Adhesive material that can induce separation as needed

Abstract

An adhesive material that provides rapid and strong adhesion on wet surfaces, which can be separated as needed. The adhesive material is formed from one or more hydrophilic polymers or copolymers to which one or more amine coupling groups are grafted via multiple cleavable physical and / or covalent bonds, and one or more crosslinking agents. When the adhesive material is applied to a wet surface, it absorbs liquid, causing it to swell and form a hydrogel layer, resulting in the formation of temporary crosslinks with the surface, followed by covalent crosslinks. By introducing a triggering agent, the cleavable physical and / or covalent bonds are cleaved, allowing the adhesive material to be separated from the surface without trauma.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the interests of U.S. Provisional Patent Application No. 63 / 034,644, “Body Fluid Resistant Tissue Adhesives,” filed on 4 June 2020, which is incorporated herein by reference in its entirety.

[0002] Statement regarding government support This invention was developed with government support under Grant EFMA-1935291, granted by the National Science Foundation. The government has certain rights in this invention.

[0003] Field of Invention The present invention relates, in general terms, to adhesive materials and methods for bonding surfaces, and more particularly to methods for bonding dry bioadhesive materials and wet tissue surfaces, wherein the adhesion formed between the adhesive material and the surface is separable as needed. [Background technology]

[0004] Background of the Invention Millions of major surgeries are performed worldwide every year. While sutures and staples are most commonly used to close wounds, achieve hemostasis, and attach implantable devices to tissues in these surgeries, bioadhesives (e.g., tissue adhesives, hemostatic agents, and tissue occlusive agents) are being considered as alternatives due to their potential advantages, such as ease of use, airtight or watertight closures, and the potential to reduce tissue damage. However, existing bioadhesives have several limitations.

[0005] It is generally understood that when two dry surfaces are brought into contact with each other, they can immediately adhere due to intermolecular forces such as hydrogen bonds, electrostatics, and van der Waals interactions. However, forming such immediate adhesion between wet surfaces, such as those in biological tissues, is extremely difficult because water separates molecules originating from the two surfaces and immediately interacts with them, preventing adhesion between them.

[0006] Furthermore, since most existing tissue adhesives are in liquid or wet hydrogel form, they face many limitations, including weak bonding, poor biocompatibility, and poor mechanical compatibility with tissue. In particular, as shown in Figures 1A-1B, these types of existing tissue adhesives rely on their molecules (e.g., monomers / macromers or polymers) to diffuse into the polymer network of the tissue for bonding, which is time-consuming and can result in weak adhesion, and the bonding process is further hindered if a liquid is present at the interface between the adhesive and the tissue.

[0007] For example, commercially available adhesives (e.g., fibrin glue, albumin-based adhesives, polyethylene glycol-based adhesives), nanoparticle solutions, and mussel-inspired adhesives form a slow bond on a wet surface (more than 1 minute), and the bond is weak (20 Jm). -2(Interfacial fracture toughness less than 1%) (See Vakalopoulos, KA et al. Mechanical strength and rheological properties of tissue adhesives with regard to colorectal anastomosis: an ex vivo study. Annals of Surgery 261, 323-331 (2015); Rose, S. et al. Nanoparticle solutions as adhesives for gels and biological tissues. Nature 505, 382-385 (2014); Lee, BP, Messersmith, PB, Israelachvili, JN & Waite, JH Mussel-inspired adhesives and coatings. Annual Review of Materials Research 41, 99-132 (2011)). Furthermore, cyanoacrylate adhesives have been shown to have drawbacks such as high cytotoxicity after curing and lack of flexibility (see Annabi, N., Yue, K., Tamayol, A. & Khademhosseini, A. Elastic sealants for surgical applications. European Journal of Pharmaceutics and Biopharmaceutics 95, 27-39 (2015); Karp, JM A Slick and Stretchable Surgical Adhesive. New England Journal of Medicine 377, 2092-2094 (2017)). Bulk hydrogels have an interfacial fracture toughness of 100-1,000 Jm when adhered to tissue. -2While it has been reported that this can be the case to some extent, this type of hydrogel requires a long pressing time of at least 10 to 30 minutes or less to form an adhesion (see Li, J. et al. Tough adhesives for diverse wet surfaces. Science 357, 378-381 (2017)).

[0008] Furthermore, during medical procedures, it is sometimes crucial to correct the position of misplaced adhesive or to retrieve implanted devices that were held in place by adhesive. However, reversible adhesives have been largely undeveloped, and those that exist all suffer from significant drawbacks. Most adhesives generally rely on harsh, biocompatible conditions such as high concentrations of metal ions, heat, and ultraviolet (UV) irradiation to separate them, which is undesirable for the adhesive, the tissue to which it is attached, and adjacent biological tissues. [Overview of the project] [Problems that the invention aims to solve]

[0009] Given the high potential of tissue adhesives, particularly in medical applications, improvements are highly desired. [Means for solving the problem]

[0010] According to one embodiment, the present invention provides an adhesive material for bonding one or more wet surfaces and for revocably separating one or more surfaces, comprising: (i) one or more hydrophilic polymers or copolymers, (ii) one or more amine coupling groups grafted via a plurality of cleavable physical bonds and / or cleavable covalent bonds; and (iv) one or more crosslinking agents, wherein the adhesive material is in the form of a film or tape having a top and a bottom surface, and when one or more of the top and / or bottom surfaces of the adhesive material are placed in contact with one or more wet surfaces, the adhesive material absorbs liquid from one or more wet surfaces, swells, forms temporary crosslinks between the dry adhesive material and the wet surfaces, and has a liquid content such that it forms covalent bonds between one or more amine coupling groups and one or more wet surfaces.

[0011] Embodiments according to this aspect may include one or more of the following features: (i) One or more hydrophilic polymers or copolymers are selected from polyacrylic acid, polyacrylamide, polyvinyl alcohol, polyhydroxyethyl methacrylate, polyethylene glycol, polyurethane, casein, albumin, gelatin, chitosan, hyaluronic acid, alginate, oxidized alginate, cellulose, oxidized cellulose, polyvinylpyrrolidone, polystyrene sulfonate, collagen, pectin, and combinations thereof. (ii) One or more amine coupling groups are selected from N-hydroxysuccinimide esters, N-hydroxysulfosuccinimide esters, aldehydes, imide esters, epoxides, isocyanates, catechols, and combinations thereof. (iii) Cleavable physical bonds are selected from hydrogen bonds, electrostatic bonds and host-guest bonds, and cleavable covalent bonds are selected from boron-oxygen bonds, phenylboronic acid esters, disulfide bonds, hydrazone bonds, imine bonds, Diels-Alder bonds, carbon-carbon / carbon-sulfur bonds and oxime bonds. Host-guest bonds are selected from α-cyclodextrin (CD) as the host and n-butyl (n-Bu) group, adamantyl group, benzyl group and trans-azobenzene group as guests; β-CD as the host and adamantyl group, t-butyl group, cyclohexyl (ester) group, cyclododecyl (amide) group, benzyl group, 2-naphthylmethyl group, 1-pyrenylmethyl group, ferrocene group, trans-azobenzene group as guests; and γ-CD as the host and cyclododecyl group, benzyl group, 2-naphthylmethyl group, 9-phenanthrylmethyl group and 1-pyrenylmethyl group as guests. (iv) One or more crosslinking agents are selected from gelatin methacrylate, methacrylated hyaluronic acid, oxidized methacrylated alginate, polycaprolactone diacrylate, N,N'-bis(acryloyl)cystamine, N,N-methylenebis(acrylamide), polyethylene glycol diacrylate, polyethylene glycol dimethacrylate, and combinations thereof.The adhesive material comprises (i) polyvinyl alcohol (PVA) and poly(acrylic acid) (PAA), which, in a dry state, (ii) N-hydroxysuccinimide (NHS) esters grafted (iii) via cleavable disulfide bonds, and includes an interpenetrating network of polyvinyl alcohol (PVA) and poly(acrylic acid) (PAA). The negatively charged carboxylic acid groups of the poly(acrylic acid) grafted with the N-hydroxysuccinimide esters promote the absorption and swelling of the dry adhesive material and further form intermolecular bonds with one or more wet tissue surfaces within 60 seconds of contact between the dry adhesive material and one or more wet surfaces. The N-hydroxysuccinimide esters grafted on the poly(acrylic acid) form cleavable covalent bonds with primary amine groups present on one or more wet surfaces. After covalent crosslinking is formed between one or more amine coupling groups and one or more wet surfaces, the swollen adhesive material transforms into a hydrogel layer. The hydrogel has a pressure of at least about 1,000 Jm. -2 It has fracture toughness. The adhesive material is in the form of a flat sheet, a perforated sheet, double-sided tape or film, or perforated double-sided tape or film. The adhesive material includes a top surface and a bottom surface, and the adhesive material further includes one or more backing layers placed on at least one of the top surface and the bottom surface. The adhesive material further includes one or more engineering solids and / or devices bonded to one or more surfaces of the adhesive material. The adhesive material is biodegradable.

[0012] In another embodiment, the present invention provides a method for bonding a wet tissue using an adhesive material and, if necessary, removing the adhesive material, comprising: (i) one or more hydrophilic polymers or copolymers, wherein (ii) one or more amine coupling groups are grafted (iii) via a plurality of cleavable physical bonds and / or cleavable covalent bonds; and (iv) one or more crosslinking agents; placing the adhesive material in contact with one or more wet surfaces of a wet tissue; allowing the adhesive material to absorb liquid from one or more wet surfaces, thereby swelling the adhesive material to form a hydrogel layer; temporarily forming crosslinks between the adhesive material and the surfaces; optionally, forming covalent bonds between one or more amine coupling groups and one or more wet surfaces; introducing an inducer under physiological conditions to cleave the cleavable physical bonds and / or cleavable covalent bonds; and separating the adhesive material from one or more surfaces.

