Adhesive non-fibrous interface and method

Abstract

A method for implanting biomaterials and devices into a patient, for example, a method comprising arranging an adhesive composition between and in contact with the surface of the biomaterial or device and the patient's tissue. The adhesive composition may be configured to form a conformal interface on the tissue surface that reduces or minimizes the infiltration of inflammatory cells at the conformal interface.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 490,669, filed Mar. 16, 2023, which is incorporated herein by reference.

[0002] Statement Regarding Federally Sponsored Research or Development This invention was made with government support under Contract No. 1 - R01 - HL153857 - 01 awarded by the National Institutes of Health and Contract No. EFMA - 1935291 awarded by the National Science Foundation. The government has certain rights in this invention.

Background Art

[0003] The foreign body reaction to transplantation can weaken the long - term functionality and reliability of biomaterials and devices in the body. In particular, as a result of the foreign body reaction, the formation of a fibrous capsule between the graft and the target tissue can usually impair the effectiveness of the graft because the fibrous capsule functions as a barrier to mechanical, electrical, chemical, optical communication, or combinations thereof. (See, for example, Chandorkar, Y. et al., ACS Biomaterials Science & Engineering 5, 19 - 44 (2018)).

[0004] To reduce fibrous film formation at the graft-tissue interface, various methods are employed, including drug-eluting coatings (e.g., Farah, S. et al., Nature Materials 18, 892-904 (2019)), hydrophilic polymer coatings (e.g., Gudipati, C. Set al., Langmuir 21, 3044-3053 (2005)), zwitterionic polymer coatings (e.g., Zhang, L. et al., Nature Biotechnology 31, 553-556 (2013)), active surfaces (e.g., Dolan, E. et al., Science Robotics 4, eaax7043 (2019)), controlled stiffness (e.g., Noskovicova, N. et al., Nature Biomedical Engineering 5, 1437-1456 (2021)), and graft size (e.g., Veiseh, O. et al., Nature Materials). Various methods have been developed, such as those described in 14,643-651 (2015).

[0005] Despite these efforts, reducing fibrous capsule formation on implanted biomaterials and devices remains an ongoing challenge in this field.

[0006] There is still a need for new solutions and strategies to improve foreign body reactions, such as preventing or reducing the formation of fibrous coatings. [Overview of the project]

[0007] This specification provides an implantation method that can delay or reduce the likelihood of fibrous capsule formation.

[0008] In one embodiment, an implantation method is provided, such as implanting a biomaterial or device into a patient. In some embodiments, the method includes arranging an adhesive composition between and in contact with the surface of the biomaterial or device and the patient's tissue. The adhesive composition may be configured to form a conformal interface on the tissue surface that reduces or minimizes the infiltration of inflammatory cells at the conformal interface. In some embodiments, the reduction or minimization of inflammatory cell infiltration delays the formation of a fibrous capsule at the conformal interface. For example, the reduction or minimization of inflammatory cell infiltration can prevent the formation of a fibrous capsule at the conformal interface for at least 28 days, at least 60 days, or at least 84 days after implantation of the biomaterial or device.

[0009] In another embodiment, compositions such as adhesive compositions are provided. In some embodiments, the adhesive composition is configured to form a conformal interface on the surface of a tissue that reduces or minimizes the infiltration of inflammatory cells at the conformal interface.

[0010] Additional embodiments are partially described below, partially evident from the description, or can be acquired by practicing the embodiments described herein. The advantages described herein can be realized and achieved by the elements and combinations specifically indicated in the appended claims. It should be understood that both the above summary and the embodiments for carrying out the invention below are merely illustrative and descriptive, and not limiting. [Brief explanation of the drawing]

[0011] [Figure 1A] This is a schematic diagram illustrating an embodiment of a non-adhesive implant including a simulated device and a non-adhesive layer. [Figure 1B] This is a schematic diagram illustrating an embodiment of in vivo transplantation involving the formation of a fibrous capsule at the graft tissue interface. [Figure 1C] This is a schematic diagram illustrating an embodiment of an adhesive implant including a simulated device, and an embodiment of an adhesive layer. [Figure 1D]This is a schematic diagram illustrating an embodiment of in vivo transplantation that does not involve the formation of a fibrous capsule at the graft tissue interface. [Figure 1E] The images show the tissue structure of the original tissue (left), an example of an adhesive graft (center), and an example of a non-adhesive graft collected 28 days after transplantation to the abdominal wall (right). [Figure 1F] The images show the tissue structure of the original tissue (left), an example of an adhesive graft (center), and an example of a non-adhesive graft collected 28 days after transplantation into the colon (right). [Figure 1G] The images show the tissue structure of the original tissue (left), an example of an adhesive graft (center), and an example of a non-adhesive graft collected 28 days after transplantation into the stomach (right). [Figure 1H] The images show the tissue structure of the original tissue (left), an example of an adhesive graft (center), and an example of a non-adhesive graft collected 28 days after transplantation into the lung (right). [Figure 1I] The images show the tissue structure of the original tissue (left), an example of an adhesive graft (center), and an example of a non-adhesive graft collected 28 days after transplantation into the heart (right). [Figure 2A] This is a schematic diagram of the various animal studies described herein. [Figure 2B] This is a series of photographs of various organs collected 28 days after transplantation in an embodiment of non-adhesive grafts. [Figure 2C] This is a series of photographs of various organs collected 28 days after transplantation in an example of an adhesive graft. [Figure 3A] These are a series of tissue images of an adhesive graft collected 28 days after transplantation to the abdominal wall, stained with Masson tricolor (left) and hematoxylin-eosin (right). [Figure 3B] These are a series of tissue images of an adhesive graft collected 28 days after transplantation to the abdominal wall, stained with Masson tricolor (left) and hematoxylin-eosin (right) at the graft-tissue interface. [Figure 3C]A series of tissue structure images stained with Masson's trichrome staining (left) and hematoxylin and eosin staining (right) of the graft - cavity interface for an adhesive graft collected on the 28th day after transplantation into the abdominal wall. [Figure 4A] Tissue structure images stained with Masson's trichrome staining (left) and hematoxylin and eosin staining (right) of the original abdominal wall tissue without an implanted graft collected on the 84th day after surgery. [Figure 4B] Tissue structure images stained with Masson's trichrome staining (left) and hematoxylin and eosin staining (right) of an embodiment of an adhesive graft collected on the 84th day after transplantation into the abdominal wall. [Figure 5] A transmission electron microscope (TEM) image of an embodiment of the adhesive graft - tissue interface. [Figure 6A] A tissue structure image stained with Masson's trichrome staining of an embodiment of a polyurethane - mimicking device collected on the 28th day after transplantation into the abdominal wall. [Figure 6B] A tissue structure image stained with hematoxylin and eosin staining of an embodiment of a polyurethane - mimicking device collected on the 28th day after transplantation into the abdominal wall. [Figure 7A] Tissue structure images stained with Masson's trichrome staining (left) and hematoxylin and eosin (right) of an embodiment of a non - adhesive graft collected on the 3rd day after transplantation into the abdominal wall. [Figure 7B] Tissue structure images stained with Masson's trichrome staining (left) and hematoxylin and eosin (right) of an embodiment of a non - adhesive graft collected on the 7th day after transplantation into the abdominal wall. [Figure 7C] Tissue structure images stained with Masson's trichrome staining (left) and hematoxylin and eosin (right) of an embodiment of a non - adhesive graft collected on the 14th day after transplantation into the abdominal wall. [Figure 7D] Tissue structure images stained with Masson's trichrome staining (left) and hematoxylin and eosin (right) of an embodiment of a non - adhesive graft collected on the 28th day after transplantation into the abdominal wall. [Figure 7E]Structural images of the adherent graft collected on the 3rd day after transplantation to the abdominal wall, stained with Masson's trichrome (left) and hematoxylin and eosin (right). [Figure 7F] Structural images of the adherent graft collected on the 7th day after transplantation to the abdominal wall, stained with Masson's trichrome (left) and hematoxylin and eosin (right). [Figure 7G] Structural images of the adherent graft collected on the 14th day after transplantation to the abdominal wall, stained with Masson's trichrome (left) and hematoxylin and eosin (right). [Figure 7H] Structural images of the adherent graft collected on the 28th day after transplantation to the abdominal wall, stained with Masson's trichrome (left) and hematoxylin and eosin (right). [Figure 7I] Depicts the thickness of the collagen layer observed for the native tissue, embodiments of the non-adherent interface, and embodiments of the adherent interface. [Figure 8A] Schematic illustration of the experimental setup of the in vitro protein adsorption assay for an embodiment of the non-adherent graft. [Figure 8B] Confocal microscope image of the in vitro albumin adsorption assay for an embodiment of the non-adherent graft. [Figure 8C] Confocal microscope image of the in vitro fibrinogen adsorption assay for the non-adherent graft. [Figure 8D] Schematic illustration of the experimental setup of the in vitro protein adsorption assay for an embodiment of the adherent graft. [Figure 8E] Confocal microscope image of the in vitro albumin adsorption assay for an embodiment of the adherent graft. [Figure 8F] Confocal microscope image of the in vitro fibrinogen adsorption assay for an embodiment of the adherent graft. [Figure 8G] Depicts the relative fluorescence intensity at the graft-substrate interface embodiments measured 30 minutes after co-culture with albumin. [Figure 8H]The relative fluorescence intensity at the graft-substrate interface, measured 30 minutes after co-culturing with fibrinogen, is depicted. [Figure 9A] This is an immunofluorescence image of a non-adherent graft collected on the third day after transplantation to the abdominal wall. [Figure 9B] This is an immunofluorescence image of an adhesive graft collected on the third day after transplantation to the abdominal wall. [Figure 9C] This is an immunofluorescence image of a non-adherent graft collected on day 7 after transplantation to the abdominal wall. [Figure 9D] This is an immunofluorescence image of an adhesive graft collected on the 7th day after transplantation to the abdominal wall. [Figure 9E] This is an immunofluorescence image of a non-adhesive graft collected 14 days after transplantation to the abdominal wall. [Figure 9F] This is an immunofluorescence image of an adhesive graft collected 14 days after transplantation to the abdominal wall. [Figure 9G] The normalized fluorescence intensity from immunofluorescence images taken 3 days after implantation of the device embodiment is depicted. [Figure 9H] The normalized fluorescence intensity from immunofluorescence images taken 7 days after implantation of the device embodiment is depicted. [Figure 9I] The normalized fluorescence intensity from immunofluorescence images taken 14 days after implantation of the device embodiment is depicted. [Figure 10A] This is an immunofluorescence image of a non-adhesive graft collected 28 days after transplantation to the abdominal wall. [Figure 10B] This is an immunofluorescence image of an adhesive graft collected 28 days after transplantation to the abdominal wall. [Figure 10C] The normalized fluorescence intensity from immunofluorescence images taken 28 days after implantation of the device embodiment is depicted. [Figure 11A] This is a schematic diagram showing cytokines and genes associated with each cell type in the embodiments of the research described herein. [Figure 11B]These are heatmaps of immune response-related cytokines and chemokines, measured using assays for non-adhesive graft-tissue interface and adhesive graft-tissue interface embodiments, collected on days 1, 3, 7, and 14 after transplantation to the abdominal wall. [Figure 11C] This paper depicts the normalized gene expression of immune response-related markers collected on day 1 after transplantation to the abdominal wall, for both non-adherent graft-tissue interface and adherent graft-tissue interface embodiments. [Figure 11D] This paper depicts the normalized gene expression of immune response-related markers collected on day 3 after transplantation to the abdominal wall, for both non-adherent graft-tissue interface and adherent graft-tissue interface embodiments. [Figure 11E] This paper illustrates the normalized gene expression of immune response-related markers collected on day 7 after transplantation to the abdominal wall, for both non-adherent graft-tissue interface and adherent graft-tissue interface embodiments. [Figure 11F] This paper depicts the normalized gene expression of immune response-related markers collected 14 days after transplantation to the abdominal wall, for both non-adherent graft-tissue interface and adherent graft-tissue interface embodiments. [Figure 12A] Immunofluorescence images of an adherent graft collected on the third day after transplantation to the abdominal wall are shown. [Figure 12B] This diagram illustrates the quantification of iNOS+ / neutrophil elastase+ and iNOS+ / CD68+ cells per unit area on day 3 after transplantation of the device embodiment. [Figure 13A] This is a principal component analysis (PCA) plot illustrating the variance of datasets from the adhesive graft-tissue interface and non-adhesive graft-tissue interface, collected on day 3 after transplantation to the abdominal wall. [Figure 13B] This is a volcanic plot showing gene expression profiles comparing embodiments of adhesive and non-adhesive graft-tissue interfaces collected on day 3 after transplantation to the abdominal wall. [Figure 13C]This paper describes the top five enriched processes from gene ontology (GO) enrichment analysis of differentially expressed genes in non-adhesive grafts and adherent graft-tissue interface embodiments collected 3 days after transplantation to the abdominal wall. [Figure 13D] This PCA plot illustrates the variance of datasets in an embodiment of adhesive and non-adhesive graft-tissue interface data collected 14 days after transplantation to the abdominal wall. [Figure 13E] This is a volcanic plot illustrating gene expression profiles when comparing the embodiment walls of the adhesive and non-adhesive graft-tissue interface collected 14 days after transplantation. [Figure 13F] This paper describes the top five enriched processes from GO enrichment analysis of differentially expressed genes in non-adhesive grafts and adherent graft-tissue interface embodiments collected 14 days after transplantation to the abdominal wall. [Figure 14A] By plotting their log2-converted expression values ​​in samples taken 3 days after implantation of the device embodiment, a bi-clustered heatmap is depicted that visualizes the expression profiles of the top 30 differentially expressed genes sorted by adjusted P-values. [Figure 14B] By plotting their log2-converted expression values ​​in samples 14 days post-implantation of the device embodiment, a bi-clustered heatmap is depicted that visualizes the expression profiles of the top 30 differentially expressed genes sorted by adjusted P-values. [Figure 15A] This is a schematic diagram illustrating an embodiment of a research design using C57BL / 6 mice. [Figure 15B] This image includes representative histological images (left) of the original tissue collected 28 days post-transplant in C57BL / 6 mice, stained with Masson's tricolor (MTS) and hematoxylin-eosin (H&E), an example of an adhesive graft (center), and an example of a non-adhesive graft (right). [Figure 15C] This is a schematic diagram illustrating an embodiment of a research design in HuCD34-NCG humanized mice. [Figure 15D] This image includes representative histological images of the original tissue stained with MTS and H&E (left), an example of an adhesive graft (center), and an example of a non-adhesive graft (right), collected 28 days post-transplant in HuCD34-NCG humanized mice. [Figure 15E] This is a schematic diagram illustrating an embodiment of a research design in HuCD34-NCG humanized pigs. [Figure 15F] This image includes representative histological images of the original tissue stained with MTS and H&E (left), an example of an adhesive graft (center), and an example of a non-adhesive graft (right), collected seven days post-transplant in pigs. [Figure 16A] This is a schematic diagram illustrating in vivo electrophysiological recording and stimulation via an embodiment of an implanted electrode having embodiments of non-adhesive grafts and adhesive graft-tissue interfaces. [Figure 16B] The R-wave amplitudes recorded through implanted electrodes, with embodiments of adhesive and non-adhesive graft-tissue interfaces, are depicted at 0, 3, 7, 14, and 28 days post-implantation in rat hearts. [Figure 16C] The images show epicardial electrocardiograms at 0, 3, 7, 14, and 28 days post-transplantation into rat hearts, after stimulation via implanted electrodes with a non-adhesive graft-tissue interface. [Figure 16D] The images show epicardial electrocardiograms at 0, 3, 7, 14, and 28 days after transplantation into rat hearts, following stimulation via implanted electrodes with an adhesive graft-tissue interface. [Figure 16E] Histological images stained with hematoxylin-eosin and Masson tricolor staining of non-adhesive grafts collected 28 days after transplantation into rat hearts are shown. [Figure 16F] Histological images stained with hematoxylin-eosin and Masson tricolor staining of an embodiment of an adhesive graft collected 28 days after transplantation into a rat heart are shown. [Modes for carrying out the invention]

