Self-righting systems, methods, and related components

Abstract

To provide self-righting articles.SOLUTION: Self-righting articles, such as self-righting capsules for administration to a subject, are generally provided. A self-righting article may be configured such that the article may orient itself relative to a surface (e.g., a surface of a tissue of a subject). The self-righting articles described herein may comprise one or more tissue engaging surfaces configured to engage (e.g., interface with, inject into, anchor) with a surface (e.g., a surface of a tissue of a subject). The self-righting article may have a particular shape and / or distribution of density (or mass) which, for example, enables the self-righting behavior of the article. The self-righting article may comprise a tissue interfacing component and / or a pharmaceutical agent (e.g., for delivery of an active pharmaceutical agent to a location internal of the subject). Upon contact of the tissue with the tissue engaging surface of the article, the self-righting article may be configured to release one or more tissue interfacing components. The tissue interfacing component may comprise a self-actuating component.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] Related Applications This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 62 / 507,647, filed May 17, 2017, entitled "SELF-RIGHTING ARTICLES"; U.S. Provisional Application No. 62 / 507,653, filed May 17, 2017, entitled "SELF-ACTUATING ARTICLES"; and U.S. Provisional Application No. 62 / 507,665, filed May 17, 2017, entitled "COMPONENTS WITH HIGH API LOADING", the entire disclosures of each of which are incorporated herein by reference in their entirety.

[0002] Field The present invention relates to self-righting systems and related components, such as self-righting articles, self-actuating articles (including, for example, self-actuating needles and / or self-actuating biopsy punches), and components having a relatively high pharmaceutical active ingredient (API) loading.

Background Art

[0003] Background The GI tract provides incredible opportunities to diagnose and treat patients. The development of smart drug delivery systems and articles to enable this has seen significant 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 delivery system with the GI mucosa. Previous attempts to do this have included the introduction of mucoadhesives, as well as texturing of one side of a two-sided system. Orally ingested drugs generally diffuse through the GI tract tissue wall and into the bloodstream. A typical pill or article that is ingested releases its cargo randomly within the GI tract and moves the cargo to the tissue wall by convection and diffusion. However, many biological agents, such as insulin, cannot move through the liquid in the GI tract, even if contained within a solid formulation, as they would be degraded, for example, by enzymes.

[0004] In addition, many pharmaceutical formulations on the market, including a very large number of vaccines, RNAs, and peptides, require administration by injection. Injection has traditionally involved the use of a liquid formulation that passes through a hollow needle and enters a vein or muscle in the body. However, these liquid formulations can destabilize the pharmaceutical active ingredient (API) and, therefore, may require refrigeration and / or dilution, which can significantly increase the bulk of the dosage.

[0005] Accordingly, there is a need for improved systems, articles, and methods. SUMMARY OF THE INVENTION MEANS FOR SOLVING THE PROBLEM

[0006] Abstract The present invention generally relates 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 comprises a first portion, a second portion adjacent to the first portion having a different average density than the first portion, and a hollow portion, and the self-healing article is configured or arranged to be encapsulated in a 000 capsule or a capsule smaller than that.

[0008] In some embodiments, the self-healing article is configured for potential encapsulation in a 000 capsule or a capsule smaller than that, but the self-healing article need not necessarily be encapsulated in such a capsule. In embodiments where the self-healing article is to be administered, such as by ingestion of the self-healing article, the self-healing article may be administered as such without being encapsulated.

[0009] ​In some embodiments, the self - restoring article comprises a first portion; a second portion adjacent to the first portion and having a different average density from the first portion; and a tissue connection component associated with the self - restoring article; and 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 - restoring article is configured to be moored at a location within the body of a subject and has at least a first portion having an average density greater than 1 g / cm 3 such that when an external applied torque of 0.09×10 -4 Nm or less acts on the longitudinal axis perpendicular to the tissue - engaging surface of the article, it is configured to maintain an orientation within 20 degrees or less from the perpendicular, and comprises at least one mooring mechanism associated with the self - restoring article.

[0011] In some embodiments, the self - restoring article is configured to be administered at a location within the body of a subject; has at least one first portion having an average density greater than 1 g / cm 3 such that the self - restoring article has a self - restoring time from 90 degrees in water that is less than or equal to 0.05 seconds; comprises a tissue - contact portion configured to contact the tissue, and at least two tissue connection components each comprising 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 at least two tissue connection components.

[0012] In another aspect, a self - actuating article is provided. In some embodiments, the article comprises an outer shell, a spring at least partially enclosed within the outer shell, a support member associated with the spring for maintaining at least a portion of the spring under a compressive strain of at least 5% under ambient conditions, and a tissue connection component associated with the spring.

[0013] In some embodiments, the article is configured to be moored at a location within the body of a subject; an outer shell; a spring at least partially enclosed by the outer shell, the spring being maintained in a at least partially compressed state under at least 5% compressive strain by a support; and at least one mooring mechanism operably coupled to the spring.

[0014] In some embodiments, the article is configured to be administered at a body location of a subject; an outer shell; a spring at least partially enclosed within the outer shell, the spring being maintained in a at least partially compressed state under at least 5% compressive strain by a support; at least two tissue connection components having tissue contact portions configured to contact tissue, each tissue contact portion comprising 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 connection components.

[0015] In another aspect, a tissue connection component is provided. In some embodiments, the component comprises a solid therapeutic agent and a support, the solid therapeutic agent being present in the tissue connection component in an amount greater than or equal to 10% by weight based on the total weight of the tissue connection component, the solid therapeutic agent and the support being substantially uniformly distributed, and the tissue connection component being configured to penetrate the tissue.

[0016] In some embodiments, the component has a tip and comprises a solid therapeutic agent and a support associated with the solid therapeutic agent, at least a portion of the solid therapeutic agent being associated with one or more tips of the tissue connection component, the solid therapeutic agent being present in the tissue connection component in an amount greater than or equal to 10% by weight based on the total weight of the tissue connection component.

[0017] In another aspect, a method is provided. In some embodiments, the method comprises administering to a subject a capsule comprising an outer shell and a self-healing article, the self-healing article comprising a first portion and a second portion adjacent to the first portion and having an average density different from that of the first portion.

[0018] In some embodiments, the method comprises administering to a subject a capsule comprising an outer shell and a self-healing article, the self-healing article comprising a first portion comprising a first material, a second portion adjacent to the first portion and comprising a second material different from the first material, and a needle associated with a pharmaceutically active agent, 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; orienting the self-healing article at a location within the subject's body such that the needle punctures tissue proximate to the location within the subject's body; and releasing at least a portion of the pharmaceutically active agent into the tissue.

[0019] In some embodiments, the method comprises administering to a subject an article comprising an outer shell, a spring at least partially encapsulated by the outer shell, a support for maintaining at least a portion of the spring under at least 5% compressive strain under ambient conditions, and a tissue connection component associated with the spring.

[0020] In some embodiments, the method comprises administering to a subject an article comprising an outer shell, a spring at least partially encapsulated by the outer shell, a support for maintaining at least a portion of the spring under at least 5% compressive strain under ambient conditions, and a tissue connection component associated with the spring; and decomposing at least a portion of the support such that the spring expands and / or the tissue connection component penetrates tissue located within the subject's body.

[0021] In some embodiments, the method is 1 g / cm 3An article comprising at least a first portion having a greater average density and at least one mooring mechanism, and administering the article to a subject configured to be held in position under a force greater than or equal to 0.6 N and / or a change in orientation greater than or equal to 30 degrees.

[0022] In some embodiments, the method comprises administering an article to a subject, the article comprising at least one tissue connection component disposed therein, each tissue connection component comprising a conductive material; releasing at least one alignment component from the article; inserting at least one alignment component into tissue at a location within the body of the subject; and applying a current generated by a power source in electrical communication with the tissue connection component between two or more tissue connection components. The article comprises a spring maintained in a at least partially compressed state under at least 5% compressive strain by a support, and each tissue connection component is operably coupled to the spring.

[0023] In another aspect, a method of forming a tissue connection component is provided. In some embodiments, the method comprises providing a solid therapeutic agent and a support; and compressing and / or heating the solid therapeutic agent and the support together using at least 1 MPa of pressure to form the tissue connection component; the tissue connection component being configured to penetrate into tissue. configured.

[0024] Other advantages and novel features of the present invention will become apparent from the following detailed description of various non-limiting embodiments of the present invention when considered in conjunction with the accompanying drawings. If the present specification and the incorporated-by-reference documents contain inconsistent and / or conflicting disclosures, the present specification shall prevail.

[0025] Non-limiting embodiments of the present invention will be described by way of example in connection with the accompanying drawings, which are schematic and not intended to be drawn to an exact scale. Each of the same or substantially the same components illustrated in these figures is typically represented by a single number. For clarity, not all components are labeled in all of the figures, and not all components are shown for each embodiment of the invention where illustration is not necessary for one of ordinary skill in the art to understand the invention. In these figures,

Brief Description of the Drawings

[0026]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Figure 11

Figure 12

Figure 13

Figure 14

Figure 15

Figure 16

Figure 17

Figure 18

Figure 19

Figure 20

Figure 21

Figure 22

Figure 23

Figure 24

Figure 25

Figure 26

Figure 27

Figure 28

Figure 29

Figure 30

Figure 31

Figure 32

Figure 33

Figure 34

Figure 35

Figure 36

Figure 37

Figure 38

Figure 39

Figure 40-1

Figure 40-2

Figure 40-3

Figure 41

Figure 42

Figure 43

Figure 44

Figure 45

Figure 46

Figure 47

Figure 48

Figure 49

Figure 50

Figure 51

Figure 52

Figure 53

Figure 54

Figure 55

Figure 56

Figure 57

Figure 58

Figure 59

Figure 60

Figure 61

Figure 62

Figure 63

Figure 64

Figure 65-1

Figure 65-2

Figure 65-3

Figure 66

Figure 67

Figure 68

Figure 69

Figure 70

Figure 71-1

Figure 71-2

Figure 72-1

Figure 72-2

Figure 72-3

Figure 73-1

Figure 73-2

Figure 73-3

Figure 73-4

Figure 73-5

Figure 74-1

Figure 74-2

Figure 74-3

Figure 74-4

Figure 75

Figure 76

Figure 77

Figure 78

Figure 79

Figure 80

Figure 81

Figure 82

Figure 83

Figure 84

Figure 85

Figure 86

Figure 87

Figure 88

[0027] **Detailed Description** **Overview** Self-healing articles, such as self-healing capsules for administration to a subject, are generally provided. In some embodiments, the self-healing article may be configured such that the article can be oriented with respect to a surface (e.g., the surface of a subject's tissue). The self-healing articles described herein may comprise one or more tissue-engaging surfaces configured to engage (e.g., align with, inject into, moor to) a surface (e.g., the surface of a subject's tissue). For example, the self-healing article may be placed in any orientation proximate the surface, and the self-healing article will (re)orient such that the tissue-engaging surface is in contact (e.g., direct contact) with the surface. In some embodiments, the self-healing article can have a particular shape and / or density (or mass) distribution, e.g., to enable the self-healing behavior of the article. In some such embodiments, a capsule containing the self-healing article can 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 gastrointestinal tract). In some embodiments, self-healing can include tissue connection components and / or pharmaceutical agents (e.g., for delivering a pharmaceutically active 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 connection components when tissue contacts the tissue-engaging surface of the article. In some cases, the tissue connection component is associated with a self-actuating component. For example, the self-healing article can comprise a self-actuating component configured to release a tissue connection component from the self-healing article when exposed to a fluid. In some cases, the tissue connection component may comprise a pharmaceutical agent (e.g., for delivery to a location within the subject's body) and / or a pharmaceutical agent may be associated therewith.

[0028] The self - restoring articles described herein can be useful, for example, as a general platform for the delivery of a wide variety of pharmaceutical agents that are typically delivered by direct injection into tissue for degradation within the GI tract. In some cases, the self - restoring articles may be configured to deliver a pharmaceutical agent to a desired location and / or at a desired time and / or over a desired period to a subject. In some embodiments, the self - restoring articles described herein can be used to deliver a sensor and / or collect a biopsy sample, for example, without the need for endoscopic observation. In certain embodiments, using the self - restoring articles described herein, one or more articles may be tethered to the surface of tissue, for example, within the GI tract. In some cases, using the self - restoring articles described herein, electrical stimulation can be applied directly to tissue.

[0029] Advantageously, in some embodiments, the self - restoring articles and / or self - actuating components described herein can be useful as a general platform for the delivery of a wide variety of pharmaceutical agents (e.g., APIs) that are typically delivered by direct injection into tissue for degradation within the GI tract. For example, the self - restoring article can be localized in a specified direction in the tissue wall (thereby, for example, a loaded drug can avoid the long - time passage of GI tract fluid before diffusion into the bloodstream). This article can, in some cases, serve as a platform for absorbing drugs that are currently degraded enzymatically within the GI tract with higher bioavailability. Additionally, the article can enable mechanical and electrical mechanisms, such as needles, plungers, anchors, sensors, etc., to operate directly against and / or within the tissue wall. Thus, in certain embodiments, the article can serve as a vehicle for delivering an electronic device or other article to the GI tract.

[0030] In some embodiments, the tissue connection component (e.g., the tissue connection component associated with the self-actuating component) can have a relatively high loading of the pharmaceutical active ingredient (e.g., a drug). For example, in certain embodiments, the tissue connection component includes a solid therapeutic agent (e.g., a solid API), and optionally, a support material (e.g., a binder such as a polymer) for the solid therapeutic agent to be present in the component in a relatively large amount (e.g., in an amount greater than or equal to 80% by weight) relative to the total weight of the tissue connection component. Such a tissue connection component can be useful for the delivery of the API dose (e.g., to a subject). Advantageously, in some embodiments, the volume required to deliver the required API dose is reduced compared to liquid formulations, enabling the creation of solid needle delivery systems at various locations / tissues (e.g., the tongue, GI mucosal tissue, skin) of a variety of drugs, and / or reducing and / or eliminating the application of an external force to inject a drug solution through a small opening of the needle. In some cases, a physiologically appropriate dose can be present in a single tissue connection component (e.g., a single tissue connection component has a relatively high API loading).

[0031] In an exemplary embodiment, the self-healing article can comprise a tissue connection component and a self-actuating component associated with the tissue connection component (e.g., a self-actuating component comprising a spring and / or a support material).

[0032] As illustrated in FIG. 1, in some embodiments, the system 100 (e.g., a self-healing article) comprises a tissue-engaging surface 150. Although the embodiments described herein refer to a single tissue alignment surface, in some embodiments, there may be two or more tissue alignment surfaces. In certain embodiments, the self-healing article may be designed and configured such that the tissue-engaging surface contacts a surface (e.g., the surface of tissue located at a position within the body of a subject, such as the surface of the subject's stomach). In some embodiments, the system 100 will self-align such that the tissue-engaging surface 150 contacts the surface (e.g., without the need for or use of an external force applied to the self-healing article). In certain embodiments, the self-healing article is configured such that an axis that is substantially perpendicular to the tissue-engaging surface is preferentially aligned parallel to the direction of gravity. As described in more detail herein, the self-healing article may be configured such that an axis that is substantially perpendicular to the tissue-engaging surface can maintain an orientation that is 20 degrees or less from vertical under an externally applied torque. In some embodiments, the self-healing article is configured such that the tissue connection component has a longest longitudinal axis that is oriented within 15 degrees from vertical when self-healed.

[0033] Without wishing to be bound by theory, the self-healing article may be designed to self-heal as a result of the density (and / or mass) distribution within the self-healing article. For example , in some embodiments, the system 100 (e.g., a self-healing article) comprises a first portion 110 and a second portion 115, and 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 can have a particular shape that enables self-healing behavior. For example, as illustrated in FIG. 1, the system 100 has a monostatic shape (e.g., a mono-monostatic shape, a rubber bock shape) indicated by the outer surface 170 of the system 100. The term "monostatic(al)" as used herein is given its ordinary meaning in the art and generally refers to a three-dimensional shape having a single stable rest position (e.g., an equilibrium point). The term "mono-mono-static(al)" as used herein is given its ordinary meaning in the art and generally refers to a three-dimensional shape having a single stable rest position and a single unstable rest position. By way of example, without wishing to be bound by theory, a sphere having a center of mass offset from its geometric center is generally considered to be a mono-mono-static 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 has a single stable equilibrium point (or orientation) and a single unstable equilibrium point (or orientation) when placed on a flat surface. For example, without wishing to be bound by theory, a rubber bock-shaped article will tend to reorient to its single stable orientation when placed on a surface in any orientation other than its single stable orientation. Such shapes are described in more detail below.

[0034] FIG. 2 shows a cross-sectional explanatory view of an exemplary system 102. In some embodiments, system 102 comprises a self-actuating component 120. The self-actuating component 120 may be configured to release, for example, a tissue connection component 130 associated with the self-actuating component 120 from the system 102 when exposed to a particular fluid. For example, in some cases, the self-actuating component 120 comprises a spring 125, and thus, when the self-actuating component is actuated, the spring 125 expands and pushes the tissue connection component 130 through a hole 140 (associated with the tissue engagement surface 150) out of the system 102. In some cases, the spring 125 comprises a support member 160 that maintains the spring 125 under compression (e.g., under at least 5% compressive strain). In some cases, the spring is 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 among these)) of the accumulated compressive energy of the spring when the support member 160 and / or the spring 125 is exposed to the fluid (e.g., such that the tissue connection component 130 is released as a result). In some embodiments, the spring is associated with the support member (e.g., at least partially encapsulated in direct contact with the support member by the support member).

[0035] In certain embodiments, the tissue connection component 130 comprises a pharmaceutically active agent. In some embodiments, the pharmaceutically active agent may be present in a relatively large amount in the tissue connection component (e.g., more than or equal to 10 wt%, more than or equal to 80 wt%, or more than or equal to 90 wt% based on the total weight of the tissue connection component). The self-healing articles described herein can, in some cases, be administered to a subject, for example, for delivery of a pharmaceutical agent. For example, in some cases, the article can be administered to the subject and the pharmaceutical agent is released from the article at a location within the subject's body. The administration of the article and the release of the pharmaceutical agent are described in more detail herein.

[0036] In some embodiments, the system is administered to a subject (e.g., orally). In certain embodiments, the system may be administered orally, rectally, intravaginally, nasally, or uretherally. Upon reaching a location within the subject's body (e.g., the gastrointestinal tract), at least a portion of the support material degrades, such that the spring extends and / or the tissue connection component aligns with (e.g., contacts, penetrates) the 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. As described above and as described herein, in some embodiments, the pharmaceutical active ingredient may be released during and / or after penetration into the tissue located within the subject's body.

[0037] By way of example, and not wishing to be limited by such an exemplary set of embodiments, the system may be orally administered to a subject. In some cases, the system may travel to the subject's stomach, sink to the bottom of the subject's stomach, and the system may self - restore, such that the tissue - engaging surface of the system contacts the stomach tissue (e.g., the system is at least partially supported by the stomach tissue). For example, as schematically illustrated in FIG. 3, an exemplary system 100 is administered to a subject (e.g., orally), and as a result, the system 100 enters the subject's digestive system 198. The system 100 travels through the digestive system 198 until it reaches the subject's stomach 199 (system 100a). In some embodiments, the system 100 sinks to the bottom of the stomach 199 (system 100b), and as a result, contacts the surface of the stomach 199. In certain embodiments, the system 100 self - restores (system 100c), such that the tissue - engaging surface 150 of the system 100 contacts the surface of the stomach 199, and the system 100 self - actuates, such that the tissue - connecting component 130 aligns with the tissue (e.g., the surface of the stomach 199) at a location within the subject's body. FIG. 3 illustrates the alignment of the tissue - connecting component with the surface of the stomach 199, but those skilled in the art will understand, based on the present teachings, that the tissue - connecting component may contact one or more layers (or other locations within the subject's body) beneath the surface of the stomach, including, for example, the mucosal layer, submucosal layer, and / or muscular tissue layer.

[0038] In some cases, as described herein, the self - restoration of the system 100 may be driven by gravity (e.g., the gravity acting on the center of mass of the system 100). After a desired period, in some embodiments, the system 100 disassembles (e.g., the tissue - connecting component 130 dissolves and / or is released) and exits the stomach 199 (system 100d). The above description is not intended to be limiting, and those skilled in the art will understand that other interactions between the systems described herein and the subject's digestive system may also occur. In some embodiments, the system 100 is a monostatic body, as described in more detail below.

[0039] The following description provides various embodiments regarding the self - restoration, self - actuation, and APIs of components with relatively high loads in the systems described in this specification. Self - restoration

[0040] As described above, in some embodiments, the self - restoring article comprises two or more portions having different average densities, such that, for example, the self - restoring article can be oriented substantially perpendicular to a surface (e.g., a surface substantially orthogonal to gravity, the surface of a tissue, e.g., the wall of the gastrointestinal tract). In some cases, the self - restoring article can have a particular shape, for example, to enable the self - restoring behavior of the article. In some embodiments, the self - restoring article can be placed (e.g., encapsulated) within a capsule. In certain embodiments, the self - restoring article is not provided within a capsule. In some embodiments, a capsule containing the self - restoring article can be administered (e.g., to deliver the self - restoring article to a location within the body of a subject such as the gastrointestinal tract). In some embodiments, the self - restoring article and / or the capsule can comprise a pharmaceutical agent (e.g., to deliver a pharmaceutically active agent to a location within the body of a subject).

[0041] The self - restoring articles described herein can be useful, for example, as a general platform for the delivery of a wide variety of pharmaceutical components that would otherwise generally be delivered by direct injection into tissue for degradation within the GI tract. As a rat platform, it can be useful. In some embodiments, the self - restoring articles described herein can be used to deliver sensors and / or collect biopsy samples, for example, without the need for endoscopic observation.

[0042] Advantageously, the self - restoring article can be localized in a specified direction in the tissue wall (thereby, for example, a loaded drug can avoid the long - time passage of GI tract fluid before diffusion into the bloodstream). As described herein, in some cases, this article can serve as a platform for absorbing drugs that are currently enzymatically degraded in the GI tract with higher bioavailability. In addition, the article can be made such that mechanical and electrical mechanisms, such as needles, plungers, anchors, sensors, etc., can operate directly against and / or into the tissue wall. Thus, in certain embodiments, the article can serve as a vehicle for delivering an electronic device or other article to the GI tract.

[0043] In some embodiments, the self - restoring article can have a particular cross - sectional shape. In certain embodiments, the shape can be any suitable cross - sectional shape, including circular, oval, triangular, irregular, trapezoidal, square or rectangular, or the like. In certain embodiments, the self - restoring article is non - spherical. In some embodiments, the self - restoring article can be monostatic and / or have only one stable point (e.g., the self - restoring article can stably maintain a particular orientation in only one given orientation). In an exemplary embodiment, the self - restoring article has a rubber bock shape and / or comprises rubber bock - shaped components. A self - restoring article having a rubber bock shape can self - restore to a particular orientation without additional force when displaced from its orientation. In some cases, the self - restoring article can self - restore in a fluid (e.g., a liquid having a relatively low viscosity, a liquid having a relatively high viscosity). Advantageously, this shape is such that the self - restoring article aligns the self - restoring article as expected and quickly, and further minimizes movement due to forces inside the GI tract. In some cases, at least the surface of the self - restoring article includes a flat surface. For example, as illustrated in FIGS. 1 and 2, in some embodiments, the tissue - engaging surface 150 can be flat.

[0044] Referring again to FIG. 1, in some embodiments, the self-healing article comprises a first portion 110 and a second portion 115 adjacent to the first portion 110 having an average density different from the first portion and / or a mass different from the first portion. For example, in some embodiments, the self-healing article comprises a first portion and a second portion adjacent to the first portion having an average density different from the first portion. For example, the first portion can have a first average density and the second portion can have a second average density 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 is greater than 1:1, may be greater than or equal to 2:1, may be greater than or equal to 2.5:1, may be greater than or equal to 3:1, may be greater than or equal to 3.5:1, may be greater than or equal to 4:1, may be greater than or equal to 4.5:1, may be greater than or equal to 5:1, may be greater than or equal to 5.5:1, may be greater than or equal to 5.5:1, may be greater than or equal to 6:1, may be greater than or equal to 6.5:1, may be greater than or equal to 7:1, may be greater than or equal to 8:1, may be greater than or equal to 9:1, or may be greater than or equal to 10:1. In certain embodiments, the ratio of the average density of the first portion to the average density of the second portion is less than or equal to 15:1, may be less than or equal to 10:1, may be less than or equal to 9:1, may be less than or equal to 8:1, may be less than or equal to 7:1, may be less than or equal to 6.5:1, may be less than or equal to 6:1, may be less than or equal to 5.5:1, may be Or equal thereto, less than 5:1 or equal thereto, less than 4.5:1 or equal thereto, less than 4:1 or equal thereto, less than 3.5:1 or equal thereto, less than 3:1 or equal thereto, less than 2.5:1 or equal thereto, less than 2:1 or equal thereto, or less than 1.5:1 or equal thereto. Combinations of the ranges mentioned above are possible (e.g., greater than or equal to 1:1 and less than or equal to 15:1). Other ranges are possible. Without wishing to be bound by theory, a self-healing article having a first portion and a second portion with different average densities may, as a result, be a self-healing article that substantially maintains a particular orientation with respect to a surface (e.g., the wall of the gastrointestinal tract). It can be a self-healing article that substantially maintains

[0045] In some embodiments, the ratio of the average density of the second portion to the average density of the first portion may be greater than 1:1, may be greater than or equal to 2:1, may be greater than or equal to 2.5:1, may be greater than or equal to 3:1, may be greater than or equal to 3.5:1, may be greater than or equal to 4:1, may be greater than or equal to 4.5:1, may be greater than or equal to 5:1, may be greater than or equal to 5.5:1, may be greater than or equal to 5.5:1, may be greater than or equal to 6:1, may be greater than or equal to 6.5:1, may be greater than or equal to 7:1, may be greater than or equal to 8:1, may be greater than or equal to 9:1, or may be greater than or equal to 10:1. In certain embodiments, the ratio of the average density of the second portion to the average density of the first portion may be less than or equal to 15:1, may be less than or equal to 10:1, may be less than or equal to 9:1, may be less than or equal to 8:1, may be less than or equal to 7:1, may be less than or equal to 6.5:1, may be less than or equal to 6:1, may be less than or equal to 5.5:1, may be less than or equal to 5:1, may be less than or equal to 4.5:1, may be less than or equal to 4:1, may be less than or equal to 3.5:1, may be less than or equal to 3:1, may be less than or equal to 2.5:1, may be less than or equal to 2:1, or may be less than or equal to 1.5:1. Combinations of the ranges mentioned above are possible (e.g., greater than or equal to 1:1 and less than or equal to 15:1). Other ranges are possible.