[0013] Embodiments according to this aspect may include one or more of the following features: (i) One or more hydrophilic polymers or copolymers are selected from polyacrylic acid, polyacrylamide, polyvinyl alcohol, polyhydroxyethyl methacrylate, polyethylene glycol, polyurethane, casein, albumin, gelatin, chitosan, hyaluronic acid, alginate, oxidized alginate, cellulose, oxidized cellulose, polyvinylpyrrolidone, polystyrene sulfonate, collagen, pectin, and combinations thereof. (ii) One or more amine coupling groups are selected from N-hydroxysuccinimide esters, N-hydroxysulfosuccinimide esters, aldehydes, imide esters, epoxides, isocyanates, catechols, and combinations thereof. (iii) Cleavable physical bonds are selected from hydrogen bonds, electrostatic bonds and host-guest bonds, and cleavable covalent bonds are selected from boron-oxygen bonds, phenylboronic acid esters, disulfide bonds, hydrazone bonds, imine bonds, Diels-Alder bonds, carbon-carbon / carbon-sulfur bonds and oxime bonds. Host-guest bonds are selected from α-cyclodextrin (CD) as the host and n-butyl (n-Bu) group, adamantyl group, benzyl group and trans-azobenzene group as guests; β-CD as the host and adamantyl group, t-butyl group, cyclohexyl (ester) group, cyclododecyl (amide) group, benzyl group, 2-naphthylmethyl group, 1-pyrenylmethyl group, ferrocene group, trans-azobenzene group as guests; and γ-CD as the host and cyclododecyl group, benzyl group, 2-naphthylmethyl group, 9-phenanthrylmethyl group and 1-pyrenylmethyl group as guests. (iv) One or more crosslinking agents are selected from methacrylate gelatin, methacrylate hyaluronic acid, oxidized methacrylate alginate, polycaprolactone diacrylate, N,N'-bis(acryloyl)cystamine, N,N'-methylenebis(acrylamide), polyethylene glycol diacrylate, polyethylene glycol dimethacrylate, and combinations thereof.The adherent material comprises an interpenetrating network of polyvinyl alcohol (PVA) and poly(acrylic acid) (PAA), where (i) the polyvinyl alcohol (PVA) and poly(acrylic acid) (PAA) are in a dry state, (ii) N-hydroxysuccinimide (NHS) esters are grafted via (iii) cleavable disulfide bonds. The PVA and PAA networks absorb liquid to dry one or more wet surfaces under a pressure of about 1 kPa or less applied for 5 seconds or less. The PAA network provides carboxylic acid groups that form immediate physical crosslinks with one or more surfaces via hydrogen bonds. Optionally, the cleavable NHS ester groups grafted to the PAA network form stable covalent crosslinks with primary amine groups on one or more surfaces. A pH-dependent de-crosslinking inducer is used to cleave the physical bonds. The pH-dependent de-crosslinking inducer is sodium bicarbonate. A biocompatible reducing agent is used to cleave the covalent bonds. The biocompatible reducing agent is glutathione. The inducer comprises a solution containing a combination of sodium bicarbonate and glutathione.

[0014] Other systems, methods, and features of the present invention will be apparent to those of ordinary skill in the art or will become apparent upon examination of the following drawings and detailed description. Such additional systems, methods, and features are all intended to be included within this description, within the scope of the present invention, and to be protected by the accompanying claims.

[0015] The accompanying drawings are included to provide a further understanding of the present invention, are incorporated in and constitute a part of this specification. The components of the drawings are not necessarily to scale, rather emphasis has been placed on clearly illustrating the principles of the present invention. The drawings serve to explain embodiments of the present invention and, in conjunction with this specification, to explain the principles of the present invention.