[0012] In some embodiments, the methods described herein include methods for implanting a biomaterial or device, such as a medical device, into the body of a patient. The patient may be a human or another mammal. The methods may include arranging adhesive compositions, such as those described herein, between (i) the biomaterial or device and (ii) the surface of the patient's tissue, and in contact with them.

[0013] The arrangement of adhesive compositions can be achieved by any known technique. For example, the method may include providing an adhesive composition to adhere to a biomaterial or device, and then bringing a tissue, e.g., the surface of a tissue, into contact with the adhesive composition. As a further example, the method may include providing a biomaterial or device, adhering an adhesive composition to the biomaterial or device, and then bringing a tissue, e.g., the surface of a tissue, into contact with the adhesive composition. As yet another example, the method may include placing an adhesive composition on a tissue, e.g., the surface of a tissue, and then bringing the adhesive composition into contact with a biomaterial or device.

[0014] In certain embodiments, the adhesive composition is advantageously configured to form a conformal interface on the tissue surface that reduces or minimizes the infiltration of inflammatory cells at the conformal interface. This reduction or minimization of inflammatory cell infiltration can prevent the formation of a fibrous film at the conformal interface for at least 28, 30, 40, 50, 60, 70, 80, 84, 90, or 100 days after implantation of the biomaterial or device.

[0015] Adhesive composition Any adhesive composition capable of forming a conformal interface may be used in the manner provided herein. An adhesive composition may be a polymer composition. The phrase “polymer composition” means any composition comprising or consisting of polymer compounds. A “polymer compound” is a compound formed by bonding together two or more monomers (e.g., three or more monomers, four or more monomers, etc.). Thus, a “polymer compound” may be a polymer, a copolymer (i.e., a polymer formed from two or more different types of monomers), an oligomer, etc., or a combination thereof. Non-limiting examples of adhesive compositions that may be used in some embodiments of the methods described herein are disclosed in U.S. Patent Application Publication No. 2020 / 0353120A1, which is incorporated herein by reference.

[0016] The polymer composition may be a crosslinked polymer composition. If the polymer composition contains a crosslinking agent bonded to two or more monomers, it is "crosslinked," and the two or more monomers bonded to the crosslinking agent are intermolecular monomers, intramolecular monomers, or a combination thereof.

[0017] The polymer composition may comprise one or more hydrophilic polymers, one or more zwitterionic polymers, or a combination thereof. The one or more hydrophilic polymers may comprise any of those known in the art. Non-limiting examples of hydrophilic polymers include polyethylene glycol, polyacrylic acid, polyacrylamide, polyvinyl alcohol, polyhydroxyethyl methacrylate, polyethylene glycol, polyurethane, casein, albumin, gelatin, chitosan, dextran, hyaluronic acid, alginate, cellulose, polyvinylpyrrolidone, polystyrene sulfonate, collagen, alginic acid, pectin, oxidized derivatives thereof, and combinations thereof. For example, alginate and cellulose may be oxidized alginate and oxidized cellulose, respectively.

[0018] One or more zwitterionic polymers may include any of those known in the art. Non-limiting examples of zwitterionic polymers include poly(phosphobetaine), poly(carboxybetaine), poly(sulfobetaine), and combinations thereof.

[0019] Adhesive compositions may contain one or more tissue coupling groups. As used herein, the phrase “tissue coupling group” refers to a functional group or a compound containing a functional group that can react with one or more tissues, for example, via one or more functional groups of the tissue, such as amines, which are located on or near the surface of the tissue. Non-limiting examples of tissue coupling groups include amine coupling groups, thiol coupling groups, cysteine ​​coupling groups, N-acetyl-cysteine ​​coupling groups, boronate ester coupling groups, and combinations thereof.

[0020] Non-limiting examples of amine coupling groups include N-hydroxysuccinimide esters (PAAc-co-NHS esters), PAAm-co-NHS, N-hydroxysuccinimide (NHS)PEG, poly(L-lactide-co-glycolide)-NHS, poly(D,L-lactide)-polyethylene glycol-CO-NHS, poly(N-isopropylacrylamide)N-hydroxysuccinimide terminus, aldehydes, imide esters, epoxides, isocyanates, catechols, and combinations thereof. Non-limiting examples of thiol coupling groups include alginates, albumin, fibrinogen, collagen, chitosan, gelatin, and combinations thereof. Non-limiting examples of cysteine ​​coupling groups include fibrinogen, collagen, and combinations thereof. Non-limiting examples of boronate ester coupling groups include acrylamide, N-isopropylacrylamide, polyvinyl alcohol (PVA), alginates, cellulose, and combinations thereof.

[0021] The adhesive composition may contain one or more crosslinking agents. Non-limiting examples of crosslinking agents include gelatin methacrylate, hyaluronic acid methacrylate, methacrylate alginate oxide, polycaprolactone diacrylate, N,N'-bis(acryloyl)cystamine, N,N'-methylenebis(acrylamide), polyethylene glycol diacrylate, polyethylene glycol dimethacrylate, and combinations thereof.

[0022] organization The tissues of the methods described herein may generally include any tissue of the patient. The tissues may be external tissues, internal tissues, or a combination thereof.

[0023] The tissue may be organ tissue, for example, the surface of an organ. In some embodiments, the tissue includes abdominal wall tissue, colon tissue, stomach tissue, lung tissue, or heart tissue.