[0046] In some embodiments, the self-healing article comprises 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 is greater than 1:1, may be greater than or equal to 2:1, may be greater than or equal to 2.5:1, may be greater than or equal to 3:1, may be greater than or equal to 3.5:1, may be greater than or equal to 4:1, may be greater than or equal to 4.5:1, may be greater than or equal to 5:1, may be greater than or equal to 5.5:1, may be greater than or equal to 5.5:1, may be greater than or equal to 6:1, may be greater than or equal to 6.5:1, may be greater than or equal to 7:1, may be greater than or equal to 8:1, may be greater than or equal to 9:1, or may be greater than or equal to 10:1. In certain embodiments, the ratio of the mass of the first portion to the mass of the second portion is less than or equal to 15:1, less than or equal to 10:1, less than or equal to 9:1, less than or equal to 8:1, less than or equal to 7:1, less than or equal to 6.5:1, less than or equal to 6:1, less than or equal to 5.5:1, or less than or equal to... Equal to, less than or equal to 5:1, less than or equal to 4.5:1, less than or equal to 4:1, less than or equal to 3.5:1, less than or equal to 3:1, less than or equal to 2.5:1, less than or equal to 2:1, or less than or equal to 1.5:1. Combinations of the ranges mentioned above are possible (e.g., greater than or equal to 1:1 and less than or equal to 15:1). Other ranges are possible. Without wishing to be bound by theory, a self-healing article having a first part and a second part of different masses can, as a result, be a self-healing article that substantially maintains a particular orientation with respect to a surface (e.g., the wall of the gastrointestinal tract).

[0047] In some embodiments, the ratio of the mass of the second portion to the mass of the first portion may be greater than 1:1, may be greater than or equal to 2:1, may be greater than or equal to 2.5:1, may be greater than or equal to 3:1, may be greater than or equal to 3.5:1, may be greater than or equal to 4:1, may be greater than or equal to 4.5:1, may be greater than or equal to 5:1, may be greater than or equal to 5.5:1, may be greater than or equal to 5.5:1, may be greater than or equal to 6:1, may be greater than or equal to 6.5:1, may be greater than or equal to 7:1, may be greater than or equal to 8:1, may be greater than or equal to 9:1, or may be greater than or equal to 10:1. In certain embodiments, the ratio of the mass of the second portion to the mass of the first portion may be less than or equal to 15:1, may be less than or equal to 10:1, may be less than or equal to 9:1, may be less than or equal to 8:1, may be less than or equal to 7:1, may be less than or equal to 6.5:1, may be less than or equal to 6:1, may be less than or equal to 5.5:1, may be less than or equal to 5:1, may be less than or equal to 4.5:1, may be less than or equal to 4:1, may be less than or equal to 3.5:1, may be less than or equal to 3:1, may be less than or equal to 2.5:1, may be less than or equal to 2:1, or may be less than or equal to 1.5:1. Combinations of the ranges mentioned above are possible (e.g., greater than or equal to 1:1 and less than or equal to 15:1). Other ranges are possible.

[0048] As illustrated in FIG. 4, system 100 may comprise a first portion 110 and a second portion 120 adjacent to the first portion 110. As used herein, when a portion is said to be “adjacent” to another portion, it may be directly adjacent to that portion (e.g., in contact with that portion), or one or more intervening components (e.g., a liquid, a hollow portion) may be present. A portion that is “directly adjacent” to another portion means that no intervening components are present.

[0049] For example, referring again to FIG. 1, the first portion 110 may occupy a first volume of the self - restoring article having a first average density and / or mass, and the second portion 115 may occupy the remaining volume of the self - restoring article having a second average density and / or mass. In certain embodiments, referring back to FIG. 4, the first portion 110 may occupy a first volume of the self - restoring article, the second portion 115 may occupy a second volume of the self - restoring article, the third portion 130 may be hollow, and / or may contain one or more (additional) components.

[0050] In some embodiments, the first portion is greater than or equal to 1 volume %, greater than or equal to 5 volume %, greater than or equal to 10 volume %, greater than or equal to 20 volume %, greater than Occupies a percentage greater than or equal to 5% by volume, greater than or equal to 30% by volume, greater than or equal to 40% by volume, greater than or equal to 45% by volume, greater than or equal to 50% by volume, greater than or equal to 55% by volume, greater than or equal to 60% by volume, greater than or equal to 65% by volume, greater than or equal to 70% by volume, greater than or equal to 75% by volume, greater than or equal to 80% by volume, greater than or equal to 90% by volume, or greater than or equal to 95% by volume. In certain embodiments, the first portion is less than or equal to 99% by volume, less than or equal to 95% by volume, less than or equal to 90% by volume, less than or equal to 80% by volume, less than or equal to 75% by volume, less than or equal to 70% by volume, less than or equal to 60% by volume, less than or equal to 55% by volume, less than or equal to 50% by volume, less than or equal to 45% by volume, less than or equal to 40% by volume, less than or equal to 30% by volume, less than or equal to 25% by volume, less than or equal to 20% by volume, less than or equal to 10% by volume, or less than or equal to 5% by volume of the total volume of the self-healing article. Combinations of the ranges mentioned above are also possible (e.g., greater than or equal to 1% by volume and less than or equal to 99% by volume, greater than or equal to 40% by volume and less than or equal to 60% by volume). Other ranges are possible.

[0051] In certain embodiments, the second portion comprises greater than or equal to 1%, greater than or equal to 5%, greater than or equal to 10%, greater than or equal to 20%, greater than or equal to 25%, greater than or equal to 30%, greater than or equal to 40%, greater than or equal to 45%, greater than or equal to 50%, greater than or equal to 55%, greater than or equal to 60%, greater than or equal to 65%, greater than or equal to 70%, greater than or equal to 75%, greater than or equal to 80%, greater than or equal to 90%, or greater than or equal to 95% of the total volume of the self-healing article. In some embodiments, the second portion comprises less than or equal to 99%, less than or equal to 95%, less than or equal to 90%, less than or equal to 80%, less than or equal to 75%, less than or equal to 70%, less than or equal to 60%, less than or equal to 55%, less than or equal to 50%, less than or equal to 45%, less than or equal to 40%, less than or equal to 30%, less than or equal to 25%, less than or equal to 20%, less than or equal to 10%, or less than or equal to 5% of the total volume of the self-healing article. Combinations of the ranges recited above are also possible (e.g., greater than or equal to 1% and less than or equal to 99%, greater than or equal to 40% and less than or equal to 60%). Other ranges are possible.

[0052] In some embodiments, the third portion (e.g., the hollow portion) may occupy more than or equal to 1%, more than or equal to 5%, more than or equal to 10%, more than or equal to 20%, more than or equal to 25%, more than or equal to 30%, more than or equal to 40%, more than or equal to 45%, more than or equal to 50%, more than or equal to 55%, more than or equal to 60%, more than or equal to 65%, more than or equal to 70%, more than or equal to 75%, more than or equal to 80%, more than or equal to 90%, or more than or equal to 95% of the total volume of the self-healing article. In certain embodiments, the third portion may occupy less than or equal to 99%, less than or equal to 95%, less than or equal to 90%, less than or equal to 80%, less than or equal to 75%, less than or equal to 70%, less than or equal to 60%, less than or equal to 55%, less than or equal to 50%, less than or equal to 45%, less than or equal to 40%, less than or equal to 30%, less than or equal to 25%, less than or equal to 20%, less than or equal to 10%, or less than or equal to 5% of the total volume of the self-healing article. Combinations of the ranges mentioned above are also possible (e.g., more than or equal to 1% and less than or equal to 99%, more than or equal to 40% and less than or equal to 60%). Other ranges are possible. In some embodiments, the third portion (e.g., the hollow portion) may occupy more than or equal to 1%, more than or equal to 5%, more than or equal to 10%, more than or equal to 20%, more than or equal to 25%, more than or equal to 30%, more than or equal to 40%, more than or equal to 45%, more than or equal to 50%, more than or equal to 55%, more than or equal to 60%, more than or equal to 65%, more than or equal to 70%, more than or equal to 75%, more than or equal to 80%, more than or equal to 90%, or more than or equal to 95% of the total volume of the self-healing article. In certain embodiments, the third portion may occupy less than or equal to 99%, less than or equal to 95%, less than or equal to 90%, less than or equal to 80%, less than or equal to 75%, less than or equal to 70%, less than or equal to 60%, less than or equal to 55%, less than or equal to 50%, less than or equal to 45%, less than or equal to 40%, less than or equal to 30%, less than or equal to 25%, less than or equal to 20%, less than or equal to 10%, or less than or equal to 5% of the total volume of the self-healing article. Combinations of the ranges mentioned above are also possible (e.g., more than or equal to 1% and less than or equal to 99%, more than or equal to 40% and less than or equal to 60%). Other ranges are possible.

[0053] 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 greater than or equal to 1:100, greater than or equal to 1:50, greater than or equal to 1:25, greater than or equal to 1:10, greater than or equal to 1:8, greater than or equal to 1:6, greater than or equal to 1:4, greater than or equal to 1:3, greater than or equal to 1:2, greater than or equal to 1:1.5, greater than or equal to 1:1.1, greater than or equal to 1:1, greater than or equal to 1.1:1, greater than or equal to 1.5:1, greater than or equal to 2:1, greater than or equal to 3:1, greater than or equal to 4:1, greater than or equal to 6:1, greater than or equal to 8:1, greater than or equal to 10:1, greater than or equal to 25:1, or greater than or equal to 50:1.In certain embodiments, the ratio of the first volume to the second volume may be less than or equal to less than 100:1, less than or equal to less than 50:1, less than or equal to less than 25:1, less than or equal to less than 10:1, less than or equal to less than 8:1, less than or equal to less than 6:1, less than or equal to less than 4:1, less than or equal to less than 2:1, less than or equal to less than 1.5:1, less than or equal to less than 1.1:1, less than or equal to less than 1:1, less than or equal to less than 1:1.1, less than or equal to less than 1:1.5, less than or equal to less than 1:2, less than or equal to less than 1:4, less than or equal to less than 1:6, less than or equal to less than 1:8, less than or equal to less than 1:10, less than or equal to less than 1:25, or less than or equal to less than 1:50. Combinations of the ranges mentioned above are also possible (e.g., greater than or equal to 1:100 and less than or equal to less than 100:1, greater than or equal to 1:10 and less than or equal to less than 10:1, 1. :2 greater than or equal to and less than or equal to less than 2:1). Other ranges are possible. Other volume ratios are possible. Without wishing to be bound by theory, in some embodiments, the ratio of the first volume occupied by the first portion to the second volume occupied by the second portion may be selected such that the center of mass of the self - restoring article has a single minimum value.

[0054] 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 or arranged to be encapsulated in a capsule having a shell (e.g., the outer surface 170 of FIG. 4 constitutes the shell). In some such embodiments, referring next to FIG. 4, the self-healing article may comprise a third portion 130 (e.g., a hollow portion). In certain embodiments, a tissue connection component and / or a pharmaceutical active ingredient can be disposed within the hollow portion.

[0055] In some embodiments, the capsule is a 000 capsule or smaller (e.g., the capsule has a shape or size as described in the USP, including but not limited to 000 capsule, 00 capsule, 0 capsule, 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, a plurality of devices can be disposed within the capsule.

[0056] In some embodiments, the self-healing article may be configured for potential encapsulation in a 000 capsule or smaller capsule, but the self-healing article need not necessarily be encapsulated in such a capsule. In embodiments where the self-healing article is to be administered, e.g., by ingestion of the self-healing article, the self-healing article may thus be administered without being encapsulated.

[0057] In certain embodiments, the self-healing article can comprise a coating on at least a portion of the outer surface of the self-healing article. In certain embodiments, a system (e.g., a system including the self-healing article) can comprise a coating (e.g., a film disposed on at least the surface of the system). In some embodiments, the coating can be coated as an aqueous or organic solvent-based polymer system, a fat, and / or a wax. In certain embodiments, the coating can include 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.

[0058] Non-limiting examples of polymers suitable for the coating include cellulose-based (e.g., hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxyethyl cellulose phthalate, ethyl cellulose, cellulose acetate phthalate, cellulose acetate trimellitate), vinyl (e.g., poly(vinyl pyrrolidone), poly(vinyl alcohol), poly(vinyl pyrrolidone)-poly(vinyl acetate) copolymer, poly(vinyl alcohol)-poly(ethylene glycol) copolymer, poly(vinyl acetate phthalate), glycol (e.g., poly(ethylene glycol)), acrylic resins (e.g., aminoalkyl methacrylate copolymer), other carbohydrates (e.g., maltodextrin, polydextrose), and combinations thereof.

[0059] Non-limiting examples of suitable colorants include natural dyes (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 lakes (FD&C Yellow #5 lake, FD&C Blue #2 lake), and D&C lakes (D&C Yellow #10 lake, D&C Red #30 lake). -lake, D&C Red #30 lake).

[0060] Non-limiting examples of suitable plasticizers include polyhydric alcohols (e.g., propylene glycol, glycerol, polyethylene glycol), acetate esters (e.g., triacetin, triethyl citrate, acetyltriethyl citrate), phthalate esters (e.g., diethyl phthalate), glycerides (e.g., acylated monoglycerides), and oils (e.g., castor oil, mineral oil).

[0061] The polymer, plasticizer, colorant, solvent, fat, and / or wax can be combined in any suitable amounts to form a coating. The coating can be applied by any suitable method, such as, for example, dip coating and / or spray atomization. Other methods of depositing the coating are also possible.

[0062] In some embodiments, a tissue connection component is associated with the self-healing article. Non-limiting examples of tissue connection components include needles (e.g., stainless steel needles, needles including APIs), biopsy punches, microneedles (e.g., microneedles including APIs), protrusions, or the like.

[0063] In certain embodiments, the tissue connection component includes a jet injection component (e.g., for liquid jet injection into tissue within a subject using a high-speed stream). In an exemplary embodiment, the jet injection component includes a chamber having a polymer portion. In certain embodiments, the polymer portion can include an acid (e.g., a weak acid) and / or a base. In some cases, a fluid (e.g., gastric fluid) enters the chamber, and as a result, reacts with the acid and / or base to form a gas. In some cases, the chamber can include a coating (e.g., such that the fluid does not contact the polymer portion under coating dissolution). In another exemplary embodiment, the jet injection component includes a plunger / piston (e.g., actuated by a spring associated with the plunger / piston) for rapidly discharging material from the system.

[0064] In some embodiments, the tissue connection component comprises a spring-actuated component. Such tissue connection components are generally described in co-owned U.S. Patent Application No. 62 / 507,653, filed May 17, 2017, entitled "SELF-ACTUATING ARTICLES", which provisional application is hereby incorporated by reference in its entirety. For example, it can be administered to a subject for a self-righting article comprising a tissue connection component (e.g., a needle), such that the self-righting article is oriented at a location within the subject's body for the tissue connection component (opponent) to pierce tissue proximate to the location within the subject's body. And in some such modified embodiments, a pharmaceutically active ingredient associated with the self-righting article can be released into and / or proximate to the tissue. In some embodiments, the tissue connection component can penetrate the tissue. In some embodiments, the tissue is penetrated with a force greater than or equal to 1 mN and less than or equal to 20,000 mN (e.g., greater than or equal to 10 mN and less than or equal to 20 mN, greater than or equal to 10 mN and less than or equal to 100 mN, greater than or equal to 100 mN and less than or equal to 20,000 mN, greater than or equal to 5,000 mN and less than or equal to 20,000 mN).

[0065] In certain embodiments, the tissue connection component can be oriented within the self-righting article such that when administered to a subject, the tissue connection component is aligned substantially orthogonally (e.g., within 15° from a right angle) to tissue within the subject's body (e.g., GI mucosal tissue). One In some embodiments, the tissue connection component may be disposed within the hollow portion of the self - restoring device such that the tissue connection component is released from the self - restoring device along the longitudinal axis of the hollow portion. For example, referring again to FIG. 2, the self - restoring article may have a longest longitudinal axis 180 that is aligned within 15 degrees from perpendicular, within 10 degrees from perpendicular, within 5 degrees from perpendicular, within 2 degrees from perpendicular, or within 1 degree from perpendicular with respect to the tissue engagement surface 150. In certain embodiments, the longest longitudinal axis 180 is parallel to the major axis of the tissue connection component 130. In some embodiments, the tissue connection component is released (e.g., when the self - actuating component 120 and / or spring 125 is actuated), such that the spring 125 unfolds along the longitudinal axis 180 and / or the tissue connection component travels parallel to the direction of the longitudinal axis 180. In some such embodiments, the tissue connection component can exit the hole 140 and enter the target tissue in a direction substantially parallel to the longitudinal axis 180. However, in other embodiments, the tissue connection component is not aligned substantially orthogonal to the tissue within the target body.

[0066] In some embodiments, the self - restoring article has a longest longitudinal axis that, when self - restored, is oriented within a range less than or equal to 15 degrees from perpendicular, less than or equal to 10 degrees from perpendicular, less than or equal to 5 degrees from perpendicular, less than or equal to 2 degrees from perpendicular, or less than or equal to 1 degree from perpendicular. In certain embodiments, the self - restoring article has a longest longitudinal axis that is oriented within a range greater than or equal to 0.1 degrees, greater than or equal to 1 degree, greater than or equal to 2 degrees, greater than or equal to 5 degrees, or greater than or equal to 10 degrees. Combinations of the ranges mentioned above are also possible (e.g., greater than or equal to 0.1 degrees and less than or equal to 15 degrees). Other ranges are possible.

[0067] In certain embodiments, the tissue connection component has a longest longitudinal axis that, when self-healing, is oriented within a range of less than or equal to 15 degrees from vertical, less than or equal to 10 degrees, less than or equal to 5 degrees, less than or equal to 2 degrees, or less than or equal to 1 degree. In some embodiments, the tissue connection component has a longest longitudinal axis that is oriented within a range of greater than or equal to 0.1 degree, greater than or equal to 1 degree, greater than or equal to 2 degrees, greater than or equal to 5 degrees, or greater than or equal to 10 degrees. Combinations of the ranges mentioned above are also possible (e.g., greater than or equal to 0.1 degree and less than or equal to 15 degrees). Other ranges are possible.

[0068] In some embodiments, the hollow portion can be cylindrical in shape. Other shapes are possible.

[0069] In an exemplary embodiment, the tissue connection component comprises a plurality of microneedles. In another exemplary embodiment, the tissue connection component comprises a single needle. In yet another exemplary embodiment, the tissue connection component comprises a biopsy component (e.g., a biopsy joe). In some cases, the tissue connection component can comprise a mooring mechanism (e.g., a hook, a mucosal adherent). The tissue connection component will be described in more detail below.

[0070] As described above, in some embodiments, the first portion comprises a first material having a first average density. In some embodiments, the first material and / or the second material can be selected to impart a particular mass and / or density to the first portion and / or the second portion.

[0071] In some embodiments, the average density of the first portion may be less than or equal to 2 g / mL, less than or equal to 1.8 g / mL, less than or equal to 1.6 g / mL, less than or equal to 1.4 g / mL, less than or equal to 1.2 g / mL, less than or equal to 1 g / mL, less than or equal to 0.8 g / mL, less than or equal to 0.6 g / mL, less than or equal to 0.4 g / mL, less than or equal to 0.2 g / mL, less than or equal to 0.1 g / mL, less than or equal to 0.05 g / mL, or less than or equal to 0.02 g / mL. In certain embodiments, the first portion has an average density greater than or equal to 0.01 g / mL, greater than or equal to 0.02 g / mL, greater than or equal to 0.05 g / mL, greater than or equal to 0.1 g / mL, greater than or equal to 0.2 g / mL, greater than or equal to 0.4 g / mL, greater than or equal to 0.6 g / mL, greater than or equal to 0.8 g / mL, greater than or equal to 1 g / mL, greater than or equal to 1.2 g / mL, greater than or equal to 1.4 g / mL, greater than or equal to 1.6 g / mL, or greater than or equal to 1.8 g / mL. Combinations of the ranges mentioned above 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 possible.

[0072] In certain embodiments, the second portion comprises 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) may be less than or equal to 20 g / mL, may be less than or equal to 18 g / mL, may be less than or equal to 16 g / mL, may be less than or equal to 14 g / mL, may be less than or equal to 12 g / mL, may be less than or equal to 10 g / mL, may be less than or equal to 8 g / mL, may be less than or equal to 6 g / mL, may be less than or equal to 4 g / mL, or may be less than or equal to 3 g / L. In certain embodiments, the average density of the second portion may be greater than or equal to 2 g / mL, may be greater than or equal to 3 g / mL, may be greater than or equal to 4 g / mL, may be greater than or equal to 6 g / mL, may be greater than or equal to 8 g / mL, may be greater than or equal to 10 g / mL, may be greater than or equal to 12 g / mL, may be greater than or equal to 14 g / mL, may be greater than or equal to 16 g / mL, or may be greater than or equal to 18 g / mL. Combinations of the ranges recited above are also possible (e.g., greater than or equal to 2 g / mL and less than or equal to 20 g / mL). Other ranges are possible. In some embodiments, the second portion may have an average density within one or more of the ranges described above in relation to the first portion (e.g., greater than or equal to 0.6 g / mL and less than or equal to 2 g / mL), and may have an average density different from the average density of the first portion.

[0073] The first portion and the second portion can be selected to have any suitable mass. In some embodiments, the first portion comprises any mass between 20 mg and 15 g, greater than or equal to 20 mg, greater than or equal to 50 mg, greater than or equal to 75 mg, greater than or equal to 100 mg, greater than or equal to 200 mg, greater than or equal to 300 mg, greater than or equal to 400 mg, greater than or equal to 500 mg, greater than or equal to 750 mg, greater than or equal to 1 g, greater than or equal to 1.5 g, greater than or equal to 2 g, greater than or equal to 3 g, greater than or equal to 4 g, greater than or equal to 5 g, greater than or equal to 7 g, greater than or equal to 10 g, greater than or equal to 15 g total mass (e.g., including all components within the first portion). In certain embodiments, the first part The portion may have a total mass of any mass between 15 g and 20 mg, less than or equal to 15 g, less than or equal to 10 g, less than or equal to 7 g, less than or equal to 5 g, less than or equal to 4 g, less than or equal to 3 g, less than or equal to 2 g, less than or equal to 1.5 g, less than or equal to 1 g, less than or equal to 750 mg, less than or equal to 500 mg, less than or equal to 400 mg, less than or equal to 300 mg, less than or equal to 200 mg, less than or equal to 100 mg, less than or equal to 75 mg, less than or equal to 50 mg, or less than or equal to 20 mg. Combinations of the ranges mentioned above are also possible (e.g., greater than or equal to 50 mg and less than or equal to 4 g, greater than or equal to 50 mg and less than or equal to 15 g). In some embodiments, the first portion or the second portion has a mass in the range greater than or equal to 20 mg and less than or equal to 15 g. In some embodiments, the first portion or the second portion has a mass in the range greater than or equal to 20 mg and less than or equal to 1 g. In some embodiments, the first portion or the second portion has a mass in the range greater than or equal to 300 mg and less than or equal to 12 g. In some embodiments, the first portion or the second portion has a mass in the range greater than or equal to 100 mg and less than or equal to 250 mg. In some embodiments, the first portion or the second portion has a mass in the range greater than or equal to 20 mg and less than or equal to 15 g. In some embodiments, the first portion or the second portion has a mass in the range greater than or equal to 1.5 and less than or equal to 6.5 g. Other ranges are possible.

[0074] In certain embodiments, the second portion may have a total mass (e.g., including all components within the second portion) that is greater than or equal to 50 mg, greater than or equal to 75 mg, greater than or equal to 100 mg, greater than or equal to 200 mg, greater than or equal to 400 mg, greater than or equal to 500 mg, greater than or equal to 750 mg, greater than or equal to 1 g, greater than or equal to 1.5 g, greater than or equal to 2 g, greater than or equal to 3 g, greater than or equal to 4 g, greater than or equal to 5 g, greater than or equal to 7 g, or greater than or equal to 10 g. In certain embodiments, the second portion may have a total mass that is less than or equal to 15 g, less than or equal to 10 g, less than or equal to 7 g, less than or equal to 5 g, less than or equal to 4 g, less than or equal to 3 g, less than or equal to 2 g, less than or equal to 1.5 g, less than or equal to 1 g, less than or equal to 750 mg, less than or equal to 500 mg, less than or equal to 400 mg, less than or equal to 200 mg, less than or equal to 100 mg, or less than or equal to 75 mg. Combinations of the ranges mentioned above are also possible (e.g., greater than or equal to 50 mg and less than or equal to 4 g, greater than or equal to 50 mg and less than or equal to 15 g). Other ranges are possible.

[0075] In some embodiments, the first material and / or the second material is 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 can be selected from the group consisting of stainless steel, iron-carbon alloy, field metal, tungsten, molybdenum, gold, zinc, iron, and titanium.

[0076] In some embodiments, the ceramic can be selected from the group consisting of hydroxyapatite, aluminum oxide, calcium oxide, tricalcium phosphate, silicate, silicon dioxide, and zirconium dioxide.

[0077] In certain embodiments, the polymer can be selected from the group consisting of polycaprolactone, polylactic acid, polyethylene glycol, polypropylene, polyethylene, polycarbonate, polystyrene, polyetheretherketone, and polyvinyl alcohol.

[0078] In an exemplary embodiment, the first material includes a metal and the second material includes a polymer.

[0079] The self-healing article generally has a geometric center (e.g., the geometric volume center). In certain embodiments, the density, mass, and / or volume of the first portion and / or the second portion can be selected such that the self-healing article exhibits self-healing behavior. For example, in some embodiments, the mass center of the self-healing article may be offset from the geometric center, such that an article suspended via an axis passing through the geometric center has a mass center that is laterally offset from the geometric center, and thus, when an external applied torque of 0.09×10 -4 Nm or less acts, it is configured to maintain an orientation of 20 degrees or less from vertical.