Brief Description of the Drawings

[0016] [Figure 1A] Schematically illustrates a tissue adhesive according to the prior art and shows an existing liquid form of a tissue adhesive. [Figure 1B]This paper provides a general overview of tissue adhesives based on prior art and illustrates existing tissue adhesives in the form of wet hydrogels. [Figure 1C] This paper provides a schematic description of tissue adhesives based on prior art and outlines the mechanism of existing tissue adhesives, which rely on the diffusion of monomers or polymers into the polymer network of the tissue for bonding. [Figure 2A] Examples of cleavable host-guest physical binding according to embodiments of the present invention are shown, including guests and corresponding binding cleavage inducers for the αCD host. [Figure 2B] Examples of cleavable host-guest physical bonds according to embodiments of the present invention are shown, including guests and corresponding cleavage-inducing substances for a βCD host. [Figure 2C] Examples of cleavable host-guest physical bonds according to embodiments of the present invention are shown, including guests and corresponding cleavage-inducing substances for a γCD host. [Figure 3] Examples of cleavable covalent bonds and corresponding bond cleavage inducing substances according to embodiments of the present invention are shown. [Figure 4A] The present invention schematically illustrates the design and mechanism of an immediate, strong, and induceably separable bioadhesive according to embodiments of the present invention, as well as the design of the bioadhesive and dry crosslinking and the induceable separation mechanism. [Figure 4B] This invention schematically illustrates the design and mechanism of an immediate, strong, and reliably separable bioadhesive according to embodiments of the present invention, and schematically illustrates the decrosslinking process of cleavable physical crosslinks with sodium bicarbonate. [Figure 4C] The present invention schematically illustrates the design and mechanism of an immediate, strong, and reliably separable bioadhesive according to embodiments of the present invention, and schematically illustrates the glutathione-mediated decrosslinking process of cleavable covalent crosslinks. [Figure 5] The requirements for adhesion and corresponding induced separation of bioadhesive materials over different time ranges according to embodiments of the present invention are schematically shown. [Figure 6A] This document shows a chemical route for synthesizing functional monomers according to embodiments of the present invention. [Figure 6B] This document shows a chemical route for synthesizing functional monomers according to embodiments of the present invention. [Figure 6C] This document shows a chemical route for synthesizing functional monomers according to embodiments of the present invention. [Figure 7] The chart shows the 1H NMR spectra of synthesized NHS ester-functional monomers having disulfide bonds according to embodiments of the present invention. [Figure 8A] The FTIR spectral chart of the bioadhesive material shows the induced separation of bioadhesive materials according to embodiments of the present invention, with peaks for carboxylic acid groups (1,698 cm-1), disulfide groups (614 cm-1), and NHS ester functional groups (1,162 and 1,232 cm-1). [Figure 8B] This invention demonstrates the induced separation of bioadhesive materials according to embodiments of the present invention, and schematically shows the verification of induced separation based on fluorescent microbeads to which primary amines are attached. [Figure 8C] This shows the induced separation of bioadhesive materials according to embodiments of the present invention, and displays a fluorescence microscope image of an initial bioadhesive sample. The scale bar is as shown in the image. [Figure 8D] This image demonstrates the induced separation of bioadhesive materials according to embodiments of the present invention, and shows a fluorescence microscopy image of a bioadhesive sample after incubation in PBS for 5 minutes. The scale bar is as shown in the image. [Figure 8E] This image demonstrates the induced separation of bioadhesive materials according to embodiments of the present invention, showing a fluorescence microscopy image of a bioadhesive sample after incubation for 5 minutes in PBS containing 0.5 SBC. The scale bar is as shown in the image. [Figure 8F] This image demonstrates the induced separation of bioadhesive materials according to embodiments of the present invention, showing fluorescence microscopy images of bioadhesive samples incubated for 5 minutes in PBS containing 0.5 M SBC and 50 mM GSH. The scale bar is as shown in the image. [Figure 8G]This image shows the induced separation of a bioadhesive material according to an embodiment of the present invention, and a photograph of a 180° peel test configuration for measuring interfacial fracture toughness. The scale bar is as shown in the image. [Figure 8H] This document demonstrates the induced separation of bioadhesive materials according to embodiments of the present invention, and shows the interfacial fracture toughness between the bioadhesive and moist porcine skin tissue after a short period of time following adhesion and application of various solutions for 5 minutes. Numerical values ​​represent the mean and standard deviation (n=4). P values ​​were determined by Student's t-test; ns indicates no significance (p>0.05); *p≦0.05; **p≦0.01; ***p≦0.001. [Figure 8I] This document demonstrates the induced separation of bioadhesive materials according to embodiments of the present invention, and shows the interfacial fracture toughness between the bioadhesive and moist porcine skin tissue after application of various solutions for 5 minutes a moderate amount of time has elapsed since adhesion. Numerical values ​​represent the mean and standard deviation (n=4). P values ​​were determined by Student's t-test; ns indicates no significance (p>0.05); *p≦0.05; **p≦0.01; ***p≦0.001. [Figure 8J] This document demonstrates the induced separation of bioadhesive materials according to embodiments of the present invention, and shows the interfacial fracture toughness between the bioadhesive and moist porcine skin tissue after a long period of time following adhesion and application of various solutions for 5 minutes. Numerical values ​​represent the mean and standard deviation (n=4). P values ​​were determined by Student's t-test; ns indicates no significance (p>0.05); *p≦0.05; **p≦0.01; ***p≦0.001. [Figure 9] Figures 3C-F show graphs illustrating the number of fluorescent microbeads adhering to the bioadhesive according to embodiments of the present invention after incubation for 5 minutes in various solutions. The numerical values ​​represent the mean and standard deviation (n=4). The p-value was determined by Student's t-test; ns indicates no significance (p>0.05); *p≦0.05; **p≦0.01; ***p≦0.001. [Figure 10]This is a schematic diagram of the configuration for a mechanical test to measure interfacial fracture toughness based on a standard 180° peel test (ASTM F2256). [Figure 11A] This shows the effect of pH on the adhesive performance of bioadhesives according to embodiments of the present invention, and illustrates various pH values ​​in the human body. [Figure 11B] This figure shows the effect of pH on the adhesive performance of bioadhesives according to embodiments of the present invention, and the interfacial fracture toughness between bioadhesives incubated in PBS with various pH settings and moist porcine skin tissue. The values ​​in Figure 11B represent the mean and standard deviation (n=3). The P-value was determined by one-way ANOVA and Tukey's multiple comparison test; ns indicates no significance (p>0.05). [Figure 12A] This graph shows the effectiveness of induceable separation of bioadhesives according to embodiments of the present invention, illustrating the interfacial fracture toughness between the bioadhesive and moist porcine skin tissue without induction and 1, 5, 10, and 30 minutes after application of the induction solution. The numerical values ​​in Figure 12A represent the mean and standard deviation (n=4). The p-values ​​were determined by Student's t-test; ns indicates no significance (p>0.05); *p≦0.05; **p≦0.01; ***p≦0.001. [Figure 12B] This graph shows the effectiveness of induced separation of bioadhesives according to embodiments of the present invention, and displays the force / width for typical displacement in a 180° peel test. [Figure 13A] Figures 3H-J show typical curves illustrating the force / width ratio against displacement in a 180° peel test after short-term bonding. [Figure 13B] Figures 3H-J show typical curves illustrating the force / width ratio against displacement in a 180° peel test after moderate bonding time. [Figure 13C] Figures 3H-J show typical curves indicating the force / width ratio against displacement in a 180° peel test after prolonged bonding. [Figure 14A]This photograph demonstrates the in vivo applicability and biocompatibility of a bioadhesive according to an embodiment of the present invention, showing that the bioadhesive immediately and firmly adheres to the subcutaneous cavity of a rat in vivo, and that it can be induced to separate. The scale bar is as shown in the image. [Figure 14B] This document demonstrates the in vivo applicability and biocompatibility of bioadhesives according to embodiments of the present invention, and shows H&E-stained tissue images to evaluate biocompatibility with respect to sham surgery. The scale bar is as shown in the image. [Figure 14C] This document demonstrates the in vivo applicability and biocompatibility of bioadhesives according to embodiments of the present invention, and shows tissue images stained with H&E to evaluate biocompatibility with respect to the separation of bioadhesives by induction. The scale bar is as shown in the image. [Figure 14D] The in vivo applicability and biocompatibility of the bioadhesive according to embodiments of the present invention are shown, and tissue images stained with H&E are shown to evaluate the biocompatibility of the implanted bioadhesive. The scale bar is as shown in the image. [Figure 14E] This figure demonstrates the in vivo applicability and biocompatibility of the bioadhesive according to embodiments of the present invention. It shows the degree of inflammation (0, normal; 1, very mild; 2, mild; 3, moderate; 4, severe; 5, very severe) in the sham surgery group, bioadhesive-induced isolation group, and bioadhesive-grafted group, evaluated by pathologists in a blinded state two weeks after subcutaneous transplantation. SM represents skeletal muscle, and GT represents granulation tissue. All experiments were repeated four times to obtain similar results. The numbers in Figure 14E represent the mean and standard deviation (n=4). The p-value was determined by Student's t-test; ns indicates no significance (p>0.05). [Figure 15A] This invention demonstrates the potential applications of bioadhesive materials according to embodiments of the present invention, illustrating with schematic diagrams the correction of incorrectly placed bioadhesive material and immediate closure using bioadhesive material on ex vivo pig lungs that have developed lacerations. [Figure 15B]This document illustrates the potential applications of bioadhesive materials according to embodiments of the present invention, and photographically describes the correction of incorrectly placed bioadhesive material and immediate closure using bioadhesive material on ex vivo pig lungs that have developed lacerations. [Figure 15C] This invention illustrates the potential applications of bioadhesive materials according to embodiments of the present invention, and schematically describes a patterned bioadhesive material for easily moving and diffusing an induced solution for impermeable devices. [Figure 15D] This invention illustrates the potential applications of bioadhesive materials according to embodiments of the present invention, and photographically describes patterned bioadhesive materials designed to facilitate the movement and diffusion of induced solutions for impermeable devices. [Figure 15E] This invention illustrates the potential applications of bioadhesive materials according to embodiments of the present invention, illustrating with schematic diagrams how the bioadhesive material immediately and firmly adheres to a beating pig heart in ex vivo conditions and can be removed as needed. [Figure 15F] This invention illustrates the potential applications of bioadhesive materials according to embodiments of the present invention, illustrating with photographs that the bioadhesive material immediately and firmly adheres to a beating pig heart in ex vivo conditions and can be removed as needed. [Figure 16A] The effects of induced separation and re-adhesion of bioadhesives according to embodiments of the present invention on adhesive performance are shown in schematic diagrams and graphs, illustrating the induced separation and re-adhesion of bioadhesive materials. [Figure 16B] The effects of induced separation and re-application of the bioadhesive according to embodiments of the present invention on its adhesive performance are shown in schematic diagrams and graphs, illustrating the interfacial fracture toughness between moist porcine skin tissue and the bioadhesive material when initially applied and when re-applied to the same tissue after induced separation. The numerical values ​​in Figure 16B represent the mean and standard deviation (n=3). The P-value was determined by Student's t-test; ns indicates no significance (p>0.05). [Modes for carrying out the invention]

[0017] Detailed explanation The definitions set forth below are useful for interpreting terms applicable to the features of the embodiments disclosed herein and are intended solely to define the components of this disclosure.

[0018] As used herein, the term “dry” in describing the adhesive materials of the present invention means that the material is below its equilibrium moisture content at the time of use. In this case, when the dry adhesive material of the present invention is placed in contact with tissue or other moist or damp (e.g., dampened with physiological saline) surface to be bonded, the material will absorb fluids (e.g., water, physiological saline, moisture, and physiological fluids such as plasma, interstitial fluid, lymph, cerebrospinal fluid, and gastrointestinal fluid) from the moist or damp surface. Generally, the liquid component of the dry adhesive material will be less than about 50% by weight based on the total weight of the dry adhesive material.

[0019] As used herein, the term “absorption” refers to the process by which atoms or molecules from the liquid on the moist surface penetrate the dry adhesive material across its surface when describing the mechanism by which a dry adhesive material absorbs water, saline solution, moisture, and physiological fluids such as plasma, interstitial fluid, lymph, cerebrospinal fluid, and gastrointestinal fluid from the moist surface to which it is in contact.

[0020] As used herein, the terms "tape" or "film" refer to a structure having a relatively large surface area relative to its thickness when describing the adhesive material of the present invention. Such a structure provides flexibility.

[0021] As used herein, the term “double-sided” refers to the adhesive on both the top and bottom surfaces of an adhesive tape or film when describing the adhesive materials of the present invention. It should be noted that while an adhesive material may be referred to as double-sided, it may be the adhesiveness of one side or both sides of the adhesive material that is utilized for a given application. For example, it may be desirable to utilize the adhesiveness of only one side of the adhesive material during use, in which case the adhesiveness of the other side is not utilized (for example, by keeping a material layer or backing material on the surface of the other side so as to disable the adhesiveness of the other side during use). In such an example, the material layer or backing material may initially be placed on both the first and second surfaces, and before bonding, only the material layer or backing material on the first surface may be peeled off so that only the adhesiveness of the first surface is utilized.

[0022] As used herein, the term “moist tissue” refers to biological tissue that contains (partially or completely covers) fluids including water, saline solution, moisture, and physiological fluids such as plasma, interstitial fluid, lymph, cerebrospinal fluid, and gastrointestinal fluid.

[0023] As used herein, the term “immediate” means, when used to describe immediate, temporary crosslinking between an adhesive material and one or more wet surfaces, that the time elapsed from the moment the adhesive material comes into contact with one or more wet surfaces is more than 0 seconds and within about 1 minute, more preferably about 50 seconds or less, more preferably about 40 seconds or less, more preferably about 30 seconds or less, more preferably about 20 seconds or less, more preferably about 15 seconds or less, more preferably about 10 seconds or less, more preferably about 9 seconds or less, more preferably about 8 seconds or less, more preferably about 7 seconds or less, more preferably about 6 seconds or less, and more preferably about 5 seconds or less.

[0024] As used herein, the term “temporary” refers, when used to describe immediate temporary crosslinking between an adhesive material and one or more wet surfaces, to a time range between the moment the immediate temporary crosslinking is formed and a sufficiently long time after the formation of that immediate temporary crosslinking, for example, more than 24 hours.

[0025] As used herein, the terms “rapid” or “fast” mean, when used to describe rapid covalent crosslinking between an adhesive material and one or more wet surfaces, that the time elapsed from the moment the adhesive material comes into contact with one or more wet surfaces is greater than 0 seconds and less than or equal to 5 minutes, more preferably less than or equal to about 4.5 minutes, more preferably less than or equal to 4 minutes, more preferably less than or equal to 3.5 minutes, more preferably less than or equal to 3 minutes, more preferably less than or equal to 2.5 minutes, more preferably less than or equal to 2 minutes, more preferably less than or equal to 1.5 minutes, and more preferably less than or equal to 1 minute.