[0024] Devices and Biomaterials Biomaterials can generally include any material or substance that provides a medical benefit to a patient, such as treatment or prevention. Biomaterials can be natural, synthetic, or a combination thereof. Biomaterials can include regenerated biomaterials. Biomaterials can include polymers, ceramics, inorganic glass, or a combination thereof. Devices can generally include any known device, such as any implantable device that provides a medical benefit to a patient, such as treatment or prevention. In some embodiments, devices include electrodes.

[0025] In some embodiments, the methods described herein enable bidirectional electrical communication between a device such as an electrode and tissue that is maintained for a desired period of time after the device is implanted in the patient. For example, bidirectional electrical communication between a device such as an electrode and tissue can be maintained for at least 10, at least 15, at least 20, at least 25, at least 28, at least 30, at least 35, at least 40, at least 45, or at least 50 days after the implantation of the device.

[0026] For example, the tissue may include cardiac tissue from the patient's heart, and the R-wave of the patient's heart recorded by the electrodes at least 10, 15, 20, 25, 28, 30, 35, 40, 45, and 50 days after electrode implantation may have an amplitude that is 0% to less than approximately 5% of the initial amplitude of the initial R-wave of the patient's heart recorded by the electrodes within 24 hours after electrode implantation. As a further example, the tissue may include cardiac tissue from the patient's heart, and the minimum stimulation current pulse amplitude for pulse regulation emitted by the electrodes may regulate the pulse of the patient's heart for at least 10, 15, 20, 25, 28, 30, 35, 40, 45, and 50 days after electrode implantation.

[0027] All referenced publications are incorporated by reference. Furthermore, if a definition or use of a term in a reference incorporated herein by reference conflicts with or is contrary to a definition of that term provided herein, the definition provided herein shall prevail, and the definition in the reference shall not prevail.

[0028] While certain aspects of the prior art have been considered to facilitate the disclosure of various embodiments, the applicant does not in any way deny these technical aspects, and this disclosure may encompass one or more of the prior art aspects considered herein.

[0029] This disclosure may address one or more known problems and defects of methods and processes. However, it is conceivable that various embodiments may prove useful in addressing other problems and defects in some areas of the art. Therefore, this disclosure should not necessarily be construed as being limited to addressing any of the specific problems or defects considered herein.

[0030] Wherever a document, act, or piece of knowledge is referenced or considered in this Specification, such reference or consideration does not imply that the document, act, or piece of knowledge, or any combination thereof, was publicly available, commonly known, part of common sense, or otherwise constituted prior art under applicable statutory provisions, or was known to be related to any attempt to resolve any problem relating to this Specification.

[0031] In the descriptions provided herein, the terms “includes,” “is,” “containing,” “having,” and “comprises” are used in a non-restrictive manner and should therefore be interpreted as “including, but not limited to.” Where a method, device, composition, material, etc. is claimed or described in the expression “includes” various steps or components, unless otherwise stated, the method, device, composition, material, etc. may also “essentially consist of” or “consist of” various steps or components.

[0032] The terms “a,” “an,” and “the” are intended to include multiple substitutes, e.g., at least one. For example, disclosures such as “a hydrophilic polymer” and “a device” mean, unless otherwise specified, to include one or more hydrophilic polymers, devices, etc., or a mixture or combination of them.

[0033] Various numerical ranges may be disclosed herein. Wherever an applicant discloses or claims any type of range, unless otherwise specified, the applicant intends to individually disclose or claim each possible number that such range can reasonably encompass, including the endpoints of that range and any subranges and combinations of subranges that are included within that range. Furthermore, all numerical endpoints of the ranges disclosed herein are approximate.

[0034] As used herein, the term "about" means plus or minus 10% of the numerical value in which it is used.

[0035] Embodiment The following is a non-limiting list of embodiments of the present disclosure.

[0036] Embodiment 1. A method for implanting a biomaterial or device into a patient, wherein the method comprises, essentially, or consists of, arranging an adhesive composition between (i) the biomaterial or device and (ii) the surface of the patient's tissue so as to be in contact with them.

[0037] Embodiment 2. The method according to Embodiment 1, wherein the patient is a human or mammal.

[0038] Embodiment 3. The method according to Embodiment 1 or 2, wherein the adhesive composition is configured to form a conformal interface on the surface of the tissue that reduces or minimizes the infiltration of inflammatory cells at the conformal interface.

[0039] Embodiment 4. The method according to Embodiment 3, wherein the reduction or minimization of inflammatory cell infiltration prevents the formation of a fibrous film at the conformal interface for at least 28, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 84, at least 90, or at least 100 days after implantation of the biomaterial or device.

[0040] Embodiment 5. The method according to any one of the prior embodiments, wherein the arrangement of adhesive compositions comprises, is essentially, or comprises providing an adhesive composition, the adhesive composition adheres to a biomaterial or device and brings the surface of the tissue into contact with the adhesive composition.

[0041] Embodiment 6. The method according to any one of Embodiments 1 to 5, wherein the arrangement of the adhesive composition comprises, essentially, or consists of, placing the adhesive composition on a tissue surface and bringing the adhesive composition into contact with a biomaterial or device.

[0042] Embodiment 7. An adhesive composition configured to form a conformal interface on the surface of a tissue that reduces or minimizes the infiltration of inflammatory cells at the conformal interface.

[0043] Biomaterials Embodiment 8. The method or adhesive composition according to any one of the prior embodiments, wherein the biomaterial includes, is essentially composed of, or consists of materials or substances that provide a medical benefit to a patient, such as treatment or prevention.

[0044] Embodiment 9. The method or adhesive composition according to any one of the prior embodiments, wherein the biomaterial is natural, synthetic, or a combination thereof.

[0045] Embodiment 10. The method or adhesive composition according to any one of the prior embodiments, wherein the biomaterial includes, is essentially, or consists of a regenerated biomaterial.

[0046] Embodiment 11. The method or adhesive composition according to any one of the prior embodiments, wherein the biomaterial includes, essentially consists of, or comprises polymers, ceramics, inorganic glass, or a combination thereof.

[0047] device Embodiment 12. The method or adhesive composition according to any one of the prior embodiments, wherein the device includes, is essentially, or consists of a portable device.

[0048] Embodiment 13. A method or adhesive composition according to any one of the prior embodiments, wherein the device provides a medical benefit to a patient, such as treatment or prevention.

[0049] Embodiment 14. A method or adhesive composition according to any one of the prior embodiments, wherein the device includes, is essentially composed of, or consists of electrodes.

[0050] Telecommunications Embodiment 15. The method or adhesive composition according to any one of the prior embodiments, wherein communication, such as telecommunications (e.g., bidirectional telecommunications), between a device (or a part thereof, e.g., an electrode) and tissue is maintained for at least 10, at least 15, at least 20, at least 25, at least 28, at least 30, at least 35, at least 40, at least 45, and at least 50 days after implantation of the device.

[0051] organization Embodiment 16. The method or adhesive composition according to any one of the prior embodiments, wherein the tissue includes, essentially consists of, or comprises external tissue, internal tissue, or a combination thereof.

[0052] Embodiment 17. The method or adhesive composition according to any one of the prior embodiments, wherein the tissue includes, essentially consists of, or comprises abdominal wall tissue, colon tissue, gastric tissue, lung tissue, or cardiac tissue.

[0053] Embodiment 18. The method or adhesive composition according to any one of the prior embodiments, wherein the tissue comprises, is essentially, or is made of cardiac tissue of the patient's heart, and at least 28 days after electrode implantation, the R wave of the patient's heart recorded by the electrode has an amplitude of 0% to less than about 5% of the initial amplitude of the initial R wave of the patient's heart recorded by the electrode within 24 hours after electrode implantation.

[0054] Embodiment 19. The method or adhesive composition according to any one of the prior embodiments, wherein the tissue comprises, is essentially, or is made of cardiac tissue of the patient's heart, and on at least 10, at least 15, at least 20, at least 25, at least 28, at least 30, at least 35, at least 40, at least 45, and at least 50 days after electrode implantation, the R wave of the patient's heart recorded by the electrode has an amplitude of 0% to less than about 5% of the initial amplitude of the initial R wave of the patient's heart recorded by the electrode within 24 hours after electrode implantation.

[0055] Embodiment 20. The method or adhesive composition according to any one of the prior embodiments, wherein the tissue comprises, is essentially, or is made of cardiac tissue of the patient's heart, and the minimum stimulation current pulse amplitude for pulse regulation emitted by the electrode is capable of regulating the pulse of the patient's heart for at least 10, at least 15, at least 20, at least 25, at least 28, at least 30, at least 35, at least 40, at least 45, and at least 50 days after the implantation of the electrode.

[0056] Adhesive composition Embodiment 21. An adhesive composition according to any one of the prior embodiments, comprising, essentially consisting of, or comprising one or more adhesive compositions disclosed by WO2020 / 231559A1 or U.S. Patent Application Publication No. 2020 / 0353120A1, which are incorporated herein by reference.

[0057] Embodiment 22. The method or adhesive composition according to any one of the prior embodiments, wherein the adhesive composition comprises, is essentially, or consists of a polymer composition such as a crosslinked polymer composition.

[0058] Embodiment 23. The method or adhesive composition according to any one of the prior embodiments, wherein the adhesive composition comprises, essentially consists of, or comprises (i) one or more hydrophilic polymers, one or more zwitterionic polymers, or a combination thereof, (ii) one or more structural coupling groups, (iii) one or more crosslinking agents, or (iv) a combination thereof.

[0059] Embodiment 24. The method or adhesive composition according to any one of the prior embodiments, wherein one or more hydrophilic polymers include, essentially consist of, or comprise polyethylene glycol, polyacrylic acid, polyacrylamide, polyvinyl alcohol, polyhydroxyethyl methacrylate, polyethylene glycol, polyurethane, casein, albumin, gelatin, chitosan, dextran, hyaluronic acid, alginate, cellulose, polyvinylpyrrolidone, polystyrene sulfonate, collagen, alginic acid, pectin, or a combination thereof.

[0060] Embodiment 25. The method according to Embodiment 24 or an adhesive composition, wherein the alginate and cellulose are, respectively, oxidized alginate and oxidized cellulose.

[0061] Embodiment 26. The method or adhesive composition according to any one of the prior embodiments, wherein one or more zwitterionic polymers include, essentially consist of, or comprise poly(phosphobetaine), poly(carboxybetaine), poly(sulfobetaine), or a combination thereof.

[0062] Embodiment 27. The method or adhesive composition according to any one of the prior embodiments, wherein one or more tissue coupling groups include, essentially consist of, or comprise amine coupling groups, thiol coupling groups, cysteine ​​coupling groups, N-acetyl-cysteine ​​coupling groups, boronate ester coupling groups, or combinations thereof.