[0080] In some embodiments, the self-healing article is 0.09×10 -4When an external applied torque of Nm or less acts, it maintains an orientation of 20° or less from the vertical. In certain embodiments, the self - restoring article is 0.09×10 -4 When an external applied torque of Nm or less acts, it 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. In some embodiments, the self - restoring article is 0.09×10 -4 When an external applied torque of Nm or less acts, it maintains an orientation greater than or equal to 1°, greater than or equal to 2°, greater than or equal to 4°, greater than or equal to 6°, greater than or equal to 8°, greater than or equal to 10°, greater than or equal to 12°, or greater than or equal to 15° from the vertical. Combinations of the ranges mentioned above are also possible (e.g., 20° or less and greater than or equal to 1°). Other ranges are possible.

[0081] In some embodiments, the self - restoring article may be characterized by having a specific self - restoring time from 90° in a particular fluid. The self - restoring time can be determined by placing the self - restoring article at 90° in the particular fluid and allowing the self - restoring object to return to a particular orientation (e.g., an orientation corresponding to the stable equilibrium (or orientation) point of the article) that is otherwise maintained by the self - restoring article in the absence of that fluid.

[0082] In certain embodiments, the fluid is oil. In some such embodiments, the self-healing article has a self-healing time of less than or equal to 0.15 seconds, less than or equal to 0.1 seconds, less than or equal to 0.05 seconds, or less than or equal to 0.02 seconds from 90° in oil. In certain embodiments, the self-healing article has a self-healing time of greater than or equal to 0.01 seconds, greater than or equal to 0.02 seconds, greater than or equal to 0.05 seconds, greater than or equal to 0.1 seconds, or greater than or equal to 0.12 seconds from 90° in oil. Combinations of the ranges mentioned above are also possible (e.g., less than or equal to 0.15 seconds and greater than or equal to 0.01 seconds). Other ranges are possible. The self-healing time in oil is determined by fully immersing the system / article.

[0083] In some embodiments, the fluid is gastric juice. In some such embodiments, the self-healing article has a self-healing time of less than or equal to 0.06 seconds, less than or equal to 0.05 seconds, less than or equal to 0.04 seconds, less than or equal to 0.03 seconds, or less than or equal to 0.02 seconds from 90° in gastric juice. In certain embodiments, the self-healing article has a self-healing time of greater than or equal to 0.005 seconds, greater than or equal to 0.01 seconds, greater than or equal to 0.02 seconds, greater than or equal to 0.03 seconds, greater than or equal to 0.04 seconds, or greater than or equal to 0.05 seconds from 90° in gastric juice. Combinations of the ranges mentioned above are also possible (e.g., less than or equal to 0.06 seconds and greater than or equal to 0.005 seconds). Other ranges are possible. The self-healing time in gastric juice is determined by fully immersing the system / article.

[0084] In certain embodiments, the fluid is mucus. In some such embodiments, the self - restoring article has a self - restoring time of less than or equal to 0.05 seconds, less than or equal to 0.04 seconds, less than or equal to 0.03 seconds, or less than or equal to 0.02 seconds from 90° in mucus. In certain embodiments, the self - restoring article has a self - restoring time of greater than or equal to 0.005 seconds, greater than or equal to 0.01 seconds, greater than or equal to 0.02 seconds, greater than or equal to 0.03 seconds, greater than or equal to 0.04 seconds, or greater than or equal to 0.045 seconds from 90° in mucus. Combinations of the ranges mentioned above are also possible (e.g., less than or equal to 0.05 seconds and greater than or equal to 0.005 seconds). Other ranges are possible. The self - restoring time in mucus is determined by completely immersing the system / article.

[0085] In some embodiments, the fluid is water. In some such embodiments, the self - restoring article has a self - restoring time of less than or equal to 0.05 seconds, less than or equal to 0.04 seconds, less than or equal to 0.03 seconds, or less than or equal to 0.02 seconds from 90° in water. In certain embodiments, the self - restoring article has a self - restoring time of greater than or equal to 0.005 seconds, greater than or equal to 0.01 seconds, greater than or equal to 0.02 seconds, greater than or equal to 0.03 seconds, greater than or equal to 0.04 seconds, or greater than or equal to 0.045 seconds from 90° in water. Combinations of the ranges mentioned above are also possible (e.g., less than or equal to 0.05 seconds and greater than or equal to 0.005 seconds). Other ranges are possible. The self - restoring time in water is determined by completely immersing the system / article.

[0086] In some embodiments, the self - restoring article comprises one or more outlets (e.g., to allow for the flow of air and / or fluid through the self - restoring article). In some embodiments, the self - restoring article comprises one or more (e.g., two or more, three or more, four or more) outlets associated with at least a portion (e.g., a first portion, a second portion) of the self - restoring article. In some such embodiments, the outlet can allow for the intrusion of a fluid (e.g., gastric juice) into at least a portion of the self - restoring article, such that, for example, a self - actuating component and / or a spring is exposed to the fluid (e.g., as a result, the self - actuating component and / or the spring actuates). For example, referring again to FIG. 2, the system 102 comprises an outlet 190 associated with at least a portion (e.g., the first portion 110) of the self - restoring article. In some cases, the outlet 190 may also be in fluid communication with the self - actuating component 120, the support 160, and / or the spring 125. The outlet, although depicted herein as being associated with the first portion of the self - restoring article in some embodiments, it will be understood by those skilled in the art based on the teachings of this specification that one or more outlets may be associated with the second portion of the self - restoring article. As described herein, although the outlet is depicted as being associated with the first portion of the self - restoring article, it will be understood by those skilled in the art based on the teachings of this specification that one or more outlets may be associated with the second portion of the self - restoring article.

[0087] In certain embodiments, the self - restoring article does not comprise an outlet.

[0088] In some embodiments, the self-healing article can have a specific size (larges) of cross-sectional dimensions. In some embodiments, the maximum cross-sectional dimension of the self-healing article may be less than or equal to 2.0 cm, may be less than or equal to 1.8 cm, may be less than or equal to 1.6 cm, may be less than or equal to 1.4 cm, may be less than or equal to 1.2 cm, may be less than or equal to 1.1 cm, may be less than or equal to 1 cm, may be less than or equal to 0.8 cm, may be less than or equal to 0.6 cm, may be less than or equal to 0.4 cm, or may be less than or equal to 0.2 cm, which includes 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 maximum cross-sectional dimension of the self-healing article is greater than or equal to 0.1 cm, greater than or equal to 0.2 cm, greater than or equal to 0.4 cm, greater than or equal to 0.6 cm, greater than or equal to 0.8 cm, greater than or equal to 1 cm, greater than or equal to 1.2 cm, greater than or equal to 1.4 cm, greater than or equal to 1.6 cm, greater than or equal to 1.8 cm, which includes any dimension greater than 0.1 cm and less than or equal to 2.0 cm (e.g., 0.3 cm, 0.5 cm... 1.7 cm, 1.9 cm, etc.). Combinations of the ranges mentioned above are also possible (e.g., less than or equal to 2 cm and greater than or equal to 0.1 cm, less than or equal to 1.1 cm and greater than or equal to 0.1 cm). Other ranges are possible.

[0089] 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 contain one or more pharmaceutical active ingredients. In certain embodiments, the pharmaceutical active ingredient is released at a location within the subject's body (e.g., within the G.I. tract).

[0090] In certain embodiments, one or more sensors may be associated with the self - healing article. For example, in some cases, one or more sensors can be used to determine the location of the self - healing article (e.g., the location within the body of a subject) and / or to induce the operation of one or more tissue - connecting components associated with the self - healing article. Non - limiting examples of suitable sensors include pH, gas, light, GPS, Bluetooth®, orientation, proximity, thermal, fluid, and others.

[0091] In some cases, one or more of the first portion and / or the second portion can be magnetic.

[0092] In an exemplary embodiment, the self - healing article is ingestible. According to certain embodiments, an ingestible self - healing article comprises 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 carrying an agent for release into the body of a subject that ingests the article. In certain embodiments, the self - healing article comprises at least a first portion having an average density greater than 1 g / cm 3 According to certain embodiments, the ratio of the average density of the first portion to the average density of the second portion is greater than or equal to 2.5:1. In certain exemplary embodiments, the self - healing article comprises a first portion comprising a first material having a first average density; and a second portion comprising a second material having a second average density different from the first average density. In certain embodiments, the self - healing article comprises a first material, a second material different from the first material, and a pharmaceutically active 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 greater than or equal to 2.5:1. In some embodiments, the self - healing article has a maximum cross - sectional dimension less than or equal to 2 cm (e.g., less than or equal to 1.1 cm).

[0093] In certain embodiments, an article has a geometric center and a center of mass offset from the geometric center such that an article suspended via an axis passing through the geometric center is subject to an externally applied torque of 0.09×10 -4 Nm or less due to gravity. According to some embodiments, the self - restoring article is configured to be encapsulated within a capsule of 000 or less. In other embodiments, the self - restoring article is not encapsulated. In certain embodiments, the self - restoring article comprises a tissue connection component associated with the self - restoring article. Some exemplary embodiments relate to an axis that is essentially perpendicular to the tissue engagement surface of a self - restoring article configured to maintain an orientation of 20 degrees or less from vertical when an externally applied torque of 0.09×10 -4 Nm or less acts. According to some embodiments, the self - restoring article has the most stable, lowest potential energy physical configuration and a self - restoring time of less than or equal to 0.05 seconds from an orientation 90 degrees off any orientation from the most stable configuration in water. According to certain embodiments, the self - restoring article has a blockage rate of less than or equal to 1% (e.g., less than or equal to 0.5%, less than or equal to 0.1%).

[0094] 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 the subject a capsule comprising an outer shell and a self - restoring article, and orienting the self - restoring article at a location within the subject such that the tissue connection component pierces tissue proximate to the location within the subject. Tissue retention

[0095] In some embodiments, an article (e.g., a self - restoring article) may be configured to be tethered to a location within a subject's body (e.g., tissue at a location within the subject's body). As noted above, in some embodiments, a self - restoring article can comprise one or more tissue - connecting components that comprise one or more tethering mechanisms (e.g., hooks, mucosal adhesives). Hooks are described in more detail below. Mucosal adhesives are described in more detail below. In some embodiments, the self - restoring article is configured to maintain an orientation of 20 degrees or less from vertical when an externally applied torque of 0.09×10 -4 Nm or less acts on a longitudinal axis perpendicular to the tissue - engaging surface of the article; and at least one tethering mechanism associated with the self - restoring article. In some cases, it may have. In another exemplary embodiment, the article can comprise a spring that is associated with (e.g., at least partially encapsulated by) a support member (e.g., such that the spring is maintained in a state of being at least partially compressed under at least 5% compressive strain by the support member); and at least one tethering mechanism operably coupled to the spring. Springs and support members are described in more detail below. Other embodiments are possible that comprise at least one tethering mechanism associated with the self - restoring article and / or self - actuating components.

[0096] In some embodiments, the tethering mechanism includes a hook (e.g., a needle with a hook). For example, as illustrated in FIG. 5, the system 104 comprises a first portion 110 and a second portion 115. In certain embodiments, the tissue - engaging surface 150 is associated with the second portion 115. In some cases, the system 104 can comprise a tissue - connecting component 130 that comprises a tethering mechanism 135. In some embodiments, the tethering mechanism 135 can be a hook . In certain embodiments, the tethering mechanism 135 is disposed within the system 104 and can be released under a desired set of conditions (e.g., via the hole 140) (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 the outer surface of the system 104.

[0097] Next, referring to FIG. 6, in certain embodiments, system 106 comprises an anchoring mechanism 135 associated with a self-actuating component 120 (e.g., comprising spring 125 and / or support 160). In certain embodiments, the self-actuating component is operative to insert the anchoring mechanism into tissue located within the subject's body when exposed to a fluid (e.g., gastric fluid) and / or under a particular set of conditions (e.g., physiological conditions of the gastrointestinal tract such as those within the stomach).

[0098] In some embodiments, the anchoring mechanism (and / or an article comprising the anchoring mechanism) is configured to remain in place within the subject's body. For example, in some embodiments, the anchoring mechanism engages a surface (e.g., the surface of tissue) at a location within the subject's body, and as a result, remains in place at that location.

[0099] Advantageously, systems comprising one or more of the anchoring mechanisms described herein may be inserted into the surface of tissue at a location within the subject's body, and these systems can maintain contact with the tissue under relatively large applied forces and / or relatively large orientation changes (e.g., due to compressive forces applied by the gastrointestinal tract and / or under high flow rates within the gastrointestinal tract). In some embodiments, the systems described herein limit flow, for example, to enable a longer contact time, without substantially blocking an opening (e.g., at the pylorus) within the gastrointestinal tract. In certain embodiments, natural replenishment of the gastrointestinal wall may enable desirable detachment and / or expulsion of the systems described herein that do not require surgical and / or endoscopic retrieval.

[0100] For example, in some embodiments, the anchoring mechanism may be inserted into the surface of the tissue at the location within the body of the subject, and the anchoring mechanism maintains contact with the tissue (e.g., the system maintains an anchored state) under a change in the orientation of the system that is greater than or equal to 1 degree, greater than or equal to 2 degrees, greater than or equal to 5 degrees, greater than or equal to 10 degrees, greater than or equal to 15 degrees, greater than or equal to 20 degrees, greater than or equal to 25 degrees, greater than or equal to 30 degrees, greater than or equal to 45 degrees, greater than or equal to 60 degrees, greater than or equal to 75 degrees, or greater than or equal to 85 degrees. In certain embodiments, the system can maintain an anchored state under a change in the orientation of the system that is less than or equal to 90 degrees, less than or equal to 85 degrees, less than or equal to 75 degrees, less than or equal to 60 degrees, less than or equal to 45 degrees, less than or equal to 30 degrees, less than or equal to 25 degrees, less than or equal to 20 degrees, less than or equal to 15 degrees, less than or equal to 10 degrees, less than or equal to 5 degrees, or less than or equal to 2 degrees. Combinations of the ranges mentioned above are also possible (e.g., greater than or equal to 1 degree and less than or equal to 90 degrees, greater than or equal to 1 degree and less than or equal to 45 degrees, greater than or equal to 2 degrees and less than or equal to 30 degrees). Other ranges are possible.

[0101] In certain embodiments, the system (e.g., comprising an anchoring mechanism) is greater than or equal to 0.002 N, greater than or equal to 0.004 N, greater than or equal to 0.006 N, greater than or equal to 0.008 N per anchoring mechanism. It is configured to stay at a position within the body of the subject under a vertical holding force against a vertical applied force that is greater than or equal to, greater than or equal to 0.01 N, greater than or equal to 0.012 N, greater than or equal to 0.014 N, greater than or equal to 0.016 N, greater than or equal to 0.018 N, greater than or equal to 0.02 N, greater than or equal to 0.025 N, greater than or equal to 0.03 N, greater than or equal to 0.04 N, greater than or equal to 0.05 N, greater than or equal to 0.1 N, greater than or equal to 0.15 N, greater than or equal to 0.2 N, greater than or equal to 0.25 N, greater than or equal to 0.3 N, greater than or equal to 0.35 N, greater than or equal to 0.4 N, greater than or equal to 0.5 N, greater than or equal to 0.6 N, greater than or equal to 0.7 N, greater than or equal to 0.8 N, or greater than or equal to 0.9 N.In some embodiments, the system has a vertical holding force against a vertical applied force of less than or equal to 1 N per mooring mechanism, less than or equal to 0.9 N, less than or equal to 0.8 N, less than or equal to 0.7 N, less than or equal to 0.6 N, less than or equal to 0.5 N, less than or equal to 0.4 N, less than or equal to 0.35 N, less than or equal to 0.3 N, less than or equal to 0.25 N, less than or equal to 0.2 N, less than or equal to 0.15 N, less than or equal to 0.1 N, less than or equal to 0.05 N, less than or equal to 0.04 N, less than or equal to 0.03 N, less than or equal to 0.025 N, less than or equal to 0.02 N, less than or equal to 0.018 N, less than or equal to 0.016 N, less than or equal to 0.014 N, less than or equal to 0.012 N, less than or equal to 0.01 N, less than or equal to 0.008 N, less than or equal to 0.006, or less than or equal to 0.004 N. Combinations of the ranges mentioned above are also possible (e.g., greater than or equal to 0.002 N and less than or equal to 1 N, greater than or equal to 0.02 N and less than or equal to 0.08 N, greater than or equal to 0.1 N and less than or equal to 1 N). Other ranges are possible. The vertical holding force described herein can be determined by inserting the mooring mechanism of the system into the surface of a tissue (e.g., ex vivo porcine stomach) to a penetration depth of at least 0.9 mm and then pulling the system in a direction perpendicular to the surface of the tissue until the system detaches from the tissue. The maximum force before the system detaches is the vertical holding force.

[0102] In some embodiments, a system (e.g., having a mooring mechanism) has a mooring force per mooring mechanism that is greater than or equal to 0.002 N, greater than or equal to 0.004 N, greater than or equal to 0.006 N, greater than or equal to 0.008 N, greater than or equal to 0.01 N, greater than or equal to 0.012 N, greater than or equal to 0.014 N, greater than or equal to 0.016 N, greater than or equal to 0.018 N, greater than or equal to 0.02 N, greater than or equal to 0.025 N, greater than or equal to 0.03 N, greater than or equal to 0.04 N, greater than or equal to 0.05 N, greater than or equal to 0.1 N, greater than or equal to 0.15 N, greater than or equal to 0.2 N, greater than or equal to 0.25 N, greater than or equal to 0.3 N, greater than or equal to 0.35 N, greater than or equal to 0.4 N, greater than or equal to 0.5 N, greater than or equal to 0.6 N, greater than or equal to 0.7 N, greater than or equal to configured to remain at a position within the body of interest under an orthogonal retention force that is greater than or equal to 0.8N, or greater than or equal to 0.9N, or greater than or equal to 1N. In some embodiments, the system has an orthogonal retention force of less than or equal to 1N, less than or equal to 0.9N, less than or equal to 0.8N, less than or equal to 0.7N, less than or equal to 0.6N, less than or equal to 0.5N, less than or equal to 0.4N, less than or equal to 0.35N, less than or equal to 0.3N, less than or equal to 0.25N, less than or equal to 0.2N, less than or equal to 0.15N, less than or equal to 0.1N, less than or equal to 0.05N, less than or equal to 0.04N, less than or equal to 0.03N, less than or equal to 0.025N, less than or equal to 0.02N, less than or equal to 0.018N, less than or equal to 0.016N, less than or equal to 0.014N, less than or equal to 0.012N, less than or equal to 0.01N, less than or equal to 0.008N, less than or equal to 0.006N, or less than or equal to 0.004N per mooring mechanism. Combinations of the ranges mentioned above are also possible (e.g., greater than or equal to 0.002N and less than or equal to 1N, greater than or equal to 0.02N and less than or equal to 0.08N, greater than or equal to 0.1N and less than or equal to 1N). Other ranges are possible. The orthogonal retention force described herein can be determined by inserting the mooring mechanism of the system into the surface of a tissue (e.g., an ex vivo porcine 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 disengages from the tissue (see, e.g., FIG. 59). The maximum force before the system disengages is the orthogonal retention force.

[0103] In some embodiments, the system is configured to remain tethered to the surface of tissue located within a subject's body under an orientation change of less than or equal to 30 degrees and an applied (e.g., perpendicular, orthogonal) force of less than or equal to 1 N.

[0104] In some embodiments, the system comprises two or more tethering mechanisms. In some cases, the system may comprise a single self - restoring article having two or more tethering mechanisms. In certain embodiments, the system comprises two or more self - restoring articles, each having one or more tethering mechanisms. In certain embodiments, the force required to disengage the tethering mechanism (e.g., vertical holding force, orthogonal holding force) can be increased by increasing the number of tethering mechanisms associated with the system. Without wishing to be bound by theory, the spacing between the tethering mechanisms may be related to the holding force of the system (e.g., vertical holding force, orthogonal holding force).

[0105] In some embodiments, the system may have an average spacing between tethering mechanisms that is greater than or equal to 0.1 mm, greater than or equal to 0.2 mm, greater than or equal to 0.3 mm, greater than or equal to 0.4 mm, greater than or equal to 0.5 mm, greater than or equal to 0.6 mm, greater than or equal to 0.7 mm, greater than or equal to 0.8 mm, greater than or equal to 0.9 mm, greater than or equal to 1 mm, greater than or equal to 1.2 mm, greater than or equal to 1.4 mm, greater than or equal to 1.5 mm, greater than or equal to 1.6 mm, greater than or equal to 1.8 mm, or greater than or equal to 2 mm. In certain embodiments, the system is less than or equal to 2.5 mm, less than or equal to 2 mm, 1. It may have an average spacing between mooring mechanisms that is less than or equal to 8 mm, less than or equal to 1.6 mm, less than or equal to 1.4 mm, less than or equal to 1.2 mm, less than or equal to 1 mm, less than or equal to 0.9 mm, less than or equal to 0.8 mm, less than or equal to 0.7 mm, less than or equal to 0.6 mm, less than or equal to 0.5 mm, less than or equal to 0.4 mm, less than or equal to 0.3 mm, or less than or equal to 0.2 mm. Combinations of the ranges mentioned above are also possible (e.g., greater than or equal to 0.1 mm and less than or equal to 2.5 mm, greater than or equal to 1 mm and less than or equal to 1.5 mm). Other ranges are possible.

[0106] The tethering mechanism can have any suitable dimensions and / or shape. For example, in some embodiments, the maximum dimension (e.g., length) of the tissue connection component comprising the tethering mechanism is less than or equal to 1 cm, less than or equal to 0.8 cm, less than or equal to 0.6 cm, less than or equal to 0.5 cm, less than or equal to 0.4 cm, less than or equal to 0.3 cm, less than or equal to 0.25 cm, less than or equal to 0.23 cm, or less than or equal to 0.2 cm. In certain embodiments, the maximum dimension (e.g., length) of the tissue connection component comprising the tethering mechanism is greater than or equal to 0.15 cm, greater than or equal to 0.2 cm, greater than or equal to 0.23 cm, greater than or equal to 0.25 cm, greater than or equal to 0.3 cm, greater than or equal to 0.4 cm, greater than or equal to 0.5 cm, greater than or equal to 0.6 cm, or greater than or equal to 0.8 cm. Combinations of the ranges mentioned above are also possible (e.g., greater than or equal to 0.2 cm and less than or equal to 1 cm, greater than or equal to 0.15 cm and less than or equal to 1 cm). Other ranges are possible.

[0107] In some embodiments, the mooring mechanism has a specific anchor length. By way of example, for a mooring mechanism comprising a hook, the anchor length corresponds to the maximum cross-sectional diameter of the bent length of the hook (e.g., the diameter of the hook excluding any unbent portions). In certain embodiments, the anchor length is greater than or equal to 10 micrometers, greater than or equal to 20 micrometers, greater than or equal to 23 micrometers, greater than or equal to 25 micrometers, greater than or equal to 30 micrometers, greater than or equal to 34 micrometers, greater than or equal to 35 micrometers, greater than or equal to 40 micrometers, greater than or equal to 50 micrometers, greater than or equal to 60 micrometers, greater than or equal to 70 micrometers, greater than or equal to 80 micrometers, greater than or equal to 90 micrometers, greater than or equal to 100 micrometers, greater than or equal to 120 micrometers, greater than or equal to 140 micrometers, greater than or equal to 160 micrometers, greater than or equal to 180 micrometers, greater than or equal to 200 micrometers, or greater than or equal to 225 micrometers. In certain embodiments, the anchor length is less than or equal to 250 micrometers, less than or equal to 225 micrometers, less than or equal to 200 micrometers, less than or equal to 180 micrometers, less than or equal to 160 micrometers, less than or equal to 140 micrometers, less than or equal to is equal to, less than 120 micrometers or equal thereto, less than 100 micrometers or equal thereto, less than 90 micrometers or equal thereto, less than 80 micrometers or equal thereto, less than 70 micrometers or equal thereto, less than 60 micrometers or equal thereto, less than 50 micrometers or equal thereto, less than 40 micrometers or equal thereto, less than 30 micrometers or equal thereto, or less than 20 micrometers or equal thereto. Combinations of the ranges mentioned above are also possible (e.g., greater than or equal to 10 micrometers and less than or equal to 250 micrometers). Other ranges are possible.

[0108] In some cases, the anchoring mechanism may be configured to have an optimal penetration depth (e.g., the depth at which the anchoring mechanism is disposed just below the surface of the tissue located within the subject's body). In some embodiments, the anchoring mechanism has a penetration depth that is greater than or equal to 0.5 mm, greater than or equal to 0.6 mm, greater than or equal to 0.7 mm, greater than or equal to 0.8 mm, greater than or equal to 0.9 mm, greater than or equal to 1 mm, greater than or equal to 1.2 mm, greater than or equal to 1.4 mm, greater than or equal to 1.5 mm, greater than or equal to 1.7 mm, greater than or equal to 1.9 mm, greater than or equal to 2 mm, greater than or equal to 2.2 mm, greater than or equal to 2.4 mm, greater than or equal to 2.5 mm, greater than or equal to 3 mm, greater than or equal to 3.5 mm, greater than or equal to 4 mm, greater than or equal to 4.5 mm, or greater than or equal to 5 mm. In certain embodiments, the anchoring mechanism has a penetration depth that is less than or equal to 6 mm, less than or equal to 5 mm, less than or equal to 4.5 mm, less than or equal to 4 mm, less than or equal to 3.5 mm, less than or equal to 3 mm, less than or equal to 2.5 mm, less than or equal to 2.4 mm, less than or equal to 2.2 mm, less than or equal to 2 mm, less than or equal to 1.9 mm, less than or equal to 1.7 mm, less than or equal to 1.5 mm, less than or equal to 1.4 mm, less than or equal to 1.2 mm, less than or equal to 1 mm, less than or equal to 0.9 mm, less than or equal to 0.8 mm, less than or equal to 0.7 mm, or less than or equal to 0.6 mm.Combinations of the ranges mentioned above are also possible (e.g., greater than or equal to 0.5 mm and less than or equal to 6 mm, greater than or equal to 0.9 mm and less than or equal to 2.5 mm). Other ranges are possible. Without wishing to be bound by theory, tissue displacement may be greater than or equal to the penetration depth of the anchoring mechanism. As a mere example and in certain sets of embodiments, the anchoring mechanism can displace tissue up to 14 mm to achieve a penetration depth of, for example, 4 mm or less.

