Double-crosslinked hydrogel composite material, preparation method therefor, and use thereof

Abstract

The present invention relates to the field of medical repair materials and particularly to a double-crosslinked hydrogel composite material, a preparation method therefor, and use thereof. The double-crosslinked hydrogel composite material comprises a physical-chemical double-crosslinked copolymer formed by reacting at least one type of acrylic monomer and at least one type of zwitterionic monomer in the presence of nanoparticles and a crosslinking agent. The double-crosslinked hydrogel composite material of the present invention has the characteristics of high mechanical strength, high adhesion strength, and swelling resistance, is low in cost, and features a preparation process that is simple and rapid and easy to regulate. Therefore, the material has very high application value.

Description

A double-crosslinked hydrogel composite material and its preparation method and application Technical Field

[0001] The present invention relates to the field of medical repair materials, and in particular to a double-crosslinked hydrogel composite material and a preparation method and application thereof. Background Art

[0002] Rapid wound healing and repair is one of the major challenges in the biomedical field and has important clinical applications and research significance. Although traditional surgical suturing is considered the gold standard for tissue closure, it has disadvantages such as complex and cumbersome procedures, time-consuming operations, high risk of secondary trauma, and easy formation of postoperative scars, making it difficult to meet the development needs of minimally invasive medicine. In this context, medical adhesives with instant hemostasis, wound closure, and adhesion functions have become a research hotspot to replace traditional surgical suturing. Currently, the most widely used adhesive materials are represented by cyanoacrylates, which have a fast onset and high adhesion strength. However, the degradation of these adhesives in physiological environments may produce toxic byproducts such as formaldehyde, which seriously restricts their clinical application in sensitive tissues.

[0003] Hydrogels possess many unique and superior properties, such as mimicking the extracellular matrix, maintaining a moist wound healing environment, and promoting cell proliferation and migration. They demonstrate potential in life science fields such as tissue regeneration and wound repair. Although a variety of adhesive hydrogels have been reported, their application is greatly limited by factors such as insufficient adhesion strength, low mechanical strength, high swelling capacity, and cumbersome preparation steps. For example, a method for preparing a self-healing antibacterial tissue adhesive hydrogel is disclosed in the invention patent publication number CN115715821A. Using acrylic acid monomers, chitosan, tannic acid, silver nitrate, a crosslinking agent, and persulfide as raw materials, they are polymerized and cross-linked at room temperature to produce a double-crosslinked hydrogel material formed by the coordination of silver ions with the pyrogallol groups in tannic acid and the formation of hydrogen bonds between the hydroxyl and pyrogallol groups of chitosan and the carboxyl groups of polyacrylic acid. This type of hydrogel material has high adhesion strength, but its swelling resistance and mechanical strength need to be further improved. Patent application CN115746208A discloses a cellulose / acrylamide mixed solution prepared by mixing functional cellulose nanoparticles with acrylamide and a thermal initiator. The solution is then polymerized at 40-70°C for 2-48 hours to produce a cellulose / acrylamide ultra-stretchable, adhesive hydrogel. However, the preparation process for this type of material is time-consuming and requires heating, resulting in high energy consumption.

[0004] Therefore, it is still quite challenging to simply, quickly and low-cost prepare adhesive hydrogel materials with high mechanical strength, high adhesion strength and good anti-swelling properties. Summary of the Invention

[0005] In view of the limitations of existing adhesive hydrogel materials, the present invention provides a low-cost, simple and fast preparation process, high mechanical strength, high adhesion strength, and good anti-swelling performance double-crosslinked hydrogel composite material, as well as its preparation method and application.

[0006] More specifically, the present invention solves the above technical problems through the following aspects.

[0007] In a first aspect, the present invention provides a double-crosslinked hydrogel composite material, comprising a physical-chemical double-crosslinked copolymer formed by reacting at least one acrylic monomer and at least one zwitterionic monomer in the presence of nanoparticles and a crosslinking agent, wherein the weight ratio of the nanoparticles to the structural units derived from the acrylic monomer is 1:(2-15), preferably 1:(3-10).

[0008] The inventors have found through research that the double-crosslinked hydrogel composite material according to the first aspect not only has the characteristics of high mechanical strength and high tissue adhesion strength, but also has good anti-swelling performance.

[0009] In a second aspect, the present invention also provides a method for preparing a double-crosslinked hydrogel composite material, preferably a double-crosslinked hydrogel composite material according to the first aspect, comprising: reacting a mixture comprising at least one acrylic monomer, at least one zwitterionic monomer, a photoinitiator, nanoparticles, a crosslinker and water under light conditions to obtain the double-crosslinked hydrogel composite material, wherein the weight ratio of the nanoparticles to the acrylic monomer is 1:(2-15), preferably 1:(3-10).