[0063] Embodiment 28. The method or adhesive composition according to any one of the prior embodiments, wherein the amine coupling group comprises, essentially consists of, or comprises N-hydroxysuccinimide esters (PAAc-co-NHS esters), PAAm-co-NHS, N-hydroxysuccinimide (NHS)PEG, poly(L-lactide-co-glycolide)-NHS, poly(D,L-lactide)-polyethylene glycol-CO-NHS, poly(N-isopropylacrylamide)N-hydroxysuccinimide terminus, aldehydes, imide esters, epoxides, isocyanates, catechols, and combinations thereof.

[0064] Embodiment 29. The method or adhesive composition according to any one of the prior embodiments, wherein the thiol coupling group comprises, essentially consists of, or comprises alginate, albumin, fibrinogen, collagen, chitosan, gelatin, or a combination thereof.

[0065] Embodiment 30. The method or adhesive composition according to any one of the prior embodiments, wherein the cysteine ​​coupling group comprises, essentially consists of, or comprises fibrinogen, collagen, or a combination thereof.

[0066] Embodiment 31. The method or adhesive composition according to any one of the prior embodiments, wherein one or more boronate ester coupling groups include, essentially consist of, or comprise acrylamide, N-isopropylacrylamide, polyvinyl alcohol (PVA), alginate, cellulose, and combinations thereof.

[0067] Embodiment 32. The method or adhesive composition according to any one of the prior embodiments, wherein one or more crosslinking agents include, essentially consist of, or comprise of, gelatin methacrylate, hyaluronic acid methacrylate, methacrylate alginate oxide, polycaprolactone diacrylate, N,N'-bis(acryloyl)cystamine, N,N'-methylenebis(acrylamide), polyethylene glycol diacrylate, polyethylene glycol dimethacrylate, or a combination thereof. [Examples]

[0068] The present invention is further illustrated by the following embodiments, which should not be construed as limiting its scope. In contrast, after reading this description, it is important to understand that there may be various other aspects, embodiments, modifications, and means of relying on them that can be suggested to those skilled in the art without departing from the spirit of the invention or the scope of the appended claims. Accordingly, other aspects of the invention will be apparent to those skilled in the art from the examination of the specifications and practices of the invention disclosed herein.

[0069] Example 1 - Preparation and testing of adhesive composition This embodiment demonstrates that the adhesive graft embodiment described herein provides mechanical integration of the graft into the target tissue and avoids fibrous film formation at the graft-tissue interface (Figures 1C and 1D).

[0070] It was hypothesized that conformal interface integration between adhesive grafts and the tissue surface minimizes the establishment of an inflammatory microenvironment (e.g., protein adsorption) and subsequent infiltration of inflammatory cells (e.g., neutrophils, monocytes, macrophages) at the graft-tissue interface, thereby avoiding collagen deposition and fibrous capsule formation in the long term (Figure 1D). In contrast, conventional non-adhesive grafts do not form conformal integration with the tissue surface, allowing inflammatory cells to infiltrate the graft-tissue interface and subsequently form a fibrous capsule (Figure 1B).

[0071] In this example, an adhesive graft was prepared comprising a simulated device (polyurethane) and an adhesive layer containing an interpenetration network between covalently crosslinked poly(acrylic acid) NHS ester and physically crosslinked poly(vinyl alcohol) (Figure 1C) (Yuk, H. et al. Nature 575, 169-174 (2019); Wu, J. et al. Science Translational Medicine 14, eabh2857 (2022)). The adhesive layer provided highly conformable and stable integration of the graft into the moist tissue (Deng, J. et al., Nature Materials 20, 229-236 (2021). In addition, non-adhesive grafts were prepared by completely swelling the same simulated device and adhesive layer in a phosphate-buffered saline (PBS) bath before transplantation, thereby removing the adhesive properties while maintaining the same chemical composition of the graft (Chen, X., et al., Proceedings of the National Academy of Sciences 117, 15497-15503 (2020)), (Figure 1A).

[0072] Figures 1A and 1B are schematic diagrams illustrating a non-adhesive graft (Figure 1A) consisting of a simulated device (polyurethane) and a non-adhesive layer, and a long-term in vivo transplant with fibrous capsule formation at the graft-tissue interface (Figure 1B). Figures 1C and 1D are schematic diagrams illustrating an adhesive graft (Figure 1C) consisting of a simulated device (polyurethane) and an adhesive layer, and a long-term in vivo transplant without fibrous capsule formation at the graft-tissue interface (Figure 1D). Figures 1E to 1I are representative tissue structure images of the original tissue (left), adhesive graft (center), and non-adhesive graft (right), collected 28 days after transplantation to the abdominal wall (Figure 1E), colon (Figure 1F), stomach (Figure 1G), lung (Figure 1H), and heart (Figure 1I), stained with Masson tricolor staining (MTS) and hematoxylin-eosin staining (H&E). The black and yellow dotted lines in the image represent the graft-tissue interface and the mesothelial-fibrous capsule interface, respectively.

[0073] For up to 84 days, both adhesive and non-adhesive grafts were implanted in a rat model in vivo onto the surface of various organs, including the abdominal wall, colon, stomach, lungs, and heart (Figure 2A). Non-adhesive grafts were sutured to the organ surface. Macroscopic observation showed that both adhesive and non-adhesive grafts remained stable at the transplant site on the organ surface (Figures 2B and 2C). Specifically, Figure 2A includes a schematic diagram illustrating the in vivo rat study. Figures 2B and 2C are photographs of various organs collected 28 days after transplantation of non-adhesive grafts (Figure 2B) and adhesive grafts (Figure 2C). The black dotted lines in the photographs indicate the graft boundaries.

[0074] To analyze the foreign body reaction and fibrous capsule formation of adhesive and non-adhesive grafts, histological analysis was performed on the original tissue, adhesive grafts, and non-adhesive grafts from various organs (Figures 1E to 1I).

[0075] Histological evaluation by blinded pathologists showed that the adhesive grafts formed conformal integration with the organ surface (i.e., mesothelium), preventing the formation of a fibrous capsule in all organs (abdominal wall, colon, stomach, lung, and heart) at 28 days post-transplant (Figures 1E-1I, and 3A, 3B). Figure 3A includes representative histological images of adhesive grafts collected at 28 days post-transplantation to the abdominal wall, stained with Masson's tricolor (left) and hematoxylin-eosin (H&E, right). The black and red dotted lines indicate the graft-tissue interface and graft-peritoneal interface, respectively. Figures 3B and 3C are representative histological images of the graft-tissue interface (Figure 3B) and graft-cavity interface (Figure 3C) of adhesive grafts collected at 28 days post-transplantation to the abdominal wall, stained with Masson's tricolor (left) and H&E (right).

[0076] In particular, the adhesive graft-tissue interface without a fibrous capsule was maintained for 84 days post-transplant (Figures 4A and 4B). Figure 4A includes representative histological images of the original abdominal wall tissue without the implanted graft, collected 84 days post-surgery, stained with Masson tricolor (MTS, left) and hematoxylin-eosin staining (H&E, right). Figure 4B includes representative histological images of the adhesive graft, collected 84 days post-transplantation to the abdominal wall, stained with MTS (left) and H&E (right). The black dotted lines in the images indicate the graft-tissue interface.

[0077] Furthermore, transmission electron microscopy (TEM) images of the adhesive graft-tissue interface showed that, 28 days post-transplant, the adhesive layer maintained a highly conformal and gapless integration with the mesothelial collagenous layer at a subcellular level (Figure 5). Figure 5 shows representative tissue structures (left) and TEM images (right) of adhesive grafts stained with Masson tricolor, collected 28 days post-transplantation to the abdominal wall. * indicates grafts.

[0078] In contrast, non-adhesive grafts induced substantial formation of a fibrous capsule at the graft-tissue interface in all organs at 28 days post-transplantation, which was consistent with the foreign body reaction to the simulated device alone (Figures 6A and 6B). Figures 6A and 6B include representative histological images of polyurethane simulated devices stained with Masson tricolor (Figure 6A) and hematoxylin-eosin (Figure 6B) collected at 28 days post-transplantation to the abdominal wall. "*" in the images indicates the graft, and the black dotted line indicates the graft-tissue interface.

[0079] Unlike the adhesive-tissue interface, the simulated device-cavity interface of the adhesive graft resulted in fibrous film formation similar to that of the non-adhesive graft (Figures 3A and 3C), further confirming that the adhesive interface is necessary to prevent fibrous film formation.

[0080] To evaluate the time course of foreign body reaction and fibrous capsule formation, histological analysis was performed on adhesive and non-adhesive grafts to the abdominal wall at 3, 7, 14, and 28 days post-transplant (Figures 7A-7H). The thickness of the collagen layer at the graft-tissue interface remained comparable to the original tissue (i.e., mesothelial thickness) of the adhesive graft at all time points (Figure 7I). In contrast, the thickness of the collagen layer at the non-adhesive graft-tissue interface increased over time due to fibrous capsule formation and was significantly thicker than both the original tissue and the adhesive graft at all time points (Figure 7I).

[0081] Figures 7A–7D are representative histological images of non-adhesive grafts stained with Masson tricolor (MTS, left) and hematoxylin-eosin (H&E, right) collected on days 3 (Figure 7A), 7 (Figure 7B), 14 (Figure 7C), and 28 (Figure 7D) after transplantation to the abdominal wall. Figures 7E–7H are representative histological images of adhesive grafts stained with MTS (left) and H&E (right) collected on days 3 (Figure 7E), 7 (Figure 7F), 14 (Figure 7G), and 28 (Figure 7H) after transplantation to the abdominal wall. * in the images indicates a graft, black dotted lines indicate the graft-tissue interface, and yellow dotted lines indicate the mesothelial-fibrous capsule (non-adhesive graft) interface or the mesothelial-skeletal muscle (adhesive graft) interface. SM, skeletal muscle; FC, fibrous capsule. Figure 7I illustrates the thickness of the collagen layer at the graft-tissue interface measured at different time points after transplantation. The blue dotted line represents the mean collagen layer thickness of the original tissue. Values ​​represent the mean and standard deviation (n=3: independent samples). Statistical significance and P-values ​​are determined by a two-sided unpaired t-test. ****P<0.0001.

[0082] To further investigate the hypothesis of this example, a series of characterizations of the main participants in the xenobiotic reaction were performed, such as in vitro protein adsorption assays, immunofluorescence analysis, Luminex quantification, quantitative PCR (qPCR), and RNA sequencing analysis. To evaluate the adhesion of proteins at the graft-tissue interface during the initial stages of the xenobiotic reaction, protein adsorption assays using fluorescently labeled albumin and fibrinogen were performed (Figure 8) (Swartzlander, M. et al. Biomaterials 41, 26-36 (2015); Hedayati, M. et al., Acta Biomaterialia 102, 169-180 (2020)). After co-culturing in protein solution for 30 minutes, the adhesive graft-substrate interface showed significantly lower protein adsorption for both fluorescently labeled albumin and fibrinogen compared to the non-adhesive graft-substrate interface (P<0.0001) (Figure 8G, Figure 8H), demonstrating that the adhesive interface has the ability to prevent nonspecific protein adsorption.