[0026] As used herein, the term “swelling” generally refers to an increase in size due to a dry adhesive material when it comes into contact with one or more wet surfaces, in order to describe absorption and swelling. Dry adhesive materials are generally in the form of tapes or films that increase in thickness by absorbing liquids.

[0027] As used herein, the term “biodegradable,” when used to describe adhesive materials, means that some or all of the implanted material is broken down and / or subsequently removed by endogenous enzymes and / or water within the living animal body.

[0028] As used herein, "engineered solid" refers to solid materials that are not biological tissues, including synthetic materials such as plastics, metals, glass, ceramics, and elastomers, as well as biomaterials processed from natural sources.

[0029] As used herein, “as needed” means removing the adhesive material from one or more surfaces to which it is attached, as needed, at any desired time after the adhesive material has been attached to the target surface, which is achieved by applying or introducing an inducing mechanism between the adhesive material, the surface and / or the surface and the adhesive material. The inducing mechanism acts to break the crosslinks between the adhesive material and one or more surfaces. In particular, by applying or introducing an inducing mechanism, it becomes possible to remove the adhesive material from the surface by simply grasping it (e.g., with tweezers or similar) and pulling the adhesive material off the surface, with little or no trauma to the surface, within about 20 minutes, more preferably within about 10 minutes, more preferably within about 5 minutes.

[0030] The present invention generally provides an adhesive material capable of adhering to and bonding wet surfaces to each other, particularly wet tissue surfaces. The adhesive material is a dry adhesive material manufactured to provide a dry crosslinking mechanism for immediate and strong adhesion to wet surfaces. In particular, the dry adhesive material is manufactured to absorb liquid from one or more wet surfaces when placed in contact with one or more wet surfaces, thereby swelling the adhesive material. By absorbing the liquid at the interface, it becomes possible to immediately form crosslinks between the adhesive material and one or more wet surfaces due to intermolecular interactions, and subsequently, covalent crosslinks are rapidly generated between the adhesive material and one or more wet surfaces (see Figures 4A-B). As shown in Figures 4A-B, cleavable physical crosslinks and covalent crosslinks are located between the hydrophilic polymer / copolymer and the chemical groups that form crosslinks with one or more wet surfaces. In addition to immediately forming strong adhesion on various wet dynamic tissues, this adhesive material can be separated from the bonded surface by using an inducing material as needed. In particular, this adhesive material can be separated from the bonded surface at any desired time via an inducing mechanism, especially a biocompatible inducing substance. For example, by bringing the adhesive material into contact with an inducing mechanism, the inducing mechanism acts to cleave cleavable physical and covalent crosslinks (as shown, for example, in Figures 4A-B), thereby making it possible to separate the adhesive material from the surface.

[0031] Therefore, the adhesive material of the present invention overcomes the limitations described above with respect to existing adhesive materials (as further shown in FIGS. 1A - C). Instead of diffusing molecules in the tissue direction, as required for existing adhesive materials, the dried adhesive material of the present invention achieves immediate strong adhesion to wet surfaces through a synergistic combination of drying of the liquid at the interface by swelling the dried adhesive material, formation of an immediate temporary crosslink, and rapid formation of a covalent crosslink between the adhesive material and one or more wet surfaces. Further, in addition to reducing tissue trauma, the adhesive material of the present invention uses an adhesive structure and induction mechanism that do not require harsh non - biocompatible induction conditions (e.g., high concentrations of metal ions, heat, ultraviolet (UV) irradiation, etc.) to remove it, and can be separated from the adhered surface as needed.

[0032] As will be further described below, the adhesive material of the present invention can achieve strong adhesion within seconds (e.g., within 5 seconds) with a high interfacial fracture toughness (e.g., over 400 J / m -2 sup, over 500 J / m -2 sup, over 600 J / m -2 sup, over 700 J / m -2 sup, over 800 J / m -2 sup, over 900 J / m -2 sup, and even over 1000 J / m -2 sup) between a variety of wet dynamic tissues (e.g., skin, tendon, stomach, muscle, heart, liver) and engineering solids in ex vivo and in vitro models. It also has a low shear modulus (e.g., about 20 kPa or less, about 15 kPa or less, and even about 10 kPa), a shear and tensile strength of about 160 kPa, and a high stretchability (e.g., about 7 times, 8 times, 9 times, and even 10 times the original dimension before stretching) comparable to the properties found in living tissues, and has been demonstrated to exhibit high biocompatibility and controllable biodegradability. As further shown, the adhesive material can be easily removed by using an induction mechanism at any time after adhesion.

[0033] In this case, the dry adhesive material of the present invention not only provides a novel concept of wet adhesion that opens up new possibilities for a wide range of applications such as tissue adhesives, biological scaffolds, drug delivery, and implantable and implantable devices, but also further provides non-traumatic removal that can be performed as needed.

[0034] Embodiments of the present invention will be described in more detail here, with examples shown in the accompanying drawings. In the drawings and description, the same or similar reference numerals are used whenever possible when referring to the same or similar parts.

[0035] According to one embodiment, the present invention provides an adhesive material comprising (i) one or more hydrophilic polymers or copolymers, (ii) one or more amine coupling groups grafted via cleavable physical bonds and / or cleavable covalent bonds, and (iv) one or more crosslinking agents.

[0036] Adhesive materials are generally in the form of dry materials, so that when placed in contact with one or more wet surfaces, such as a wet tissue, they absorb liquid from one or more wet surfaces and remove liquid from the interface between the adhesive material and the wet surfaces. This absorption of liquid causes the dry material to swell. When the dry adhesive material absorbs liquid and swells, an immediate, temporary crosslinking is obtained between the adhesive material and the wet surfaces, and subsequently, as further described herein, a covalent coupling or crosslinking is rapidly formed between the adhesive material and one or more wet surfaces.

[0037] According to embodiments of the present invention, (i) one or more hydrophilic polymers or copolymers are selected from, but are not limited to, any conventional hydrophilic polymers that absorb water in a dry state, including, but are not limited to, polyacrylic acid, polyacrylamide, polyvinyl alcohol, polyhydroxyethyl methacrylate, polyethylene glycol, polyurethane, casein, albumin, gelatin, chitosan, hyaluronic acid, alginate, oxidized alginate, cellulose, oxidized cellulose, polyvinylpyrrolidone, polystyrene sulfonate, collagen, pectin, and combinations thereof. Since the adhesive materials of the present invention can be used in a wide range of biomedical applications, the polymers and copolymers used in the present invention are preferably biocompatible (however, for non-biomedicinal applications, it may not be necessary to use only biocompatible polymer materials). According to preferred embodiments, one or more hydrophilic polymers include one or more negatively charged groups such as poly(acrylic acid), casein, albumin, alginate, etc., which impart desirable hygroscopicity for rapid absorption and removal of interfacial liquid on a wet surface.

[0038] According to embodiments of the present invention, (ii) one or more amine coupling groups are selected from, but are not limited to, conventional amine coupling groups, including N-hydroxysuccinimide esters, N-hydroxysulfosuccinimide esters, aldehydes, imide esters, epoxides, isocyanates, catechols, and combinations thereof. Since the adhesive material can be used in a wide range of biomedical applications, the amine coupling groups used in the present invention are preferably biocompatible (however, for non-biomedicinal applications, it may not be necessary to use only biocompatible amine coupling groups). This type of amine coupling group is configured such that one or more amine coupling groups can be grafted onto one or more hydrophilic polymers via cleavable bonds, and these one or more amine coupling groups are then configured to form covalent crosslinks with the wet surface on which the adhesive material is used.

[0039] According to embodiments of the present invention, (iii) cleavable physical bonds are selected from, but are not limited to, conventional bonds of this type, and include hydrogen bonds, electrostatic bonds, host-guest bonds including α-cyclodextrin (CD) as the host and n-butyl (n-Bu) group, adamantyl group, benzyl group, trans-azobenzene group as the guest; β-CD as the host and adamantyl group, t-butyl group, cyclohexyl (ester) group, cyclododecyl (amide) group, benzyl group, 2-naphthylmethyl group, 1-pyrenylmethyl group, ferrocene group, trans-azobenzene group as the guest; and γ-CD as the host and cyclododecyl group, benzyl group, 2-naphthylmethyl group, 9-phenanthrylmethyl group, 1-pyrenylmethyl group as the guest (see, for example, Figure 2). Cleavable covalent bonds can also be selected from conventional types of bonds, and are not limited to these, but include boron-oxygen bonds such as boronic acid-diols and phenylboronic acid esters, disulfide bonds, hydrazone bonds, imine bonds, Diels-Alder bonds, carbon-carbon / carbon-sulfur bonds such as trithiocarbonates (TTC) and thiuram disulfide (TDS), and oxime bonds (see, for example, Figure 2).

[0040] According to embodiments of the present invention, (iv) one or more crosslinking agents are selected from, but are not limited to, conventional crosslinking agents, but include, gelatin methacrylate, methacrylated hyaluronic acid, oxidized methacrylated alginate, polycaprolactone diacrylate, N,N'-bis(acryloyl)cystamine, N,N'-methylenebis(acrylamide), polyethylene glycol diacrylate, polyethylene glycol dimethacrylate, and combinations thereof. Since this adhesive material can be used in a wide range of biomedical applications, the crosslinking agents used in the present invention are preferably biocompatible (however, for non-biomedicinal applications, it may not be necessary to use only biocompatible crosslinking agents).