[0109] Advantageously, a system comprising the anchoring mechanism described herein may remain in place for a relatively long period of time under physiological conditions and fluid flow (e.g., when exposed to a fluid flowing at approximately 0.1 m / s). For example, in some embodiments, a system comprising the anchoring mechanism may be located on the surface of tissue within a subject for a period of time greater than or equal to 1 hour, greater than or equal to 2 hours, greater than or equal to 4 hours, greater than or equal to 8 hours, greater than or equal to 12 hours, greater than or equal to 24 hours, greater than or equal to 2 days, greater than or equal to 3 days, greater than or equal to 5 days, greater than or equal to 7 days remain for a period equal to or longer than 10 days. In certain embodiments, the system remains for a period less than or equal to 14 days, less than or equal to 10 days, less than or equal to 7 days, less than or equal to 5 days, less than or equal to 3 days, less than or equal to 2 days, less than or equal to 24 hours, less than or equal to 12 hours, less than or equal to 8 hours, less than or equal to 4 hours, or less than or equal to 2 hours. Combinations of the ranges mentioned above are also possible (e.g., longer than or equal to 1 hour and less than or equal to 14 days). Other ranges are possible. In some cases, the tethering mechanism may be configured to remain for a relatively very long period under physiological conditions and fluid flow. For example, in certain embodiments, the tethering mechanism remains at a tissue surface location within the subject's body for a period longer than or equal to 1 month, longer than or equal to 2 months, longer than or equal to 3 months, longer than or equal to 6 months, or longer than or equal to 1 year. In some embodiments, the tethering mechanism remains at a tissue surface location within the subject's body for a period less than or equal to 2 years, less than or equal to 1 year, less than or equal to 6 months, less than or equal to 3 months, or less than or equal to 2 months. Combinations of the ranges mentioned above are also possible (e.g., longer than or equal to 1 hour and less than or equal to 2 years, longer than or equal to 1 month and less than or equal to 2 years). Other ranges are possible.

[0110] The tethering mechanism described herein can include any suitable material. In some embodiments, the tethering mechanism material is relatively non-degradable. In certain embodiments, the tethering mechanism may be configured to degrade within a particular period of time. In some embodiments, the tethering mechanism is configured to degrade within one or more of the ranges of time described above in a situation where it is staying. For example, in some embodiments, the tethering mechanism is configured to degrade in a period that is longer than or equal to 1 hour, longer than or equal to 2 hours, longer than or equal to 4 hours, longer than or equal to 8 hours, longer than or equal to 12 hours, longer than or equal to 24 hours, longer than or equal to 2 days, longer than or equal to 3 days, longer than or equal to 5 days, longer than or equal to 7 days, or longer than or equal to 10 days (e.g., thus, the system no longer stays at the position in the body of the subject). In certain embodiments, the tethering mechanism is configured to degrade in a period that is less than or equal to 14 days, less than or equal to 10 days, less than or equal to 7 days, less than or equal to 5 days, less than or equal to 3 days, less than or equal to 2 days, less than or equal to 24 hours, less than or equal to 12 hours, less than or equal to 8 hours, less than or equal to 4 hours, or less than or equal to 2 hours. Combinations of the ranges mentioned above are also possible (e.g., longer than or equal to 1 hour and less than or equal to 14 days). Other ranges are possible. In some cases, the tethering mechanism may be configured to degrade in a period that is longer than or equal to 1 month, longer than or equal to 2 months, longer than or equal to 3 months, longer than or equal to 6 months, or longer than or equal to 1 year (e.g., thus, the system no longer stays at the position in the body of the subject).In some embodiments, the mooring mechanism can disassemble in a period of less than 2 years or equal thereto, less than 1 year or equal thereto, less than 6 months or equal thereto, less than 3 months or equal thereto, or less than 2 months or equal thereto. Combinations of the ranges mentioned above are also possible (e.g., longer than or equal to 1 hour and less than or equal to 2 years, longer than or equal to 1 month and less than or equal to 2 years). Other ranges are possible.

[0111] In some cases, the mooring mechanism may include a conductive material, as described below. Electrical stimulation

[0112] In some embodiments, the systems, articles, and methods described herein may be useful for delivering electrical stimulation to a location within a subject's body. Advantageously, the systems described herein can be administered orally (e.g., in a capsule) as compared to conventional methods such as endoscopic placement and / or attachment of an electrical device for delivering transient electrical stimulation to the gastrointestinal tract. In some embodiments, the system comprises one or more mooring mechanisms, wherein at least one mooring mechanism comprises 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., introduction of an API into tissue within the subject's body during application of a local current). In certain embodiments where the systems described herein are configured for iontophoresis, the system may comprise a first tissue connection component (e.g., contained within a first self-healing article) having a conductive tip; and a second tissue connection component (e.g., a blunt-ended cylinder) configured to contact but not penetrate the tissue (e.g., contained within a second self-healing article). In some embodiments, one or more electrodes may be in electrical communication with the first and / or second tissue connection components.

[0113] In some embodiments, a system (e.g., a self-healing system) comprises two or more tissue connection components. In certain embodiments, each of the tissue connection components comprises a tissue contact portion configured to contact a tissue. In some cases, the tissue contact portion may be conductive. In certain embodiments, the tissue contact portion may be electrically insulating.

[0114] In some embodiments, the tissue contact portion comprises a first conductive portion and a second insulating portion. In some such embodiments, the conductive portion may be configured to be in electrical communication with the tissue, and the insulating portion may be configured not to be in electrical communication with the tissue.

[0115] 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 the tissue (e.g., the length for gastric muscle stimulation may correspond to the outer muscle layer (e.g., 2 - 4 mm), and the length for SI mucosa may be, for example, 0.1 - 1 mm). In some cases, the insulating portion may be configured to prevent the tissue's digestive fluid and / or mucus coating from contacting the conductive portion (e.g., without wishing to be bound by theory, the digestive fluid and mucus coating are generally conductive, and thus, in some cases, may prevent electrical stimulation from reaching the underlying tissue).

[0116] The tissue contact portion can have any suitable ratio of the conductive portion to the insulating portion. For example, in some embodiments, the conductive portion is present in the tissue contact portion in an amount greater than or equal to 0.1%, greater than or equal to 0.5%, greater than or equal to 1%, greater than or equal to 2%, greater than or equal to 5%, greater than or equal to 10%, greater than or equal to 20%, greater than or equal to 30%, greater than or equal to 40%, greater than or equal to 50%, greater than or equal to 60%, greater than or equal to 70%, greater than or equal to 80%, or greater than or equal to 90% of the total surface area of the tissue contact portion of the tissue connection component. In certain embodiments, the conductive portion is present in the tissue contact portion in an amount less than 100%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, less than 2%, less than 1%, or less than 0.5% of the total surface area of the tissue contact portion of the tissue connection component. Combinations of the ranges mentioned above are also possible (e.g., greater than or equal to 0.1% and less than or equal to 100%, greater than or equal to 10% and less than or equal to 100%, greater than or equal to 30% and less than or equal to 90%). Other ranges are possible. In some embodiments, the tip of the tissue contact portion is conductive and the remainder of the tissue contact portion is insulating. or equal to, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, less than 2%, less than 1%, or less than 0.5% of the total surface area of the tissue contact portion of the tissue connection component. Combinations of the ranges mentioned above are also possible (e.g., greater than or equal to 0.1% and less than or equal to 100%, greater than or equal to 10% and less than or equal to 100%, greater than or equal to 30% and less than or equal to 90%). Other ranges are possible. In some embodiments, the tip of the tissue contact portion is conductive and the remainder of the tissue contact portion is insulating.

[0117] In certain embodiments, the insulating portion is present in the tissue contacting portion in an amount greater than or equal to 10%, greater than or equal to 20%, greater than or equal to 30%, greater than or equal to 40%, greater than or equal to 50%, greater than or equal to 60%, greater than or equal to 70%, greater than or equal to 80%, or greater than or equal to 90% of the total surface area of the tissue contacting portion of the tissue connection component. In certain embodiments, the insulating portion is present in the tissue contacting portion in an amount less than or equal to 100%, less than or equal to 90%, less than or equal to 80%, less than or equal to 70%, less than or equal to 60%, less than or equal to 50%, less than or equal to 40%, less than or equal to 30%, or less than or equal to 20% of the total surface area of the tissue contacting portion of the tissue connection component. Combinations of the ranges mentioned above are also possible (e.g., greater than or equal to 10% and less than or equal to 100%, greater than or equal to 30% and less than or equal to 90%). Other ranges are possible.

[0118] In some embodiments, the system comprises a self-healing article as described herein and at least one tissue connection component, each tissue connection component comprising a tissue contact portion configured to contact a tissue associated with each tissue connection component. In certain embodiments, the system comprises two or more self-healing articles as described herein, each self-healing article comprising at least one tissue connection component, each tissue connection component comprising a tissue contact portion configured to contact a tissue. For example, in an exemplary set of embodiments, a single self-healing article comprising two or more tissue connection components can be administered, and a power source electrically communicating with the two or more tissue connection components can be disposed in the self-healing article, such that a current can be applied to a tissue in direct contact with the tissue contact portion of the tissue connection component. In another exemplary set of embodiments, two (or more) self-healing articles each comprising at least one tissue connection component can be administered, and a power source electrically communicating with the self-healing article can be disposed in the self-healing article, such that such means of conservation will be applied to a tissue in direct contact with the tissue contact portion of each tissue connection component from each self-healing article. Other combinations are possible. Those skilled in the art will appreciate how to combine self-healing articles, tissue connection components, and tissue contact portions based on the teachings herein.

[0119] As described herein, in some embodiments, a system comprising a self-healing article and / or a self-acting article can be administered, the system comprising at least one tissue connection component disposed within the article (e.g., a self-describing article and / or a self-acting article). The system can be administered, resulting in at least one alignment struct The components are released from the article and / or inserted into the tissue at a location within the body of the subject. In certain embodiments, an electric current can be applied (e.g., causing an informed communication with the tissue connection components by a power source) such that the electric current flows between two or more tissue connection components. In some such embodiments, the tissue connection components are not in electrical communication with the tissue.

[0120] The conductive portion can include any suitable conductive material. Non-limiting examples of suitable conductive materials include conductive polymers, silver, copper, gold, stainless steel, platinum, zinc, and steel. Other conductive materials are possible.

[0121] The insulating portion can include any suitable electrically insulating material. Non-limiting examples of suitable insulating materials include polymers such as parylene, polycaprolactone, and polyethylene. Other insulating materials are possible.

[0122] In some cases, the conductive material and / or the insulating material can be provided as a coating on the tissue connection components. In certain embodiments, the tissue contact portion can include a bulk material that includes the conductive and / or insulating material.

[0123] In some embodiments, the current applied (e.g., applied between tissue contact portions to electrically stimulate tissue) may be greater than or equal to 0.001 milliamperes, greater than or equal to 0.01 milliamperes, greater than or equal to 0.1 milliamperes, greater than or equal to 0.5 milliamperes, greater than or equal to 1 milliamperes, greater than or equal to 5 milliamperes, greater than or equal to 10 milliamperes, greater than or equal to 50 milliamperes, greater than or equal to 100 milliamperes, or greater than or equal to 250 milliamperes. In certain embodiments, the applied current may be less than or equal to 500 milliamperes, less than or equal to 250 milliamperes, less than or equal to 100 milliamperes, less than or equal to 50 milliamperes, less than or equal to 10 milliamperes, less than or equal to 5 milliamperes, less than or equal to 1 milliamperes, less than or equal to 0.5 milliamperes, less than or equal to 0.1 milliamperes, or less than or equal to 0.01 milliamperes. Combinations of the ranges mentioned above are also possible (e.g., greater than or equal to 0.001 milliamperes and less than or equal to 500 milliamperes, greater than or equal to 0.1 milliamperes and less than or equal to 10 milliamperes). Other ranges are possible. The current can be applied using any suitable means, including, for example, an external power source (e.g., a battery).

[0124] In certain embodiments, the system is configured to remain in position within the body of the subject under a force greater than or equal to 0.1 N (e.g., greater than or equal to 0.6 N) and / or an orientation change greater than or equal to 30 degrees, as described above. Self-actuating

[0125] For example, self-actuating articles are generally provided that include self-actuating tissue connection components, such as self-actuating needles, self-actuating tethering mechanisms, and / or self-actuating biopsy punches. Advantageously, in some embodiments, the self-actuating articles described herein can be useful as a general platform for the delivery of a wide variety of pharmaceuticals that are typically delivered by direct injection into tissue for degradation within the GI tract. Using the self-actuating articles described herein, the sensors, electrical stimulations, and anchor systems described herein can also be delivered to tissue and / or a biopsy sample can be taken without the need for endoscopic observation. In some embodiments, the article comprises a spring (e.g., a coil spring, a wave spring, a Belleville washer, a beam, a membrane, a material having specific mechanical recovery properties). The term spring is not intended to be limited to coil springs, and it will be understood by those skilled in the art that it generally encompasses any reversibly compressible material and / or component such that when the compressive force applied to the material / component is released, the material / component returns substantially (e.g., within 40%, 50%, 60%, 70%, 80%, 90%, 95% of the length of the material / component before compression, or any percentage therebetween) to the uncompressed length of the material / component under ambient conditions. In certain embodiments, the term spring of the self-actuating article may be provided as an expansion component or may further comprise an expansion component. It will be understood by those skilled in the art that the term expansion component includes reversibly and irreversibly compressible materials and is a component that, when stimulated with respect to the expansion component and / or when restraint is released, the expansion component expands in at least one direction (e.g., along its length). In some embodiments, the expansion component includes a gas composition (e.g., a mixture of baking soda and vinegar) that expands a gas volume expansion component.

[0126] In certain embodiments, the term spring of the self-actuating article may be provided as an expansion component or may further comprise an expansion component. It will be understood by those skilled in the art that the term expansion component includes reversibly and irreversibly compressible materials and is a component that, when stimulated with respect to the expansion component and / or when restraint is released, the expansion component expands in at least one direction (e.g., along its length). In some embodiments, the expansion component includes a gas composition (e.g., a mixture of baking soda and vinegar) that expands a gas volume expansion component.

[0127] In some embodiments, the spring and / or expansion component can be extended in at least one direction by thermal expansion, swelling (e.g., due to fluid absorption), gas-driven processes, pneumatic processes, hydraulic processes, electric motors, magnetic mechanisms, torsion spring mechanisms, chemical gas generators, and / or autocatalytic reactions. In an exemplary set of embodiments, the spring and / or expansion component can be extended in at least one direction when the spring and / or expansion component is exposed to a fluid (e.g., gastrointestinal fluid).

[0128] In some cases, the spring and / or expansion component can be actuated by any suitable actuation mechanism (e.g., can be extended in at least one direction and then return to its uncompressed length of the component). Non-limiting examples of suitable actuation mechanisms include release of a pressure differential, electric timers, optical sensors, color sensors, enzymatic sensors, capacitance, magnetism, actuation by applied stress (e.g., shape memory materials), external actuation (e.g., reaction with a gastrointestinal fluid such as gastric acid), and combinations thereof. In an exemplary set of embodiments, the spring and / or expansion component is actuated by interaction (e.g., reaction) with a gastrointestinal fluid.

[0129] In some cases, the actuation mechanism displaces the tissue connection component by a specific distance (e.g., a distance less than or equal to 10 mm, less than or equal to 8 mm, less than or equal to 6 mm, less than or equal to 4 mm, less than or equal to 2 mm) and / or a specific force (e.g., a force greater than or equal to 0.1 N, greater than or equal to 0.3 N, greater than or equal to 0.5 N, greater than or equal to 1 N, greater than or equal to 1.5 N).

[0130] As illustrated in FIG. 21, in some embodiments, the article 100 comprises a spring 110 and a support member 120 associated with (e.g., operably coupled to) the spring 110. The support member 120 maintains the spring under compressive strain under a first set of conditions (e.g., ambient conditions (e.g., room temperature, atmospheric pressure, and relative humidity)) in certain embodiments. In some embodiments, the support member releases the spring from compressive strain at least partially (e.g., at least a portion of the support member disassembles) under a second set of conditions different from the first set of conditions. For example, in some embodiments, the second set of conditions includes physiological conditions (e.g., at about 37° C. or at about 37° C. in a physiological fluid such as gastric fluid).

[0131] In some cases, the spring 110 can be the adjacent (e.g., directly adjacent) support member 120. As used herein, when a component is said to be "adjacent" to another component, it may be directly adjacent to (e.g., in contact with) that component, or there may be one or more intervening components. A component that is "directly adjacent" to another component means that there are no intervening components. In some cases, the spring may be at least partially embedded in the support member. In certain embodiments, the spring is coated with the support member.

[0132] In certain embodiments, referring again to FIG. 21, article 100 comprises an outer shell 170 (e.g., such that spring 110 is at least partially enclosed within outer 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 greater than or equal to 3 mm, greater than or equal to 4 mm, or greater than or equal to 5 mm. In certain embodiments, the thickness of the coating can be less than or equal to 6 mm, less than or equal to 5 mm, or less than or equal to 4 mm. Combinations of the ranges mentioned above are also possible (e.g., greater than or equal to 3 mm and less than or equal to 6 mm). 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, polyvinyl pyrrolidone, polyvinyl alcohol).

[0133] The support material can have any suitable cross-sectional dimension. In some embodiments, the average cross-sectional dimension of the support material may be greater than or equal to 0.1 mm, greater than or equal to 0.5 mm, greater than or equal to 1 mm, greater than or equal to 2 mm, greater than or equal to 3 mm, greater than or equal to 4 mm, or greater than or equal to 5 mm. In certain embodiments, the average cross-sectional dimension of the support material may be less than or equal to 10 mm, less than or equal to 6 mm, less than or equal to 5 mm, less than or equal to 4 mm, less than or equal to 3 mm, less than or equal to 2 mm, less than or equal to 1 mm, or less than or equal to 0.5 mm. Combinations of the ranges mentioned above are also possible (e.g., greater than or equal to 0.1 mm and less than or equal to 10 mm). Other ranges are possible.

[0134] In some embodiments, the support material, spring, and / or expansion component are configured to dissolve (e.g., in an acidic environment, in a pH-neutral environment, in water, in a basic environment), melt at physiological temperature (e.g., 37 °C), change rigidity (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 degassing, by leakage), and include one or more materials.

[0135] Advantageously, the configuration and / or material used for the support material can make it possible to adjust the dissolution of the support material. In some cases, the dissolution of the support material can be adjusted so that the tissue connection component is released from the article at a desired location and / or at a desired time point.

[0136] The support material can include any suitable material. Non-limiting examples of suitable materials include sugars and their 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, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene oxide, diethyl pyrocarbonate, hydrogel). Other materials are also possible. Without wishing to be bound by theory, the support material can be selected to be relatively brittle (e.g., such that the spring is released when the support material dissolves).

[0137] In certain embodiments, the support material may be configured to have a particular structure that provides a desired dissolution profile. For example, in some embodiments, the support material may be configured to have a defect control mode (e.g., degradation into small pieces at relatively predictable locations) and / or to provide structural integrity of the support material so as to improve the dissolution profile.

[0138] In some embodiments, the support member has desirable mechanical properties (e.g., the spring has desirable mechanical properties for relatively quickly restoring at least a portion of its uncompressed length). For example, in certain embodiments, the support member may have a limiting stress greater than or equal to 0.01 N, greater than or equal to 0.1 N, greater than or equal to 0.5 N, greater than or equal to 1 N, greater than or equal to 2 N, greater than or equal to 3 N, greater than or equal to 5 N, greater than or equal to 7 N, greater than or equal to 10 N, greater than or equal to 15 N, greater than or equal to 20 N, greater than or equal to 25 N, greater than or equal to 30 N, greater than or equal to 35 N, greater than or equal to 40 N, greater than or equal to 45 N, greater than or equal to 50 N, or greater than or equal to 60 N (including any limiting stress value therebetween). In certain embodiments, the support member may have a limiting stress less than or equal to 70 N, less than or equal to 60 N, less than or equal to 50 N, less than or equal to 45 N, less than or equal to 40 N, less than or equal to 35 N, less than or equal to 30 N, less than or equal to 25 N, less than or equal to 20 N, less than or equal to 15 N, less than or equal to 10 N, less than or equal to 7 N, less than or equal to 5 N, less than or equal to 3 N, less than or equal to 2 N, less than or equal to 1 N, less than or equal to 0.5 N, or less than or equal to 0.1 N (including any limiting stress value therebetween). Combinations of the ranges mentioned above are also possible (e.g., greater than or equal to 10 N and less than or equal to 70 N, greater than or equal to 30 N and less than or equal to 45 N). Other ranges are possible.The critical stress is generally the maximum force that a support member can hold before cracking (e.g., as applied by an adjacent spring), critical stress:.

Number

[0139] In some embodiments, the support member maintains at least a portion of the spring under a first set of conditions at 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%. In certain embodiments, the support member maintains at least a portion of the spring under a first set of conditions at a compressive strain less than or equal to 90%, less than or equal to 80%, less than or equal to 70%, less than or equal to 60%, less than or equal to 50%, less than or equal to 40%, less than or equal to 30%, less than or equal to 25%, less than or equal to 20%, less than or equal to 15%, or less than or equal to 10%.

[0140] In certain embodiments, the spring returns to a length that is greater than or equal to 10%, greater than or equal to 20%, greater than or equal to 30%, greater than or equal to 40%, greater than or equal to 50%, greater than or equal to 60%, greater than or equal to 70%, greater than or equal to 80%, greater than or equal to 85%, greater than or equal to 90%, greater than or equal to 95%, greater than or equal to 98%, or greater than or equal to 99% of the length of the spring before and / or in the absence of the application of compressive strain (e.g., by a support member), including any percentage between 10% and 99% thereof, within a time of 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 second, or less than 0.01 second. In some embodiments, the spring returns to a length that is less than or equal to 100%, less than or equal to 99%, less than or equal to 98%, less than or equal to 95%, less than or equal to 90%, less than or equal to 85%, less than or equal to 80%, less than or equal to 75%, less than or equal to 70%, less than or equal to 60%, less than or equal to 50%, less than or equal to 40%, less than or equal to 30%, or less than or equal to 20% of the length of the spring before and / or in the absence of the application of compressive strain, including any percentage between 20% and 100% thereof. Advantageously, the use of the springs and support members described herein can enable the release of tissue connection components (e.g., needles) associated with (e.g., operably coupled to) the springs, such that the tissue connection components contact and / or penetrate the tissue proximate the article. By way of illustrative example, in some embodiments, a needle associated with a spring is administered to a subject, such that when the support member degrades, the spring returns and the needle is pushed into the tissue proximate the article such that the needle penetrates the tissue (e.g., the GI mucosal layer).In some such embodiments, the pharmaceutical active ingredient can be delivered to the tissue by the tissue connection component. For example, in some embodiments, the article contains the pharmaceutical active ingredient, and thus when the spring is released at a location within the subject's body, the pharmaceutical active ingredient is released (e.g., into the tissue proximate to the location within the subject's body). In other embodiments, the spring is opened by the support material. Once released, a biopsy can be performed (e.g., by a tissue connection component such as a biopsy device). Referring again to FIG. 21, in some embodiments, the article 100 comprises a tissue connection component 115 associated with the spring 110. The tissue connection component (e.g., a needle, a hook, a component with a high API load) will be described in more detail herein.

[0141] In certain embodiments, the tissue connection component includes a needle, a patch or array of needles (e.g., microneedles), a biopsy component, a hook, a mucoadhesive patch, or a combination thereof.

[0142] In some embodiments, the spring includes an elastic material. In certain embodiments, the spring includes a material selected from the group consisting of nitinol, metal, polymer, and combinations thereof.

[0143] In certain embodiments, the spring may have a specific spring constant. For example, in some embodiments, the spring constant of the spring is greater than or equal to 100 N / m, greater than or equal to 150 N / m, greater than or equal to 200 N / m, greater than or equal to 250 N / m, greater than or equal to 300 N / m, greater than or equal to 350 N / m, greater than or equal to 400 N / m, greater than or equal to 450 N / m, greater than or equal to 500 N / m, greater than or equal to 600 N / m, greater than or equal to 700 N / m, greater than or equal to 800 N / m, greater than or equal to 900 N / m, greater than or equal to 1000 N / m, greater than or equal to 1100 N / m, greater than or equal to 1200 N / m, greater than or equal to 1300 N / m, or greater than or equal to 1400 N / m, less than or equal to 1500 N / m, less than or equal to 1800 N / m, or greater than or equal to 2000 N / m, and may include any spring constant between these values.In certain embodiments, the spring constant of the spring may be less than or equal to 2200 N / m, less than or equal to 2000 N / m, less than or equal to 1800 N / m, less than or equal to 1500 N / m, less than or equal to 1400 N / m, less than or equal to 1300 N / m, less than or equal to 1200 N / m, less than or equal to 1100 N / m, less than or equal to 1000 N / m, less than or equal to 900 N / m, less than or equal to 800 N / m, less than or equal to 700 N / m, less than or equal to 600 N / m, less than or equal to 500 N / m, less than or equal to 450 N / m, less than or equal to 400 N / m, less than or equal to 350 N / m, less than or equal to 300 N / m, less than or equal to 250 N / m, less than or equal to 200 N / m, or less than or equal to 150 N / m, including any spring constant between these values. Combinations of the ranges mentioned above are also possible (e.g., greater than or equal to 100 N / m and less than or equal to 500 N / m, greater than or equal to 100 N / m and less than or equal to 1500 N / m). Other ranges are possible.

[0144] In some embodiments, the spring may be 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 along the longitudinal axis of the spring as compared to the uncompressed length of the spring. or equal thereto, or a length longer than or equal to 15 mm, and is compressed (e.g., by a support member). In certain embodiments, the spring is compressed to a length less than or equal to 20 mm, less than or equal to 15 mm, less than or equal to 12 mm, less than or equal to 10 mm, less than or equal to 9 mm, less than or equal to 8 mm, less than or equal to 7 mm, less than or equal to 6 mm, less than or equal to 5 mm, less than or equal to 4 mm, less than or equal to 3 mm, or less than or equal to 2 mm along the longitudinal axis of the spring as compared to the uncompressed length of the spring. Combinations of the ranges mentioned above are also possible (e.g., longer than or equal to 1 mm and less than or equal to 5 mm, longer than or equal to 5 mm and less than or equal to 10 mm). Other ranges are possible.