[0083] Figures 8A–8C include a schematic diagram illustrating the experimental setup for non-adherent grafts (Figure 8A), and representative confocal microscopy images of the in vitro albumin (Figure 8B) and fibrinogen (Figure 8C) adsorption assays. Figures 8D–8F include a schematic diagram illustrating the experimental setup for adherent grafts (Figure 8D), and representative confocal microscopy images of the in vitro albumin (Figure 8E) and fibrinogen (Figure 8F) adsorption assays. Figures 8G and 8H depict the relative fluorescence intensity at the graft-substrate interface, measured 30 minutes after co-culturing albumin (Figure 8G) and fibrinogen (Figure 8H). The values ​​in Figures 8G and 8H represent the mean and standard deviation (n=5). Statistical significance and P-values ​​are determined by a two-sided unpaired t-test. ****P<0.0001.

[0084] To investigate immune cell infiltration and subsequent fibrous capsule formation at the graft-tissue interface, immunofluorescence staining and normalized immunofluorescence intensity analysis were performed on fibroblasts (αSMA, collagen III), neutrophils (neutrophil elastase), macrophages (CD68 from panmacrophages, iNOS and vimentin from pro-inflammatory macrophages, CD206 from anti-inflammatory macrophages), T cells (CD3), and fibrosis (collagen I) (Figures 9 and 10). Normalized fluorescence intensity analysis showed that at all time points (P ≤ 0.01), except for αSMA expression at post-transplant day 3 (P = 0.117), the adherent graft-tissue interface exhibited significantly lower expression of fibroblasts (αSMA, collagen III), neutrophils (neutrophil elastase), and fibrosis (collagen I) compared to the non-adherent graft-tissue interface (Figures 9G-9I).

[0085] Figures 9A, 9C, and 9E include representative immunofluorescence images of non-adherent grafts collected on days 3 (Figure 9A), 7 (Figure 9C), and 14 (Figure 9F) after transplantation to the abdominal wall. Figures 9B, 9D, and 9F include representative immunofluorescence images of adherent grafts collected on days 3 (Figure 9B), 7 (Figure 9D), and 14 (Figure 9F) after transplantation to the abdominal wall. In the immunofluorescence images, cell nuclei were stained with 4′,6-diamidino-2-phenylindole (DAPI, blue). Green fluorescence corresponds to the expression of fibroblasts (αSMA), vimentin, neutrophils (neutrophil elastase+), and macrophages (CD68, CD206, iNOS), while red fluorescence corresponds to the expression of type 1 collagen (collagen I), type 3 collagen (collagen III), and T cells (CD3). In the images, * indicates the graft, the white dotted line indicates the graft-tissue interface, and the yellow dotted line indicates the mesothelial-fibrous capsule (non-adhesive graft) interface or the mesothelial-skeletal muscle (adhesive graft) interface. Figures 9G to 9I depict the normalized fluorescence intensity from immunofluorescence images at different time points: 3 days post-transplant (Figure 9G), 7 days post-transplant (Figure 9H), and 14 days post-transplant (Figure 9I). The values ​​in Figures 9G to 9I represent the mean and standard deviation (n=3: independent samples). Statistical significance and P-values ​​were determined by a two-sided unpaired t-test, and ns (not significant) indicates that the result is not statistically significant. *P<0.05, **P≦0.01, ***P≦0.001, ****P<0.0001.

[0086] Furthermore, the adhesive graft-tissue interface showed lower expression of immune cells such as neutrophils (neutrophil elastase+), macrophages (CD68+, iNOS+, vimentin+, CD206+), and T cells (CD3+) at all time points compared to the non-adhesive graft-tissue interface, with the exception of iNOS expression on post-transplant day 3 (P=0.317) (Figures 9G-9I).

[0087] Figure 10A includes representative immunofluorescence images of non-adherent grafts collected 28 days after transplantation to the abdominal wall. Figure 10B includes representative immunofluorescence images of adherent grafts collected 28 days after transplantation to the abdominal wall. In the immunofluorescence images, cell nuclei are stained with 4′,6-diamidino-2-phenylindole (DAPI, blue), green fluorescence corresponds to the expression of fibroblasts (αSMA) and macrophages (CD68), and red fluorescence corresponds to the expression of type I collagen (collagen I) and T cells (CD3). "*" in the images indicates grafts, white dotted lines indicate the graft-tissue interface, and yellow dotted lines indicate the mesothelial-skeletal muscle interface. Figure 10C depicts the normalized fluorescence intensity from immunofluorescence images 28 days post-transplantation. The values ​​in Figure 10C represent the mean and standard deviation (n=3: independent samples). Statistical significance and p-values ​​are determined by a two-sided, unpaired t-test, where ns (not significant) indicates that the result is not statistically significant. ****P<0.0001.

[0088] To further describe the immune response at the graft-tissue interface, immune cell-related cytokines / chemokines and genes were profiled using Luminex quantification and qPCR analysis, respectively (Figure 11). Multiple protein assays at the adherent graft-tissue interface on day 1 post-transplantation to the abdominal wall showed an increasing trend in several cytokines (IL-1α, IL-1β, MCP-1), followed by a decreasing trend at days 3 and 7 post-transplantation compared to the non-adherent graft-tissue interface (Figure 11B), suggesting the presence of different immune populations at a very early stage. In particular, the adherent graft-tissue interface at days 1, 3, and 7 post-transplantation showed lower levels of various pro-inflammatory cytokines and chemokines (IL-18, CCL3, CCL5) compared to the non-adherent graft-tissue interface at all time points evaluated (Figure 11B). Inflammatory cytokines such as G-CSF and IL-12p70 show increased expression at the adhesive graft-tissue interface on days 3 and 7 post-transplant compared to the non-adhesive graft-tissue interface, and the non-adhesive graft-tissue interface is known to inhibit the secretion of pro-inflammatory cytokines during the acute phase of the foreign body reaction (Rutella, S. et al., The Journal of Immunology 175, 7085-7091 (2005)).

[0089] qPCR analysis showed no difference in neutrophil marker S100a8 expression on day 1, but a significant decrease was observed at subsequent time points (days 3 and 7) in the adhesive graft-tissue interface, which was consistent with the collected immunofluorescence data. This suggests that although initial neutrophil recruitment was similar, likely due to the surgery performed, the adhesive graft-tissue interface saw a rapid neutrophil elimination followed by the long-term persistence seen in non-adhesive grafts.

[0090] Furthermore, Nos2 expression was significantly higher at the adherent graft-tissue interface on days 1 and 3 post-transplant compared to the non-adherent graft-tissue interface (P ≤ 0.01) (Figures 11C-11E). This higher expression of Nos2 coincided with increased levels of inflammatory modulating cytokines (G-CSF, IL-12p70) during the acute phase (Figure 11B), which has been previously reported to mediate the inflammatory response through the activation of iNOS or the inhibition of pro-inflammatory cytokine secretion (Cassini-Vieira, P. et al., Mediators of Inflammation 2015, 138461 (2015)).

[0091] Figure 11A illustrates cytokines and genes associated with each cell type in Luminex and q-PCR studies. Figure 11B is a heatmap of immune response-related cytokines and chemokines measured using Luminex assays at the non-adherent and adherent graft-tissue interface collected on days 1, 3, and 7 after transplantation to the abdominal wall. Figures 11C–11F illustrate normalized gene expression of immune response-related markers at the non-adherent and adherent graft-tissue interface collected on day 1 (Figure 11C), day 3 (Figure 11D), day 7 (Figure 11E), and day 14 (Figure 11F) after transplantation to the abdominal wall. The values ​​in Figures 11C–11F represent the mean and standard deviation (n=9: 3 samples per animal). Statistical significance and P-values ​​were determined by a two-sided unpaired t-test, and ns (not significant) indicates that the result was not statistically significant. *P<0.05, **P≦0.01, ***P≦0.001, ****P<0.0001.

[0092] To further investigate the source of Nos2 during the acute phase (post-transplant days 1 and 3), double immunofluorescence staining was performed for iNOS / neutrophil elastase and iNOS / CD68 (Figure 12A). Immunofluorescence staining showed a higher density of iNOS+ neutrophils than macrophages on post-transplant day 3, indicating that the adhesive graft-tissue interface favors a subset of iNOS-producing neutrophils (Figure 12B) (see, for example, Saini, R. et al. Journal of Leukocyte Biology 79, 519-528 (2006)).

[0093] Figure 12A includes representative immunofluorescence images of adherent grafts collected on day 3 after transplantation to the abdominal wall. In the immunofluorescence images, cell nuclei are stained with 4′,6-diamidino-2-phenylindole (DAPI, blue), with green fluorescence corresponding to macrophage (CD68) and neutrophil (neutrophil elastase+) expression, and red fluorescence corresponding to iNOS expression. * in the image indicates the graft, and the white dotted line in the image indicates the graft-tissue interface. Figure 12B illustrates the quantification of iNOS+ / neutrophil elastase+ and iNOS+ / CD68+ cells per unit area on day 3 post-transplantation. The values ​​in Figure 12B represent the mean and standard deviation (n=3: independent samples). Statistical significance and P-value are determined by a two-sided unpaired t-test. **P≦0.01.

[0094] On post-transplant day 7, immune cell-related genes (neutrophil S100a8, monocyte Ly6c, Cd11b, pro-inflammatory macrophages Nos2, Cd86, Tgfb1, anti-inflammatory macrophages Mrc1, Il10, and T cell Il2) showed significantly lower expression at the adherent graft-tissue interface compared to the non-adherent graft-tissue interface (P<0.05) (Figure 11E). On post-transplant day 14, immune response-related genes (Cd86, Mrc1, Tgfb1, Il2) still showed significantly lower expression at the adherent graft-tissue interface compared to the non-adherent graft-tissue interface (P≦0.01) (Figure 11F). Fibrosis-related genes (Colla1, Acta2) showed significantly lower expression at the adhesive graft-tissue interface compared to the non-adhesive graft-tissue interface (P ≤ 0.01) on days 3, 7, and 14 post-transplant (Figures 11D-11F).

[0095] To further investigate differences in gene expression, bulk RNA sequencing of the graft-abdominal wall interface was performed on both adherent and non-adherent grafts at 3 and 14 days post-transplant (Figure 13). Principal component analysis (PCA) revealed clusters of separate samples from the adherent and non-adherent graft-tissue interface at each time point, which showed different transcriptomics profiles (Figures 13A, 13D). In addition, gene expression difference analysis of the non-adherent graft-tissue interface versus the adherent graft-tissue interface showed moderate differences at 3 days post-transplant, with 40 downregulated genes and 33 upregulated genes, as shown in the volcano plot (Figure 13B) and heatmap (Figure 14A). On day 14 post-transplant, 513 genes with significantly different expression levels were identified at the non-adhesive graft-tissue interface compared to the adhesive graft-tissue interface, of which 357 were downregulated and 156 were upregulated (Figures 13E and 14B).

