On-demand stripping hydrogel with high biological wet tissue adhesion and preparation method thereof

Abstract

The invention provides an on-demand stripping hydrogel with high biological wet tissue adhesion and a preparation method of the on-demand stripping hydrogel. The hydrogel is obtained by combining a hydrophobic amino acid acrylamide derivative and a hydrophilic monomer with a temperature-sensitive monomer and polymerizing. According to the hydrophobic amino acid vinyl monomer phenylalanine derivative provided by the invention, carboxyl and a benzene ring are in a special structure of the same structural unit, so that a hydration layer of a tissue interface can be effectively damaged, and the strength of a matrix can be enhanced by forming stable multiple hydrogen bonds; and strong adhesion (60kPa) can be realized after the adhesive is contacted with wet biological tissues for 5 seconds. The biocompatibility is good, clinical application is facilitated, and a new choice is provided for replacing surgical suture to achieve wound closure and rapid hemostasis clinically.

Description

Technical Field

[0001] The present invention relates to the technical field of polymer hydrogels, and in particular to an on-demand peeling hydrogel with high biological wet tissue adhesion through temperature-driven reversible phase transition, as well as a preparation method and application thereof. Background Art

[0002] Acute tissue injury is often accompanied by massive bleeding, which can easily lead to serious symptoms such as hypotension and multiple organ dysfunction. According to statistics from the World Health Organization, approximately five million people die each year worldwide from acute tissue trauma caused by traffic accidents, natural disasters, surgery and other factors. At present, the use of sutures and staples is the main means of emergency hemostasis and wound closure in clinical practice, but its operation is relatively complicated and requires the application of large local stress to the tissue, which can easily cause postoperative infection, leakage, secondary tissue damage and other problems. It is challenging to apply it to fragile visceral tissues and emergency scenarios. As a biomedical material with easy operation, excellent tissue compliance and good biocompatibility, hydrogel-based tissue adhesives can be quickly applied to irregular tissue wounds. In recent years, it has gradually developed into an effective auxiliary and alternative to traditional surgical suturing and stapling. However, achieving interfacial wet bonding remains challenging due to two main reasons: First, solutions such as tissue exudates, blood, and tissue contents form a hydration layer on the surface of biological tissues, which affects and hinders direct contact and chemical bonding between the hydrogel and biological tissues; and second, water molecules that penetrate into the polymer network through osmosis disrupt the intermolecular interactions of the hydrogel matrix, thereby weakening the mechanical properties and structural stability of the hydrogel adhesive matrix. Therefore, effectively eliminating the interference of interfacial water molecules is the key to developing hydrogel biological tissue adhesives with strong and durable bonding properties.

[0003] Current design strategies for wet tissue adhesives are primarily inspired by marine organisms. Inspired by the underwater adhesion of mussels, molecules with catechol structures can effectively penetrate the interfacial hydration layer and achieve strong wet adhesion by forming multiple interactions with biological tissues. However, when used in emergency situations such as hemorrhage, once these adhesives form a strong and stable bond with the interface, subsequent correction of misaligned adhesion and non-destructive, on-demand peeling can be difficult, potentially causing secondary damage to damaged tissues / organs and compromising subsequent clinical treatment. Summary of the Invention

[0004] The present invention aims to solve the problem of how to achieve the characteristics of in-situ wet bonding of biological tissue adhesives triggered by body temperature and gentle peeling on demand triggered by room temperature; and to provide a mechanism for temperature-driven phase transition to drive in-situ wet bonding and gentle peeling on demand of biological tissue adhesives.

[0005] The present invention aims to overcome the shortcomings of existing technologies by providing a bio-tissue adhesive that can be peeled on demand and its preparation method. The adhesive is prepared by a one-pot free radical polymerization of hydrophobic amino acid acrylamide monomers and hydrophilic monomers combined with temperature-sensitive vinyl monomers to produce a bio-tissue adhesive with high wet tissue adhesion.

[0006] To achieve the above object, the technical solution adopted by the present invention is:

[0007] In one aspect, the present invention provides an on-demand peelable hydrogel with high biological wet tissue adhesion, wherein the hydrogel is prepared by free radical polymerization of a hydrophobic amino acid vinyl monomer, a hydrophilic monomer, and a thermosensitive monomer.

[0008] Furthermore, the structure of the hydrophobic amino acid vinyl monomer is shown in formula (I):

[0009]

[0010] Furthermore, the ratio of the number of structural units among the hydrophobic amino acid vinyl monomer, the hydrophilic monomer and the thermosensitive monomer is 1:(9-13):(0.5-2).