[0041] According to a preferred embodiment, the adhesive material, in its as-prepared (before drying) form, comprises (i) one or more hydrophilic polymers in about 5 w / w% to about 50 w / w%; (ii) one or more amine coupling groups in about 1 w / w% to about 10 w / w% (iii) grafted via cleavable physical and / or covalent bonds; (iv) one or more crosslinking agents in about 0.05 w / w% to about 0.15 w / w%; and the remainder being deionized water.

[0042] According to a particular embodiment of the present invention, the adhesive material is a bioadhesive material formed from an interpenetrating network of polyvinyl alcohol (PVA) and poly(acrylic acid) (PAA), wherein in a dry state, (ii) N-hydroxysuccinimide (NHS) esters are grafted via cleavable disulfide bonds. The immediate adhesion of the adhesive material depends on the removal of interfacial water and / or other physiological fluids (e.g., saline solution, interstitial fluid, intracellular fluid, etc.) from the wet surface (especially a wet tissue surface) by the highly hygroscopic PAA network in the bioadhesive (see, for example, Figure 4A), and the immediate formation of physical crosslinks such as hydrogen bonds and electrostatic interactions between the surface and the material. Subsequently, the cleavable NHS esters of the bioadhesive material and primary amine groups on the tissue surface form covalent crosslinks, further improving long-term adhesive stability and strength (Figure 4A).

[0043] According to a preferred embodiment, the adhesive material is a poly(vinyl alcohol) (PVA)-based adhesive material. The PVA-based adhesive material according to an embodiment of the present invention, in its as-prepared (pre-dried) form, preferably comprises about 20 w / w% to about 40 w / w%, more preferably about 25 w / w% to about 35 w / w%, and even more preferably about 30 w / w% of polyacrylic acid; about 5 w / w% to about 15 w / w%, more preferably about 10 w / w% of PVA; about 0.5 w / w% to about 1.5 w / w% of PAAc-disulfide-NHS ester, more preferably about 1 w / w% of PAAc-disulfide-NHS ester; about 0.01 w / w% to about 0.1 w / w% of poly(ethylene glycol methacrylate) (PEGDMA), more preferably about 0.05 w / w% of PEGDMA; and the remainder being deionized water.

[0044] According to an exemplary embodiment, the gelatin-based adhesive, in its as-prepared (pre-dried) form, comprises about 35 w / w% polyacrylic acid, about 10 w / w% PVA, about 1 w / w% PAAc-disulfide-NHS ester, about 0.05 w / w% PEGDMA, and the remainder being deionized water.

[0045] According to embodiments of the present invention, the adhesive material has a top surface and a bottom surface. Preferably, the adhesive material is generally in the form of a sheet, tape, or film (any of which may be perforated, partially perforated, or not perforated) having a top surface and a bottom surface. In a preferred embodiment, the adhesive material comprises a removable backing layer or an integrated (non-removable) material layer disposed on one or more adhesive surfaces. For example, one or more removable backing layers may be disposed on one or more adhesive surfaces, particularly for the purpose of facilitating the handling of the adhesive material and protecting it from moisture. If necessary, one or more integrated material layers may be disposed on one or more adhesive surfaces so that one or more surfaces or a portion of a surface is non-adhesive, particularly for the purpose of using one side or a portion of a surface.

[0046] For example, a removable backing layer may be placed over the entire top surface of an adhesive material, while an integrated material layer may be placed over the entire bottom surface. In this case, by removing the backing layer before use, only the adhesion of the top surface of the adhesive material can be utilized during application. Similarly, a removable backing layer may be placed over both the top and bottom surfaces, and by removing the backing layer before use, the adhesion of both the top and bottom surfaces of the adhesive material can be utilized during application. In some applications, it may be desirable to combine one or more removable backing layers placed on one surface (e.g., the top surface) with one or more integrated material layers also placed on the same surface (e.g., the top surface), so that only the adhesion of the surface (e.g., the top surface) where the removable backing layers are located can be utilized by removing the backing layers from these areas, while the adhesion of the surface (e.g., the top surface) where the integrated backing layers are located cannot be utilized. For example, an integrated material layer can be placed on the central part of the top surface of the adhesive material, while one or more removable backing layers can be placed on the portion surrounding the central part of the top surface. In this way, when the removable backing layer is removed, the top surface of the adhesive material will adhere to the wet surface along the outer or peripheral portion of the adhesive material, while the central part of the adhesive material will not adhere because the integrated material layer is not removed.

[0047] An integrated material layer or removable backing layer is provided to prevent the material from adhering before the intended use. In this case, the removable backing layer or integrated material layer neutralizes the adhesive properties of the material. An integrated material layer or removable backing layer is provided to prevent the material from adhering outside the target tissue while it is attached to moist tissue and thereafter. In this case, the integrated material layer or removable backing layer exhibits non-adhesion to moist biological tissue. The removable backing layer or integrated material layer can be placed directly on one or more surfaces of the adhesive material (i.e., with nothing in between). In some embodiments, a layer, adhesive, or other substance used to bond these materials together is placed between one or more surfaces of the adhesive material and the integrated material layer or removable backing layer. The removable backing layer or integrated material layer can be made of any material that prevents the adhesive material from adhering to a moist surface. The integrated material layer or removable backing layer can be made of any material that does not exhibit adhesion to moist biological tissue. In particular as described herein, the adhesive material, when placed in contact with a wet surface, is in the form of a dry material that absorbs liquid from the wet surface, thereby swelling. This absorption of liquid and swelling of the dry adhesive material immediately forms a temporary crosslink between the adhesive material and the wet surface, followed by the rapid formation of a covalent coupling or crosslink between the adhesive material and the wet surface. In this case, the removable backing layer or integrated material layer can generally be made of any material that prevents the adhesive material from contacting the surface. In this case, the integrated material layer or backing material layer can generally be made of any material that does not form an adhesive interface with wet biological tissue. When using the adhesive material of the present invention, the removable backing layer or integrated material layer should be made of a biocompatible material. According to embodiments of the present invention, the removable backing layer is made of paper coated with polyethylene or any hydrophobic polymer and a film of poly(methyl methacrylate) or any hydrophobic polymer.This type of removable backing layer can be directly bonded to one or more surfaces of an adhesive material, or it can be bonded using a layer of adhesive or another adhesive such as an acrylic adhesive. According to embodiments of the present invention, the integrated material layer is made of a silicone elastomer, thermoplastic polyurethane, hydrogel, or any other biocompatible material that does not adhere to wet tissue. This type of integrated material layer can be directly bonded to one or more surfaces of an adhesive material.

[0048] According to embodiments of the present invention, the adhesive material is in the form of a dry film or tape that can be directly applied to a target surface (for example, after removing a removable material layer or backing layer provided on one or more surfaces of the adhesive material without performing any other preparatory steps). For example, in a moist physiological environment, biological tissue is generally covered with a thin layer of water. When the adhesive material of the present invention is applied, this water or liquid becomes a liquid at the interface between the tissue and the applied adhesive, which usually prevents the rapid formation of a strong bond between the tissue and the adhesive. To achieve immediate and strong adhesion on moist tissue, the adhesive of the present invention employs a drying crosslinking mechanism that removes the liquid at the interface and forms adhesion on the moist tissue (for example, as shown in Figure 4A). For example, (i) one or more hydrophilic polymers or copolymers (e.g., PVA and PAA meshes) of the dry adhesive material can absorb the liquid at the interface and dry the moist tissue surface while being gently pressed (e.g., 1 kPa) for a few seconds (preferably less than 5 seconds). Simultaneously, the PAA network (or other suitable hydrophilic polymer / copolymer network) of the adhesive material provides a large number of groups (e.g., carboxylic acid groups) that can immediately form physical crosslinks (i.e., hydrogen bonds) with the tissue surface (see Figures 4A and 45). Furthermore, cleavable amine (e.g., NHS ester) groups grafted onto the PAA network (or other suitable hydrophilic polymer / copolymer network) form stable covalent crosslinks (i.e., amide bonds) with the abundant primary amine groups present on the tissue surface within minutes (see, for example, Figures 4A and 45). The bioadhesive, after swelling following adhesion to the tissue surface, exhibits an elasticity of at least 7 times and a fracture toughness of 1,000 Jm -2 This results in a thin layer of hydrogel.

[0049] According to the present invention, the strong adhesion between the adhesive material and the desired surface (e.g., a moist tissue surface) depends on both physical and covalent crosslinking, the relative contributions of which vary depending on different time scales of adhesion. In the short term (<5 minutes), adhesion between the adhesive material and the surface is dominated by immediate physical crosslinking (i.e., hydrogen bonding). As this equilibrates and the carboxylic acid groups in the adhesive material are neutralized, causing the adhesive to lose its ability to form physical crosslinks with the tissue surface, the contribution of physical crosslinking to adhesion decreases over time (e.g., as shown in Figures 4B and 5). Therefore, over longer time periods, the contribution of covalent crosslinking (i.e., amide bonding) to adhesion gradually increases (Figure 5).

[0050] The timing at which it becomes necessary to separate the adhesive of the present invention from a surface can vary from immediately after application (for example, when the adhesive must be repositioned due to initial misplacement) to within a few minutes to a few hours after application (for example, when temporarily applied adhesive during surgery is subsequently removed for final repair) or even several days to several weeks after application (for example, when an implanted device implanted using adhesive material is removed). Therefore, the present invention provides an adhesive material having an induceable separation mechanism, wherein the induceable separation mechanism is biocompatible and effective over a wide time range.

