subject's body.

19. 18. The article of claim 17, wherein the liquid active pharmaceutical agent and the chamber are constructed and arranged such that when the article is oriented with the first axis oriented along the direction of gravity and the tissue interface component is interacting with the tissue, the center of gravity of the liquid is disposed below the geometric center relative to the surface of the tissue.

20. 20. The article of claim 18, wherein the liquid active pharmaceutical agent and the chamber are constructed and arranged such that when the article is oriented with the first axis oriented along the direction of gravity and the tissue interface component is interacting with the tissue, the center of gravity of the liquid is disposed closer to the surface of the tissue than the geometric center of the article.

21. The article has a viscosity of 1 g / cm ３ The article of any one of claims 1 to 20 having an average density of greater than or equal to 100%.

22. The article of any of claims 1 to 21, wherein the chamber includes a movable wall, the movable wall configured to expel a liquid active pharmaceutical agent from the chamber.

23. 23. The article of claim 22, wherein the chamber includes a cylindrical wall, and the movable wall of the chamber includes a plunger in slidable engagement with the cylindrical wall.

24. 24. The article of claim 22 or 23, wherein the tissue interface component is operably coupled to the self-actuating component, the tissue interface component comprising an inlet, an outlet, and a channel fluidly connected to the inlet and the outlet.

25. 25. The article of claim 24, wherein the channel is configured to be in fluid communication with the chamber containing the liquid active pharmaceutical ingredient upon activation of an activation mechanism.

26. 26. The article of any of claims 22-25, wherein the tissue interface component forms or includes an injection needle operably coupled to the first spring component, and wherein upon at least partial disintegration of the support material, the first spring component is operable from a first configuration to a second configuration, and wherein when the first spring component is in the first configuration, the injection needle is retained within the article, and the injection needle is configured to be advanced from the article into the lumen wall by movement of the first spring component from the first configuration to the second configuration.

27. 27. The article of claim 26, wherein the injection needle extends through the chamber when the first spring is in the first configuration and / or when the first spring is in the second configuration.

28. 28. The article of claim 27, wherein the injection needle includes a tissue-piercing end, a second end portion opposite the tissue-piercing end, and a sidewall extending between the tissue-piercing end and the second end portion, the sidewall including a side hole disposed such that fluid communication is established between the chamber and the tissue-piercing end of the injection needle when the first spring component is in the second configuration.

29. 30. The article of claim 28, wherein when the first spring component is in the first configuration, the side hole is positioned outside of the chamber containing the liquid active pharmaceutical agent.

30. 30. The article of claim 28 or 29, wherein the chamber further comprises an end wall disposed opposite the movable wall, the end wall comprising a pierceable seal, and wherein when the first spring component assumes the first configuration, the tissue-piercing end of the injection needle is embedded in the pierceable seal, and when the first spring component assumes the second configuration, the injection needle pierces the pierceable seal.

31. 31. The article of any of claims 24-30, wherein the actuation mechanism includes a second spring component releasably held in a compressed state, the second spring component configured to be released from the compressed state to drive the movable wall to expel liquid active pharmaceutical agent from the chamber when the first spring component moves from the first configuration to the second configuration.

32. 32. The article of claim 31 , wherein the first spring component is coaxially disposed, such as radially within the second spring component, with at least partial axial overlap between the first spring component and the second spring component.

33. 33. The article of any of claims 24 to 32, wherein the actuation assembly includes a third spring component releasably held in a compressed state, said third spring component configured to release upon expulsion of all or a predetermined portion of the expulsible liquid active pharmaceutical agent from said chamber, said release of said third spring component causing said injection needle to retract relative to the article housing.

34. 34. The article of claim 33, wherein the third spring component is coaxially disposed, such as radially within the first spring component, with at least partial axial overlap between the third spring component and the first spring component.

35. The article of any of claims 24-32, wherein the tissue interface component is at least partially soluble or softens after activation / penetration.

36. 24. The article of any of claims 17-23, wherein the tissue interface component includes a jet injector component, and the first spring component is configured to expel a liquid active pharmaceutical agent through the jet injector component at a permeation rate that enables the liquid active pharmaceutical agent to permeate into the gastric submucosa of the luminal wall.

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