[0011] Furthermore, the hydrophobic amino acid vinyl monomer is selected from one or more of N-acryloylalanine (AL), N-acryloylvaline (AV), N-acryloylphenylalanine (APA), N-acryloylleucine (ALE), N-acryloylisoleucine (AIL), N-acryloyltryptophan (ATP), N-acryloylmethionine (AMT), N-acryloylalaninamide (ALN), N-acryloylvalinamide (AVN) and N-acryloylphenylpropionamide (APN); the hydrophilic monomer is selected from acrylic acid (AA), methacrylic acid (MAA), 2-hydroxyethyl acrylate (HEA), hydroxyethyl methacrylate (HEMA), acrylamide (AM), N-trimethylolmethylacrylamide (THMA), N,N-dimethylacrylamide (THMA), N-hydroxyethyl methacrylate (HEA), N-hydroxyethyl methacrylate (HEMA), N-trimethylol methacrylamide (THMA), N,N-dimethylacrylamide (THMA), N-hydroxyethyl methacrylate (HEA), N-hydroxyethyl methacrylate (HEMA), N-trimethylol methacrylamide (THMA), N,N-dimethylacrylamide (THMA), N-trimethylol meth ... One or more of dimethicone (DMA), N-hydroxyethylacrylamide (HEAA), 1-vinyl-2-pyrrolidone (NVP), N-acryloylaspartic acid (AASP), N-acryloylglutamate (AGLU), N-acryloylglycine (AG), N-acryloyltyrosine (AT), N-acryloylserine (AS), N-acryloylthreonine (AT) and N-acryloylglutamine (AGT); the temperature-sensitive monomer is selected from N-isopropylacrylamide (NIPAM), polyethylene glycol methyl ether methacrylate (OEGMA), N-vinylcaprolactam (NVCL), 2-(2-methoxyethoxy)ethyl methacrylate (MEO2MA), N-vinylpyrrolidone (NVP), and hydroxypropyl acrylate (HPA).

[0012] On the other hand, the present invention provides a method for preparing the on-demand peeling hydrogel with high biological wet tissue adhesion as described above, the method comprising the following steps: S1, fully dissolving the hydrophobic amino acid vinyl monomer, hydrophilic monomer and thermosensitive monomer in an aqueous solution to obtain a colorless and transparent mixed liquid; S2, adding an initiator and an initiator promoter to the mixed liquid at room temperature and mixing them evenly to complete free radical polymerization to obtain a polymer; S3, storing the polymer in an environment below room temperature to obtain the on-demand peeling hydrogel with high biological wet tissue adhesion.

[0013] Furthermore, the total concentration of the hydrophobic amino acid vinyl monomer and the hydrophilic monomer is 6.7 to 7.7 M, wherein the concentration ratio of the hydrophobic amino acid vinyl monomer to the hydrophilic monomer is 0.7 to 6:7; optionally, the concentration of the thermosensitive unit monomer is 0.2 to 1.0 mol / L.

[0014] Furthermore, the initiator is selected from one or more of potassium persulfate, ammonium persulfate and azobisisobutylimidazoline hydrochloride; and the initiator accelerator is N,N,N',N'-tetramethylethylenediamine.

[0015] Furthermore, the added amount of the initiator is 0.5-2% of the total mass of the hydrophobic amino acid vinyl monomer, the hydrophilic monomer and the thermosensitive monomer; and the added amount of the initiator accelerator is greater than 0 and less than or equal to 30% of the mass of the initiator.

[0016] Furthermore, in step S1, the method of sufficient dissolution is selected from one or more of heating, ultrasound and vortex oscillation; in step S2, the temperature of free radical polymerization is 20-80° C., and the reaction time is 2-12 hours.

[0017] The present invention provides the use of the above-mentioned on-demand peelable hydrogel with high biological wet tissue adhesion in the fields of wound closure and rapid hemostasis.

[0018] Compared with the prior art, the on-demand peeling hydrogel with high biological wet tissue adhesion provided by the present invention and its preparation method and application have at least the following advantages:

[0019] The hydrogel is obtained by combining hydrophobic amino acid acrylamide derivatives and hydrophilic monomers with temperature-sensitive monomer polymerization. The hydrophobic amino acid vinyl monomer phenylalanine derivative provided by the present invention has a special structure in which the carboxyl group and the benzene ring are located in the same structural unit, which can not only achieve effective destruction of the tissue interface hydration layer, but also can enhance the strength of the matrix by forming stable multiple hydrogen bonds, and can achieve strong adhesion (60kPa) in 5 seconds of contact with moist biological tissue. Further, through the mechanism of temperature-driven phase transition and the structure-activity relationship between phase transition and macroscopic performance, a multifunctional biological tissue adhesive has been developed that can achieve rapid hemostasis and closure of tissue trauma such as arteries, heart, and liver under physiological conditions, and can respond to temperature stimulation and be gently peeled off on demand.

[0020] (1) The on-demand peelable hydrogel with high biological wet tissue adhesion provided by the present invention is simple and convenient to use, has strong and stable bonding ability, and can form a strong and stable bond with wet tissue only by body temperature triggering, and the bonding interface is not affected by external water molecules. In addition, the hydrogel exhibits strong and stable wet adhesion to various organ tissues in the body (heart, liver, lungs, stomach, arteries), and has the potential for promoting tissue wound closure and rapid hemostasis;

[0021] (2) The on-demand peeling hydrogel with high biological wet tissue adhesion provided by the present invention can achieve firm wet adhesion and gentle on-demand peeling of different types of biological tissues under physiological conditions, meeting the requirements of rapid hemostasis and sealing of clinical tissue trauma and subsequent non-destructive on-demand peeling applications;

[0022] (3) The preparation and operation methods of the on-demand peelable hydrogel with high biological wet tissue adhesion provided by the present invention are simple and quick. The polymer hydrogel is prepared by a one-step free radical polymerization process, which is convenient for low-temperature storage and forms a strong and firm wet bond with tissue when used, triggered by body temperature.