[0010] The present invention can obtain a double-crosslinked hydrogel composite material with high mechanical strength, high adhesion strength and good anti-swelling performance through a one-step method, and the preparation process is simple, rapid and easy to control.

[0011] In a third aspect, the present invention also provides the use of the double-crosslinked hydrogel composite material according to the first aspect or the double-crosslinked hydrogel composite material obtained by the method according to the second aspect as a wound repair material, preferably a suture-free wound repair material, and more preferably a tissue patch.

[0012] According to the above scheme, the present invention provides a double-crosslinked hydrogel composite material with high mechanical strength, high adhesion strength, and good anti-swelling properties, as well as a method for preparing the above-mentioned material or product, which has low cost, a simple and rapid preparation process, and is easy to control. After research, the inventors found that by controlling the components, content, and / or ratio of each structural unit in the hydrogel composite material, the synergistic effect between physical crosslinking (such as hydrogen bonding, electrostatic interaction, etc.) and chemical crosslinking (covalent bonding) and / or nanoparticle dispersion reinforcement can be adjusted to form a three-dimensional polymer network with uniformly distributed nanoparticles, resulting in a double-crosslinked hydrogel composite material with excellent mechanical strength, adhesion strength, and anti-swelling properties. This overcomes the problems of traditional biocompatible hydrogel materials such as insufficient adhesion strength, low mechanical strength, and easy swelling during tissue repair.

[0013] The beneficial effects of the present invention include:

[0014] (1) The double-crosslinked hydrogel composite material of the present invention has high adhesion strength and can be used as a tissue patch by bonding instead of suturing. The actual operation is fast and convenient. After 6 peel-and-stick cycles, it still maintains a high and stable adhesion strength.

[0015] (2) The double-crosslinked hydrogel composite material of the present invention has significantly enhanced mechanical strength due to the construction of organic-inorganic hybrid and physical-chemical crosslinking systems;

[0016] (3) The anti-swelling properties of the double-crosslinked hydrogel composite material of the present invention are greatly improved, so that it can be used as a tissue patch both on the body surface and in the body;

[0017] (4) The thickness and shape of the double-crosslinked hydrogel composite material of the present invention can be freely adjusted according to the thickness and shape of the mold, and is suitable for a variety of tissue defect surfaces and different injury types.

[0018] Other features and advantages of the present application will be described in detail in the subsequent detailed description. DETAILED DESCRIPTION

[0019] The specific implementation methods of the present application are described in detail below, but it should be noted that the scope of protection of the present application is not limited by these specific implementation methods, but is determined by the claims in the appendix.

[0020] Except for the Examples section, any specific numerical value disclosed herein (including the endpoints of a numerical range) is not limited to the exact value of the numerical value, but should be understood to also include values ​​close to the exact value, such as all possible values ​​within the range of ±5% of the exact value. Moreover, for the disclosed numerical range, any combination of the endpoints of the range, the endpoints and the specific point values ​​within the range, and the specific point values ​​can be combined to form one or more new numerical ranges, and these new numerical ranges should also be considered to be specifically disclosed herein.

[0021] Unless otherwise specified, the terms used herein have the same meaning as commonly understood by those skilled in the art. If a term is defined herein and its definition is different from the commonly understood meaning in the art, the definition herein shall prevail.

[0022] In this application, except for the contents explicitly stated, any matters or issues not mentioned are directly applicable to aspects known in the art without any changes. Moreover, any embodiment described herein can be freely combined with one or more other embodiments described herein, and the technical solutions or technical ideas formed thereby are deemed to be part of the original disclosure or original record of this application, and should not be regarded as new content not disclosed or anticipated herein, unless a person skilled in the art considers that the combination is obviously unreasonable.

[0023] The expressions "comprising" or "including" in this application should be interpreted as including all the specifically mentioned features as well as optional, additional, and unspecified features. As used herein, the use of the term "comprising" also discloses solutions in which other features than the specifically mentioned features are not present, for example, the expressions "consisting essentially of" and "consisting of.

[0024] The term "nanoparticle" according to the present application refers to a particle of a substance with a size in the range of 10 nm to 500 nm.

[0025] The term "acrylic monomer" according to the present application refers to a monomer based on an α,β-monoethylenically unsaturated carboxylic acid, such as acrylic acid and its derivatives retaining the carboxyl group, such as methacrylic acid, ethacrylic acid, etc., which is preferably represented by the following formula:

[0026] where R 1 Represents H, CH3 or C2H5.