[0145] In certain embodiments, the spring is configured to release a desired amount of the spring's stored compressive energy (e.g., when the support member is exposed to a fluid such as gastrointestinal fluid). For example, the spring and / or the support member can be exposed to a fluid, and when the support member at least partially dissolves, the spring at least partially releases the stored compressive energy to displace, for example, a tissue connection component operably coupled to the spring (e.g., to release it into tissue located within the body of the subject). 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% (including any percentage between these values) of the spring's stored compressive energy. In certain embodiments, the spring is configured to release at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or at least 99% (including any percentage between these values) of the spring's stored compressive energy (e.g., when the support member is exposed to a fluid such as gastrointestinal fluid). In certain embodiments, the spring is configured to release less than 100% or equal to, less than 99%, less than 98%, less than 96%, less than 94%, less than 92%, or less than 91% of the spring's stored compressive energy.In some embodiments, the spring is configured to release a percentage that is less than or equal to 90%, less than or equal to 80%, less than or equal to 70%, less than or equal to 60%, less than or equal to 50%, less than or equal to 40%, less than or equal to 30%, or less than or equal to 20% of the spring's stored compressive energy (including any percentage between these values) (e.g., when the support is exposed to a fluid such as gastrointestinal fluid). Combinations of the ranges mentioned above are also possible (e.g., at least 92% and less than 98% of the spring's stored compressive energy, at least 94% and less than 96% of the spring's stored compressive energy, at least 10% and less than or equal to 99%). Other ranges are possible.

[0146] In some embodiments, the spring is configured to release the spring's stored compressive energy within any suitable time of exposure of the support to a fluid and / or mechanical failure of the support (e.g., cracking, breaking). For example, in some embodiments, the spring is configured to release at least 10% of the spring's stored compressive energy within less than 5 ms, less than 4 ms, less than 3 ms, less than 2 ms, less than 1 ms, less than 0.5 ms, or less than 0.2 ms of a mechanical failure of the support. In certain embodiments, the spring is configured to release the spring's stored compressive energy within a time exceeding 0.1 ms of a mechanical failure of the support, exceeding 0.2 ms, exceeding 0.5 ms, exceeding 1 ms, exceeding 2 ms, exceeding 3 ms, or exceeding 4 ms. Combinations of the ranges mentioned above are also possible (e.g., within a time less than 5 ms and exceeding 1 ms, within a time less than 2 ms and exceeding 0.1 ms). Other ranges are possible.

[0147] In certain embodiments, the spring is configured to release at least 10% (e.g., at least 90%) of the spring's stored compressive energy within a time 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, from the exposure of the support to the fluid. In some embodiments, the spring is configured to release the spring's stored compressive energy within a time greater than 30 seconds, greater than 1 minute, greater than 3 minutes, greater than 5 minutes, greater than 7 minutes, or greater than 9 minutes, including any time between these values. Combinations of the ranges mentioned above (e.g., within a time less than 10 minutes and greater than 30 seconds, within a time less than 7 minutes and greater than 5 minutes). Other ranges are possible.

[0148] Any combination of the ranges mentioned above is also possible. For example, in certain embodiments, the spring is configured to release at least 10% (e.g., at least 90%) of the spring's stored compressive energy within 10 minutes from the exposure of the support to the fluid. In certain embodiments, the spring is configured to release at least 10% (e.g., at least 90%) of the spring's stored compressive energy within 30 seconds from the exposure of the support to the fluid. In some embodiments, the spring is configured to release less than 100% or an equal percentage of the spring's stored compressive energy within 10 minutes from the exposure of the support to the fluid. In certain embodiments, the spring is configured to release less than 100% or an equal percentage of the spring's stored compressive energy within 30 seconds of the exposure of the support to the fluid.

[0149] In certain embodiments, the spring is configured to release at least 10% (e.g., at least 90%) of the spring's stored compressive energy within 5 ms from a mechanical failure of the support member. In certain embodiments, the spring is configured to release at least 10% (e.g., at least 90%) of the spring's stored compressive energy within 0.1 ms from a mechanical failure of the support member. In some embodiments, the spring is configured to release less than 100% or an equal percentage of the spring's stored compressive energy within 5 ms from a mechanical failure of the support member. In certain embodiments, the spring is configured to release less than 100% or an equal percentage of the spring's stored compressive energy within 0.1 ms from a mechanical failure of the support member.

[0150] The spring can have any suitable cross-sectional dimension. In some embodiments, the maximum cross-sectional dimension of the (uncompressed) spring is greater than or equal to 1 mm, greater than or equal to 2 mm, greater than or equal to 3 mm, greater than or equal to 4 mm, or greater than or equal to 5 mm. In certain embodiments, the maximum cross-sectional dimension of the (uncompressed) spring is less than or equal to 10 mm, less than or equal to 6 mm, less than or equal to 5 mm, less than or equal to 4 mm, less than or equal to 3 mm, or less than or equal to 2 mm. Combinations of the ranges mentioned above are also possible (e.g., greater than or equal to 1 mm and less than or equal to 10 mm). Other ranges are possible.

[0151] In some embodiments, the article is administered (e.g., orally) to a subject. In certain embodiments, the article can be administered orally, rectally, vaginally, nasally, or urethrally. In certain embodiments, at least a portion of the support member reaches a location within the subject's body (e.g., the digestive tract). Upon decomposition, as a result, the spring elongates and / or the tissue connection component aligns with the tissue located in the subject's body (e.g., contacts the tissue, penetrates the tissue). 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 within the buccal cavity, within the venous system (e.g., artery), within the respiratory system (e.g., lung), within the renal system, within the urinary system, or within the digestive system. As described above and as described herein, in some embodiments, the pharmaceutical active ingredient is released during and / or after penetration into the tissue located in the subject's body.

[0152] In some embodiments, the tissue connection component comprises a needle and the tissue is penetrated with a force greater than or equal to 1 mN and less than or equal to 100 mN (e.g., greater than or equal to 10 mN and less than or equal to 20 mN). In certain embodiments, the tissue connection component comprises a plurality of microneedles and the tissue is penetrated with a force greater than or equal to 100 mN and less than or equal to 10 N (e.g., greater than or equal to 1 N and less than or equal to 2 N, greater than or equal to 100 mN and less than or equal to 6 N).

[0153] In some cases and as described herein, the article can be oriented such that the longitudinal axis of the tissue connection component is orthogonal to the tissue located adjacent to the article (e.g., within a range of less than or equal to 10% of 90°, less than or equal to 5%, or less than or equal to 1%). In some embodiments, the self-actuating article described herein (e.g., comprising a tissue connection component) may be associated with one or more self-righting articles. Non-limiting examples of suitable self-righting articles are generally described in co-owned U.S. Patent Application No. 62 / 507,647, filed May 17, 2017, entitled "SELF-RIGHTING ARTICLES", which provisional application is hereby incorporated by reference in its entirety.

[0154] In an exemplary embodiment, the article comprises an outer shell; a spring at least partially encapsulated within the outer shell; a support member associated with the spring for maintaining at least a portion of the spring under ambient conditions at a compression strain of at least 5%; and a tissue connection component operably coupled to the spring. In certain embodiments, the article comprises a tissue connection component and a spring associated with the tissue connection component, and the spring is maintained in a partially compressed state under a compression strain of at least 5% by the support member. 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 ms from a mechanical failure of the support member. According to certain embodiments, the article compresses a pharmaceutical agent associated with the tissue connection component. In some embodiments, the article includes a self-healing article associated with the tissue connection component. High API

[0155] In some embodiments, as described above and herein, the system comprises a component (e.g., a tissue connection component) that includes a solid therapeutic agent (e.g., a solid API) and a second material (e.g., a support for the solid API such as a binder and / or polymer) such that the solid therapeutic agent is present in the component in an amount greater than or equal to 10% by weight relative to the total weight of the tissue connection component. Such a tissue connection component can be useful for the delivery of an API dose (e.g., to a subject). Advantageously, in some embodiments, the volume required to deliver the required API dose is reduced compared to liquid formulations, enabling the creation of solid needle delivery systems at various locations / tissues (e.g., tongue, GI mucosal tissue, skin) for a variety of drugs, and / or reducing and / or eliminating the application of an external force to inject a drug solution through a small opening of the needle. In some cases , a physiologically appropriate dose can be present in a single tissue connection component (e.g., a single tissue connection component has a relatively high API loading).

[0156] 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 can be in liquid form. In certain embodiments, the API can be...

[0157] In some embodiments, the tissue connection component includes a needle, a biopsy component, a protrusion, a plurality of microneedles, a hook, a mucoadhesive patch, or a combination thereof. In certain embodiments, as described herein and above, the tissue connection component is configured to penetrate tissue (e.g., skin, tongue, tissue of the GI tract, e.g., GI mucosal tissue). In some embodiments, the tissue is penetrated with a force greater than or equal to 1 mN and less than or equal to 20 N (e.g., greater than or equal to 10 mN and less than or equal to 20 mN, greater than or equal to 1 mN and less than or equal to 100 mN, greater than or equal to 20 mN and less than or equal to 1 N, greater than or equal to 1 N and less than or equal to 20 N, greater than or equal to 10 N and less than or equal to 20 N).

[0158] Advantageously, a tissue connection component comprising a needle and / or a plurality of microneedles with a relatively high (e.g., greater than or equal to 10 wt% relative to the total weight of the component) API loading can reduce the number of needles and / or the overall size of the microneedle array required to deliver a particular API dose significantly compared to conventional microneedles (e.g., generally containing less than 10 wt% loading and / or requiring a plurality of microneedles, on the order of thousands to tens of thousands of microneedles, to deliver a similar dose).

[0159] In some embodiments, the tissue connection component has a specific maximum dimension (e.g., length). In certain embodiments, the maximum dimension of the tissue connection component may be greater than or equal to 1 mm, may be greater than or equal to 2 mm, may be greater than or equal to 3 mm, may be greater than or equal to 5 mm, may be greater than or equal to 7 mm, may be greater than or equal to 10 mm, may be greater than or equal to 12 mm, may be greater than or equal to 15 mm, may be greater than or equal to 20 mm, may be greater than or equal to 25 mm, may be greater than or equal to 30 mm, or may be greater than or equal to 50 mm. In some embodiments, the maximum dimension of the tissue connection component may be less than or equal to 100 mm, may be less than or equal to 50 mm, may be less than or equal to 30 mm, may be less than or equal to 25 mm, may be less than or equal to 20 mm, may be less than or equal to 15 mm, may be less than or equal to 12 mm, may be less than or equal to 10 mm, may be less than or equal to 7 mm, may be less than or equal to 5 mm, may be less than or equal to 3 mm, or may be less than or equal to 2 mm. Combinations of the ranges mentioned above are also possible.

[0160] In certain embodiments, the tissue connection component may be greater than or equal to 0.25 mm, may be greater than or equal to 0.5 mm, may be greater than or equal to 0.6 mm, may be greater than or equal to 0.7 mm, may be greater than or equal to 0.8 mm, may be greater than or equal to 0.9 mm, may be greater than or equal to 1 mm, may be greater than or equal to 1.1 mm, may be greater than or equal to 1.2 mm, may be greater than or equal to 1.3 mm, and so on. i. having an average cross-sectional dimension (e.g., diameter) that is greater than or equal to 1.4 mm, greater than or equal to 1.5 mm, greater than or equal to 1.7 mm, greater than or equal to 1.9 mm, greater than or equal to 2.5 mm, greater than or equal to 3.0 mm, greater than or equal to 4.0 mm, or greater than or equal to 5.0 mm. In some embodiments, the tissue connection component has an average cross-sectional dimension that is less than or equal to 6.0 mm, less than or equal to 5.0 mm, less than or equal to 4.0 mm, less than or equal to 3.0 mm, less than or equal to 2.5 mm, less than or equal to 1.9 mm, less than or equal to 1.7 mm, less than or equal to 1.5 mm, less than or equal to 1.4 mm, less than or equal to 1.3 mm, less than or equal to 1.2 mm, less than or equal to 1.1 mm, less than or equal to 1 mm, less than or equal to 0.9 mm, less than or equal to 0.8 mm, less than or equal to 0.7 mm, or less than or equal to 0.6 mm, or less than or equal to 0.5 mm. Combinations of the ranges mentioned above are also possible (e.g., greater than or equal to 0.5 mm and less than or equal to 2.0 mm). Other ranges are possible.

[0161] In some embodiments, the tissue connection component can comprise a plurality of microneedles. In some such embodiments, the plurality of microneedles can have a specific base maximum cross-sectional dimension (e.g., the diameter of the base), a specific height, and / or a specific spacing.

[0162] In some embodiments, the average diameter of the bases of the plurality of microneedles may be greater than or equal to 100 micrometers, greater than or equal to 150 micrometers, greater than or equal to 200 micrometers, greater than or equal to 250 micrometers, greater than or equal to 300 micrometers, greater than or equal to 350 micrometers, greater than or equal to 400 micrometers, or greater than or equal to 450 micrometers. In certain embodiments, the average diameter of the bases of the plurality of microneedles may be less than or equal to 500 micrometers, less than or equal to 450 micrometers, less than or equal to 400 micrometers, less than or equal to 350 micrometers, less than or equal to 300 micrometers, less than or equal to 250 micrometers, less than or equal to 200 micrometers, or less than or equal to 150 micrometers. Combinations of the ranges mentioned above are also possible (e.g., greater than or equal to 100 micrometers and less than or equal to 500 micrometers). Other ranges are possible.

[0163] In certain embodiments, the average height of the plurality of microneedles is higher than or equal to 0.1 mm, higher than or equal to 0.2 mm, higher than or equal to 0.5 mm, higher than or equal to 0.7 mm, higher than or equal to 1 mm, higher than or equal to 1.2 mm, higher than or equal to 1.5 mm, or higher than or equal to 2 mm. In some embodiments, the average height of the plurality of microneedles is less than or equal to 2.5 mm, less than or equal to 2 mm, less than or equal to 1.5 mm, less than or equal to 1.2 mm, less than or equal to 1 mm, less than or equal to 0.7 mm, less than or equal to 0.5 mm, or less than or equal to 0.2 mm. Combinations of the ranges mentioned above are also possible (e.g., higher than or equal to 0.1 mm and less than or equal to 2. 5 mm). Other ranges are possible.

[0164] In some cases, the average spacing of the plurality of microneedles (e.g., the spacing between adjacent microneedles among the plurality of microneedles) may be greater than or equal to 100 micrometers, greater than or equal to 200 micrometers, greater than or equal to 300 micrometers, greater than or equal to 400 micrometers, greater than or equal to 500 micrometers, greater than or equal to 600 micrometers, greater than or equal to 700 micrometers, greater than or equal to 800 micrometers, greater than or equal to 900 micrometers, greater than or equal to 1000 micrometers, greater than or equal to 1100 micrometers, greater than or equal to 1200 micrometers, greater than or equal to 1300 micrometers, greater than or equal to 1400 micrometers. In certain embodiments, the average spacing of the plurality of microneedles may be less than or equal to 1500 micrometers, less than or equal to 1400 micrometers, less than or equal to 1300 micrometers, less than or equal to 1200 micrometers, less than or equal to 1100 micrometers, less than or equal to 1000 micrometers, less than or equal to 900 micrometers, less than or equal to 800 micrometers, less than or equal to 700 micrometers, less than or equal to 600 micrometers, less than or equal to 500 micrometers, less than or equal to 400 micrometers, less than or equal to 300 micrometers, or less than or equal to 200 micrometers. Combinations of the ranges mentioned above are also possible (e.g., greater than or equal to 100 micrometers and less than or equal to 1500 micrometers). Other ranges are also possible.

[0165] Advantageously, in some embodiments, the tissue connection component (e.g., the needle) dissolves relatively rapidly, thereby reducing and / or eliminating the risk of secondary penetration by components in undesirable locations. In some embodiments, the maximum cross-sectional dimension (e.g., length) of the component is designed to be delivered so as to prevent pain and / or unwanted perforation of the GI tract in any organ that the component is intended to target.

[0166] In some embodiments, the tissue connection component comprises a base portion and a tip portion. For example, as illustrated in FIG. 28, the tissue connection component 100 comprises a base portion 110 and a tip portion 115. In some embodiments, the base portion and / or the tip portion comprises a mucoadhesive material. Non-limiting examples of suitable mucoadhesive materials include polymers such as poly(vinyl alcohol), hydroxylated methacrylate, and poly(methacrylic acid), polyacrylates (e.g., polyacrylic acid, thiolated poly(acrylic acid), Carbopol®), cyanoacrylate, sodium carboxymethyl cellulose, hyaluronic acid, hydroxypropyl cellulose, polycarbophil, chitosan, mucin, alginate, xanthan gum, gellan, poloxamer, cellulose acetate phthalate, methyl cellulose, hydroxyethyl cellulose, poly(amidoamine) dendrimer, poly(dimethylsiloxane), poly(vinylpyrrolidone), polycarbophil, combinations thereof, and copolymers thereof.

[0167] In some embodiments, the base portion and / or the tip portion comprises a solid therapeutic agent (e.g., API) and, if present, a second material, such that the solid therapeutic agent is present in the tissue connection component in an amount greater than or equal to 10% by weight relative to the total weight of the tissue connection component. No. In certain embodiments, the solid therapeutic agent is present in the tissue connection component in an amount greater than or equal to 10 wt%, greater than or equal to 20 wt%, greater than or equal to 30 wt%, greater than or equal to 40 wt%, greater than or equal to 50 wt%, greater than or equal to 60 wt%, greater than or equal to 70 wt%, greater than or equal to 80 wt%, greater than or equal to 90 wt%, greater than or equal to 95 wt%, greater than or equal to 98 wt%, or greater than or equal to 99.1 wt% based on the total weight of the tissue connection component. In some embodiments, the solid therapeutic agent is present in the tissue connection component in an amount less than or equal to 100 wt%, less than or equal to 99 wt%, less than or equal to 98 wt%, less than or equal to 95 wt%, less than or equal to 90 wt%, less than or equal to 80 wt%, less than or equal to 70 wt%, less than or equal to 60 wt%, less than or equal to 50 wt%, less than or equal to 40 wt%, less than or equal to 30 wt%, or less than or equal to 20 wt% based on the total weight of the tissue connection component. Combinations of the ranges mentioned above are also possible (e.g., greater than or equal to 10 wt% and less than or equal to 100 wt%, greater than or equal to 80 wt% and less than or equal to 100 wt%). Other ranges are possible. In an exemplary set of embodiments, the solid therapeutic agent is present in the tissue connection component in an amount greater than or equal to 80 wt% and less than or equal to 100 wt% based on the total weight of the tissue connection component.

[0168] In certain embodiments, the solid therapeutic agent is present in the base portion in an amount greater than or equal to 0 wt%, greater than or equal to 5 wt%, greater than or equal to 10 wt%, greater than or equal to 20 wt%, greater than or equal to 30 wt%, greater than or equal to 40 wt%, greater than or equal to 50 wt%, greater than or equal to 60 wt%, greater than or equal to 70 wt%, greater than or equal to 80 wt%, greater than or equal to 90 wt%, greater than or equal to 95 wt%, greater than or equal to 98 wt%, or greater than or equal to 99 wt% 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 less than or equal to 100 wt%, less than or equal to 99 wt%, less than or equal to 98 wt%, less than or equal to 95 wt%, less than or equal to 90 wt%, less than or equal to 80 wt%, less than or equal to 70 wt%, less than or equal to 60 wt%, less than or equal to 50 wt%, less than or equal to 40 wt%, less than or equal to 30 wt%, less than or equal to 20 wt%, less than or equal to 10 wt%, or less than or equal to 5 wt% based on the total weight of the base portion. Combinations of the ranges mentioned above are also possible (e.g., greater than or equal to 10 wt% and less than or equal to 100 wt%, greater than or equal to 80 wt% and less than or equal to 100 wt%). Other ranges are possible. In an exemplary embodiment, the base portion consists essentially of only the solid therapeutic agent.

[0169] In certain embodiments, the solid therapeutic agent is present in the tip portion in an amount greater than or equal to 0 wt%, greater than or equal to 5 wt%, greater than or equal to 10 wt%, greater than or equal to 20 wt%, greater than or equal to 30 wt%, greater than or equal to 40 wt%, greater than or equal to 50 wt%, greater than or equal to 60 wt%, greater than or equal to 70 wt%, greater than or equal to 80 wt%, greater than or equal to 90 wt%, greater than or equal to 95 wt%, greater than or equal to 98 wt%, or greater than or equal to 99 wt% based on the total weight of the tip portion. In some embodiments, the solid therapeutic agent is present in the tip portion in an amount less than or equal to 100 wt%, less than or equal to 99 wt%, less than or equal to 98 wt%, less than or equal to 95 wt%, less than or equal to 90 wt%, less than or equal to 80 wt%, less than or equal to 70 wt%, less than or equal to 60 wt%, less than or equal to 50 wt%, less than or equal to 40 wt%, less than or equal to 30 wt%, less than or equal to 20 wt%, less than or equal to 10 wt%, or less than or equal to 5 wt% based on the total weight of the tip portion. Combinations of the ranges mentioned above are also possible (e.g., greater than or equal to 10 wt% and less than or equal to 100 wt%, greater than or equal to 80 wt% and less than or equal to 100 wt%). Other ranges are possible. In an exemplary embodiment, the tip portion consists essentially of only the solid therapeutic agent. In another exemplary embodiment, the tip portion is substantially free of the solid therapeutic agent.

[0170] In certain embodiments, the tissue attachment component includes a solid therapeutic agent in an amount greater than or equal to 10 wt% (e.g., greater than or equal to 80 wt%) based on the total weight of the tissue attachment component, regardless of the construction of the base portion and / or the tip portion.

[0171] In certain embodiments, the tissue attachment component comprises a therapeutic agent (e.g., a solid therapeutic agent) that is more than or equal to 0.1 mg, more than or equal to 0.5 mg, more than or equal to 0.8 mg, more than or equal to 1 mg, more than or equal to 1.5 mg, more than or equal to 2 mg, more than or equal to 2.5 mg, more than or equal to 3 mg, more than or equal to 4 mg, more than or equal to 5 mg, more than or equal to 7 mg, or more than or equal to 9 mg. In certain embodiments, the tissue attachment component comprises a therapeutic agent that is less than or equal to 10 mg, less than or equal to 9 mg, less than or equal to 7 mg, less than or equal to 5 mg, less than or equal to 4 mg, less than or equal to 3 mg, less than or equal to 2.5 mg, less than or equal to 2 mg, less than or equal to 1.5 mg, less than or equal to 1 mg, less than or equal to 0.8 mg, less than or equal to 0.5 mg, or less than or equal to 0.2 mg. Combinations of the ranges mentioned above are also possible (e.g., more than or equal to 0.1 mg and less than or equal to 10 mg). Other ranges are possible.

[0172] 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 tip portions of the tissue attachment component. For example, in some embodiments, the solid therapeutic agent and the second material (if present) are substantially uniformly distributed within the tissue attachment component (e.g., within the base portion and / or within the tip portion). In some cases, the solid therapeutic agent can be a coating (e.g., disposed on a portion of the tip) such that the tissue attachment component comprises more than or equal to 10 wt% of the solid therapeutic agent relative to the total weight of the tissue attachment component.

[0173] In some embodiments, the tissue connection component may comprise an additional coating. In some embodiments, the additional coating may include a material configured to slow down the dissolution time, for example, compared to the dissolution of the tissue connection component without the additional coating. 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 possible. In some embodiments, the additional coating may be configured such that the solid therapeutic agent is released over a specific period. For example, in some embodiments, the additional coating is solid The therapeutic agent is configured to be released for a period of less than 6 months or equal thereto, less than 3 months or equal thereto, less than 1 month or equal thereto, less than 2 weeks or equal thereto, less than 1 week or equal thereto, less than 4 days or equal thereto, less than 2 days or equal thereto, less than 1 day or equal thereto, less than 12 hours or equal thereto, less than 6 hours or equal thereto, less than 3 hours or equal thereto, less than 1 hour or equal thereto, less than 30 minutes or equal thereto, less than 15 minutes or equal thereto, less than 10 minutes or equal thereto, less than 5 minutes or equal thereto, or less than 2 minutes or equal thereto (e.g., when an additional coating is exposed to a fluid such as gastric juice). In certain embodiments, the additional coating is configured such that the solid therapeutic agent is released for a period of longer than 1 minute or equal thereto, longer than 2 minutes or equal thereto, longer than 5 minutes or equal thereto, longer than 10 minutes or equal thereto, longer than 15 minutes or equal thereto, longer than 30 minutes or equal thereto, longer than 1 hour or equal thereto, longer than 3 hours or equal thereto, longer than 6 hours or equal thereto, longer than 12 hours or equal thereto, longer than 1 day or equal thereto, longer than 2 days or equal thereto, longer than 4 days or equal thereto, longer than 1 week or equal thereto, longer than 2 weeks or equal thereto, longer than 1 month or equal thereto, or longer than 3 months or equal thereto. Combinations of the ranges mentioned above are also possible (e.g., longer than 1 minute or equal thereto and less than 1 day or equal thereto, longer than 1 day or equal thereto and less than 2 weeks or equal thereto, longer than 1 week or equal thereto and less than 6 months or equal thereto). Other ranges are possible.

[0174] In certain embodiments, the tissue connection component comprises a plurality of microneedles that include the solid therapeutic agent and a second material, if present.

[0175] In some embodiments, at least a portion of the solid therapeutic agent is present on at least the surface of the tip. In certain embodiments, at least a portion of the second material is present on at least the surface of the tip.

[0176] The tissue connection component described herein can be formed using any suitable method. In some embodiments, the tissue connection component is formed by providing the solid therapeutic agent and the 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 connection component. In some embodiments, the second material (if present) and the solid therapeutic agent are heated to form the tissue connection component.