[0023] (4) The on-demand peelable hydrogel with high biological wet tissue adhesion provided by the present invention has good biocompatibility. The hydrogel patch obtained by free radical polymerization of hydrophobic amino acid derivatives, hydrophilic monomers, and temperature-sensitive vinyl monomers has excellent biocompatibility, which is conducive to clinical translation and provides a new option for clinically replacing surgical sutures to achieve wound closure and rapid hemostasis. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 This is a graph showing the wet adhesive strength test results of the hydrogel provided in Example 5 at different temperatures;

[0025] Figure 2 Graph showing the wet bonding strength and switching efficiency test results of the hydrogel provided in Example 5 with various porcine tissues;

[0026] Figure 3 This is a graph showing the rheological test results of the gel modulus as a function of temperature provided in Example 5;

[0027] Figure 4 These are the results of low-field nuclear magnetic resonance (NMR) tests of the gels provided in Examples 1, 2, 3, 4, 5, 6, and 7. DETAILED DESCRIPTION

[0028] The following embodiments are merely some of the embodiments of the present invention, rather than all of them. Therefore, the detailed description of the embodiments of the present invention provided below is not intended to limit the scope of the claimed invention, but rather merely represents selected embodiments of the present invention. All other embodiments derived by those skilled in the art based on the embodiments of the present invention without creative effort are intended to fall within the scope of protection of the present invention.

[0029] In the present invention, unless otherwise specified, all equipment and raw materials can be purchased from the market or are commonly used in the industry. The methods in the following embodiments, unless otherwise specified, are all conventional methods in the art.

[0030] In one embodiment, the hydrophobic amino acid vinyl monomer corresponding to the hydrophobic amino acid vinyl structural unit is selected from one or more of N-acryloylalanine, N-acryloylvaline, N-acryloylphenylalanine, N-acryloylleucine, N-acryloylisoleucine, N-acryloyltryptophan, N-acryloylmethionine, N-acryloylalaninamide, N-acryloylvalinamide and N-acryloylphenylalanamide.

[0031] In one embodiment, the hydrophilic monomer corresponding to the hydrophilic structural unit is selected from one or more of acrylic acid, methacrylic acid, 2-hydroxyethyl acrylate, hydroxyethyl methacrylate, acrylamide, N-trihydroxymethyl methacrylamide, N,N-dimethylacrylamide, N-hydroxyethyl acrylamide, 1-vinyl-2-pyrrolidone, N-acryloyl aspartic acid, N-acryloyl glutamic acid, N-acryloyl glycine, N-acryloyl tyrosine, N-acryloyl serine, N-acryloyl threonine and N-acryloyl glutamine.

[0032] In one embodiment, the temperature-sensitive monomer is selected from N-isopropylacrylamide, polyethylene glycol methyl ether methacrylate, N-vinylcaprolactam, 2-(2-methoxyethoxy)ethyl methacrylate, N-vinyl pyrrolidone, and hydroxypropyl acrylate.

[0033] The method for preparing the on-demand peeling hydrogel with high biological wet tissue adhesion comprises the following steps:

[0034] S1. Fully dissolving a hydrophobic amino acid vinyl monomer, a hydrophilic monomer, and a thermosensitive vinyl monomer in an aqueous solution to obtain a colorless and transparent mixed solution;

[0035] S2. At room temperature, add initiator and initiator accelerator and mix them evenly to complete free radical polymerization;

[0036] S3. Soaking the polymer in deionized water to obtain the on-demand peeling hydrogel with high biological wet tissue adhesion.

[0037] In one embodiment, the total concentration of the hydrophobic amino acid vinyl monomer and the hydrophilic monomer is 6.7 to 7.7 mol / L;

[0038] The concentration of the thermosensitive vinyl unit monomer is 0.2-1.0 mol / L.

[0039] In one embodiment, the concentration of the thermosensitive vinyl unit monomer is 0.2 to 1.0 mol / L;

[0040] In one embodiment, the initiator is selected from one or more of potassium persulfate, ammonium persulfate and azobisisobutylimidazoline hydrochloride;

[0041] The initiator accelerator is N,N,N',N'-tetramethylethylenediamine.

[0042] In one embodiment, the amount of the initiator added is 0.5 to 2% of the total mass of the hydrophobic amino acid vinyl monomer, the hydrophilic monomer, and the zwitterionic monomer;

[0043] The added amount of the initiator accelerator is 0 to 30% of the mass of the initiator.

[0044] In one embodiment, in step S1, the method of fully dissolving is selected from one or more of heating, ultrasound and vortex oscillation;

[0045] In step S2, the polymerization temperature is 20 to 80° C., and the polymerization reaction time is 2 to 12 hours;

[0046] In step S3, the storage temperature should be lower than room temperature.

[0047] Examples 1-19 are provided based on the preparation method of the on-demand peeling hydrogel with high biological wet tissue adhesion provided above.

[0048] The hydrophobic amino acid vinyl monomer mentioned in the present invention is obtained according to the method described in the references Biomacromolecules 2021, 22, 1297-1304; Sci. Adv. 2023, 9, eadg4031.

[0049] Example 1: P(APA 0.7 -AA 7.0 )

[0050] Free radical copolymerization of APA and AA monomers: 153 mg APA and 504 mg AA were dissolved in 1 mL deionized water by heating at 60°C, ultrasonicating, vortexing, etc., so that the concentration of APA was 0.7 mol / L and the concentration of AA was 7.0 mol / L. After complete dissolution, the mixed solution was cooled to room temperature, 3.28 mg ammonium persulfate was added as an initiator, and 0.98 mg N,N,N',N'-tetramethylethylenediamine was added as an initiator promoter. After mixing evenly, the mixture was placed in a 60°C oven and allowed to stand for 3 hours to initially obtain a hydrogel. The hydrogel was stored in an environment below room temperature to obtain an on-demand peeling hydrogel with high biological wet tissue adhesion.