[0096] To explore the functional significance of genes with differential expression, gene ontology (GO) enrichment analysis was performed. On day 3 post-transplant, interferon production and regulation of striated muscle tissue development were found to be abundant at the non-adhesive graft-tissue interface, indicating inflammatory and fibrotic processes, while cell proliferation and growth processes were found to be abundant at the adhesive graft-tissue interface (Figure 13C). Similar analysis of samples on day 14 post-transplant demonstrated that processes mainly related to fibrosis, such as muscle cell differentiation, myofibrils, and muscle structure development, were highly abundant at the non-adhesive graft-tissue interface, while angiogenesis, neurogenesis, and proliferation were mainly abundant at the adhesive graft-tissue interface (Figure 13F).

[0097] Figure 13A illustrates a principal component analysis (PCA) plot illustrating the variance of adherent graft (red dots, n=4) and non-adherent graft (black dots, n=4)-tissue interface datasets collected on day 3 post-abdominal wall transplantation. Figure 13B is a volcano plot showing gene expression profiles when comparing adherent and non-adherent graft-tissue interfaces collected on day 3 post-abdominal wall transplantation. Colored (blue and red) data points represent genes that satisfy a fold change (FC) threshold greater than 1 or less than -1, and a false detection rate (FDR) less than 0.05. Figure 13C illustrates the top five enriched processes from gene ontology (GO) enrichment analysis of genes with differing expression at the non-adherent (red) and adherent (blue)-tissue interfaces collected on day 3 post-abdominal wall transplantation. Figure 13D is a PCA plot illustrating the variance of adherent graft (red dots, n=4) and non-adherent graft (black dots, n=4)-tissue interface datasets collected 14 days after transplantation to the abdominal wall. Figure 13E is a volcano plot showing gene expression profiles when comparing adherent and non-adherent graft-tissue interfaces collected 14 days after transplantation to the abdominal wall. Colored (blue and red) data points represent genes that satisfy the FC threshold greater than 1 or less than -1, and FDR < 0.05. Figure 13F depicts the top 5 enriched processes from GO enrichment analysis of genes with differing expression at the non-adherent (red) and adherent (blue)-tissue interfaces collected 14 days after transplantation to the abdominal wall.

[0098] Figures 14A and 14B are bi-clustering heatmaps that visualize the expression profiles of the top 30 differentially expressed genes, sorted by adjusted P-values, by plotting their log2-transformed expression values ​​in samples taken 3 days (Figure 14A) and 14 days (Figure 14B) post-transplant. The dendrograms were created from word hierarchical clustering.

[0099] To test diverse animal models, embodiments of adhesive and non-adhesive grafts were implanted onto the abdominal wall surface of immunocompetent C57BL / 6 mice and HuCD34-NCG humanized mice (Figures 15A and 15C). Immunocompetent C57BL / 6 mice are known to induce fibrosis and xenobiotic reactions similar to those observed in human patients, while HuCD34-NCG humanized mice typically exhibit an immune response similar to that of humans.

[0100] Tissue structure analysis showed that in both the C57BL / 6 mouse model (Figure 15B) and the HuCD34-NCG mouse model (Figure 15D) of this example, the adhesive graft-tissue interface did not exhibit observable fibrous capsule formation compared to the original tissue 28 days post-transplant. In contrast, the non-adhesive graft-tissue interface showed substantial fibrous capsule formation in both mouse models of this example (Figures 15B and 15D).

[0101] To test human-scale anatomical structures, embodiments of adhesive and non-adhesive grafts were implanted in a pig model (Figure 15E). Macroscopic observation demonstrated that the adhesive grafts in this embodiment maintained stable integration with the surface of the pig's abdominal wall 7 days post-implantation in vivo. Histological analysis showed that the adhesive grafts formed conformal integration with the tissue surface without the formation of a fibrous capsule at the graft-tissue interface 7 days post-implantation in the abdominal wall (Figure 15F). In contrast, the non-adhesive graft-tissue interface exhibited substantial fibrous capsule formation (Figure 15F), which was consistent with the rodent model.

[0102] In vivo intraperitoneal transplantation in a pig model: Female domestic pigs (female, 50 kg, 20 weeks old) were placed in a supine position, their abdomens were shaved, and aseptically prepared. An incision was made along the ventral midline using a blade and extended using an electrosurgical unit if instructed. The linea alba was incised, bluntly penetrated the peritoneum, and the incision was extended to align with the skin incision. The small intestine was removed from the body and isolated using a moist plastic wrap sponge. Embodiments of adhesive or non-adhesive grafts were then applied to the surface of the abdominal wall and small intestine and adhered (n=4 for each group). The small intestine was thoroughly washed and returned to the abdomen. The entire peritoneal cavity was washed and aspirated, and then the entire peritoneal cavity was washed and aspirated again. The abdominal incision was then closed. On post-transplant day 7, the animals were humanely euthanized, the abdominal wall and small intestine of interest were resected, and fixed in 10% formalin for 24 hours for histological analysis.

[0103] To explore the potential utility of adhesive graft-tissue interfaces, we demonstrated long-term in vivo electrophysiological recordings and stimulation enabled by implantable electrodes with adhesive interfaces in a rat model (Figure 16).

[0104] For continuous in vivo monitoring and modulation of the electrocardiogram, electrodes with adhesive or non-adhesive interfaces were implanted on the epicardial surface of animals, and electrophysiological recordings or stimulation were performed at 0, 3, 7, 14, and 28 days post-implantation (Figure 16A). The amplitude of the R wave recorded with electrodes with adhesive interfaces was consistently maintained throughout the study period (28 days post-implantation), while the amplitude of the R wave recorded with electrodes with non-adhesive interfaces showed a substantial decrease over time (Figure 16B). In the case of electrophysical stimulation, the minimum stimulation current pulse amplitude required to successfully regulate the cardiac pulse gradually increased until 7 days post-implantation, and ultimately, electrodes with non-adhesive interfaces were unable to regulate the cardiac pulse at longer time points (Figure 16C).

[0105] In contrast, electrodes with adhesive interfaces exhibited a consistent minimum stimulation current pulse amplitude for pulse regulation and successfully maintained their ability to regulate the heart's pulse throughout the study period (28 days post-implantation) (Figure 16D). These results were consistent with the histological findings from tissues collected on post-implantation day 28, where electrodes with non-adhesive interfaces showed encapsulation and physical separation from the epicardial surface by a thick fibrous capsule (Figure 16E). In contrast, electrodes with adhesive interfaces showed conformal contact with the epicardial surface on post-implantation day 28 without forming a fibrous capsule (Figure 16F).

[0106] Figure 16A includes a schematic illustrative diagram of in vivo electrophysiological recordings and stimulation via implanted electrodes with non-adhesive or adhesive graft-tissue interfaces. Figure 16B depicts recorded R-wave amplitudes via implanted electrodes with non-adhesive (black) and adhesive (red) graft-tissue interfaces at 0, 3, 7, 14, and 28 days post-implantation in rat hearts. Inset plots show representative recorded waveforms. Figures 16C and 16D are representative epicardial electrocardiograms after stimulation via implanted electrodes with non-adhesive (Figure 16C) and adhesive (Figure 16D) graft-tissue interfaces at 0, 3, 7, 14, and 28 days post-implantation in rat hearts. Figures 16E and 16F are representative histological images of non-adhesive grafts (Figure 16E) and adhesive grafts (Figure 16F) collected 28 days after transplantation into rat hearts, stained with hematoxylin-eosin (H&E, top) and Masson's tricolor staining (MTS, bottom). * in the images indicates grafts, and the yellow dotted line indicates the graft-tissue interface. The values ​​in Figure 16B represent the mean and standard deviation (n=5: independent samples).

[0107] In this embodiment, the following procedure was used.

[0108] Preparation of adhesive grafts: The adhesive layer of the adhesive grafts was prepared based on previously reported methods (Yuk, H. et al., Nature 575, 169-174 (2019); Wu, J. et al., Science Translational Medicine 14, eabh2857 (2022)). To prepare the adhesive stock solution, 35 w / w% acrylic acid and 7 w / w% polyvinyl alcohol (M w (146,000-186,000, 99+% hydrolysis), 0.2 w / w% α-ketoglutaric acid, and 0.05 w / w% N,N'-methylene-bisacryloamide were added to nitrogen-purged deionized water. Then, 30 mg of N-hydroxysuccinimide acrylate per 1 mL of the stock solution was dissolved to prepare an adhesive precursor solution.

[0109] A precursor solution was poured onto a glass mold with a spacer (100 μm thick) and irradiated in a UV chamber (354 nm, 12 W power) for 30 minutes to prepare an adhesive hydrogel. The adhesive hydrogel was completely dried under airflow and a vacuum desiccator to prepare a dried adhesive layer. A simulated device of an adhesive graft was introduced by spin-coating a polyurethane resin (HydroThane, AdvanSource Biomaterials) onto the dried adhesive layer.

[0110] Preparation of non-adhesive grafts: To prepare non-adhesive grafts, adhesive grafts were immersed overnight in a sterile phosphate-buffered saline (PBS) bath. During this process, the adhesive layer of the graft reached a state of equilibrium swelling and became non-adhesive, losing its ability to form physical (hydrogen bonds) and covalent (amide bonds) crosslinks with the tissue (Chen, X., et al., Proceedings of the National Academy of Sciences 117, 15497-15503 (2020)).

[0111] Preparation of implantable electrodes: To prepare implantable electrodes, an adhesive layer or a non-adhesive layer was integrated into the gold electrode. The surface of the gold electrode was treated with oxygen plasma for 3 minutes (30W power, Harrick Plasma) to activate surface functionalization, and then immersed in a cysteamine hydrochloride solution (50 mM deionized water) at room temperature for 1 hour.

[0112] After functionalization, the gold electrodes were thoroughly washed with deionized water and dried with a nitrogen stream. The functionalized gold electrodes were cut into 2 mm diameter circles and placed on adhesive hydrogels (two electrodes per graft). Electrode lead wires (AS633, Cooner Wire) were connected to the gold electrodes, and a polyurethane insulating layer (HydroThane, AdvanSource Biomaterials) was introduced onto the gold electrodes. The assembled grafts were completely dried under airflow and vacuum desiccator to prepare adhesive implantable electrodes. To prepare non-adhesive implantable electrodes, the adhesive implantable electrodes were immersed overnight in a sterile PBS bath. All samples were prepared aseptically and further disinfected under UV light for 1 hour before use.