[0027] According to the present application, the term "zwitterionic monomer" refers to a monomer having both a cationic group and an anionic group in the molecule, wherein the cationic group is, for example, an ammonium group, a phosphonium group, an imidazolium group, etc., and the anionic group is, for example, a sulfate group, a sulfonate group, a carboxylate group, etc.

[0028] The term "physical crosslinking" according to the present application refers to reversible dynamic crosslinking formed by non-covalent interactions, such as hydrogen bonds, electrostatic interactions, ion-dipole interactions, metal ion complexation, or hydrophilic-hydrophobic interactions.

[0029] The term "chemical crosslinking" according to the present application refers to stable crosslinking formed by covalent bonding.

[0030] The term "total amount of the double-crosslinked hydrogel composite material" according to the present application refers to the initial total weight of the gel material after the double-crosslinked hydrogel composite material is formed by the preparation method according to the present invention and before any drying step, unless otherwise specifically stated.

[0031] The term "total dry weight of the dual-crosslinked hydrogel composite material" according to the present application refers to the total weight of the gel material excluding the water content, unless otherwise specifically stated.

[0032] The term "room temperature" according to the present application refers to a temperature of about 20-25°C.

[0033] All patent and non-patent literature, including but not limited to textbooks and journal articles, mentioned herein are incorporated by reference in their entirety.

[0034] In a first aspect, the present invention provides a double-crosslinked hydrogel composite material, comprising a physical-chemical double-crosslinked copolymer formed by reacting at least one acrylic monomer and at least one zwitterionic monomer in the presence of nanoparticles and a crosslinking agent, wherein the weight ratio of the nanoparticles to the structural units derived from the acrylic monomer is 1:(2-15), preferably 1:(3-10).

[0035] According to some embodiments of the present invention, the weight ratio of nanoparticles to structural units derived from acrylic monomers in the double-crosslinked hydrogel composite material can be 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, or within a range consisting of any two of the aforementioned values. Repeated experiments have shown that when the weight ratio of nanoparticles to structural units derived from acrylic monomers is within the aforementioned specific range, particularly within the preferred range, the comprehensive performance of the hydrogel composite material in terms of mechanical strength, adhesive strength, and anti-swelling properties is significantly improved compared to hydrogel materials that do not contain nanoparticles or have a weight ratio that is too low or too high.

[0036] According to some embodiments of the present invention, the total content of the structural units derived from acrylic monomers and zwitterionic monomers in the double cross-linked hydrogel composite is 20-50% by weight, preferably 30-35% by weight, based on the total amount of the double cross-linked hydrogel composite as 100% by weight. For example, in some embodiments, the total content of the structural units derived from acrylic monomers and zwitterionic monomers can be 20% by weight, 25% by weight, 30% by weight, 35% by weight, 40% by weight, 45% by weight, 50% by weight, or within a range consisting of any two of the above values, based on the total amount of the double cross-linked hydrogel composite as 100% by weight. Through repeated experiments, it was verified that when the total content of the structural units derived from acrylic monomers and zwitterionic monomers in the double cross-linked hydrogel composite is within the above-mentioned specific range, particularly within the preferred range, a hydrogel with suitable mechanical properties for tissue patch applications can be obtained.

[0037] According to some embodiments of the present invention, based on the total weight of the double-crosslinked hydrogel composite being 100 weight %, the content of the structural units derived from acrylic acid monomers in the double-crosslinked hydrogel composite may be 15-45 weight %, preferably 25-35 weight %. For example, in some embodiments, the content of the structural units derived from acrylic acid monomers may be 15 weight %, 16 weight %, 17 weight %, 18 weight %, 19 weight %, 20 weight %, 21 weight %, 22 weight %, 23 weight %, 24 weight %, 25 weight %, 26 weight %, 27 weight %, 28 weight %, 29 weight %, 30 weight %, 31 weight %, 32 weight %, 33 weight %, 34 weight %, 35 weight %, 36 weight %, 37 weight %, 38 weight %, 39 weight %, 40 weight %, 41 weight %, 42 weight %, 43 weight %, 44 weight %, 45 weight %, or within a range consisting of any two of the above values.

[0038] According to some embodiments of the present invention, based on the total weight of the double-crosslinked hydrogel composite being 100 weight %, the content of the structural units derived from zwitterionic monomers in the double-crosslinked hydrogel composite may be 1-8 weight %, preferably 1-6 weight %. For example, in some embodiments, the content of the structural units derived from zwitterionic monomers may be 1 weight %, 2 weight %, 3 weight %, 4 weight %, 5 weight %, 6 weight %, 7 weight %, 8 weight %, or within a range consisting of any two of the foregoing values.