[0051] Example 2: P(APA 0.7 -AA 6.8 -NIPAM 0.2 )

[0052] Free radical copolymerization was carried out with APA, AA and NIPAM monomers: 153 mg APA, 490 mg AA and 22.636 mg NIPAM were dissolved in 1 mL deionized water by heating at 60°C, ultrasonication, vortex oscillation, etc., so that the concentration of APA was 0.7 mol / L, the concentration of AA was 6.8 mol / L, and the concentration of NIPAM was 0.2 mol / L. After complete dissolution, the mixed solution was cooled to room temperature, 3.4 mg ammonium persulfate was added as an initiator, and 1.02 mg N,N,N',N'-tetramethylethylenediamine was added as an initiator accelerator. After mixing evenly, the mixture was placed in a 60°C oven and allowed to stand for 3 hours to initially obtain a hydrogel. The hydrogel was stored in an environment below room temperature to obtain an on-demand peeling hydrogel with high biological wet tissue adhesion.

[0053] Example 3: P(APA 0.7 -AA 6.6 -NIPAM 0.4 )

[0054] Free radical copolymerization was carried out with APA, AA and NIPAM monomers: 153 mg APA, 476 mg AA and 45.3 mg NIPAM were dissolved in 1 mL deionized water by heating at 60°C, ultrasonication, vortex oscillation, etc., so that the concentration of APA was 0.7 mol / L, the concentration of AA was 6.6 mol / L, and the concentration of NIPAM was 0.4 mol / L. After complete dissolution, the mixed solution was cooled to room temperature, 3.37 mg ammonium persulfate was added as an initiator, and 1.01 mg N,N,N',N'-tetramethylethylenediamine was added as an initiator accelerator. After mixing evenly, the mixture was placed in a 60°C oven and allowed to stand for 3 hours to initially obtain a hydrogel. The hydrogel was stored in an environment below room temperature to obtain an on-demand peeling hydrogel with high biological wet tissue adhesion.

[0055] Example 4: P(APA 0.7 -AA 6.4 -NIPAM 0.6 )

[0056] Free radical copolymerization was carried out with APA, AA and NIPAM monomers: 153 mg APA, 461 mg AA and 67.9 mg NIPAM were dissolved in 1 mL deionized water by heating at 60°C, ultrasonication, vortex oscillation, etc., so that the concentration of APA was 0.7 mol / L, the concentration of AA was 6.4 mol / L, and the concentration of NIPAM was 0.6 mol / L. After complete dissolution, the mixed solution was cooled to room temperature, 3.40 mg ammonium persulfate was added as an initiator, and 1.02 mg N,N,N',N'-tetramethylethylenediamine was added as an initiator accelerator. After mixing evenly, the mixture was placed in an oven at 60°C and allowed to stand for 3 hours to initially obtain a hydrogel. The hydrogel was stored in an environment below room temperature to obtain an on-demand peeling hydrogel with high biological wet tissue adhesion.

[0057] Example 5: P(APA 0.7 -AA 6.2 -NIPAM 0.8 )

[0058] Free radical copolymerization was carried out with APA, AA and NIPAM monomers: 153 mg APA, 446 mg AA and 90.53 mg NIPAM were dissolved in 1 mL deionized water by heating at 60°C, ultrasonication, vortex oscillation, etc., so that the concentration of APA was 0.7 mol / L, the concentration of AA was 6.2 mol / L, and the concentration of NIPAM was 0.8 mol / L. After complete dissolution, the mixed solution was cooled to room temperature, 3.45 mg ammonium persulfate was added as an initiator, and 1.03 mg N,N,N',N'-tetramethylethylenediamine was added as an initiator accelerator. After mixing evenly, the mixture was placed in a 60°C oven and allowed to stand for 3 hours to initially obtain a hydrogel. The hydrogel was stored in an environment below room temperature to obtain an on-demand peeling hydrogel with high biological wet tissue adhesion.

[0059] Example 6: P(APA 0.6 -AA 6.1 -NIPAM 0.9 )

[0060] Free radical copolymerization was carried out with APA, AA and NIPAM monomers: 153 mg APA, 439 mg AA and 101.84 mg NIPAM were dissolved in 1 mL deionized water by heating at 60°C, ultrasonication, vortex oscillation, etc., so that the concentration of APA was 0.7 mol / L, the concentration of AA was 6.1 mol / L, and the concentration of NIPAM was 0.9 mol / L. After complete dissolution, the mixed solution was cooled to room temperature, 3.47 mg ammonium persulfate was added as an initiator, and 1.04 mg N,N,N',N'-tetramethylethylenediamine was added as an initiator accelerator. After mixing evenly, the mixture was placed in a 60°C oven and allowed to stand for 3 hours to initially obtain a hydrogel. The hydrogel was stored in an environment below room temperature to obtain an on-demand peeling hydrogel with high biological wet tissue adhesion.