[0113] In vitro protein adsorption assay: Gelatin hydrogel (10 w / v%, 300 g Bloom, Sigma-Aldrich) was used as the substrate for the in vitro protein adsorption assay. Adhesive or non-adhesive grafts were cut into 5 mm diameter circles using a biopsy punch and placed on the gelatin hydrogel. The sample was then added to 5 mg mL -1 The samples were incubated for 30 minutes in a solution containing albumin (A13101, Thermo Fisher) or fibrinogen (F13191, Thermo Fisher) tagged with a fluorescent agent. After incubation, the samples were washed three times with fresh PBS to remove unattached proteins. The samples were imaged using a confocal microscope (SP8, Leica) with a confocal plane implanted at the gelatin hydrogel-graft interface under a pitch model with excitation / emission at 495 nm / 515 nm (for albumin) and 495 nm / 635 nm (for fibrinogen). The relative fluorescence intensity of the absorbed proteins was calculated using Image J (version 2.1.0).

[0114] In vivo intraperitoneal transplantation: Female Sprague-Dawley rats (225–250 g, 12 weeks old, Charles River Laboratories) were used for all in vivo studies. Prior to transplantation, all specimens were prepared using sterile techniques and further disinfected under UV light for 1 hour. For in vivo intraperitoneal transplantation, animals were anesthetized in the anesthesia room before surgery using isoflurane (2–3% isoflurane in oxygen), and anesthesia was maintained during surgery using a nasal cone. Abdominal hair was removed, and animals were placed on a heating pad during surgery. The abdominal wall, colon, or stomach was exposed through an abdominal incision. Adhesive grafts (10 mm wide, 10 mm long) were applied to the surface of the abdominal wall (n=4 at each time point), colon (n=4), or stomach (n=4) by gently pressing with a surgical spatula or fingertip. Non-adhesive grafts (10 mm wide, 10 mm long) were transplanted to the surface of the abdominal wall (n=4 at each time point), colon (n=4), or stomach (n=4) by suturing the corners of the sample (8-0 Prolene, Ethicon). The abdominal wall muscle and skin incisions were closed by suturing (4-0 Vicryl, Ethicon). Animals were euthanized by CO2 inhalation on days 3, 7, 14, 28, and 84 post-transplant. Abdominal wall tissue, colon tissue, or stomach tissue of interest was excised and fixed in 10% formalin for 24 hours for histological analysis and immunofluorescence analysis. All animals in this study survived and maintained normal health based on daily monitoring by MIT DCM veterinary staff.

[0115] In vivo intrathoracic transplantation: For intrathoracic transplantation, animals were anesthetized in the anesthesia room before surgery using isoflurane (2-3% isoflurane in oxygen), and anesthesia was maintained during surgery using a nasal cone. Chest hair was removed, endotracheal intubation was performed, and the animals were connected to a mechanical ventilator (RoVent, Kent Scientific). The animals were placed on a heating pad during surgery. The lung or heart was exposed via thoracotomy, and the pericardium was removed using fine forceps for heart transplantation. Adhesive grafts (10 mm wide, 10 mm long) were applied to the surface of the lung (n=4) or heart (n=4) by gently pressing with a surgical spatula or fingertip. Non-adhesive grafts (10 mm wide, 10 mm long) were transplanted to the surface of the lung (n=4) or heart (n=4) by suturing the corners of the specimen (8-0 Prolene, Ethicon). Muscle and skin incisions were closed with sutures (4-0 Vicryl, Ethicon). Animals were ventilated with 100% oxygen until autonomous respiration was restored. On day 28 post-transplant, animals were euthanized by CO2 inhalation. Lung or heart tissue of interest was excised and fixed in 10% formalin for 24 hours for histological analysis and immunofluorescence analysis. All animals in this study survived and maintained normal health conditions based on daily monitoring.

[0116] In vivo electrophysiological studies: Prior to implantation, adhesive and non-adhesive implantable electrodes were prepared using sterile techniques and further disinfected under UV light for 1 hour. For in vivo epicardial electrode implantation, animals were anesthetized in the anesthesia room using isoflurane (2-3% isoflurane in oxygen) before surgery, and anesthesia was maintained during surgery using a nasal cone. Chest and back hair was removed, endotracheal intubation was performed, and the animals were connected to a mechanical ventilator (RoVent, Kent Scientific). The animals were placed on a heating pad during surgery. The heart was exposed via thoracotomy, and the pericardium was removed using fine forceps for epicardial implantation. Adhesive implantable electrodes were applied to the left ventricular surface (n=4) by gently pressing with a surgical spatula or fingertip. Non-adhesive implantable electrodes were implanted to the left ventricular surface (n=4) by suturing to the corners of the sample (8-0 Prolene, Ethicon). Next, the lead wire was passed through a subcutaneous tunnel dorsally from the ventral exit site near the left fourth intercostal space. The dorsal end of the lead wire was inserted through the subcutaneous port. The subcutaneous port was placed between the animal's scapulae by intermittent sutures (4-0 Vicryl, Ethicon) and covered with a protective aluminum cap (VABRC, Instech Laboratories). The muscle and skin incisions were closed with sutures (4-0 Vicryl, Ethicon). The animal was ventilated with 100% oxygen until autonomic respiration was restored.

[0117] On days 0, 3, 7, 14, and 28 post-transplant, each animal was anesthetized and connected to data acquisition hardware (PowerLab, AD Instrument) and software (LabChart Pro 7, AD Instrument) for electrophysiological recording and stimulation using the implanted electrodes. For electrophysiological recording, the data acquisition hardware was connected to the implanted electrodes through a dorsal subcutaneous port. Epicardial signals were recorded and R-wave amplitude was evaluated. For electrophysiological stimulation, an external stimulator (FE180, AD Instrument) was connected to the implanted electrodes through a dorsal subcutaneous port. Unipolar rectangular current pulses (0.5 ms, 0-3 mA, 5-7 Hz) were used for continuous ventricular pulse regulation, while surface electrocardiogram (ECG) was monitored to evaluate the capture threshold. On day 28 post-transplant, the animals were euthanized by CO2 inhalation. Cardiac tissue of interest was excised and fixed in 10% formalin for 24 hours for histological analysis. All animals in this study survived and maintained normal health conditions based on daily monitoring.

[0118] Immunofluorescence analysis: The expression of target markers (αSMA, collagen I, CD68, CD3, CD206, iNOS, vimentin, collagen III, neutrophil elastase) was analyzed after immunofluorescence staining of the collected tissues. Prior to immunofluorescence analysis, paraffin-embedded and fixed tissues were sliced ​​and prepared on slides. The slides were deparaffinized and rehydrated with deionized water. Antigen recovery was performed using a steam method, in which the slides were steamed in IHC-Tek epitope recovery solution (IW-1100) for 35 minutes, followed by cooling for 20 minutes. The slides were then washed three times with PBS for 5 minutes each cycle. After washing, the slides were diluted with IHC-Tek antibody diluents to obtain the following primary antibodies: (1:200 mouse anti-αSMA (ab7817, Abcam); 1:200 mouse anti-CD68 (ab201340, Abcam); 1:100 rabbit anti-CD3 (ab5690, Abcam); 1:200 rabbit anti-collagen I (ab21286, Abcam)); 1:1000 rabbit anti-CD206 (ab64693, Abcam); Slides were incubated at room temperature for 1 hour with 1:500 mouse anti-vimentin (ab8978, Abcam), 1:1000 rabbit anti-collagen III (ab283694, Abcam), 1:2000 rabbit anti-iNOS (ab283655, Abcam), 1:200 mouse anti-iNOS (GTX60599, GeneTex), and 1:50 rabbit anti-neutrophil elastase (bs-6982R, Bioss). The slides were then washed three times with PBS and incubated for 30 minutes with Alexa Fluor 488-labeled anti-rabbit or anti-mouse secondary antibody (1:200, Jackson Immunoresearch) or Alexa Fluor 594-labeled donkey anti-mouse secondary antibody (1:200, Jackson Immunoresearch). The slides were washed with PBS and then counterstained with propidium iodide for 20 minutes. A laser confocal microscope (SP8, Leica) was used to acquire images. The fluorescence intensity of the expressed antibody was quantified using ImageJ (version 2.1.0). All images were converted to 8-bit binary images, and fluorescence intensity was calculated using normalization analysis. All analyses were blinded to the experimental conditions.

[0119] Luminex quantitative analysis: Abdominal muscle wall samples of interest were collected on days 1, 3, and 7 post-transplant. The collected samples were snap-frozen in liquid nitrogen and homogenized with TissueLyser LT (Qiagen) according to the manufacturer's instructions. The concentrations of cytokines and chemokines (RECYTMAG-65K, Milliplex) associated with the immune response were measured using Luminex multiplex assays.

[0120] qPCR analysis: RNA was isolated from samples that were snap-frozen in liquid nitrogen immediately after excision using the TRIzol protocol (Invitrogen). All samples were homogenized and normalized by loading 1 μg of total RNA in all cases for reverse transcription using the SuperScript First Strand cDNA synthesis kit (Invitrogen). Complementary DNA (1:20 dilution) was amplified by qPCR using the following primers: Mrc1 (5′-AACTTCATCTGCCAGCGACA-3′; reverse: 5′-CGTGCCTCTTTCCAGGTCTT-3′), Tgfb1 (5′-AGTGGCTGAACCAAGGAGAC-3′; reverse: 5′-CCTCGACGTTTGGGACTGAT-3′), Nos2 (5′-TGGTGAGGGGACTGGACTTT-3′; reverse: 5′-CCAA CTCTGCTGTTCTCCGT-3′), Cd86(5′-AGACATGTGTAACCTGCACCAT-3′; reverse: 5′-TACGAGCTCACTCGGGCTTA-3′), Col1a1(5′-ATGCTGAA TCGTCCCACCAG-3′; Reverse: 5′-ATGTCCCGGCAGGATTTGAA-3′), Acta2(5′-GGATCAGCGCCTTCAGTTCT-3′; Reverse: 5′-AGGGCTAGAAGGGTAGCAC A-3′), Il2(5′-CCAAGCAGGCCACAGAATTG-3′; inverse: 5′-TCCAGCGTCTTCCAAGTGAA-3′), S100a8(5′-CGAAGAGTTCCTTGTGTTGGTG-3′; inverse: 5′-AGCTCTGTTACTCCTTGTGGC-3′), Ly6c(5′-ACCTGGTCACAGAGAGGAAGT-3′; inverse: 5′-AGCAGTTAGCATTAAGTGGGACT-3′), Il10(5 ′-TTGAACCACCCGGCATCTAC-3′; reverse: 5′-CCAAGGAGTTGCTCCCGTTA-3′), Cd11b(5′-GACTCCGCATTTGCCCTACT-3′; reverse: 5′-GCTGCCCACAATGAGTGGTA-3′), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH)(5′-CACCATCTTCCAGGAGCGAG-3′; reverse: 5′-CCACGACATACTCAGCACCA-3′).The samples were incubated in a real-time cyclizer, Agilent MX3000P, at 95°C for 15 seconds, and at 60°C for 1 minute and 10 minutes. GAPDH was used as the reference gene for normalization and analysis. Relative quantification of gene expression was performed using comparative CT (ΔΔCT) method.