[0039] According to some embodiments of the present invention, the content of structural units derived from the crosslinking agent in the double-crosslinked hydrogel composite material is 0.1-0.5% by weight, preferably 0.2-0.3% by weight, based on the total amount of the double-crosslinked hydrogel composite material as 100% by weight. For example, in some embodiments, the content of structural units derived from the crosslinking agent can be 0.1% by weight, 0.2% by weight, 0.3% by weight, 0.4% by weight, 0.5% by weight, or within a range consisting of any two of the above values. Repeated experiments have shown that when no crosslinking agent is present, the hydrogel material is amorphous and cannot form a patch; when the crosslinking agent content is too high, the synergistic effect between chemical crosslinking and physical crosslinking and / or dispersion strengthening is weakened, and the overall performance of the hydrogel material is reduced.

[0040] According to some embodiments of the present invention, the content of nanoparticles in the double-crosslinked hydrogel composite is 3-12.8% by weight, preferably 5-9% by weight, based on the total amount of the double-crosslinked hydrogel composite as 100% by weight. For example, in some embodiments, the content of nanoparticles can be 3% by weight, 4% by weight, 5% by weight, 6% by weight, 7% by weight, 8% by weight, 9% by weight, 10% by weight, 11% by weight, 12% by weight, or within a range consisting of any two of the above values. Without wishing to be bound by any particular theory, it is believed that nanoparticles can, on the one hand, act as reversible physical crosslinking sites in the three-dimensional polymer network, participate in the construction of the double-crosslinked system, and increase the energy dissipation of the gel network; on the other hand, more significant performance improvements can be achieved through diffusion strengthening. Through repeated experiments, it has been verified that when no nanoparticles are present or their content is too low, the mechanical strength of the hydrogel material is insufficient, the swelling rate is too high, and it is not suitable for use as a tissue patch; when the nanoparticle content is too high, the synergistic effect between diffusion strengthening and physical crosslinking and chemical crosslinking is weakened, and the overall performance of the hydrogel material is reduced.

[0041] According to some embodiments of the present invention, the weight ratio of the structural units derived from zwitterionic monomers to the structural units derived from acrylic monomers in the double-crosslinked hydrogel composite material is 1:(5-20), preferably 1:(10-15). For example, in some embodiments, the weight ratio of the structural units derived from zwitterionic monomers to the structural units derived from acrylic monomers can be 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, or within a range consisting of any two of the above values. Through repeated experiments, it has been verified that when the weight ratio of the structural units derived from zwitterionic monomers to the structural units derived from acrylic monomers is within the above-mentioned specific range, particularly within the preferred range, the mechanical strength, adhesion strength, and swelling resistance of the hydrogel composite material are significantly improved relative to hydrogel materials having too low or too high a weight ratio.

[0042] According to some embodiments of the present invention, the nanoparticles are biocompatible inorganic nanoparticles, in particular inorganic nanoparticles having surface functional groups (e.g., hydroxyl groups, carboxyl groups), preferably nanoparticles selected from at least one of nano-bioactive glass, silica, zinc oxide, hydroxyapatite, titanium dioxide, and boron nitride, more preferably nanoparticles of nano-bioactive glass, hydroxyapatite and / or silica.

[0043] According to some embodiments of the present invention, the nanoparticles have a particle size of 10-500 nm, preferably 50-500 nm, more preferably 80-300 nm, and even more preferably 80-150 nm. When the nanoparticle size is greater than 500 nm, the nanoparticles may leak or seep out of the hydrogel; when the nanoparticle size is less than 10 nm, the nanoparticles may be unevenly dispersed, such as significantly agglomerated.

[0044] According to some embodiments of the present invention, the acrylic monomer is selected from at least one of acrylic acid, methacrylic acid, and ethacrylic acid.

[0045] According to some embodiments of the present invention, the zwitterionic monomer is selected from at least one of a methacryloxy-containing zwitterionic monomer and a sulfobetaine zwitterionic monomer; preferably selected from at least one of [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide, sulfobetaine vinylimidazole, and sulfobetaine methacrylate, more preferably sulfobetaine methacrylate and / or [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide.

[0046] According to some embodiments of the present invention, the crosslinking agent is selected from compounds having at least two acrylate functional groups, preferably selected from at least one of polyethylene glycol dimethacrylate, polypropylene glycol dimethacrylate, polyethylene glycol diacrylate, and trimethylolpropane trimethacrylate, more preferably polyethylene glycol dimethacrylate.