[0061] Example 7: P(APA 0.7 -AA6-NIPAM1)

[0062] Free radical copolymerization of APA, AA and NIPAM monomers: 153 mg APA, 432.42 mg AA and 113.18 mg NIPAM were dissolved in 1 mL deionized water by heating at 60°C, ultrasonication, vortex oscillation, etc., so that the concentration of APA was 0.7 mol / L, the concentration of AA was 6.0 mol / L, and the concentration of NIPAM was 1.0 mol / L. After complete dissolution, the mixed solution was cooled to room temperature, 3.49 mg ammonium persulfate was added as an initiator, and 1.05 mg N,N,N',N'-tetramethylethylenediamine was added as an initiator accelerator. After mixing evenly, the mixture was placed in a 60°C oven and allowed to stand for 3 hours to initially obtain a hydrogel. The hydrogel was stored in an environment below room temperature to obtain an on-demand peeling hydrogel with high biological wet tissue adhesion.

[0063] Example 8: P(APA 0.5 -AA 6.2 -NIPAM 0.8 )

[0064] Free radical copolymerization was carried out with APA, AA and NIPAM monomers: 110 mg APA, 446 mg AA and 90.53 mg NIPAM were dissolved in 1 mL deionized water by heating at 60°C, ultrasonicating, vortexing, etc., so that the concentration of APA was 0.5 mol / L, the concentration of AA was 6.2 mol / L, and the concentration of NIPAM was 0.8 mol / L. After complete dissolution, the mixed solution was cooled to room temperature, 3.23 mg ammonium persulfate was added as an initiator, and 0.96 mg N,N,N',N'-tetramethylethylenediamine was added as an initiator promoter. After mixing evenly, the mixture was placed in an oven at 60°C and allowed to stand for 3 hours to initially obtain a hydrogel. The hydrogel was stored in an environment below room temperature to obtain an on-demand peeling hydrogel with high biological wet tissue adhesion.

[0065] Example 9: P(APA 0.6 -AA 6.2 -NIPAM 0.8 )

[0066] Free radical copolymerization was carried out with APA, AA and NIPAM monomers: 131.5 mg APA, 446 mg AA and 90.53 mg NIPAM were dissolved in 1 mL deionized water by heating at 60°C, ultrasonication, vortex oscillation, etc., so that the concentration of APA was 0.6 mol / L, the concentration of AA was 6.2 mol / L, and the concentration of NIPAM was 0.8 mol / L. After complete dissolution, the mixed solution was cooled to room temperature, 3.34 mg ammonium persulfate was added as an initiator, and 1.0 mg N,N,N',N'-tetramethylethylenediamine was added as an initiator promoter. After mixing evenly, the mixture was placed in an oven at 60°C and allowed to stand for 3 hours to initially obtain a hydrogel. The hydrogel was stored in an environment below room temperature to obtain an on-demand peeling hydrogel with high biological wet tissue adhesion.

[0067] Example 10: P(APA 0.8 -AA 6.2 -NIPAM 0.8 )

[0068] Free radical copolymerization was carried out with APA, AA and NIPAM monomers: 175 mg APA, 446 mg AA and 90.53 mg NIPAM were dissolved in 1 mL deionized water by heating at 60°C, ultrasonication, vortex oscillation, etc., so that the concentration of APA was 0.8 mol / L, the concentration of AA was 6.2 mol / L, and the concentration of NIPAM was 0.8 mol / L. After complete dissolution, the mixed solution was cooled to room temperature, 3.56 mg ammonium persulfate was added as an initiator, and 1.06 mg N,N,N',N'-tetramethylethylenediamine was added as an initiator promoter. After mixing evenly, the mixture was placed in a 60°C oven and allowed to stand for 3 hours to initially obtain a hydrogel. The hydrogel was stored in an environment below room temperature to obtain an on-demand peeling hydrogel with high biological wet tissue adhesion.

[0069] Example 11: P(APA 0.9 -AA 6.2 -NIPAM 0.8 )

[0070] Free radical copolymerization was carried out with APA, AA and NIPAM monomers: 197 mg APA, 446 mg AA and 90.53 mg NIPAM were dissolved in 1 mL deionized water by heating at 60°C, ultrasonication, vortex oscillation, etc., so that the concentration of APA was 0.9 mol / L, the concentration of AA was 6.2 mol / L, and the concentration of NIPAM was 0.8 mol / L. After complete dissolution, the mixed solution was cooled to room temperature, 3.66 mg ammonium persulfate was added as an initiator, and 1.10 mg N,N,N',N'-tetramethylethylenediamine was added as an initiator accelerator. After mixing evenly, the mixture was placed in a 60°C oven and allowed to stand for 3 hours to initially obtain a hydrogel. The hydrogel was stored in an environment below room temperature to obtain an on-demand peeling hydrogel with high biological wet tissue adhesion.

[0071] Example 12: P(AL 0.7 -AA 6.2 -NIPAM 0.8 )

[0072] Free radical copolymerization of AL, AA and NIPAM monomers: 100 mg AL, 446 mg AA and 90.53 mg NIPAM were dissolved in 1 mL of deionized water by heating at 60°C, ultrasonicating, vortexing, etc., so that the concentration of AL was 0.7 mol / L, the concentration of AA was 6.2 mol / L, and the concentration of NIPAM was 0.8 mol / L. After complete dissolution, the mixed solution was cooled to room temperature, 3.18 mg ammonium persulfate as an initiator, and 0.95 mg N,N,N',N'-tetramethylethylenediamine as an initiator accelerator were added. After mixing evenly, the mixture was placed in a 60°C oven and allowed to stand for 3 hours to initially obtain a hydrogel. The hydrogel was stored in an environment below room temperature to obtain an on-demand peelable hydrogel with high biological wet tissue adhesion.