[0051] The present invention provides an adhesive material having both physical crosslinks and covalent crosslinks that can be cleaved as needed by using a biocompatibility-inducing solution (Figure 4A). In particular, physical crosslinks can be cleaved by pH-dependent decrosslinking, especially through the cleavage of hydrogen bond physical crosslinks. Sodium bicarbonate (SBC) is an example of an inducer that can be used to induce cleavage via pH-dependent decrosslinking (e.g., Figure 4B). To provide an adhesive material having cleavable covalent crosslinks, novel functional monomers are synthesized to introduce cleavable disulfide bonds between NHS ester groups (amine groups) and one or more hydrophilic polymers or copolymers (e.g., PAA networks) (see, for example, Figures 6 and 7). In this case, a biocompatible reducing agent such as glutathione (GSH) is used as an inducer to cleave these covalent crosslinks. When an adhesive bonded to a surface via cleavable covalent bonds is brought into contact with this type of inducer, the suspended thiol groups in the inducer (e.g., GSH) cleave the disulfide bonds of the bioadhesive to thiol groups, thereby cleaving the covalent crosslinks between the bioadhesive and the tissue surface (Figure 4C). It is beneficial that the adhesive material of the present invention and the associated cleavage mechanism, involving the cleavage of both physical and covalent bonds, can be achieved under physiological conditions.

[0052] The adhesive material of the present invention has high processability and can be flexibly manufactured in a wide range of shapes, such as flat sheets, perforated sheets, and tape-like wound materials, to meet various requirements, although it is not limited to these. This adhesive material also has several properties that are favorable for biological applications. In particular, the swollen adhesive material has a low shear modulus of approximately 20 kPa and an elasticity of about 7 times its original length before swelling, and therefore exhibits properties equivalent to soft tissue. The dried adhesive material can also be manufactured to have very high biocompatibility and biodegradability depending on its composition.

[0053] To evaluate the adhesion and induced separation performance of the adhesive material of the present invention, total internal reflection Fourier transform infrared spectroscopy (ATR-FTIR) analysis was used. First, carboxylic acid groups (1,698 cm⁻¹) were found in the adhesive material. -1 ), NHS ester group (1,162 and 1,232 cm) -1 ) and disulfide groups (614cm) -1 We confirmed that the adhesive was incorporated (see Figure 8A). To verify that physical and covalent crosslinking of the adhesive could be induced, 0.5 M SBC and 50 mM GSH in PBS were used as induction solutions. Primary amine-bonded fluorescent microbeads were used as a model to evaluate adhesion and separation between the adhesive and the amine-rich surface of the microbeads (Figure 8B). Fluorescence microscopy images of the bioadhesive incubated in PBS containing amine-bonded fluorescent microbeads for 30 minutes showed that the microbeads were stably adhered to the adhesive of the present invention by physical and covalent crosslinking between the adhesive and the microbead surface (see Figures 7C and 78). The bioadhesive with these fluorescent microparticles was incubated in PBS alone, in PBS containing 0.5 M SBC, and in PBS containing 0.5 M SBC and 50 mM GSH for 5 minutes each. The bioadhesive incubated in PBS alone did not show a significant change in the number of adhered fluorescent microbeads (Figures 8D and 89). Bioadhesives incubated in PBS containing 0.5 M SBC showed a significant decrease in the number of adhered fluorescent microbeads, although a substantial portion of the microbeads remained adhered (Figures 8E and 89). In contrast, bioadhesives incubated in PBS containing 0.5 M SBC and 50 mM GSH showed almost complete separation of the adhered fluorescent microbeads (Figures 8F and 89). These results indicate that the adhesion of the amine-rich surface of microbeads to the adhesive is stable under physiological conditions, and that both physical crosslinking (by SBC) and covalent crosslinking (by GSH) cleavage are required for complete separation by induction.

[0054] Furthermore, the effect of the induced separation mechanism of the present invention on adhesive performance was analyzed. In this analysis, the interfacial fracture toughness between the adhesive material and moist porcine skin tissue was measured according to the standard test for tissue adhesives (180° peel test, ASTM F2256) (Figures 8G and 8J). As shown in Figures 8H-J, the adhesive material of the present invention exhibited an interfacial fracture toughness of 400 Jm when applied to moist porcine skin tissue and gently pressed for less than 5 seconds (e.g., 1 kPa). -2 The adhesive demonstrated the ability to form a strong bond exceeding [a certain threshold] and to bond immediately and strongly. Furthermore, since this adhesive was demonstrated to form a strong bond immediately under various physiological pH conditions, it has the potential to be used in various locations on the human body (Figure 11).

[0055] To analyze the induced separation, the following were applied to the adhesives of the present invention adhered to pig skin: PBS alone, PBS containing 50 mM GSH, PBS containing 0.5 M SBC, and PBS containing 0.5 M SBC and 50 mM GSH. Interfacial fracture toughness was then measured (Figures 12 and 13). With respect to short-term adhesion (inducing solution applied 1 minute after adhesion formation), the interfacial fracture toughness measured in samples treated with SBC-containing solutions (PBS containing 0.5 M SBC, PBS containing 0.5 M SBC and 50 mM GSH) was significantly reduced, while the difference between the sample treated with the GSH-only solution (PBS containing 50 mM GSH) and the sample treated with PBS alone was negligible (Figure 8H). This demonstrates that SBC and its ability to cleave physical crosslinks play a crucial role in inducing separation of short-term adhesion (separation shortly after adhesion, e.g., 1 minute after adhesion). For moderate-duration adhesion (applied 30 minutes after adhesion formation), all samples except those treated with PBS alone showed significantly lower interfacial fracture toughness compared to those treated with PBS alone. Furthermore, the interfacial fracture toughness of samples treated with solutions containing both SBC and GSH (PBS containing 0.5M SBC and 50mM GSH) was significantly lower compared to samples treated with solutions containing either SBC or GSH (PBS containing 50mM GSH or PBS containing 0.5M SBC) (Figure 7I). This demonstrates that both SBC and GSH, and their ability to cleave both physical and covalent crosslinks, play a crucial role in the induced separation of adhesives after moderate time has elapsed since adhesion. For long-duration adhesion (solution applied 12 hours after adhesion formation), samples treated with GSH-containing solutions (PBS containing 50mM GSH and PBS containing 0.5M SBC and 50mM GSH) showed significantly lower interfacial fracture toughness compared to the other samples. Furthermore, the difference between samples treated with a solution containing only SBC (0.5M SBC-containing PBS) and samples treated with PBS alone was negligible (Figure 8J).This demonstrates that the ability to cleave GSH and its covalent crosslinks plays a crucial role in induced separation after prolonged adhesion. These results demonstrate that induced solutions of PBS containing 0.5 M SBC and its 50 mM GSH can cleave both physical crosslinks (by SBC) and covalent crosslinks (by GSH), substantially reducing interfacial fracture toughness over a wide time range after adhesion formation (Figures 4 and 5).

[0056] To evaluate the ability of the adhesive material to rapidly form a strong adhesion that can be induced to separate in vivo in moist tissue, adhesive patches according to the present invention were adhered to the muscle layer of the subcutaneous cavity of rats, and then separation of the bioadhesive was induced as needed (Figure 14A). The adhesive patch layer, which was gently pressed against the muscle layer of rats for 5 seconds, was demonstrated to form an adhesion strong enough to resist peeling with tweezers. To separate the adhered adhesive patch as needed, an induction solution was applied to the subcutaneous cavity of rats for 5 minutes. The adhesive patch separated as needed, and no damage was observed to the underlying tissue surface (Figure 14A). The biocompatibility of the adhesive and the induced separation process in vivo was further evaluated in a rat dorsal subcutaneous transplantation model (Figures 14B-E). Histological evaluations conducted by pathologists in a blinded environment showed that the inflammatory response induced by the induced solution and the induced separation process two weeks after surgery was mild, comparable to the inflammatory response observed in the sham surgery control group (surgery without transplantation) (Figures 14B, C, and E). Furthermore, histological evaluations two weeks after transplantation of the bioadhesive showed that the inflammatory response was mild to moderate (Figures 14D and E). These results demonstrate the biocompatibility of the adhesive material and its induced separation according to the present invention.

[0057] Bioadhesives that can be induced and non-traumatically separated as needed can find potential applications in various clinical settings across different timeframes. In short timeframes, bioadhesives may be mistakenly and improperly adhered to tissue surfaces, requiring immediate correction for successful surgical treatment. In such clinical settings, the induced separation provided by the adhesive material of the present invention allows for immediate correction of improperly adhered adhesive without damaging the underlying tissue. In medium timeframes, emergency treatment of clinically unstable patients often requires a final repair after the initial surgery (for example, temporary adhesion for several hours to temporarily close an organ during initial damage control surgery). In such clinical settings, the induced separation of the adhesive material of the present invention allows for the removal of adhesive applied during the initial surgery, as needed, for subsequent final repair. In long timeframes, various medical devices, such as cannulas and drains during cardiac surgery and drug depots in local chemotherapy for cancer, need to be removed several days to several weeks after implantation. In such clinical settings, the induced separation properties and mechanisms of the adhesive material of the present invention enable not only secure fixation of the device but also trauma-free retrieval.

[0058] To investigate the applicability of the separable adhesive material of the present invention, an ex vivo proof of principle was performed using pig organs. To demonstrate the potential advantage of the adhesive material of the present invention, which adheres immediately and strongly under such conditions and can be induced to separate, it was demonstrated that the adhesive, which initially only partially sealed a lacerated pig lung (3 cm incision), could be repositioned without issue (Figure 15A). As shown in Figure 15B, the improperly adhered adhesive material was easily removed 5 minutes after application of the induction solution. Importantly, the pig lung was then rapidly and airtightly sealed without any loss of adhesive performance by applying new adhesive (Figure 16).