[0121] RNA sequencing analysis: RNA extraction, library preparation, and sequencing reactions were performed at GENEWIZ, LLC. Total RNA was extracted using the Qiagen RNeasy Plus Universal mini-kit according to the manufacturer's instructions (Qiagen). The extracted RNA samples were quantified using a Qubit 2.0 fluorometer (Life Technologies), and RNA integrity was confirmed using an Agilent TapeStation 4200 (Agilent Technologies). The RNA sequencing library was prepared using the Illumina NEBNext Ultra RNA Library Prep kit according to the manufacturer's instructions (NEB). Briefly, mRNA was first enriched with oligo(dT) beads. The enriched mRNA was fragmented at 94°C for 15 minutes. Subsequently, cDNA for the first and second strands was synthesized. The cDNA fragments were repaired at the ends, adenylated at the 3' end, and ligated with a universal adapter. Indexing and library enrichment were then performed by limited-cycle PCR. The sequence library was validated using an Agilent TapeStation (Agilent Technologies) and quantified using a Qubit 2.0 Fluorometer (Invitrogen) and quantitative PCR (KAPA Biosystems). The sequence library was clustered on one lane of a flow cell. After clustering, the flow cell was loaded into an Illumina HiSeq 4000 instrument, and the samples were sequenced using a 2x150bp paired-end (PE) configuration. Image analysis and base calling were performed using HiSeq Control Software (HCS). The raw sequence data (bcl files) generated from the Illumina HiSeq were converted to fastq files and demultiplexed using Illumina's bcl2fastq 2.17 software. One mismatch was acceptable for index sequence identification.

[0122] Read quality was evaluated using FastQC, and the data were preprocessed using Cutadapt (Martin, M. et al., EMBnet. Journal 17, 10-12 (2011)) to remove adapters according to best practices. Gene expression for the mRatBN7.2 transcriptome (Ensembl release 104) (Cunningham, F. et al., Nucleic Acids Research 47, D745-D751 (2019)) was quantified using STAR (Dobin, A. et al., Bioinformatics 29, 15-21 (2013)) and featureCounts (Liao, Y. et al., Bioinformatics 30, 923-930 (2014)). Gene expression difference analysis was performed using DESeq2 (Love, MI et al., Genome Biology 15, 550 (2014)), while functional enrichment studies were conducted using ClusterProfiler (Yu, G. et al., Omics: A Journal of Integrative Biology 16, 284-287 (2012)). Genes with log2|magnification change| ≥ 1 and false detection rate (FDR) ≤ 0.05 were considered statistically significant.

Claims

1. A method for implanting a biomaterial or device into a patient, wherein the method is The adhesive composition is arranged between (i) the biomaterial or the device and (ii) the surface of the patient's tissue, and in contact with them. A method wherein the adhesive composition is configured to form a conformal interface on the surface of the tissue that reduces or minimizes the infiltration of inflammatory cells at the conformal interface.

2. The method according to claim 1, wherein the reduction or minimization of the infiltration of inflammatory cells prevents the formation of a fibrous capsule at the conformal interface for at least 28 days after the implantation of the biomaterial or the device.

3. The method according to claim 1, wherein the device includes electrodes.

4. The method according to claim 3, wherein bidirectional electrical communication between the electrode and the tissue is maintained for at least 28 days after the implantation of the electrode.

5. The method according to claim 4, wherein the tissue comprises cardiac tissue of the patient's heart, and at least 28 days after the implantation of the electrode, the R wave of the patient's heart recorded by the electrode has an amplitude of 0% to less than 5% of the initial amplitude of the initial R wave of the patient's heart recorded by the electrode within 24 hours after the implantation of the electrode.

6. The method according to claim 4, wherein the tissue comprises cardiac tissue of the patient's heart, and the minimum stimulation current pulse amplitude for pulse regulation emitted by the electrode regulates the pulse of the patient's heart for at least 28 days after the implantation of the electrode.

7. The method according to claim 1, wherein the tissue includes abdominal wall tissue, colon tissue, stomach tissue, lung tissue, or heart tissue.

8. The arrangement of the adhesive composition is To provide the adhesive composition, wherein the adhesive composition adheres to the biomaterial or the device, The method according to claim 1, comprising bringing the surface of the tissue into contact with the adhesive composition.

9. The arrangement of the adhesive composition is Distributing the adhesive composition onto the surface of the tissue, The method according to claim 1, comprising bringing the adhesive composition into contact with the biomaterial or the device.

10. The method according to claim 1, wherein the adhesive composition comprises a crosslinked polymer composition.

11. The adhesive composition (i) one or more hydrophilic polymers, one or more zwitterionic polymers, or a combination thereof (ii) One or more tissue coupling groups, (iii) One or more crosslinking agents, (iv) The method according to claim 1, comprising a combination thereof.

12. The method according to claim 11, wherein the one or more hydrophilic polymers are selected from the group consisting of polyethylene glycol, polyacrylic acid, polyacrylamide, polyvinyl alcohol, polyhydroxyethyl methacrylate, polyethylene glycol, polyurethane, casein, albumin, gelatin, chitosan, dextran, hyaluronic acid, alginate, cellulose, polyvinylpyrrolidone, polystyrene sulfonate, collagen, alginic acid, pectin, and combinations thereof.

13. The method according to claim 12, wherein the alginate and the cellulose are, respectively, oxidized alginate and oxidized cellulose.

14. The method according to claim 11, wherein one or more zwitterionic polymers are selected from the group consisting of poly(phosphobetaine), poly(carboxybetaine), poly(sulfobetaine), and combinations thereof.

15. The method according to claim 11, wherein the one or more structural coupling groups are selected from the group consisting of amine coupling groups, thiol coupling groups, cysteine ​​coupling groups, N-acetyl-cysteine ​​coupling groups, boronate ester coupling groups, and combinations thereof.

16. The method according to claim 15, wherein the amine coupling group is selected from the group consisting of N-hydroxysuccinimide ester (PAAc-co-NHS ester), PAAm-co-NHS, N-hydroxysuccinimide (NHS) PEG, poly(L-lactide-co-glycolide)-NHS, poly(D,L-lactide)-polyethylene glycol-CO-NHS, poly(N-isopropylacrylamide) N-hydroxysuccinimide terminus, aldehyde, imide ester, epoxide, isocyanate, catechol, and combinations thereof.

17. The method according to claim 15, wherein the thiol coupling group is selected from the group consisting of alginate, albumin, fibrinogen, collagen, chitosan, gelatin, and combinations thereof.

18. The method according to claim 15, wherein the cysteine ​​coupling group is selected from the group consisting of fibrinogen, collagen, and combinations thereof.

19. The method according to claim 15, wherein the one or more boronate ester coupling groups are selected from the group consisting of acrylamide, N-isopropylacrylamide, polyvinyl alcohol (PVA), alginate, cellulose, and combinations thereof.

20. The method according to claim 11, wherein the one or more crosslinking agents are selected from the group consisting of gelatin methacrylate, hyaluronic acid methacrylate, methacrylate alginate oxide, polycaprolactone diacrylate, N,N'-bis(acryloyl)cystamine, N,N'-methylenebis(acrylamide), polyethylene glycol diacrylate, polyethylene glycol dimethacrylate, and combinations thereof.

21. An adhesive composition configured to form a conformal interface on a tissue surface that reduces or minimizes the infiltration of inflammatory cells at the conformal interface, according to the method of any one of claims 1 to 20.

22. An adhesive composition configured to form a conformal interface on the surface of a tissue that reduces or minimizes the infiltration of inflammatory cells at the conformal interface.

23. The adhesive composition (i) one or more hydrophilic polymers, one or more zwitterionic polymers, or a combination thereof (ii) One or more tissue coupling groups, (iii) One or more crosslinking agents, (iv) The adhesive composition according to claim 22, comprising a combination thereof.

24. The adhesive composition according to claim 23, wherein the one or more hydrophilic polymers are selected from the group consisting of polyethylene glycol, polyacrylic acid, polyacrylamide, polyvinyl alcohol, polyhydroxyethyl methacrylate, polyethylene glycol, polyurethane, casein, albumin, gelatin, chitosan, dextran, hyaluronic acid, alginate, cellulose, polyvinylpyrrolidone, polystyrene sulfonate, collagen, alginic acid, pectin, and combinations thereof.

25. The adhesive composition according to claim 24, wherein the alginate and the cellulose are, respectively, oxidized alginate and oxidized cellulose.

26. The adhesive composition according to claim 23, wherein one or more zwitterionic polymers are selected from the group consisting of poly(phosphobetaine), poly(carboxybetaine), poly(sulfobetaine), and combinations thereof.

27. The adhesive composition according to claim 23, wherein the one or more structural coupling groups are selected from the group consisting of amine coupling groups, thiol coupling groups, cysteine ​​coupling groups, N-acetyl-cysteine ​​coupling groups, boronate ester coupling groups, and combinations thereof.

28. The adhesive composition according to claim 27, wherein the amine coupling group is selected from the group consisting of N-hydroxysuccinimide ester (PAAc-co-NHS ester), PAAm-co-NHS, N-hydroxysuccinimide (NHS) PEG, poly(L-lactide-co-glycolide)-NHS, poly(D,L-lactide)-polyethylene glycol-CO-NHS, poly(N-isopropylacrylamide)N-hydroxysuccinimide terminus, aldehyde, imide ester, epoxide, isocyanate, catechol, and combinations thereof.

29. The adhesive composition according to claim 27, wherein the thiol coupling group is selected from the group consisting of alginate, albumin, fibrinogen, collagen, chitosan, gelatin, and combinations thereof.

30. The adhesive composition according to claim 27, wherein the cysteine ​​coupling group is selected from the group consisting of fibrinogen, collagen, and combinations thereof.

31. The adhesive composition according to claim 27, wherein the one or more boronate ester coupling groups are selected from the group consisting of acrylamide, N-isopropylacrylamide, polyvinyl alcohol (PVA), alginate, cellulose, and combinations thereof.

32. The adhesive composition according to claim 23, wherein the one or more crosslinking agents are selected from the group consisting of gelatin methacrylate, hyaluronic acid methacrylate, methacrylate alginate oxide, polycaprolactone diacrylate, N,N'-bis(acryloyl)cystamine, N,N'-methylenebis(acrylamide), polyethylene glycol diacrylate, polyethylene glycol dimethacrylate, and combinations thereof.

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