[0073] Example 13: P(AV 0.7 -AA 6.2 -NIPAM 0.8 )

[0074] Free radical copolymerization of AV, AA and NIPAM monomers: 120 mg AV, 446 mg AA and 90.53 mg NIPAM were dissolved in 1 mL of deionized water by heating at 60°C, ultrasonication, vortexing, etc., so that the concentration of AV was 0.7 mol / L, the concentration of AA was 6.2 mol / L, and the concentration of NIPAM was 0.8 mol / L. After complete dissolution, the mixed solution was cooled to room temperature, 3.28 mg ammonium persulfate as an initiator, and 0.98 mg N,N,N',N'-tetramethylethylenediamine as an initiator promoter were added. After mixing evenly, the mixture was placed in a 60°C oven and allowed to stand for 3 hours to initially obtain a hydrogel. The hydrogel was stored in an environment below room temperature to obtain an on-demand peeling hydrogel with high biological wet tissue adhesion.

[0075] Example 14: P(ALE 0.7 -AA 6.2 -NIPAM 0.8 )

[0076] Free radical copolymerization of ALE, AA and NIPAM monomers: 130 mg of ALE, 446 mg of AA and 90.53 mg of NIPAM were dissolved in 1 mL of deionized water by heating at 60°C, ultrasonicating, vortexing, etc., so that the concentration of ALE was 0.7 mol / L, the concentration of AA was 6.2 mol / L, and the concentration of NIPAM was 0.8 mol / L. After complete dissolution, the mixed solution was cooled to room temperature, 3.33 mg of ammonium persulfate as an initiator, and 0.99 mg of N,N,N',N'-tetramethylethylenediamine as an initiator accelerator were added. After mixing evenly, the mixture was placed in a 60°C oven and allowed to stand for 3 hours to initially obtain a hydrogel. The hydrogel was stored in an environment below room temperature to obtain an on-demand peelable hydrogel with high biological wet tissue adhesion.

[0077] Example 15: P(AIL 0.7 -AA 6.2 -NIPAM 0.8 )

[0078] Free radical copolymerization of AIL, AA and NIPAM monomers: 130 mg AIL, 446 mg AA and 90.53 mg NIPAM were dissolved in 1 mL deionized water by heating at 60°C, ultrasonication, vortex oscillation, etc., so that the concentration of AIL was 0.7 mol / L, the concentration of AA was 6.2 mol / L, and the concentration of NIPAM was 0.8 mol / L. After complete dissolution, the mixed solution was cooled to room temperature, 3.33 mg ammonium persulfate was added as an initiator, and 0.99 mg N,N,N',N'-tetramethylethylenediamine was added as an initiator accelerator. After mixing evenly, the mixture was placed in a 60°C oven and allowed to stand for 3 hours to initially obtain a hydrogel. The hydrogel was stored in an environment below room temperature to obtain an on-demand peeling hydrogel with high biological wet tissue adhesion.

[0079] Example 16: P(ATP 0.7 -AA 6.2 -NIPAM 0.8 )

[0080] Free radical copolymerization with ATP, AA and NIPAM monomers: 181 mg ATP, 446 mg AA and 90.53 mg NIPAM were dissolved in 1 mL of deionized water by heating at 60°C, ultrasonicating, vortexing, etc., so that the concentration of ATP was 0.7 mol / L, the concentration of AA was 6.2 mol / L, and the concentration of NIPAM was 0.8 mol / L. After complete dissolution, the mixed solution was cooled to room temperature, 3.59 mg ammonium persulfate as an initiator, and 1.08 mg N,N,N',N'-tetramethylethylenediamine as an initiator accelerator were added. After mixing evenly, the mixture was placed in a 60°C oven and allowed to stand for 3 hours to initially obtain a hydrogel. The hydrogel was stored in an environment below room temperature to obtain an on-demand peelable hydrogel with high biological wet tissue adhesion.

[0081] Example 17: P(APA 0.7 -MAA 6.2 -NIPAM 0.8 )

[0082] Free radical copolymerization was carried out with APA, MAA and NIPAM monomers: 153 mg APA, 534 mg MAA and 90.53 mg NIPAM were dissolved in 1 mL deionized water by heating at 60°C, ultrasonicating, vortexing, etc., so that the concentration of APA was 0.7 mol / L, the concentration of MAA was 6.2 mol / L, and the concentration of NIPAM was 0.8 mol / L. After complete dissolution, the mixed solution was cooled to room temperature, 4.03 mg ammonium persulfate was added as an initiator, and 1.20 mg N,N,N',N'-tetramethylethylenediamine was added as an initiator accelerator. After mixing evenly, the mixture was placed in a 60°C oven and allowed to stand for 3 hours to initially obtain a hydrogel. The hydrogel was stored in an environment below room temperature to obtain an on-demand peeling hydrogel with high biological wet tissue adhesion.