[0059] In other embodiments, it has been demonstrated that adhesive devices according to the present invention immediately and firmly integrate with moist dynamic tissue and can be removed as needed. Many devices do not readily penetrate the induced solution of the present invention, so a patterned bioadhesive was designed to facilitate the movement and diffusion of the induced solution to the adhesive interface (Figure 15C). As shown in Figure 15D, the patterned bioadhesive according to the present invention is placed on an impermeable thermoplastic polyurethane (TPU) film. This facilitates the movement and diffusion of the induced solution (colored red with food coloring) throughout the bonded device. A simulated device consisting of gold-plated polyimide and the patterned bioadhesive according to the present invention was demonstrated to quickly and firmly adhere to a beating (simulating heartbeat by supplying pressurized air) ex vivo pig heart and be removable as needed (Figure 15E). Because the adhesive material of the present invention has the ability to bond immediately and strongly, when the bioadhesive device was attached to a beating pig heart, a strong and stable bond could be formed within 5 seconds. Furthermore, by applying an induction solution, the bonded device could be removed within 5 minutes without causing trauma (Figure 15F). Therefore, the ability of the adhesive material of the present invention to immediately form a strong bond on moist, dynamic tissue and to separate as needed may be particularly advantageous for the integration of implantable devices and potentially trauma-free removal.

[0060] In addition to providing this beneficial, optionally retrievably separable mechanism, the adhesive material of the present invention can be used with commercially available cyanoacrylate adhesives (e.g., Histoacryl Flex). TM Dermabond TM ), albumin-based adhesives (e.g., Bioglue) TM ), polyethylene glycol-based adhesives (for example, CoSeal) TM DuraSeal TM ), fibrin glue (for example, Tisseel TMIn addition to the above, it provides faster and superior adhesive performance compared to existing tissue adhesives such as nanoparticle solutions and UV-curable surgical adhesives. The adhesive material of the present invention is applicable to a wide range of moist tissues such as skin, tendons, stomach, muscle, heart, and liver. In this case, the adhesive may be particularly useful as a promising alternative to sutures or stapling in the surgical repair or closure of wounds. The property of fast and strong adhesion to dry adhesive materials is also highly desirable for attaching various functional devices to dynamically deformable tissues, and therefore it is possible to immediately obtain strong adhesion between moist tissue and various engineering solids such as hydrogels, silicon, titanium, polydimethylsiloxane (PDMS), polyimide, and polycarbonate that cannot be achieved with existing tissue adhesives. In other words, the dry adhesive material of the present invention can be used to attach one or more various engineering solids to one or more moist tissue surfaces.

[0061] Accordingly, the present invention provides an improved tissue adhesive in the form of a dry film or tape, which may be a dry double-sided film or tape for use in specific applications, based on a dry crosslinking mechanism, that adheres rapidly and strongly to a variety of wet tissues and devices. Because this adhesive material has dry, storable and ready-to-use properties, it is easy to store, distribute, and use for extended periods (e.g., more than two weeks) without compromising performance. In this case, the adhesive material of the present invention eliminates the difficulties of storing perishable liquids or wet gels, which were common with existing tissue adhesives, as well as the inconvenience of having to mix reagents immediately before each use. Furthermore, this adhesive material has a simple composition and high flexibility in its manufacture. In this case, it can offer considerable economic advantages and may facilitate the rapid and widespread adoption and replacement of existing materials. The novel potential of this adhesive material, with its excellent adhesion to various surfaces including wet tissues and its ability to be removed as needed without causing trauma to vulnerable tissues, addresses a long-standing series of challenges with existing tissue adhesives and can provide new opportunities for future developments in tissue engineering, drug delivery, and biocompatible devices. The dry crosslinking mechanism for wet adhesion will inspire future adhesive designs for use in wet and aquatic environments. [Examples]

[0062] Materials and methods for exemplary embodiments Synthesis of NHS ester-functional monomers containing disulfide bonds To prepare NHS ester-functional monomers containing disulfide bonds, 2,2'-disulfanediyldiacetic acid (1.8 g, 10.0 mmol) and acetic anhydride (8.0 mL) were added to a 100 mL round-bottom flask containing a magnetic stirring bar. The mixture was stirred at room temperature for 3 hours to obtain a homogeneous solution (Figure 6A). The solvent was then removed under vacuum to obtain 1,4,5-oxaditiepane-2,7-dione as a pale yellow oil. This oil was directly added to a mixture of 2-hydroxyethyl methacrylate (1.9 g, 15.0 mmol), 4-dimethylaminopyridine (DMAP; 12.0 mg, 1.0 mmol), and dichloromethane anhydride (DCM) (15 mL). After stirring the solution overnight at room temperature, the reaction was terminated by adding 30 mL of saturated NaHCO3 solution (Figure 6B). The mixture was then acidified to pH=2.0 with 1 M HCl and extracted with DCM. The organic phase was dried overnight over Na2SO4 and then concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography, using a mixture of MeOH and DCM (v / v=1 / 20) as the eluent, to obtain 6-(2-(methacryloyloxy)ethoxy)hept-6-enoic acid. Next, 6-(2-(methacryloyloxy)ethoxy)hept-6-enoic acid (2.94 g, 10.0 mmol) was dissolved in anhydrous DCM (30 ml) and stirred with N-hydroxysuccinimide (NHS; 1.15 g, 10 mmol) in an ice bath for 30 minutes. Then, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC; 1.55 g, 10 mmol) in DCM (20 ml) was added dropwise to the above mixture. This solution was stirred overnight at room temperature under a nitrogen atmosphere (Figure 6C). The crude product was purified by silica gel flash column chromatography using a mixture of petroleum ether and ethyl acetate (v / v=1 / 1) as the eluent, yielding a colorless liquid product. 1H NMR(400MHz,CDCl3,δ):6.17(p,1H,-CH2),5.59(q,1H,-CH2),4.44-4.33(m,4H,-OCH 2CH2O-), 3.83-3.68(d,4H,-CH2SSCH2-), 2.85(s,-CH2-CH2-)1.94(s,3H,-CH3) (Figure 7).

[0063] Preparation of bioadhesives To prepare the bioadhesive, polyvinyl alcohol (PVA; Mw=146,000~186,000, 7 w / w%), acrylic acid (AAc; 35 w / w%), α-ketoglutaric acid (0.2 w / w%), and poly(ethylene glycol methacrylate) (PEGDMA; Mn=550, 0.05 w / w%) were dissolved in deionized water. Next, a functional monomer (NHS ester functional monomer with disulfide bonds) (100 mg) was dissolved in acetone (1 ml) and added to the above stock solution (10 ml) to obtain a precursor solution. The precursor solution was then poured into a glass mold with a spacer (thickness 210 μm unless otherwise specified) and cured in an ultraviolet (UV) chamber (284 nm, power 10 W) for 30 minutes. As a non-adhesive layer, a 10 w / w% thermoplastic polyurethane solution was spin-coated on the cured bioadhesive at 400 rpm for 30 seconds and completely dried. The prepared bioadhesive was sealed in a plastic bag containing a desiccant (small silica gel pouch) and stored at -20°C until use. To create patterns in the bioadhesive, various patterns were cut into a large sheet of the bioadhesive using a laser cutter (Epilog). Weighing paper (VWR) was used as a removable liner for the bioadhesive.

[0064] Preparation of induction solution To prepare the induction solution, 0.5 M sodium bicarbonate (SBC) and reduced L-glutathione (GSH) were dissolved in PBS. The induction solution was filtered using a 0.2 μm sterile syringe filter before use. To verify the inductionable separation of bioadhesives, primary amine-bonded fluorescent microbeads (FluoSpheres) were used. TMThe bioadhesive was incubated in PBS containing Thermo Fisher Scientific for 30 minutes at room temperature. The sample was then incubated for an additional 5 minutes in various induction solutions, followed by thorough washing with clean PBS to remove any non-adhering microparticles. The presence of adhered microbeads was characterized using a fluorescence microscope (LV10, Nikon Corporation), and the number of adhered microbeads was counted using Image-J.

[0065] Mechanical testing Tissue samples to be stored for more than 10 minutes before mechanical testing were sprayed with a large amount of 0.01 w / v% sodium azide solution (in PBS) and covered with the sample, then sealed in a plastic bag to prevent tissue degradation and dehydration. Unless otherwise specified, all tissue and engineering solid surfaces were washed with PBS, and then the adhesive material was bonded to the tissue by pressing it for 5 seconds (a pressure of 1 kPa could be applied with a mechanical tester or equivalent weight). To measure interfacial fracture toughness, a 2.5 cm wide bonded sample was prepared and tested using a mechanical tester (load cell 2.5 kN, Zwick / Roell Z2.5) with a standard 180° peel test (ASTM F2256). All tests were conducted with a constant peel speed of 50 mm min. -1 The experiment was conducted as follows: When the delamination process entered a steady state, the measured force reached a plateau region. Interfacial fracture toughness was determined by doubling the force in the plateau region and dividing it by the width of the tissue sample (Figure 10). A hydrophilic nylon filter (pore size 1 μm, TISCH Scientific) was attached as a high-rigidity backing material for the adhesive material. A poly(methyl methacrylate) film (thickness 50 μm; Goodfellow) was attached as a high-rigidity backing material for the tissue using a cyanoacrylate adhesive (Krazy Glue). Unless otherwise specified, interfacial fracture toughness was measured 5 minutes after the application of the induction solution.