[0177] In some embodiments, the tissue connection 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 connection component is formed using a pressure less than or equal to 1.4 GPa, less than or equal to 1.2 GPa, less than or equal to 1 GPa, less than or equal to 900 MPa, less than or equal to 600 MPa, less than or equal to 300 MPa, less than or equal to 150 MPa, less than or equal to 100 MPa, less than or equal to 75 MPa, or less than or equal to It is formed using a pressure equal to, less than or equal to 50 MPa, less than or equal to 40 MPa, less than or equal to 30 MPa, less than or equal to 25 MPa, less than or equal to 20 MPa, less than or equal to 15 MPa, less than or equal to 12 MPa, less than or equal to 10 MPa, less than or equal to 7 MPa, less than or equal to 5 MPa, less than or equal to 3 MPa, or less than or equal to 2 MPa. Combinations of the ranges mentioned above are also possible (e.g., a pressure of at least 1 MPa and less than or equal to 100 MPa, a pressure of at least 20 MPa and less than or equal to 100 MPa, a pressure of at least 100 MPa and less than or equal to 1.4 GPa). Other ranges are possible.

[0178] In certain embodiments, the tissue connection component can be formed at a specific temperature. For example, in some embodiments, the tissue connection component is formed at a temperature greater than or equal to 50 °C, greater than or equal to 60 °C, greater than or equal to 70 °C, greater than or equal to 80 °C, greater than or equal to 90 °C, greater than or equal to 100 °C, or greater than or equal to 120 °C. In some embodiments, the tissue connection component is formed at a temperature less than or equal to 150 °C, less than or equal to 130 °C, less than or equal to 120 °C, less than or equal to 110 °C, less than or equal to 100 °C, less than or equal to 90 °C, less than or equal to 80 °C, less than or equal to 70 °C, or less than or equal to 60 °C. Combinations of the ranges mentioned above are also possible (e.g., greater than or equal to 50 °C and less than or equal to 130 °C). Other temperatures and ranges are possible.

[0179] Advantageously, the tissue connection component may have desirable mechanical properties (e.g., Young's modulus) such that, for example, the tissue connection component can properly penetrate the tissue of the gastrointestinal tract. In some embodiments, the Young's modulus of the tissue connection component is greater than or equal to 100 MPa (e.g., greater than or equal to 125 MPa, greater than or equal to 150 MPa, greater than or equal to 175 MPa, greater than or equal to 200 MPa, greater than or equal to 250 MPa, greater than or equal to 300 MPa, or greater than or equal to 350 MPa). In certain embodiments, the tissue connection component has a Young's modulus less than or equal to 400 MPa, less than or equal to 350 MPa, less than or equal to 300 MPa, less than or equal to 250 MPa, less than or equal to 200 MPa, less than or equal to 175 MPa, less than or equal to 150 MPa, less than or equal to 125 MPa, or less than or equal to 100 MPa. Combinations of the ranges mentioned above are also possible (e.g., greater than or equal to 100 MPa and less than or equal to 250 MPa, greater than or equal to 100 MPa and less than or equal to 400 MPa). Other ranges are possible.

[0180] In some cases, the tissue connection component may be configured to penetrate to a specific depth into the human gastrointestinal mucosa tissue with a specific force. For example, the tissue connection component has a force less than or equal to 20 N (e.g., less than or equal to 10 N, less than or equal to 5 N, less than or equal to 1 N, less than or equal to 500 mN, less than or equal to 100 mN, less than or equal to 50 mN, less than or equal to 20 mN, less than or equal to 15 mN, less than or equal to 10 mN, less than or equal to 5 mN) and a depth greater than or equal to 1 mm (e.g., greater than or equal to 2 mm, greater than or equal to 3 mm... It may be configured to penetrate to a depth that is less than, or greater than or equal to 4 mm.

[0181] In some embodiments, the second material comprises a polymerizable monomer and / or a polymer. In certain embodiments, the second material is biodegradable. Non-limiting examples of materials suitable for the second material include polyethylene glycol, polyvinyl pyrrolidone, polylactic acid, polysaccharides (e.g., maltose, lactose, starch, cellulose), gum arabic, methylcellulose, gelatin, tragacanth, clay, HPMC, stearic acid, sodium stearate, magnesium stearate, talc, polyethylene glycol, mineral oil, preservatives (e.g., phenol, parabens, cetrimide), antioxidants (e.g., gallic acid, tocopherol), derivatives thereof, and combinations thereof.

[0182] In some embodiments, the tissue attachment component comprises a coating having a yield strength greater than or equal to 50 MPa (e.g., greater than or equal to 60 MPa, greater than or equal to 70 MPa, or greater than or equal to 80 MPa).

[0183] In some embodiments, the coating may be composed of a thin film metal, ceramic, or diamond-like coating (DLC). In some embodiments, the tissue attachment component does not comprise a coating.

[0184] In some embodiments, the coating may be composed of a corrosive material (e.g., iron, zinc, aluminum or an alloy) such that the coating disintegrates to provide a therapeutic agent when the coating contacts the physiological environment. In certain embodiments, the coating may include a polymer described herein, such as parylene.

[0185] In some cases, the tissue connection component may be configured to deliver a specific amount of pharmaceutically active agent per square centimeter of the target tissue. For example, in some embodiments, the tissue connection component delivers more than or equal to 0.01 μg, more than or equal to 0.05 μg, more than or equal to 0.1 μg, more than or equal to 0.2 μg, more than or equal to 0.5 μg, more than or equal to 0.7 μg, more than or equal to 1 μg, more than or equal to 2 μg, more than or equal to 5 μg, or more than or equal to 10 μg of a pharmaceutical agent per square centimeter of the target tissue proximate to the penetration location of the tissue connection component. In certain embodiments, the tissue connection component is configured to deliver less than or equal to 20 μg, less than or equal to 5 μg, less than or equal to 2 μg, less than or equal to 1 μg, less than or equal to 0.7 μg, less than or equal to 0.5 μg, less than or equal to 0.2 μg, less than or equal to 0.1 μg, or less than or equal to 0.05 μg of a pharmaceutical agent per square centimeter of the tissue. Combinations of the ranges mentioned above are also possible (e.g., more than or equal to 1 μg and less than or equal to 20 μg). In some embodiments, the tissue connection component delivers more than or equal to 1 μg of a pharmaceutical agent per square centimeter of the target tissue over any suitable period (e.g., longer than or equal to 0.1 second, longer than or equal to 0.5 second, longer than or equal to 1 second, longer than or equal to 5 seconds, longer than or equal to 30 seconds, longer than or equal to 1 minute, longer than or equal to 5 minutes, longer than or equal to 10 minutes, longer than or equal to 30 minutes, longer than or equal to 1 hour, longer than or equal to 4 hours, longer than or equal to 24 hours, longer than or equal to 48 hours, longer than or equal to 72 hours, longer than or equal to 96 hours configured to deliver for a period longer than or equal to

[0186] In certain embodiments, the tissue connection component comprises a binder (e.g., in some cases, the second material is the 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 containing ethanol or other Class 3 organic solvents (e.g., acetic acid, heptane, acetone, formic acid, isobutyl acetate, etc.).

[0187] In an exemplary embodiment, the article comprises a solid pharmaceutical active agent that is more than or equal to 80% by weight relative to the total weight of the article. In certain embodiments, the article comprises a pharmaceutical active agent that is more than or equal to 1 mg. According to some embodiments, the pharmaceutical agent is selected from the group consisting of bacteriophage, DNA, mRNA, insulin, human growth hormone, monoclonal antibodies, adalimumab, epinephrine, and ondansetron. In certain exemplary embodiments, the pharmaceutical active agent is poured into a mold for forming 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, gelatin, a polymer, such as PVA, PEG, PCL, PVA or PVP, and / or ethanol. According to certain embodiments, the article has a Young's modulus that is greater than or equal to 100 MPa. In some embodiments, the article is configured to penetrate at least 1 mm into human gastrointestinal mucosal tissue with a force of less than or equal to 20 mN. According to certain embodiments, the article is configured to deliver at least 1 mg of the pharmaceutical agent per square centimeter of the target tissue, and / or the article comprises more than or equal to 1 mg of the pharmaceutical active agent per square centimeter.

[0188] A particular exemplary embodiment is a method of forming an article, the method comprising introducing into a mold a composition comprising a solid pharmaceutical agent that is more than 80% by weight relative to the total weight of the composition, applying a pressure greater than or equal to 1 MPa 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 "pharmaceutically active ingredient" (also referred to as "drug" or "therapeutic agent") is a drug that is administered to a subject for the purpose of treating or preventing a disease, disorder or other clinically recognized condition, and that has a clinically significant effect on the subject's body for treating and / or preventing the disease, disorder or condition. Agent

[0189] According to some embodiments, the compositions and methods described herein are compatible with one or more therapeutics, diagnostics, and / or enhancers, such as drugs, nutrients, microorganisms, in vivo sensors, and tracers. In some embodiments, the active agent is a therapeutic, nutraceutical, prophylactic, or diagnostic agent. Although most of this specification describes the use of therapeutic agents, other agents included herein are also possible.

[0190] Agents can include, but are not limited to, any synthetic or naturally occurring bioactive compound or composition that, when administered to a subject (e.g., a human or non-human animal), induces a desired pharmacological, immunological, and / or physiological effect by local and / or systemic action. For example, compounds or chemicals that have traditionally been considered drugs, vaccines, and biologics are useful or potentially useful in the context of certain embodiments, and a Such specific agents include, but are not limited to, molecules used in the fields of treatment, diagnosis and / or improvement, such as proteins, peptides, hormones, nucleic acids, gene constructs, etc., for the medical or veterinary treatment, prevention, diagnosis and / or alleviation of diseases or illnesses (e.g., HMG co-A reductase inhibitors (statins) such as rosuvastatin; non-steroidal anti-inflammatory drugs such as meloxicam; selective serotonin reuptake inhibitors such as escitalopram; antithrombotic agents such as clopidogrel; steroid agents 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 colchicine; antihistamines such as loratadine and cetirizine; opioids such as loperamide; proton pump inhibitors such as omeprazole; anti-(retro)viral agents such as entecavir, dolutegravir, rilpivirine and cabotegravir; antibiotics such as doxycycline, ciprofloxacin and azithromycin; anti-malarial agents; and synthroid / levothyroxine); substance abuse treatment (e.g., methadone and varenicline); family planning (e.g., hormonal contraceptives); performance enhancement (e.g., stimulants such as caffeine); and nutrition and dietary supplements (e.g., proteins, folic acid, calcium, iodine, iron, zinc, thiamine, niacin, vitamin C, vitamin D and other vitamin or mineral supplements).

[0191] In certain embodiments, the active agent is one or more specific therapeutic agents. As used herein, the term "therapeutic agent," also referred to as a "drug," is an agent that is administered to a subject for the purpose of treating or preventing a disease, disorder, or other clinically recognized condition, and that has a clinically significant effect on the subject's body for treating and / or preventing the disease, disorder, or condition. A list 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 Edition, 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 Edition (1999) or subsequent editions The 8th Edition (2006), Mark H. Beers and Robert Berkow (Eds.), Merck Publishing Group, or in the case of animals, The Merck Veterinary Manual, 9th Edition, Kahn, C.A. (Ed.), Merck Publishing Group, 2005; and can be found in the "Approved Drug Products with Therapeutic Equivalence and Evaluations" ("Orange Book") issued by the U.S. Food and Drug Administration (F.D.A). Examples of drugs approved for human use are listed by the FDA in Title 21, Code of Federal Regulations, Parts 330.5, 331 - 361, and 440 - 460, which are incorporated herein by reference, and drugs for veterinary use are listed by the FDA in Title 21, Code of Federal Regulations, Parts 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, antipyretics, antidepressants, antiepileptic drugs, antipsychotics, neuroprotective agents, antiproliferative agents such as anticancer agents, antihistamines, antimigraine drugs, hormones, prostaglandins, antimicrobials (including antibiotics, antifungals, antivirals, antiparasitic drugs), antimuscarinics, anxiolytics, bacteriostatics, immunosuppressants, sedatives, hypnotics, antipsychotics, bronchodilators, anti - asthma drugs, cardiovascular therapeutics, anesthetics, anticoagulants, enzyme inhibitors, steroids, steroid or non - steroid anti - inflammatory agents, corticosteroids, dopamine agonists, electrolytes, gastrointestinal drugs, muscle relaxants, nutrients, vitamins, parasympathomimetics, stimulants, anorectics, and narcolepsy therapeutics. Nutritional supplements can also be incorporated into the drug delivery device. These can be vitamins, nutritional supplements such as calcium or biotin, or natural components such as plant extracts or phytohormones.

[0192] 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, halofantrine, doxycycline, clindamycin, artemisinin and artemisinin derivatives. In some embodiments, the antimalarial drug is artemisinin or a derivative thereof. Exemplary artemisinin derivatives include artemether, dihydroartemisinin, arteether and artesunate. In certain embodiments, the artemisinin is artesunate.

[0193] In another embodiment, the therapeutic agent is an immunosuppressant. Exemplary immunosuppressants include glucocorticoids, cytostatic agents (e.g., alkylating agents, antimetabolites, and cytotoxic antibodies), antibodies (e.g., antibodies against T cell receptors or Il-2 receptors), drugs acting on immunophilins (e.g., cyclosporine, tacrolimus, and sirolimus) and other drugs (e.g., interferon, opioid, TNF binding protein, mycophenolate, and other small molecules such as fingolimod).

[0194] In certain embodiments, the therapeutic agent is a hormone or a derivative thereof. Non-limiting examples of hormones include insulin, growth hormone (e.g., human growth hormone), vasopressin, melatonin, thyroxine, thyroid-stimulating hormone-releasing hormone, glycoprotein hormones (e.g., luteinizing hormone, follicle-stimulating hormone, thyroid-stimulating hormone), eicosanoids, estrogen, progestin, testosterone, estradiol, cortisol, adrenaline, and other steroids.

[0195] 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 between 200 Daltons and 400 Daltons, between 400 Daltons and 1000 Daltons, or between 500 Daltons and 2500 Daltons.

[0196] In some embodiments, the therapeutic agent is a pharmaceutically active agent such as insulin, nucleic acid, peptide, bacteriophage, DNA, mRNA, human growth hormone, monoclonal antibody, adalimumab, epinephrine, GLP-1 receptor agonist, semaglutide, liraglutide, dulaglitide, exenatide, factor VIII, small molecule drug, progest tin (progrstin), vaccine, subunit vaccine, recombinant vaccine, polysaccharide vaccine , and conjugate vaccine, toxoid vaccine, influenza vaccine, herpes zoster vaccine, pneumococcal conjugate vaccine, MMR vaccine, tetanus vaccine, hepatitis vaccine, HIV vaccine Ad4-env clade C, HIV vaccine Ad4-mGag, DNA vaccine, RNA vaccine, etanercept, infliximab, filgastrim, glatiramer acetate, rituximab, bevacizumab, any molecule encapsulated in nanoparticles, epinephrine, lysozyme, glucose-6-phosphate dehydrogenase, other enzymes, certolizumab pegol, ustekinumab, ixekizumab, golimumab, brodalumab, gusellu,ab (gusellu,ab), secukinumab, omalizumab, TNF alpha inhibitor, interleukin inhibitor, vedolizumab, octreotide, teriperatide, CRISPR Cas9, insulin glargine, insulin detemir, insulin lispro, insulin aspart, human insulin, antisense oligonucleotide, and ondansetron.

[0197] In an exemplary embodiment, the therapeutic agent is insulin.

[0198] In some embodiments, the tissue connection component described herein includes two or more types of therapeutic agents.

[0199] In certain embodiments, the therapeutic agent is present in the tissue connection component at a concentration such that upon release from the tissue connection component, the therapeutic agent elicits a therapeutic response.

[0200] In some cases, the therapeutic agent can be present at a concentration below the minimum concentration generally associated with the active therapeutic agent (e.g., at a microdose concentration). For example, in some embodiments, the tissue connection component includes a first therapeutic agent (e.g., a steroid) at a relatively low dose (e.g., without wishing to be bound by theory, a low dose of a therapeutic agent, such as a steroid, can mediate the foreign body response of the subject at a location within the subject's body (e.g., in response to contact by the tissue connection component)). In some embodiments, the concentration of the therapeutic agent is a microdose less than and / or equal to 100 μg and / or 30 nMol. However, in other embodiments, the therapeutic agent is not provided at a microdose and is present in one or more of the amounts listed above.

[0201] In some embodiments, the tissue connection component comprises a self-actuating component. Such self-actuating tissue connection components are generally described in co-owned U.S. Patent Application No. 62 / 507,653, filed May 17, 2017, entitled "SELF-ACTUATING ARTICLES", which provisional application is hereby incorporated by reference in its entirety.

[0202] In some embodiments, the tissue connection component is administered to a subject (e.g., orally). In certain embodiments, the article can be administered orally, rectally, intravaginally, nasally, or urethrally. In certain embodiments, the tissue connection component (e.g., and / or the API contained therein) is administered by contacting the subject's skin with the component. In an exemplary embodiment, the tissue connection component (e.g., and / or the API contained therein) is administered by contacting the buccal tissue of the subject (e.g., lips, palate region, cheeks, sublingual, tongue) with the component. In yet another exemplary embodiment, the tissue connection component is administered orally and, upon reaching a location within the subject's body (e.g., GI tract, e.g., colon, duodenum, ileum, jejunum, stomach, buccal space, esophagus, etc.), the tissue connection component aligns (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 connection component penetrates the subject's tissue and at least a portion of the support material and / or pharmaceutically active agent dissolves within the subject's tissue.

[0203] Advantageously, administration of a tissue connection component having a relatively high API loading to the GI tract may enable effective API delivery compared to conventional methods. For example, without wishing to be bound by theory, drug delivery by infusion into the GI tract has been demonstrated to have high bioavailability compared to other methods.

[0204] In some embodiments, the system includes a self-healing article (e.g., configured to be localized at a position within a subject's body in a specific orientation), a self-activating component (e.g., configured to activate when exposed to a fluid such as gastrointestinal fluid under a certain set of conditions), and a tissue connection component associated with the self-activating component, and includes an API associated with the tissue connection component. In certain embodiments, the system includes a self-healing article, a self-activating component, and a tissue connection component associated with the self-activating component. In some embodiments, the system includes a self-activating component and a tissue connection component associated with the self-activating component. In certain embodiments, the system includes a self-healing article and includes an API associated with the self-healing article. In some embodiments, the system includes a tissue connection component and includes an API associated with the tissue connection component. In some embodiments, the system includes a self-activating component and a tissue connection component associated with the self-activating component, and includes an API associated with the tissue connection component. The self-healing article, the self-activating component, the tissue connection component, and the API and related configurations are described above and are explained herein.

[0205] "Subject" refers to any animal such as a mammal (e.g., a human). Non-limiting examples of subjects include humans, non-human primates, dairy cows, horses, pigs, sheep, goats, dogs, cats, or rodents such as mice, rats, hamsters, birds, fish, or guinea pigs. Generally, the present invention relates to use in humans. In some embodiments, the subject may exhibit a beneficial effect on health, for example, when the self-healing article is administered.

[0206] As used herein, "fluid" is given its ordinary meaning, i.e., a liquid or a gas. A fluid cannot maintain a defined shape for an observable period of time and will flow to fill a container into which it is placed. Thus, a fluid can have any suitable viscosity that allows for flow. If two or more fluids are present, one of ordinary skill in the art can independently select each fluid from essentially any fluid (liquids, gases, and the like).

Examples

[0207] The following examples are for illustrative purposes of certain specific embodiments described herein, including certain aspects of the present invention, but do not illustrate the full scope of the present invention. (Example 1) Self - restoring article

[0208] Provided is a self - restoring article that has a specific shape and / or density distribution and can be encapsulated, if desired, in a standard "000" capsule, "00" capsule, or a capsule that may be smaller or larger. For example, the density distribution and / or shape are 1. The design has only one stable point and one unstable point and will thus always restore to a single configuration and orientation; 2. The design of the article has a relatively short restoration time from any possible orientation to its stable configuration; 3. The design minimizes destabilizing effects sensed from forces within the GI tract, such as fluid flow and muscle contraction; and / or 4. The design allows for the mounting of articles of various shapes and weights to a system by means of hollow gaps created at specific locations on the article such as density distributions and / or shapes.

[0209] In some cases, the article shape is drawn within the right two quadrants of the Cartesian plane and results from a smooth curve that rotates about the y-axis. The shape has several prominent features. It has a flat bottom perpendicular to the y-axis that transitions to a high-curvature corner and then gradually decreases its curvature as the curve continues. The flat bottom section of the curve can help meet the third specification of the article. Since the bottom is flat and surrounded by steep-cornered sections, a greater force is required to push the article sideways. This is similar to the mechanism where an ellipsoid wobbles when pushed instead of a cube.

[0210] The remainder of the curve can be optimized to meet the first and second specifications using the following equations. The restoration time of the article is calculated from the following angular motion equation:

Number

Number

[0211] In some cases, an article can be manufactured from two different materials, one having a high density and the other having a low density. The density ratio is defined such that the center of mass of the shape is located at the origin of the coordinate system. The lower half of the plane is made of the high-density material, while the upper part of the plane is made of the low-density material. To maintain the material density achievable from currently available materials, certain holes and improvements can be added to the prototype, which will be described by way of examples. These holes and improvements are also utilized for the accommodation of the article within the system and are thus considered when determining the density of other materials.

[0212] Once the 3D shape is designed, the recovery time from a given orientation can be tested by using the above equation. The weight and volume of the article determine the acting force, which in turn determines the torque. The weight and volume of the article are set not only by the density of the material but also by the generated curve. The measured values of the distance and angle used to determine the torque are determined solely by the generated curve. The curve is generated by drawing a smooth curve passing through a series of points of the radial coordinates using a set of angular coordinates. Thereafter, the code varies the distance of the coordinates of the points until the minimum set of recovery times is achieved. (Example 2)

[0213] A solid shape created by rotating a smooth curve defined around the y-axis (Example: Figure 7). This shape is manufactured using 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 density ratio of the two materials should be between 6:1 and 16:1. The points in Figure 7 depict an object that can fit within a capsule (Figure 8) such as a 000 capsule, but the article can be scaled to any length.

[0214] This shape was tested for its ability to recover with respect to ellipsoids and spheres having the same volume and similar dimensions. The objects were tested at 1000 FPS under a high-speed camera in several different liquids including water, oil, and gastric juice, as well as on different surfaces including plastic and pig stomach tissue. The results (Figs. 9 - 12) showed that the article not only had a faster recovery time at angles closer to a stable orientation, but also had a faster recovery time overall. Since the article is most likely to start near its stable orientation, this shape makes the article better than other shapes.

[0215] The articles were also tested for their ability to remain in their returned position by placing them on a tilting mixer. The mixer was set to tilt 15 degrees in each direction at 50 rpm. The articles never left their stable orientation, while the spheres tilted 18 degrees from their optimal orientation and the ellipsoids tilted 31 degrees from their optimal orientation (Figs. 13 - 16).

[0216] The objects were also placed in vitro in a suspended, intact pig stomach using a plastic tube as an artificial esophagus and the number of times they landed in the correct orientation was compared to spheres made only of PCL. Of the 60 tests for each of the objects conducted in a water-filled stomach, an oil-filled stomach, and an empty stomach, it was found that the article having the shape described in Fig. 7 landed in the correct orientation every time, while the spheres landed in the correct orientation only 25% of the time.

[0217] Furthermore, similar experiments were conducted in vivo. Six self-healing articles and six articles of the same shape but without self-healing ability were supplied to anesthetized pigs by gastric tube. Subsequently, the pigs were shaken vigorously to simulate walking. After shaking the pigs, they were placed under X-ray, and the number of articles remaining in the correct orientation was counted. These articles were identified by placing metal pieces inside them (Figure 14). The self-healing articles already had hemispheres with metal in the lower half, which were displayed as complete circles if self-healed and as crescent moons with a notch if not self-healed. Circular washers were placed inside the target articles, which were shown as complete circles if self-healed or as distorted ellipses if not restored. 65 / 66 self-healing tests showed the correct orientation after shaking, while only 7 / 31 control articles showed the correct orientation. (Example 3)

[0218] An object having the same shape as described in Example 2 but incorporating holes, outlets, and slits into the article. Such holes and slits could be used to allow fluid to enter the system or to store the object within the system (Figure 19). These slits can be used to hollow out the article and keep the density ratio at a reasonable value achievable using available materials. For example, by hollowing out the top section of the article, a higher density material can be used for filling the remaining top region. The higher density material is allowed because the constraints on the article are only the outer shape and the center of mass. When making holes, the article should attempt to maintain an axisymmetric or as close to axisymmetric as possible state.

[0219] Examples of these holes and slits include, but are not limited to, the following: 1. A cylinder having a radius smaller than the radius of the article centered on the y-axis. 2. A conical cross-section centered on the y-axis whose radius can change as the radius of the system changes. 3. A vertical linear cut having a predetermined width from the top or bottom of the system. 4. Any other type of cut to the article that maintains the overall integrity of the system. (Example 4)

[0220] An object having a shape similar to that described in Examples 2 and 3 but incorporating a drug delivery article into the system. This article may be a solid or hollow needle loaded with a drug. It may also be a hollow needle connected to a reservoir, or a series of needles loaded with or coated with a drug. Other drug delivery articles such as patches are also possible.

[0221] In the case of needles, they could be housed inside the system or outside it. When housed outside the system, they could be connected by an adhesive or fitted into the framework of the article. When housed inside the system, it could be housed in a hole drilled in the article. too.

[0222] Needle puncture could also be actuated passively from the gravity on the article. In this implementation, the weight of the article could push the needle into the tissue. (Example 5)

[0223] An object having a shape similar to that described in Examples 2 to 4 but incorporating electronic components into the system.

[0224] By adding electronic components to the article in combination with an anchor, the article could also be used as a gastric retention electronics mechanism. The sensor could approach the tissue wall or be close to the inside of the GI 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 gastric wall region or the inside of the stomach depending on its placement on the system. (Example 6)

[0225] An object (Figure 20) having the same shape as described in Examples 2 to 4 but capable of remotely attaching other articles to the system.

[0226] By applying a gravitational and / or adhesive force to the walls of the system, the patient could swallow other capsules filled with new articles or drugs and the system could cause them to aggregate with each other. Such forces could be generated by magnets, adhesives, vacuum, or any number of other mechanisms.