[0083] Example 18: P(APA 0.7 -HEAA 6.2 -NIPAM 0.8 )

[0084] Free radical copolymerization was carried out with APA, HEAA and NIPAM monomers: 153 mg APA, 735 mg HEAA and 90.53 mg NIPAM were dissolved in 1 mL deionized water by heating at 60°C, ultrasonication, vortex oscillation, etc., so that the concentration of APA was 0.7 mol / L, the concentration of HEAA was 6.2 mol / L, and the concentration of NIPAM was 0.8 mol / L. After complete dissolution, the mixed solution was cooled to room temperature, 4.89 mg ammonium persulfate was added as an initiator, and 1.46 mg N,N,N',N'-tetramethylethylenediamine was added as an initiator accelerator. After mixing evenly, the mixture was placed in a 60°C oven and allowed to stand for 3 hours to initially obtain a hydrogel. The hydrogel was stored in an environment below room temperature to obtain an on-demand peeling hydrogel with high biological wet tissue adhesion.

[0085] Example 19: P(APA 0.7 -AG 6.2 -NIPAM 0.8 )

[0086] Free radical copolymerization was carried out with APA, AG and NIPAM monomers: 153 mg APA, 801 mg AG and 90.53 mg NIPAM were dissolved in 1 mL deionized water by heating at 60°C, ultrasonicating, vortexing, etc., so that the concentration of APA was 0.7 mol / L, the concentration of AG was 6.2 mol / L, and the concentration of NIPAM was 0.8 mol / L. After complete dissolution, the mixed solution was cooled to room temperature, 5.22 mg ammonium persulfate was added as an initiator, and 1.57 mg N,N,N',N'-tetramethylethylenediamine was added as an initiator promoter. After mixing evenly, the mixture was placed in an oven at 60°C and allowed to stand for 3 hours to initially obtain a hydrogel. The hydrogel was stored in an environment below room temperature to obtain an on-demand peeling hydrogel with high biological wet tissue adhesion.

[0087] Example 19: P(APA 0.7 -AASP 6.2 -NIPAM 0.8 )

[0088] Free radical copolymerization was carried out with APA, AASP and NIPAM monomers: 153 mg APA, 1160 mg AASP and 90.53 mg NIPAM were dissolved in 1 mL deionized water by heating at 60°C, ultrasonication, vortex oscillation, etc., so that the concentration of APA was 0.7 mol / L, the concentration of AASP was 6.2 mol / L, and the concentration of NIPAM was 0.8 mol / L. After complete dissolution, the mixed solution was cooled to room temperature, 7.02 mg ammonium persulfate was added as an initiator, and 2.11 mg N,N,N',N'-tetramethylethylenediamine was added as an initiator accelerator. After mixing evenly, the mixture was placed in an oven at 60°C and allowed to stand for 3 hours to initially obtain a hydrogel. The hydrogel was stored in an environment below room temperature to obtain an on-demand peeling hydrogel with high biological wet tissue adhesion.

[0089] Example 19: P(APA 0.7 -AA 6.2 -NVCL 0.8 )

[0090] Free radical copolymerization was carried out with APA, AA and OEGMA monomers: 153 mg APA, 446 mg AA and 111.38 mg NVCL were dissolved in 1 mL deionized water by heating at 60°C, ultrasonication, vortex oscillation, etc., so that the concentration of APA was 0.7 mol / L, the concentration of AA was 6.2 mol / L, and the concentration of NVCL was 0.8 mol / L. After complete dissolution, the mixed solution was cooled to room temperature, 3.55 mg ammonium persulfate was added as an initiator, and 1.07 mg N,N,N',N'-tetramethylethylenediamine was added as an initiator promoter. After mixing evenly, the mixture was placed in a 60°C oven and allowed to stand for 3 hours to initially obtain a hydrogel. The hydrogel was stored in an environment below room temperature to obtain an on-demand peeling hydrogel with high biological wet tissue adhesion.

[0091] Example 20: P(APA 0.7 -AA 6.2 -OEGMA 0.8 )

[0092] Free radical copolymerization of APA, AA and OEGMA monomers: 153 mg APA, 446 mg AA and 116.8 mg OEGMA were dissolved in 1 mL deionized water by heating at 60°C, ultrasonication, vortex oscillation, etc., so that the concentration of APA was 0.7 mol / L, the concentration of AA was 6.2 mol / L, and the concentration of OEGMA was 0.8 mol / L. After complete dissolution, the mixed solution was cooled to room temperature, 3.58 mg ammonium persulfate was added as an initiator, and 1.07 mg N,N,N',N'-tetramethylethylenediamine was added as an initiator accelerator. After mixing evenly, the mixture was placed in a 60°C oven and allowed to stand for 3 hours to initially obtain a hydrogel. The hydrogel was stored in an environment below room temperature to obtain an on-demand peeling hydrogel with high biological wet tissue adhesion.

[0093] Effect test:

[0094] Figure 1 The wet adhesion strength of the hydrogel provided in Example 5 to pig skin at different temperatures was demonstrated. The wet adhesion strength gradually increased with increasing temperature. The wet adhesion strength reached 70 kPa, significantly superior to other hydrogel patches (Adv. Mater. 2023, 35, 2209606; Adv. Funct. Mater. 2024, 34, 2401030).

[0095] Figure 2 It was demonstrated that the hydrogel provided in Example 5 exhibited strong wet bonding strength and fast and efficient switching efficiency with different pig tissues (including liver, lung, heart, stomach, artery, and skin).