[0066] Characterization using FTIR The chemical composition of the adhesive material was characterized using a germanium total internal reflection (ATR) crystal (55°) with a transmission Fourier transform infrared spectrophotometer (FTIR 6700, ThermoFisher).

[0067] In Vivo Biocompatibility Assessment All animal surgeries were reviewed and approved by the Committee on Animal Care at the Massachusetts Institute of Technology. Female Sprague Dawley rats (225–250g, Charles River Laboratories) were used for all in vivo studies. Before transplantation, the adhesive was prepared using aseptic techniques and further sterilized under ultraviolet light for 3 hours. Rats were anesthetized in an anesthesia room using isoflurane (1–2% isoflurane in oxygen) for transplantation into the dorsal subcutaneous space. Anesthesia was maintained using a nasal mask. The dorsal hair was removed, and the animals were placed on a warming pad during surgery. A 1–2 cm incision was made in the skin of the middle of the animal's dorsum for each graft to reach the subcutaneous space. Blunt dissection was performed from the incision toward the scapula to create space for graft placement. In the sham surgery group, no graft was placed in the subcutaneous pocket (n=4). In the group where isolation could be induced, a bioadhesive (10 × 20 mm) was placed in the subcutaneous pocket created by the incision described above, and isolation was performed 5 minutes after applying 1 mL of induction solution (n=4). In the group where bioadhesive was transplanted, a bioadhesive (10 mm wide, 20 mm long) was placed in the subcutaneous pocket created by the incision described above, and isolation was not performed (n=4). The incision was closed with a nodular suture (4-0 Vicryl, Ethicon), and 3-6 ml of physiological saline was injected subcutaneously. A maximum of three grafts were placed per animal, and care was taken to ensure that the created subcutaneous pockets did not overlap. Two weeks after transplantation, the animals were euthanized by CO2 inhalation. The subcutaneous region of the target area was excised and fixed in 10% formalin for 24 hours for histological analysis.

[0068] Histological treatment Fixed tissue samples were immersed in 70% ethanol and submitted to the Hope Babette Tang (1983) Histology Facility at the Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, for histological processing and hematoxylin-eosin (H&E) staining. Histological evaluation was performed by blinded pathologists, and the degree of inflammation in the tissue surrounding the subcutaneous graft was assessed on a scale of 0 to 5 (0: normal or absent; 1: very mild or minimal; 2: mild; 3: moderate; 4: severe or prominent; 5: very severe). The degree of acute inflammation was based on neutrophil count. The degree of chronic inflammation was based on the presence of lymphocytes, macrophages, and plasma cells. The degree of inflammation was assessed based on the presence (absent, minimal, moderate, or prominent) of indicators in each histological sample as a whole. Representative images for each group are shown in the corresponding figures.

[0069] Ex Vivo Exam All ex vivo experiments were reviewed and approved by the Massachusetts Institute of Technology's Animal Experimentation Committee. To correct misplaced bioadhesive, lacerations were made in the lobes of pig lungs using a razor blade (3 cm long). Air was then introduced (pressure 25 mmHg) through a tube connected to the upper trachea to allow air leakage to be observed. To represent misplacement and incomplete closure, a bioadhesive (2.5 cm wide, 5 cm long) was pressed and applied for 5 seconds to cover a portion of the laceration in the injured lung lobe. The misplaced bioadhesive was covered with medical gauze, and an induction solution was applied to the gauze. Five minutes after applying the induction solution, the misplaced bioadhesive was removed with tweezers. To close the exposed laceration, new bioadhesive was applied to completely cover the laceration, and the airtightness of the closure was confirmed by repeatedly inflating and deflating the pig lung.

[0070] A simulated device, comprising gold-plated polyimide and patterned bioadhesive (2 cm wide and 4 cm long, with a bioadhesive pattern 1 mm wide and 1.5 mm spaced), was attached to a beating ex vivo pig heart for bonding and, if necessary, removing a bioadhesive device. A tube was connected to the cardiac aorta, and pressurized air was programmed to simulate beating, using a microdispenser (Ultimus TM The devices were delivered to pig hearts using a Nordson EFD. After attaching the devices while the heart was beating, they were maintained at room temperature for 3 hours while the heartbeat continued, and then firmly attached by pulling with tweezers. The bioadhesive devices were covered with medical gauze, and the induction solution was applied to the gauze. Five minutes after applying the induction solution, the bioadhesive devices were removed with tweezers, and the surface of the pig heart was examined for tissue damage. If the experiment lasted more than one hour at room temperature, the heart was covered with a towel soaked in a 0.01 w / v% sodium azide solution (in PBS) to prevent dehydration and degradation.

[0071] statistical analysis MATLAB software was used to evaluate the statistical significance of all comparative trials in this study. Parametric tests were performed assuming that all data variances were normally distributed, but formal tests were not performed. In statistical analyses comparing multiple samples, Tukey's multiple comparison test was performed following one-way ANOVA, and the p-value threshold was set. * p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.001 was set. For the statistical analysis between the two data groups, a two-sample Student's t-test was performed, and the significance threshold was set. * p ≤ 0.05, ** p ≤ 0.01, *** We set p ≤ 0.001.

Claims

1. An adhesive material for bonding one or more wet surfaces and for reliably separating the one or more wet surfaces, (i) one or more hydrophilic polymers or copolymers, wherein (ii) one or more amine coupling groups are grafted via (iii) a plurality of cleavable physical bonds and cleavable covalent bonds, and (iv) one or more crosslinking agents. The invention comprises, and further comprises a network of interpenetrating polyvinyl alcohol (PVA) and poly(acrylic acid) (PAA) in which, in a dry state, N-hydroxysuccinimide (NHS) esters are grafted via cleavable disulfide bonds. It is in the form of an elastic film or elastic tape having an upper surface and a lower surface, When one or more of the top and / or bottom surfaces of the adhesive material are placed in contact with the one or more wet surfaces, the hydrophilic polymer in the adhesive material absorbs liquid from the one or more wet surfaces, swells, and forms temporary physical crosslinks between the dry adhesive material and the wet surfaces, and has a liquid content such that it forms covalent bonds between the one or more amine coupling groups and the one or more wet surfaces. The cleavable physical bond is selected from hydrogen bonds, electrostatic bonds and host-guest bonds, and the cleavable covalent bond is selected from boron-oxygen bonds, phenylboronic acid esters, disulfide bonds, hydrazone bonds, imine bonds, Diels-Alder bonds, carbon-carbon / carbon-sulfur bonds and oxime bonds. The host-guest bond is selected from α-cyclodextrin (CD) as the host and n-butyl (n-Bu) group, adamantyl group, benzyl group and trans-azobenzene group as guests; β-CD as the host and adamantyl group, t-butyl group, cyclohexyl (ester) group, cyclododecyl (amide) group, benzyl group, 2-naphthylmethyl group, 1-pyrenylmethyl group, ferrocene group and trans-azobenzene group as guests; and γ-CD as the host and cyclododecyl group, benzyl group, 2-naphthylmethyl group, 9-phenanthrylmethyl group and 1-pyrenylmethyl group as guests. An adhesive material in which the aforementioned wet surface is covered with an aqueous medium.

2. The adhesive material according to claim 1, wherein the (i) one or more hydrophilic polymers or copolymers are selected from polyacrylic acid, polyacrylamide, polyvinyl alcohol, polyhydroxyethyl methacrylate, polyethylene glycol, polyurethane, casein, albumin, gelatin, chitosan, hyaluronic acid, alginate, alginate oxide, cellulose, cellulose oxide, polyvinylpyrrolidone, polystyrene sulfonate, collagen, pectin, and combinations thereof.

3. The adhesive material according to claim 1, wherein the (ii) one or more amine coupling groups are selected from N-hydroxysuccinimide esters, N-hydroxysulfosuccinimide esters, aldehydes, imide esters, epoxides, isocyanates, catechols, and combinations thereof.

4. The adhesive material according to claim 1, wherein the (iv) one or more crosslinking agents are selected from gelatin methacrylate, methacrylated hyaluronic acid, oxidized methacrylated alginate, polycaprolactone diacrylate, N,N'-bis(acryloyl)cystamine, N,N'-methylenebis(acrylamide), polyethylene glycol diacrylate, polyethylene glycol dimethacrylate, and combinations thereof.

5. The negatively charged carboxylic acid groups of the poly(acrylic acid) grafted with N-hydroxysuccinimide ester promote the absorption and swelling of the liquid in the dry adhesive material, and further form intermolecular bonds with the one or more wet tissue surfaces within 60 seconds of contact between the dry adhesive material and the one or more wet surfaces, according to claim 1.

6. The adhesive material according to claim 1, wherein the N-hydroxysuccinimide ester grafted onto the poly(acrylic acid) forms cleavable covalent bonds with primary amine groups present on the one or more wet surfaces.

7. The dried adhesive material according to claim 1, wherein after the covalent crosslinks are formed between the one or more amine coupling groups and the one or more wet surfaces, the swollen adhesive material transforms into a layer of hydrogel.

8. The hydrogel contains at least about 1,000 Jm －２ The adhesive according to claim 7, having fracture toughness.

9. The adhesive material according to claim 1, in the form of a flat sheet, a perforated sheet, double-sided tape or film, or perforated double-sided tape or film.

10. The adhesive material according to claim 9, further comprising a top surface and a bottom surface, and one or more backing material layers disposed on at least one of the top surface and the bottom surface.

11. The adhesive material according to claim 1, further comprising one or more engineering solids and / or devices bonded to one or more surfaces of the adhesive material.

12. The adhesive material according to claim 1, which is biodegradable.

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