[0227] For example, magnets could be attached to the walls of the system, or to the walls of the electronic sensor. The patient could first swallow the self-restoring system and moor it to the tissue wall as described in Example 4. The patient could then ingest another capsule containing the electronic sensor. The magnetic force generated between the two articles from the positioned magnets would enable the attachment of the two systems. Since the electronic sensor would be moored to the tissue wall, the electronic sensor could remain in the stomach even if it did not have any gastric retention properties. This system could enable any type of article to have gastric retention properties. (Example 7) Self-activating article

[0228] The device could also be activated actively. This could include mechanisms such as shape memory nitinol, expandable elastomers, or compressed springs. The compressed spring could be immobilized in a solid biodegradable and biocompatible polymer or sugar (e.g., sucrose, maltose). This mechanism was shown to function in vivo (Figure 22). These mechanisms could then be housed within the cavity section of the article or outside the article. Methods of tethering the device to the system article include, but are not limited to, magnets, tying knots, and application of adhesives.

[0229] Digging further into the example of the spring, in some cases it may be desirable for the needle to penetrate the submucosa of the GI tract to deliver the drug. For example, the needle needs to penetrate at least 1 mm into the tissue. If the needle penetrates more than 5 mm into the tissue, the patient will bear the risk of perforation. For this reason, the spring can be compressed between 1 and 5 mm. Also, the amount of force required to penetrate the GI tissue is generally small, approximately 1 - 10 mN, but it may require a force of about 100 mN to penetrate the muscular layer of the stomach that lies between the mucosal layer and the submucosa. In some cases, the spring will have sufficient force when compressed and will push against the tissue with a force that is 3 to 10 times the safety factor added to 100 mN. This means that the spring could have a spring constant of approximately 100 - 250 N / m in some cases (Figure 23). This means that the spring could have a spring constant of approximately 100 - 250 N / m in some cases (Figure 23).

[0230] Furthermore, the compressed spring can be encapsulated in a material that can hold such force. The material may be brittle, for example, such that the spring can escape from the material all at once. Brittle materials, such as (crystallized) sugar, will generally crack quickly and completely when subjected to a given stress. Caramelized sucrose generally breaks under a stress of 0.1 Mpa. If a compressed spring applies a force of 1 N to the sucrose coating the spring, the sucrose coating could be at least 3.56 mm in diameter to accommodate the spring. Any additional caramelized sucrose added to the coating could also be used as a time-limiting mechanism for the device (for example, although not wishing to be bound by theory, the thickness of the coating could be at least proportional to the time required to break down the coating).

[0231] Using modeling software that executes diffusion mass transfer problems related to interface balance, it was determined that the spring coated with sucrose between 4 and 6 mm can be delayed in operation for 1 to 4 minutes when the sucrose-coated spring is dissolved in water. This was confirmed by experiments (Figs. 24-25). It was revealed that a delay of at least 20 seconds is sufficient for the operation to occur in the stomach rather than in the mouth or esophagus.

[0232] To confirm that the liquid reaches the sucrose and initiates this dissolution process, outlets can be added to the top and bottom of the device to allow fluid flow. These outlets, for example, provide a way for the air trapped inside to escape. They may also be hydraulic to allow easy passage of water.

[0233] In some cases, the tethering device will allow the system to adhere to the tissue wall of the GI tract by physical or chemical means. Such devices could include, for example, a needle with a hook, a mucoadhesive patch, a capture and closure mechanism (Fig. 26), vacuum suction, or any number of other mechanisms. The tethering device could also be placed at the bottom of the device to ensure it faces the tissue wall.

[0234] When the tethering device uses a hook, such as a needle with a hook, the tethering device could reach the muscle layer of the tissue that lies between the mucosal layer and the submucosal layer. Fig. 27 shows a histological slide of a gastric tissue section penetrated by a device that penetrates the muscle layer of interest. This penetration was caused by using a spring coated with sugar such as the above, compressed to 6 mm and having a spring constant of 210 N / m. (Example 8) High API loading

[0235] A solid soluble needle (e.g., a tissue connection component) containing a high concentration of API (e.g., a solid therapeutic agent) and a binder (e.g., a support material) was formed. This API may consist of anything from small molecules to peptide drugs and vaccines. The production of the needle used one or both of heat and pressure to create it. The pressure can be applied by a pill press, a hydraulic press, centrifugation, or any other method for applying a large amount of force. The applied force is 1 - 3 metric tons per 100 cm 2 but may be higher if the API is not damaged and may be lower if sufficient heat is applied. Heat is provided either convectively or conductively by a heat gun, furnace, or similar device up to the melting temperature of the binder used. In the examples below, PEG was used due to its relatively low melting point and relatively high plasticity level. Heat and pressure are used sequentially or simultaneously to press a mixture of powdered API and binder into an in-plane or out-of-plane mold as described in the examples below can be.

[0236] A dissolvable tissue connection component containing a binder and a solid API loaded with a two-digit percentage is described. This tissue connection component (e.g., a needle) can be applied to the skin, GI tract, or any other area of the body. In some cases, the needle uses the API in powder form. These needles were created by applying pressure and / or heat to the powder mixture. This is a different method from the traditional soluble needles that are pulled out or solvent cast, but such traditional methods may also be used. Such needles can be added to the actuator to obtain sufficient force to penetrate the body.

[0237] The GI tube provides an opportunity such as those not believed to be for such needle formulations. The walls of certain regions of the GI tube are generally thick and have a very large surface area, so these needles could be extended and expanded to hold a much larger amount of drug compared to microneedles. For example, a formulation using an 80 wt% insulin loading enables delivery of 1 milligram of API with needles having a diameter of less than 600 μm and a length of 3.3 mm. Such needles could be delivered to the stomach without the risk of perforation. In addition, less than 100 conical needles having a length of 1 mm and a base diameter of 450 μm could deliver the same dosage of API to the small intestine with less risk of perforation. (Example 9)

[0238] In-plane molds were used to create the needles in a projection two-dimensional design. The needles may be less than 2 mm in diameter or larger, but larger needles may impede penetration. The needles may also be less than 1 centimeter in length. The needles may be blunt or have a tip angle. Lasers with a small focal diameter can be used to create in-plane molds, and the tip radius is limited only by this measurement. Larger molecular weight proteins, or proteins with a low likelihood of aggregation such as BSA, may use a larger amount of binder. However, needles with a tip radius of 40 micrometers using 100% insulin can also be created. The amount of binder used can, in some cases, help control the dosage of API given and the integrity of the needles. When 20 - 30 w / w percentage of binder was added to the mixture, no problems associated with binding were observed. Needles (Figs. 29 - 30) with the following dimensions (510 μm × 510 μm × 3.3 mm) in an 80% API / 20% PEG 200k formulation for both insulin and BSA.

[0239] It is also possible to manufacture a needle having two parts, one containing the API and the other not containing the API. This enables the creation of needles in which only the tip contains the drug. Previous literature has shown that when a needle penetrates, it creates a crater within the penetrated tissue that prevents the needle from fully entering. Loading the drug at the tip helps ensure that the entire API dose is delivered. This type of needle can be created by creating a partition on the needle mold, loading only the binder on one side and the API + binder on the other side. Since both manufacturing methods contain the same binder, both sides will fuse under either pressure or heat to create one needle (Figure 31).

[0240] The high insulin-loaded needles were shown to rapidly dissolve in PBS at 37°C within 20 minutes (Figure 32). The dissolution profiles of the three needles also indicate the uniformity of the drug loading in each of these needles. Furthermore, Instron machines were used to test these needles for their strength in order to perform crushing tests. The needles behaved in a profile similar to that of a ductile material. This is natural since most of the needle is made of PEG (Figures 33 - 34). Finally, the penetration force of these needles was tested in the human stomach. It was found that the needles penetrated completely with a force of 18 mN (Figure 35). (Example 10)

[0241] The out-of-plane mold can create needles with three-dimensional shapes. This mold was created by first using a 3D printer to fabricate a solid female mold. Such a printer can create a tip radius of approximately 1 micrometer. Then, to preserve / maintain the sharpness of the tip seen in the printed prototype, a small grain size was used and an evaporator was used to coat this female mold with a thin 10-μm chromium layer and another 200-μm copper layer to create a metal shell. Next, to generate the male mold, several millimeters of nickel were electroplated onto the copper layer. The resulting nickel mold was then separated from the female mold, flattened, and smoothed to allow for an even force distribution.

[0242] Needles were created by placing powder in a mold and compressing it in one of the following ways: 1. Fill the top of the mold with powder and compress to create a needle and base all made from one formulation (Figure 36). 2. Fill the top of the mold with powder and compress to create a needle and base all made from one formulation. Then separate the base plate, leaving the needle in the mold. Then re-press the mold using a formulation without API. Remove the entire pressed device, leaving a needle containing the API formulation connected to a base plate without API (Figure 37). 3. Loosely fill the holes in the mold with the API formulation. Then place a formulation without API on top of the API formulation. Press the entire device at once, leaving the API formulation inside the needle tip, and the formulation without API at the needle base and on the base plate (Figure 38).

[0243] These needles have strong integrity as shown by axial load testing on an Instron machine. Needles from method 3 started with a tip radius of less than 10 μm and after applying a force of 0.06 N to the top, the tip had a tip radius of 34 μm (Figure 39). (Example 11)

[0244] This example demonstrates the formation of a tissue attachment component containing 95 wt% insulin (e.g., API) and 5 wt% hydroxypropyl methylcellulose (HPMC) (e.g., binder material). As described herein, insulin and HPMC were pressed together using a pressure above 1 MPa. A photograph of the component is shown in Figure 40A. The component was shown to withstand a force of over 62.7 N before cracking (Figures 40B - 40C).

[0245] A tissue attachment component containing 100 wt% insulin was also formed.

[0246] Insulin was used as the API and extruded with PCL to produce another tissue connection component. The percentage of recovered insulin was quantified and is shown in FIG. 40D. Insulin dimer formation was also tested, demonstrating that insulin is stable up to temperatures of 120° C. to 150° C. or less (FIG. 40E). (Example 12)

[0247] The following examples demonstrate the formation of tissue connection components comprising multiple microneedles with high API loading amounts.

[0248] Briefly, as illustrated in FIG. 41, the API was poured into the mold and pressed into the microneedle cavities. The mold was then centrifuged to push the API into the tips of the microneedle cavities. In some cases, a binder was added to the mold. The mold was centrifuged again to push the binder into the microneedle cavities. The microne -dles were left to dry for 1 to 3 days. The microneedles were removed from the mold and were immediately ready for use. In some cases, the microneedles contained at least 1 mg of API.

[0249] To visualize the distribution of the API in the microneedles, FITC-dextrans having molecular weights of 3 to 5 kDa (e.g., similar to that of insulin) and 20 to 22 kDa (e.g., similar to that of some human growth hormones) were used in place of the API in the method outlined above and then imaged using confocal microscopy. FIGS. 42A-42B show the distribution of FITC-dextran in the microneedles. In some cases, the FITC-dextran was most clearly concentrated in the upper 1 / 3 to upper 2 / 3 of the microneedles (e.g., at the tip).

[0250] Microneedles were also fabricated as described above using insulin as the API. All microneedle patches were imaged prior to application to the buccal space of pigs. The microneedle patches were inserted into different regions (tongue, sublingual, cheek, lip, and palate) of the buccal space of pigs (under anesthesia) in vivo for different times of 5, 15, and 30 seconds. The microneedle patches were tested as controls (labeled as control (30s) in Figure 43) and were placed only on the surface of the tissue (for example, thus any possible degradation would be related to the moisture of the placement surface rather than degradation within the tissue). All microneedle patches were imaged again after application.

[0251] Figure 43 shows the dissolution of microneedles on pig tongue, sublingual, cheek, lip, and palate tissues over 30 seconds. This experiment demonstrates that in some cases, the microneedles can dissolve and deliver the API to the tissue in less than 30 seconds and in some cases less than 15 seconds or less than 5 seconds.

[0252] Microneedles were fabricated again as described in Example 5 using insulin as the API. Here, the microneedle patches were inserted into ex vivo human tissue (e.g., human cheek) for different periods of 5, 15, and 30 seconds. Figure 44 shows the dissolution of the microneedles over time. (Example 13)

[0253] The following examples demonstrate the in vivo dissolution of API-loaded microneedles at the target in vivo location.

[0254] Microneedles were fabricated as described in Example 12 using insulin as the API. The microneedle patches were inserted in vivo into different regions (tongue, sublingual, buccal, lip, and palate) of the buccal space and the small intestine (SI) of anesthetized pigs. Blood samples were taken at set times (0, 2.5, 5, 7.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 70, 80, 90, 100, 110, 120, 135, 150, 165, 180, 210, and 240 minutes), and insulin concentrations were quantified therefrom. Figures 45-46 show plots of the blood concentrations of insulin after microneedle application to the small intestine (Figure 45) and palate tissue (Figure 46) for various API loadings (1.4 mg, 1.6 mg, 2.01 mg, 2.42 mg, and 3.56 mg).

[0255] Microneedles were also fabricated as described in Example 12 using human growth hormone (hGH) as the API. The microneedle patches were inserted in vivo into different regions (tongue, sublingual, buccal, lip, and palate) of the buccal space and the small intestine (SI) of anesthetized pigs. Blood samples were taken at set times (0, 2.5, 5, 7.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 70, 80, 90, 100, 110, 120, 135, 150, 165, 180, 210, and 240 minutes), and hGH concentrations were quantified therefrom. Figures 47-48 show plots of the blood concentrations of hGH after microneedle application to the lip (Figure 47) and palate (Figure 48) for various API loadings (1.75 mg, 2.35 mg, 2.13 mg).

[0256] Microneedles were also fabricated using hGH with sorbitol (e.g., sugar) as the binder. Figure 49 shows a plot of the blood concentration of hGH after microneedle application to the lip of a pig in vivo. (Example 14)

[0257] The following example demonstrates the formation of tissue attachment components with high monoclonal antibody loadings.

[0258] The dosage of adalimumab was lyophilized and subjected to relatively high pressure (3 mT or less) and / or relatively high heat (70 °C or less). PEG 200K was used as a binder. An ELISA assay was performed to confirm the antibody activity. Figure 50 shows a plot of the activity of lyophilized adalimumab after exposure to high pressure and high heat. Virtual exemplary embodiments

[0259] (Embodiment 1) An encapsulating article having the ability to rapidly orient itself to the tissue wall of the GI tract. a. The article, wherein the shape of the article can be represented by rotating the curve of FIG. 7 about the y-axis. b. The article, manufactured from a biodegradable and biocompatible polymer (e.g., PCL) or metal (e.g., stainless steel) or a combination thereof. c. The article, having two distinct compartments defined by the x-axis in FIG. 7, manufactured using materials having different densities with a density ratio of 6 to 16:1.

[0260] (Embodiment 2) The article according to Embodiment 1, which may be a cavity so as to retain self-healing ability with holes or outlets such as cylinders, conical cross-sections, rectangular cross-sections or other geometric shapes.

[0261] (Embodiment 3) The article according to Embodiment 1, which can hold a drug delivery system manufactured using a needle (hollow or solid) or a patch and an actuating mechanism. a. The article, wherein the actuating mechanism can be shape memory nitinol. b. The article, wherein the actuating mechanism can be a compressed spring. c. The article, wherein the actuating mechanism can be gravity. d. The article, wherein the actuating mechanism can be an inflating material. e. The article, wherein the needle may be attached to a drug reservoir. f. The article, wherein the needle may be manufactured from a formulation. g. The article, wherein the needle can accommodate the formulation.

[0262] (Embodiment 4) The article according to Embodiment 3b, wherein the spring has a spring constant between 100 and 250 N / m, is compressed by 1 to 5 mm, and is coated with caramelized sucrose of 3.6 to 6 mm.

[0263] (Embodiment 5) The article according to Embodiment 1, which may be connected to an anchoring system to maintain gastric retention. a. The article, wherein the anchoring mechanism is a needle with a hook. b. The article, wherein the anchoring mechanism is a bare trap mechanism. c. The article, wherein the anchoring mechanism is a mucoadhesive patch. d. The article, wherein the anchoring mechanism is vacuum suction.

[0264] (Embodiment 6) The article according to Embodiment 1, which may be attached to another ingestion capsule by a magnet, a chemical adhesive, a vacuum force or other attractive forces.

[0265] (Embodiment 7) The article according to Embodiment 1, which may be connected to an electronic system such as a sensor. a. The article, wherein the electronic system is housed within the article. b. The article, wherein the electronic system is ingested in a separate capsule and then adheres to a self-restoring system.

[0266] (Embodiment 8) A device having an actuating mechanism. a. The device, wherein the actuating mechanism may be shape memory nitinol. b. The device, wherein the actuating mechanism may be a compressed spring. c. The device, wherein the actuating mechanism may be gravity. d. The device, wherein the actuating mechanism may be an inflating material. e. The device, wherein the needle may be attached to a drug reservoir. f. The device, wherein the needle may be manufactured with a formulation. g. The device, wherein the needle can accommodate a formulation.

[0267] (Embodiment 9) The device according to embodiment 8b, wherein the spring has a spring constant between 100 and 250 N / m, is compressed by 1 to 5 mm, and is coated with caramelized sucrose of 3.6 to 6 mm.

[0268] (Embodiment 10) The device according to embodiment 8, which may be connected to an anchoring system to maintain gastric retention. a. The device, wherein the anchoring mechanism is a needle with a hook. b. The device, wherein the anchoring mechanism is a bear trap mechanism. c. The device, wherein the anchoring mechanism is a mucoadhesive patch. d. The device, wherein the anchoring mechanism is vacuum suction.

[0269] (Embodiment 11) A pressed and / or heated formulation of a powder API and a binder, having an API loading greater than 10% w / w, formed into an implantable object. a. The implantable object is a micro-needle having a height of 0.3 to 1.5 mm and a base diameter of 200 μm to 700 μm. b. The implantable object is shaped like a conventional needle having a diameter of 1.5 mm or less and a length of 10 cm or less. c. The implantable object has a shape like a protrusion having a diameter of 2 mm or less in any direction.

[0270] (Embodiment 12) The penetration shape, wherein the API and the binder are concentrated in the top portion of the object, and the bottom portion of the object is only the binder.

[0271] (Embodiment 13) The penetration shape manufactured by pressing a powder, having structural integrity for penetrating through GI tissue.

[0272] (Embodiment 14) An insertion shape produced by pressing a powder, having structural integrity for penetrating through the skin.

[0273] (Embodiment 15) An insertion shape, the tip of which is made using another brittle material such as sugar.

[0274] (Embodiment 16) An insertion shape, the tip of which is made by cutting and milling an existing tip of a shape.

[0275] (Embodiment 17) An insertion shape produced by pressing an API and a binder into an in-plane mold.

[0276] (Embodiment 18) An insertion shape produced by pressing an API and a binder into an out-of-plane mold.

[0277] (Embodiment 19) An insertion shape produced by pressing an API and a binder in a pill press. (Embodiment 20) A formulation of a powdered API and a binder, pressed and / or heated, wherein the binder is a PEG having a molecular weight between 5000 and 1 million.

[0278] (Embodiment 21) A formulation of a powdered API and a binder, pressed and / or heated, wherein the API is insulin or another peptide.

[0279] (Embodiment 22) A formulation of a powdered API and a binder, pressed and / or heated, wherein the API is a nucleic acid.

[0280] (Embodiment 23) A pressed and / or heated formulation of a powdered API, a binder, and an anti-adhesive agent, wherein the anti-adhesive agent is selected from waxes, oils, and stearates such as magnesium stearate, sodium stearyl fumarate, etc. (Example 15) Retention mechanism

[0281] The following examples demonstrate the formation and use of the retention mechanism associated with the system described herein.

[0282] This addendum to the present disclosure discusses a method by which a device can be tethered to the tissue wall of the GI tract using a hooked needle. The needle can be advanced into the GI tract from a self-aligning device by a mounted spring mechanism (Figure 51). There is an optimal way to position the needle so that the device can be retained in the stomach with greater strength, including the penetration depth (Figure 52) and the hook size ( Figure 53). For example, a 32-gauge needle needs to displace the tissue by at least 1.9 mm to actually penetrate the inner lining of the stomach. This means that in some cases, the device needs to eject the needle this distance in order to produce a latching effect. If the device ejects the needle even further, the needle will continue to penetrate the tissue and will maintain the latching fixture on the tissue. The hook size refers to the length of the bend at the extreme tip of the needle. The needle is usually sharpened to a good point, but this part of the needle was deliberately bent to create a hook at the end. As this hook gets larger, the penetration force of the needle increases. A 30-μm hook showed a length that balanced the penetration force and the amount of tissue latched. As can be seen from Figure 54, the hook grips the stomach tissue and provides a vertical holding force to the device. This holding force is particularly useful for the device to withstand expulsion by peristaltic movement. The same experiment was also conducted in the human stomach using a needle with a 30-μm hook, and it was revealed that the device was latched onto the tissue (Figure 55). The human stomach requires a slightly greater insertion depth compared to the pig's stomach. It was also revealed that latching occurs in the small intestine of pigs (Figures 56 - 58).

[0283] The hook at the tip of the needle provides a way to tether the device to the tissue and provides vertical retention force, but the major forces in the stomach act perpendicular to the inner lining of the stomach and are provided by fluid flow. To test this, the system was inserted into tissue pieces and pushed down with a constant force using a probe to determine the horizontal retention force of the device (Figure 59). By inserting more needles into the tissue, the relative horizontal retention force increased linearly with each additional needle (Figure 60). The needles also provide a greater retention force the further apart they are from each other (Figure 61). The needle tethering device was able to withstand forces not only from the probe but also from fluid flow. Figures 62 - 63 show an in vitro setup that models fluid flow in the stomach. The device was attached to a tissue piece suspended vertically from the ground and exposed to a pulsatile flow of 0.1 m / s for one week. Each device had only one needle that tethered the device to the tissue. The device with the straight needle lasted one day on the tissue, while the device with the hooked needle lasted a full week on the tissue. Horizontal tissue tests were also performed in a survival pig model (Figures 64, 65A). These experiments, performed in two different animals, demonstrated that the device was retained with equal force in vivo and ex vivo. On average, the device had a retention for between 0.6 - 0.8 N and was rotated 30 degrees before detaching from the tissue.

[0284] Since the GI tube contains a thick layer of highly conductive mucus on its tissue, the shaft of the needle was coated with a 5-μm parylene layer for insulation. Only the base and tip of the needle were conductive, allowing electricity to flow through the tissue rather than the mucus (Figure 66). The entire system consisted of a power source, a self-actuating device with a needle-shaped probe, and a microcontroller for regulating the pulses that provided the stimulation (Figure 67). The electrical components had to be insulated to prevent short circuits. All of these components easily fit inside the 000 capsule. Figures 68 and 69 show the effects of changes in probe size and the effects of changes in the fixed distance between the power source and the probe. The distance between the probes had a significant impact on the resistance of the complete circuit and thus, when the voltage was fixed, varied the amount of current passing through the system. Surprisingly, changes in probe size had little effect on the current. This is most likely due to the fact that the main factor in the circuit is the tissue, not the probe. Figure 70A shows the measured voltage from the circuit produced by the final device embedded in the tissue wall. The background noise shown in Figure 70B is negligible compared to the output generated by the circuit. A microcontroller was used to program electrical pulses into the circuit. This circuit had a parylene coating was created by using needles and attaching them to a self-actuating system connected to a constant voltage source and inserting these probes into the tissue wall. The self-healing / self-actuating system had a metal bottom, but this bottom was coated with parylene to insulate it. These graphs demonstrate that the device can actually deliver the programmed current to the tissue wall of the GI tube.

[0285] Hooked needles have potential safety concerns. First, they should not pierce tissue. Gastric tissue is about 5 mm thick, and small intestine tissue is about 1 - 1.5 mm thick. Both of these tissues are stretchable, and the needle can displace the tissue a distance longer than their depth before piercing them. For the small intestine, the needle can displace the tissue by 5.9 mm ± 1.1 mm in a sample size of tissues from a total of n = 15 pigs from three different pigs. The lowest recorded value was 4.5 mm. For the stomach, it is difficult to displace the tissue by a full 1 centimeter, but if the displacement is done slowly, the tissue will not be pierced by the displacement. For safety, it is ideal to keep the needle at the thickness of the tissue, especially when the needle will be inserted rapidly.

[0286] The needle can be non - degradable or degrade very slowly to provide gastric retention ability. This brings the possibility of leaving the needle in the tissue for a long time. However, since the tissue in the GI tract regenerates very quickly, the needle will eventually be expelled from the tissue. As long as the needle maintains its attached state to the device, it is also possible to recover these needles using a recovery protocol. For example, the device could be removed by endoscopic observation, or it could be attached to another swallowed device, such as an adhesive hydrogel, using host / guest interactions.

[0287] Finally, when the needle is separated from the device or the device detaches from the tissue, the device must pass safely through the GI tract. The literature states that there is no risk of perforation for pointed objects, one - dimensional objects less than 1 cm in length. Generally, when the needle is less than 1 cm in length, the risk of perforation is almost non - existent. However, the ideal length for safety and perforation can be influenced by the tissue type, subject type (e.g., animal, human), and tissue location in some cases, and can be longer than 1 cm in some cases. Predictive Examples

[0288] 1. A device using hooks to latch onto the tissue wall of a GI tube 2. The hooks used are between 10 and 250 μm in length, with approximately 30 μm being optimal. 3. The hooks penetrate the tissue between 1 and 3 mm. 4. Space the hooks at least 1.5 mm apart. 5. The hooks are non - degradable. 6. The needle with hooks is less than 1 cm in length. 7. More than one hook can be used per device. 8. The hooks provide a vertical holding force. 9. The inserted object provides a horizontal holding force. 10. Metal needles can be used for electrical stimulation. 11. A circuit can be made from one device with two needle - like probes or two devices each having one needle - like probe. 12. The entire mechanism of the device can be fitted inside a 000 capsule and ingested. 13. Since the inner lining of the stomach peels off, the retention of the device is temporary.

[0289] In humans, and in several animals such as pigs, the stomach is at the end of the esophagus (a long fibromuscular tube connecting to the mouth where food enters the GI tract). The stomach, the main site of food digestion in the human body, is a significant space providing a retention time of 1 - 4 hours. To digest food, the stomach contains gastric acid which creates a low - pH environment, as well as many enzymes that break down food into amino acids, such as pepsin. Through muscular movement, the stomach applies a translational force of approximately 0.2 N to its contents, and this translational force aids in solution movement. When the food is sufficiently broken down, it passes through the pyloric sphincter into the duodenum and reaches the small intestine. To protect itself from the harsh environment inside, the inner surface of the stomach has a mucus coating that is 40 - 450 μm thick. Under the mucosa is the muscularis mucosa, a thin layer composed of smooth muscle fibers. The muscularis mucosa separates the mucosa from the submucosa that covers the main muscle fibers of the stomach used for contraction.