[0096] Figure 3 The rheological test diagram of the hydrogel modulus provided in Example 5 as it changes with temperature is shown. From the results, it can be seen that around 37°C, the hydrogel modulus has a sudden decrease, indicating that the phase separation is resolved at this time. The smaller modulus indirectly confirms that the hydrogel resolves phase separation at a temperature close to the skin.

[0097] Figure 4 The low-field NMR test results for the hydrogels provided in Examples 1, 2, 3, 4, 5, 6, and 7 are shown. As can be seen, as the hydrophilic monomer content decreases and the thermosensitive monomer content increases, the internal hydrogen bond strength increases, and phase separation becomes more likely. These results demonstrate that the hydrogels provided by this invention possess stable and durable on-demand peeling properties.

[0098] The on-demand peelable hydrogel with high biological wet tissue adhesion prepared by the present invention has good biocompatibility, cheap and easily available raw materials, excellent mechanical properties, fast and firm tissue wet adhesion characteristics, and can be gently peeled off on demand. It has important clinical significance and practical value for emergency injury treatment, and provides a new option for clinically replacing surgical sutures to achieve wound closure and rapid hemostasis.

Claims

1. A peel-on-demand hydrogel with high biological wet tissue adhesion, characterized in that The hydrogel is prepared by free radical polymerization of a hydrophobic amino acid vinyl monomer, a hydrophilic monomer and a thermosensitive monomer.

2. The peel-on-demand hydrogel with high biological wet tissue adhesion according to claim 1, characterized in that The structure of the hydrophobic amino acid vinyl monomer is shown in formula (I):

3. The peel-on-demand hydrogel with high biological wet tissue adhesion according to claim 2, characterized in that The ratio of the number of structural units among the hydrophobic amino acid vinyl monomer, the hydrophilic monomer and the thermosensitive monomer is 1:(9-13):(0.5-2).

4. The peel-on-demand hydrogel with high biological wet tissue adhesion according to claim 1, characterized in that The hydrophobic amino acid vinyl monomer is selected from one or more of N-acryloylalanine, N-acryloylvaline, N-acryloylphenylalanine, N-acryloylleucine, N-acryloylisoleucine, N-acryloyltryptophan, N-acryloylmethionine, N-acryloylalaninamide, N-acryloylvalinamide and N-acryloylphenylalanamide; The hydrophilic monomer is selected from one or more of acrylic acid, methacrylic acid, 2-hydroxyethyl acrylate, hydroxyethyl methacrylate, acrylamide, N-trishydroxymethyl methacrylamide, N,N-dimethylacrylamide, N-hydroxyethyl acrylamide, 1-vinyl-2-pyrrolidone, N-acryloyl aspartic acid, N-acryloyl glutamic acid, N-acryloyl glycine, N-acryloyl tyrosine, N-acryloyl serine, N-acryloyl threonine and N-acryloyl glutamine; The temperature-sensitive monomer is selected from N-isopropyl acrylamide, polyethylene glycol methyl ether methacrylate, N-vinyl caprolactam, 2-(2-methoxyethoxy)ethyl methacrylate, N-vinyl pyrrolidone, and hydroxypropyl acrylate.

5. The method for preparing the peel-on-demand hydrogel with high biological wet tissue adhesion according to any one of claims 1 to 4, characterized in that: The method comprises the following steps: S1, fully dissolving the hydrophobic amino acid vinyl monomer, hydrophilic monomer and thermosensitive monomer in an aqueous solution to obtain a colorless and transparent mixed solution; S2. Adding an initiator and an initiator accelerator to the mixed solution at room temperature and mixing them uniformly to complete free radical polymerization to obtain a polymer; S3. Storing the polymer in an environment below room temperature to obtain the on-demand peeling hydrogel with high biological wet tissue adhesion.

6. The method for preparing the peel-on-demand hydrogel with high biological wet tissue adhesion according to claim 5, characterized in that: The total concentration of the hydrophobic amino acid vinyl monomer and the hydrophilic monomer is 6.7 to 7.7 M, wherein the concentration ratio of the hydrophobic amino acid vinyl monomer to the hydrophilic monomer is 0.7 to 6:7; Optionally, the concentration of the thermosensitive unit monomer is 0.2-1.0 mol / L.

7. The method for preparing the peel-on-demand hydrogel with high biological wet tissue adhesion according to claim 6, characterized in that: The initiator is selected from one or more of potassium persulfate, ammonium persulfate and azobisisobutylimidazoline hydrochloride; The initiator accelerator is N,N,N',N'-tetramethylethylenediamine.

8. The method for preparing the peel-on-demand hydrogel with high biological wet tissue adhesion according to claim 6, wherein: The amount of the initiator added is 0.5-2% of the total mass of the hydrophobic amino acid vinyl monomer, the hydrophilic monomer and the thermosensitive monomer; The added amount of the initiator accelerator is greater than 0 and less than or equal to 30% of the mass of the initiator.

9. The method for preparing the peel-on-demand hydrogel with high biological wet tissue adhesion according to claim 6, wherein: In step S1, the method of fully dissolving is selected from one or more of heating, ultrasound and vortex oscillation; In step S2, the temperature of the free radical polymerization is 20 to 80° C., and the reaction time is 2 to 12 hours.

10. Use of the on-demand peelable hydrogel with high biological wet tissue adhesion according to any one of claims 1 to 4 in the field of wound closure and rapid hemostasis.

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