[0290] The system was designed to ensure its placement so that the needle penetrates the inner membrane of the stomach. Using the rubber bock theory, a self - restoring shape was previously designed so that the device can invert with the needle pointing downwards in gastric acid. The device itself was manufactured from two different elements. The heavier bottom element was manufactured from stainless steel, while the upper element was manufactured using polycaprolactone (PCL). A needle is at the center of the device and is attached to a constricted spring coated with sugar. When the sugar dissolves, the spring functions as a self - injector, ejecting the needle from inside the device and allowing it to be inserted into the inner layer of muscle, as shown in Figure 51. To increase the retention ability of the needle, an Instron machine was used to apply a force of 1 N to the needle and bend its tip as shown in Figure 51. This hook at the end of the needle was created to help the needle lock onto the muscle fibers near the pyloric orifice in the distal stomach, as shown in Figure 54.

[0291] An ex-vivo model was created using porcine tissue to determine the maximum force required to disengage the needle from the inner lining of the stomach. This was because the porcine digestive tract had been proven to be a good model of its human counterpart. To confirm this, preliminary ex-vivo experiments were conducted. To do so, a 10 cm x 10 cm section of tissue was cut from the stomach of a Yorkshire pig. The porcine tissue was then fixed between two acrylic plates, with the inner side of the stomach facing upwards under a plate having a hole with a diameter of approximately 3 cm in the center. These plates were then placed on an Instron machine composed of a moving arm having a force sensor accurate to 0.1 mN internally. Using this arm of the Instron, a needle with a stainless-steel hook adhered to a screw was fixed in place. To determine the force required to penetrate the tissue, the Instron arm was lowered at a constant speed of 0.1 mm / second until it reached a depth of 5 mm, during which the device recorded the latching force required to reach that layer. Thereafter, this experiment was repeated using tissue from the stomach of a human cadaver. As shown in FIGS. 52 and 55, the human stomach showed very similar characteristics and produced almost equivalent results compared to the porcine tests.

[0292] Similar experiments were conducted using porcine tissue, which had been revealed to be a strong model of its human counterpart, to determine the ideal penetration depth to maximize the retention force. To determine the ideal penetration depth to maximize the retention force, the Instron arm was lowered at a constant speed of 0.1 mm / second until it reached penetrations of 1 mm, 3 mm, or 5 mm into the tissue. In this experiment, the Instron recorded the latching force required to reach its penetration layer, as shown in FIG. 56.

[0293] To verify this measurement and to determine which layer of the tissue maximized the anchoring force, the needle was stained with surgical dye prior to use. Once the experiment was complete, the tissue was fixed in paraffin. The needle insertion site was found by creating tissue sections by making parallel lateral cuts every 10 micrometers. Once the location was identified, the site was analyzed under an inverted microscope to determine the penetration depth. These histological findings also confirmed that the needle had become anchored to the muscle fibers in the mucosal musculae layer beneath the submucosa of the stomach's inner membrane.

[0294] Finally, to determine the force required to dislodge the needle tethered to the stomach's inner membrane, a similar experiment was conducted. A needle with a stainless - steel hook attached to a screw was mounted on the Instron's moving arm. Then, the arm was lowered at a constant speed of 0.1 mm / second until the needle penetrated 2.5 mm into the fixed fresh porcine tissue. Once this distance was reached, the arm was raised at a constant speed of 0.1 mm / second until the needle detached from the tissue. Throughout this experiment, the Instron recorded the penetration depth and the force applied to remove the needle from the tissue. This experiment was repeated several times, and it was found that the average values of the force required for penetration into the tissue and needle detachment were 3.86 mN and 10 mN, respectively.

[0295] From the determination of the force required to dislodge the needle tethered to the stomach's inner membrane and the confirmation that porcine tissue exhibits similar properties to that of the human stomach, a computational model was created to determine the ability of a self - restoring device with a hooked needle to maintain its position within the human stomach. Additionally, this model was used to determine whether a self - restoring device with variable auxiliaries designed for various applications has the ability to retain in the stomach.

[0296] According to the literature, the characteristic fluid flow rate in the stomach was found to be 2 - 3 mm / s, and its Reynolds number was determined to be approximately 0.1 - 30. This Reynolds number indicates that the flow in the stomach is laminar and is dominated by viscous forces. Therefore, the Stokes' law, which is derived from the Navier - Stokes equations modeled for small spheres in viscous fluids, can be used to determine the drag force on the device. This equation is shown in Equation 1 (where F is the drag force, r is the radius of the device, v is the velocity of the liquid, and μ is the dynamic viscosity of the liquid). F = 6π×r×v×μ Equation 1

[0297] To use this equation, the dynamic viscosity of gastric acid must be found. According to the literature, the dynamic viscosity of gastric acid can vary greatly based on the rheological properties of the gastric contents. When a diet of 10% glucose solution is ingested, the gastric contents can be modeled as a Newtonian fluid with a viscosity of 10 -3 Pa·s and a density of 1 kg / L. However, some foods have been shown to have viscosities as high as 10 Pa·s. Even the introduction of 1% of a more viscous food has been shown to increase the viscosity of gastric acid. As a result, it was difficult to establish an average dynamic viscosity. However, for this first - order simulation, it was assumed that the digested food was glucose - based and thus the dynamic viscosity was approximately 10 -3 Pa·s.

[0298] Using the radius of a self - restoring device attached to a 4 - mm needle and the Stokes' equation presented in Equation 1, the drag force on the device can be determined. This drag force is established to be 2.26×10 -7 N as shown using Equation 2. F = 6π×0.004 m×0.003 m / s×0.001 Pa·s = 2.26×10 -7 N Equation 2

[0299] As previously mentioned, this force is significantly lower than the force required to disengage the device as determined by ex-vivo experiments using an Instron, so it would allow the ability to attach another prosthesis to the self-healing device using a surgical non-absorbable suture that could be used in a wide range of applications that are intended to be discussed in Chapter 4. Equation 1 was used to calculate the resistance force for these devices, which would likely have a maximum radius of 4.5 mm to fit snugly into the 00 capsule, and the resistance force for each device was found to be 2.54×10 -7 N.

[0300] When determining the conditions necessary to disengage the needle from the inner lining of the stomach, it is also important to consider torque. Using the forces found for the self-healing device and the prosthesis, torque can be calculated using Equation 3 (where τ is torque, r is the moment arm, and F is force). τ = r×F Equation 3 τ = r×F Equation 3

[0301] Next, this equation can be used to generate a plot when the moment arm in the equation is the length of the needle from the tissue to the bottom of the device (1.25 mm). As shown in Figure 65B, a graph was generated to compare the number of prostheses attached to the self-healing device with the torque applied by the resistance force (the red dotted line indicates the maximum torque that can be applied to the system before the needle disengages. This value was determined from the force required to disengage the needle in an ex-vivo experiment on an Instron using the length of the needle from 1.25 mm of tissue to the bottom of the device as the moment arm). However, as shown in this plot, even a device with nine prostheses will only receive a torque that is several orders of magnitude less than what is required to disengage it.

[0302] From Figure 65B, it can be determined that the drag torque remains several orders of magnitude smaller than the torque required to detach the device from the gastric mucosa. However, as previously mentioned, since this dynamic viscosity does not take into account the food effect, a second model must be created. During the chewing process, the food is ground into small spherical food chunks, which then travel down the esophagus and into the stomach. When these food chunks reach the stomach, they mix with gastric acid to form gruel. Studies have shown using sieving and laser diffraction measurements that the size can vary depending on the texture of the ingested food by these individual chewed particles. For example, raw vegetables produce food chunks that are on average larger than 2 mm, while more than half of the nut particles are less than 1 mm in diameter. 26 。

[0303] Due to this large variation in the size of the food chunks, a model was created to determine whether the food chunks can exert enough torque to detach the device when they collide with the self - restoring device. This simulation was created on the premise of not attaching an auxiliary body to the device, but it should be noted that the needle needs to overcome the torque from the food chunks in addition to its own resistance. To do this, it was assumed that the food density is 1000 kg / m 3 and that the food chunks would shrink by an average of 50% upon collision with the self - restoring device while moving with gastric acid at 3 mm / s. The length of the food chunks was considered to range from 0.1 mm to 100 mm to cover all possible diameters. However, as shown in Figure 65C, even if the torque exerted by the food chunks were to increase by an order of magnitude depending on the texture of the food chunks, the torque applied to the self - restoring device would still be much smaller than that required to detach the device (the red dotted line indicates the maximum torque that can be applied to the system before the needle detaches. This value was determined from the force required to detach the needle in an ex - vivo experiment on an Instron, using the length of the needle from 1.25 mm of tissue to the bottom of the device as the moment arm).

[0304] In addition to verifying that the device can withstand the forces present in the stomach using computer simulations, experiments were planned to test its retention ability from preliminary measurements of the determined penetration depth and withdrawal force. This chapter will discuss the in-vitro and in-vivo tests necessary to properly simulate the stomach conditions to determine whether the device can withstand withdrawal.

[0305] In-vitro experiments were planned to test the ability of the microposts to maintain their position within the inner lining of the stomach despite the action of the resistance force from the gastric flow. To do this, Tygon PVC tubes were connected to each other to create a closed circuit attached to a water pump. A 10 cm x 10 cm section of tissue was cut from the stomach of a Yorkshire pig and fitted inside the vertically oriented tube. Then, three self-restoring devices with hooked needles were placed on top of this tissue. In addition, three self-restoring devices with unhooked needles, three self-restoring devices without needles, and three spherical objects the same size as the self-restoring devices were placed on the tissue as controls. Then, water was introduced into the system, the pump was turned on, and the pump sent the fluid at 0.1 m / s. Figure 57 illustrates the method by which this experiment was conducted.

[0306] The system was operated for one week to determine the ability of the hooked needles to withstand fluid flow by comparing them to their counterparts. As shown in Figure 58, all of the controls were detached by the second day, but the self-restoring devices with hooked needles were able to maintain their position throughout the week, corroborating the results of the computer simulation.

[0307] Based on the positive results from synthetic stomach experiments that confirmed the predictions from computer simulations, in-vivo tests for several days were planned for the pig model. Using an overtube, four self-restoring devices with hooked needles were placed in a straight line on the right side of the stomach. Another four self-restoring devices with normal needles were similarly placed on the left side of the stomach so that they could be distinguished. On the 2nd and 3rd days, an endoscope was used to monitor whether any of the self-restoring devices had moved. However, when the experiment was conducted, all of the devices, whether hooked or not, did not maintain their positions in the stomach.

[0308] There are several possible explanations for why the devices detached in the pig's stomach. Further experiments must be conducted in-vitro to clarify the characteristics of their retention ability in order to determine whether the devices are less elastic than the predicted computational model. The protocols for some of these experiments will be described in Chapter 4. However, detachment could also be due to differences between the human stomach and the pig model, such as motility. Unlike humans, who digest food in the stomach for 1 to 4 hours, pigs can take more than 6 hours to advance their meals to the small intestine. 27 In addition, based on observations, the food boluses in pigs are much larger than their human counterparts, which would increase the force exerted on the device by collisions. Finally, pigs eat large amounts several times a day to keep their stomachs full, while humans exert a greater relaxation of food intake restrictions.

[0309] Ex-vivo experiments on an Instron machine were conducted to determine the force required to penetrate the gastric mucosa, the depth required to ensure maximum retention, and the force required to remove the hooked needle. Two to three computational models were created and utilized this data to validate a self-restoring device with a hooked needle that would be able to hold its position regardless of the gastric condition and associated effects it encounters. In-vitro experiments were performed to simulate drag forces and ensure that the self-restoring device would not detach when exposed to fluid flow. From the positive results of this experiment, in-vivo tests were conducted using a porcine model, but no hooked needles were able to somehow hold their positions over the course of several days of investigation.

[0310] The long-term retention of microposts in the gastric mucosa creates several applications. As previously mentioned, this enables the sustained delivery of drugs such as insulin, which traditionally had to be administered daily. This also results in a viable oral delivery method for biological agents that traditionally had to be injected due to enzymatic degradation in the gastric environment.

[0311] Such microposts could serve as an anchor in the stomach for other devices that were not previously able to maintain a long retention time within the GI tract. These devices could be attached to the self-restoring device using non-absorbable sutures and exist in the stomach as an adjunct. One potential application could be for Bluetooth® low energy for medical monitoring. This technology is for physicians and It is creating a growing field that has the potential to help medical practitioners monitor the condition of their home patients. For example, a small Bluetooth® monitor that can fit into a 00 capsule, when used in combination with a long-term needle retention device, could monitor various properties in the stomach, such as pH or temperature changes. Finally, electrical stimulation of the stomach has shown promise with respect to addressing several clinical problems, such as gastroparesis and obesity. The auxiliary body attached to the self-healing device is a battery, and when this is created within a multi-needle system, an electrical circuit could be created with the inner lining of the stomach that could facilitate this stimulation.

[0312] Figure 51: Schematic of a self-healing system used for tissue localization and injection of a micro-post with a hook. An example of a 32-gauge stainless steel needle with a hook is shown on the left.

[0313] Figure 52: Penetration into porcine stomach tissue using a micro-post with a hook shows that the maximum penetration force is required at a depth of 1.9 mm for both 23 mm and 30 mm hooks.

[0314] Figure 53: Penetration into porcine stomach tissue using a micro-post with a hook shows that the force required to disengage the self-healing system was maximized using 1.9 mm and 2.4 mm hooks when the hook was 30 mm long.

[0315] Figure 54: Micro-post with a hook attached to the muscular fibers of porcine stomach tissue.

[0316] Figure 55: Penetration into human stomach tissue using a micro-post with a hook shows that the force required to disengage the self-healing system from the body and pyloric antrum tissue was maximized when the penetration depth was 5 mm.

[0317] Figure 56: Penetration into porcine small intestine tissue using a micro-post with a hook shows that the force required to disengage the self-healing system reached a plateau after 1.5 mm of penetration.

[0318] Figure 57: Penetration into porcine small intestine tissue using a hook-equipped micropost shows that the height at which the tissue can be lifted reached a plateau after 1.5 mm of penetration.

[0319] Figure 58: A hook-equipped micropost attached to porcine small intestine tissue itself.

[0320] Figure 59: Model of a horizontal tissue retention test. The probe pushes down a device tethered to the tissue by a needle, and the force required to dislodge the device is recorded.

[0321] Figure 60: It is shown that the force required to dislodge the self-restoring system increases linearly with the number of needles inserted into porcine stomach tissue.

[0322] Figure 61: It is shown that the force required to dislodge the self-restoring system from porcine stomach tissue increases statistically significantly when the three needles are placed further apart.

[0323] Figures 63A - 63B: Schematic diagram demonstrating the plan of an in-vitro experiment in which a self-aligning device is tethered to porcine stomach tissue while receiving pulsatile flow (Figure 63A). A graph demonstrating that three devices with hook-equipped microposts maintained their positions for a full week, in contrast to other systems that detached in less than two days (Figure 63B).

[0324] Figure 64: A graph demonstrating that there is no statistically significant difference between the in-vivo tethering force and the ex-vivo tethering force of the self-aligning device to porcine stomach. Ex-vivo measurements represent a study using three separate tissue samples from different stomachs.

[0325] Figure 65A: A graph demonstrating in-vivo that a tethered self-aligning device can hold its position while rotating by 30 degrees or less and receiving a force between 0.5 N and 0.75 N when encountering a force parallel to the stomach tissue using a pig model. Peaks and valleys are the result of the animal's respiration.

[0326] Figure 66: A schematic diagram demonstrating how a parylene-coated electrical probe bypasses mucus and conducts electricity through tissue. Without the coating, electricity would flow through the lower-resistance mucus and not stimulate the tissue.

[0327] Figure 67: A diagram demonstrating an electrical stimulation pill that includes two probes and a self-aligning device containing a power source and a programmable microcontroller encapsulated in an insulating shell (e.g., PDMS). An appropriate electrical circuit is connected to this system using insulated wires. This circuit is completed through the tissue. The entire system can be packaged in a 000 capsule.

[0328] Figure 68: A graph demonstrating that the current does not change significantly as the radius of a tissue-stimulating electrical probe increases when powered by two silver oxide batteries (1.55 V, 6.8 mm coin batteries).

[0329] Figure 69: A graph demonstrating that the current decreases as the distance between tissue-stimulating electrical probes increases when powered by two silver oxide batteries (1.55 V, 6.8 mm coin batteries).

[0330] Figures 70A and 70B: An electrical probe powered by a voltage source applies a pulsed stimulation through tissue as measured by an oscilloscope (Figure 70A). This can be compared to the background voltage measured within the tissue (Figure 70B). (Example 16) Exemplary System (SOMA)

[0331] The following examples demonstrate the fabrication and design of the exemplary self - restoring systems described herein.

[0332] The self - orienting ability of the exemplary system (SOMA) helps ensure that the device is correctly positioned to insert microposts into the tissue wall and, in some embodiments, addresses concerns regarding the safety and efficacy associated with insertion by delivering the microposts with sufficient force to reach only the submucosal layer. The natural gastric ecology provides a wide safety margin during the insertion event. It has been shown that the microposts will use a force greater than an additional 4 Newtons to penetrate through the outer muscular layer, an adjacent tissue layer, in some cases. SOMA was fabricated from materials tested for biocompatibility in both rats and pigs. Its small form factor generally prevents obstruction in the lower GI tract. SOMA has a smaller volume than the FDA - approved daily - dosing OROS system (φ9 mm × 15 mm), a non - degradable drug delivery system that results in an obstruction rate of approximately one in 29 million. When tested in vivo, SOMA showed no signs of obstruction, did not perforate tissue, and delivered a similar amount of API over a 2 - hour period compared to subcutaneous - placed microposts. The unique shape of SOMA results in a mechanism optimized for micropost delivery to the stomach.

[0333] A mono - monostatic body optimized for rapid self - orientation (Figs. 71A - 71D) that has the ability to withstand external forces (e.g., fluid flow, peristaltic motion, movement) when reaching a stable point was designed. For example, the upper compartment of the turtle shell, known as the carapace, has a high curvature to aid in self - orientation, while the lower compartment, known as the plastron, has a lower curvature to increase stability. The soft tissue of the turtle occupies the lower region of the shell, and thus the center of mass moves towards the plastron, further stabilizing the preferred orientation. Since self - orienting devices generally rely on a low center of mass compared to their center of volume, a combination of polycaprolactone (PCL) and 316L stainless steel was used to create this density gradient. Materials of similar density, such as polypropylene and field metal functions, were used interchangeably during the in vitro prototyping process. Since stainless steel is not normally used in oral devices, its oral toxicity was evaluated in rats during both acute and sub - chronic studies. Consistent with other studies in stainless steel in the GI cavity, including those related to orthodontics, no signs of inflammation or toxicity were observed (Fig. 75).

[0334] An axisymmetric shape described by a planar curve C in polar coordinates (r,θ) that minimizes the average time required for the object to orient to the GI tract tissue wall from 36 different angles while maximizing the torque required to tilt the device from its preferred orientation was designed using the fmincon function in MATLAB. As described below, the Newton's angular motion equation was used to calculate the theoretical orientation time. During the initial speculation about the shape, a geometric model of the turtle shell was utilized, which combines a hyperbola for representing the carapace and a low - curvature arc for representing the plastron. Mimicking the mass distribution of the turtle, in this model, the upper part of the device was made hollow and used to accommodate the actuating mechanism and API microposts. In addition, the device was scaled down to have a relatively small volume.

[0335] The fabricated optimized shape version was compared with spheres and ellipsoids of uniform density. Self-orientation and destabilization tests were performed in vitro using high-speed photography to validate the computer modeling (Figure 2A, Figure 72A). The optimal shape oriented fastest in 69% of all possible orientations and on average oriented more rapidly than other shapes (Figure 72B). The device reached its preferred orientation in less than 100 ms from more than 85% of all starting angles in an ideal environment. When placed in liquids found in the GI tract, such as oil, gastric juice, mucus, and water, the optimized device showed little deceleration due to viscous effects compared to the ellipsoid (Figure 72C). The device also showed strong elasticity after orientation to its preferred state compared to other shapes. This is because it did not tilt by more than 1 degree when exposed to mixing at 50 rpm on an inclined shaker with a movable range of ±15 degrees (Figure 72D).

[0336] After identifying the final shape, the shape was tested 300 times in an ex vivo experimental setting of a pig's stomach and 60 times in vivo in fasting animals for self-orientation and mucosal engagement persistence. Simulated tests of walking and extensive exercise stress in vivo were performed by 180-degree rotation and 30-degree tilt of the animal model. To measure proper device orientation, endoscopic observation of the pig was performed after abdominal agitation (Figure 72E), and X-ray imaging was performed (Figure 76). The optimized device oriented 100% in each test, while a control device of the same shape made only of PCL oriented with a 50% probability. When six SOMA prototypes were administered to a pig at once, no evidence of GI obstruction or other adverse clinical effects was observed (Figure 77). By using a device with rapid and consistent self-orientation ability in vivo, drug delivery activation events in the direction of the tissue generally occurred.

[0337] After creating the localized system, compression-processed API microposts were fabricated. Compared to liquid or solvent-cast formulations, the compression solid formulation delivered up to 100 times more API per unit volume. 80% human insulin and 20% 200k molecular weight polyethylene glycol under a pressure of 550 MPa By compressing a mixture of polyethylene (ethylene) oxide (PEO), 0.5 mg of insulin was loaded onto a sharp conical structure having measurements of 1.7 mm in height and 1.2 mm in diameter and attached it to a shaft portion made of a degradable biocompatible polymer such as PEO and hydroxypropylmethylcellulose (Figs. 73A - 73B).

[0338] Mechanical and chemical property analysis studies ensured the stability of the microposts. Raman spectroscopy measurements of the compression - processed microposts revealed a uniform API distribution across the entire micropost tip and verified the protein structure of the API after high - pressure exposure (Fig. 78, Table 1). In the compression test, a Young's modulus of 730 ± 30 MPa and an ultimate strength of 20.0 ± 0.7 MPa, such as those of PEO, were measured, thereby ensuring the integrity of the microposts in the presence of external forces (Fig. 79). The in vitro dissolution profile demonstrated complete dissolution within 60 minutes (Fig. 80). Stability studies conducted at 40 °C showed that solid insulin and PEO microposts remained stable in a dry environment for 16 weeks, maintaining a purity higher than 80% and less than 5% high - molecular - weight protein (HMWP) formation (Fig. 81). This is comparable to the 4 - week stability of liquid formulations. Using the same compression concept, a micropost having both a tip and a shaft composed entirely of insulin due to the absence of a binder was fabricated using 100% insulin. The 100% insulin microposts were utilized in SOMA to increase the insertion payload.

Table 1

[0339] The insertion profile of insulin microposts into porcine gastric tissue in vivo was evaluated. A custom-made controllable stage (Figure 82) was used to insert the tip at a speed of 0.2 mm / s, and a force of approximately 1 N was generally used to displace the tissue by more than 7 mm (Figure 73D). Using this measurement as a boundary condition, a time-delay actuating mechanism was implemented in a SOMA that has the ability to insert drug-loaded microposts into gastric tissue without causing perforation. A spring was used as the power source, for example, due to its low space requirement and its ability to release energy instantaneously along a single axis. A stainless-steel spring that provides a force of 1.7 - 5 N (k = 0.1 - 0.5 N / mm) at full compression was mounted on the SOMA. The spring accelerated a 1-mm micropost and then inserted the micropost 5 mm into the tissue. After actuation, they remained inside the device. Histological examination results from the SOMA insertion event were directly compared with those from in vivo porcine stomachs where a stained Carr-Locke needle was manually inserted (Figure 73E). Micro-computed tomography (CT) imaging confirmed that the spring was able to propel a barium sulfate-loaded micropost from the SOMA into ex vivo porcine tissue, for example, by less than 2 mm (Figure 73C). Tissue images from in vivo in-situ experiments demonstrated that the insulin microposts were inserted into the submucosa of porcine gastric tissue after being ejected from the SOMA with a 5-N spring (Figures 73F and 73H) and reached the same depth as the Carr-Locke needle. To ensure a safety margin for the insertion force, stainless-steel microposts were ejected into ex vivo porcine tissue using a 9-N steel spring (k = 1.13 N / mm). Even with additional force and momentum applied, the stainless-steel microposts did not perforate the tissue (Figures 73G and 73I).

[0340] To adjust the time such that the actuating event occurs in the stomach rather than the mouth or esophagus, crystallized sugars and sugar-like materials, such as sucrose and isomalt, were identified as useful spring encapsulation materials. The brittle nature of the material allows, for example, the spring to fully release within 1 ms after the coating diameter has dissolved to the critical size. Simulation in COMSOL and in vitro experiments demonstrated the ability to tune and release the spring over a quarter period with a standard deviation of 11.4 s (Figures 83A - 83E). The entire spring actuating system easily fits into the hollow portion of the SOMA, but the holes placed on the spring allow digestive fluids to penetrate and reach the encapsulation material.

[0341] Insulin-loaded microposts were administered to pigs, and blood glucose levels and blood insulin levels were measured over a 2-hour period. Microposts inserted into the tissue, delivered intragastrically by SOMA and subcutaneously by manual injection, released at a nearly zero-order kinetic rate (Figures 74A - 74D) (n = 5). Laparotomy and gastrotomy were also performed to manually place the microposts into the stomach, and this delivery method resulted in pharmacokinetic uptake comparable to SOMA (Figures 84A - 84D). Human insulin levels in pig plasma remained within the range of 10 - 70 pM throughout the sampling period. Manually inserted microposts fabricated from PEO 200K and human insulin, as well as SOMA delivery microposts manufactured from 100% human insulin, buried approximately 280 ± 20 μg of API beneath the tissue as estimated from weight measurements and histological examinations. All micropost insertion methods produced a blood glucose-lowering effect, and microposts inserted into the stomach produced a more significant drop compared to subcutaneously administered microposts. This data was compared to a study utilizing SOMA (n = 5) designed to localize in the stomach without inserting the microposts into the tissue. Pigs administered non-inserted SOMA experienced...

Claims

【Claim 1】 The invention described in the drawings.

Images