[0047] According to some embodiments of the present invention, the number average molecular weight (M n ) is 150-700. For example, in some embodiments, the number average molecular weight (M n ) can be 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, or within a range consisting of any two of the above values. For example, when the cross-linking agent is polyethylene glycol diacrylate, its number average molecular weight can be 150-250. For example, when the cross-linking agent is polyethylene glycol dimethacrylate, its number average molecular weight can be 550-700.

[0048] According to some embodiments of the present invention, based on the total weight of the double-crosslinked hydrogel composite as 100 weight%, the water content in the double-crosslinked hydrogel composite is 55-70 weight%. For example, in some embodiments, the water content can be 55 weight%, 56 weight%, 57 weight%, 58 weight%, 59 weight%, 60 weight%, 61 weight%, 62 weight%, 63 weight%, 64 weight%, 65 weight%, 66 weight%, 67 weight%, 68 weight%, 69 weight%, 70 weight%, or within a range consisting of any two of the above values.

[0049] According to some embodiments of the present invention, based on the total dry weight of the double-crosslinked hydrogel composite material as 100 weight%, the total content of structural units derived from acrylic monomers and zwitterionic monomers in the double-crosslinked hydrogel composite material can be 60-93 weight% on a dry weight basis, preferably 70-90 weight%; the content of structural units derived from acrylic monomers can be 55-90 weight% on a dry weight basis, preferably 60-85 weight%; the content of structural units derived from zwitterionic monomers can be 2.5-15 weight% on a dry weight basis, preferably 3-10 weight%; the content of nanoparticles can be 6-30 weight% on a dry weight basis, preferably 10-20 weight%; and the content of structural units derived from the crosslinking agent can be 0.2-1 weight% on a dry weight basis, preferably 0.4-0.7 weight%.

[0050] According to some embodiments of the present invention, the tensile strength of the double-crosslinked hydrogel composite material is 80-130 kPa. In some embodiments, the tensile strength of the double-crosslinked hydrogel composite material may be greater than 80 kPa, preferably greater than 85 kPa, and more preferably greater than 90 kPa. The tensile strength may be measured in accordance with the national standard GB / T 528-2009, including but not limited to the methods described herein. For example, the tensile strength may also be measured in accordance with the national standard GB / T 1040-2006.

[0051] According to some embodiments of the present invention, the double-crosslinked hydrogel composite material has an adhesion strength of 25-50 kPa. In some embodiments, the adhesion strength of the double-crosslinked hydrogel composite material can be greater than 25 kPa, preferably greater than 30 kPa, and more preferably greater than 35 kPa. Adhesion strength can be measured in accordance with pharmaceutical industry standard YY / T 0729.2-2009, including but not limited to the methods described herein.

[0052] According to some embodiments of the present invention, the swelling ratio of the double-crosslinked hydrogel composite material tested at a constant temperature of 25° C. for 48 hours is less than 100%, preferably less than 80%.

[0053] According to some embodiments of the present invention, the double-crosslinked hydrogel composite material has a thickness of 0.5-5 mm, preferably 1-2 mm.

[0054] In a second aspect, the present invention provides a method for preparing a double-crosslinked hydrogel composite material, preferably a method for preparing the double-crosslinked hydrogel composite material according to the first aspect, comprising:

[0055] A mixture comprising at least one acrylic monomer, at least one zwitterionic monomer, a photoinitiator, nanoparticles, a crosslinking agent, and water is reacted under light conditions to obtain the double-crosslinked hydrogel composite material, wherein the weight ratio of the nanoparticles to the acrylic monomer is 1:(2-15), preferably 1:(3-10).

[0056] According to some embodiments of the present invention, the weight ratio of the nanoparticles to the acrylic monomer in the mixed solution can be 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, or within a range consisting of any two of the above values.

[0057] According to some embodiments of the present invention, the reaction conditions include:

[0058] The reaction is carried out at room temperature; and / or,

[0059] The reaction is carried out under ultraviolet light; and / or,

[0060] The illumination time is 5-20 minutes, preferably 8-15 minutes.

[0061] According to some embodiments of the present invention, the reaction is carried out in a mold having a thickness of 0.5-5 mm, preferably 1-2 mm. The length and width of the mold, or the shape of its horizontal cross section, are not limited and can be adjusted according to application requirements.

[0062] According to some embodiments of the present invention, UV irradiation can be performed using any suitable UV light source known in the art, such as a UV light source having a wavelength of 365 nm and a light intensity of 60-100 mW / cm 2 LED light source.

[0063] According to some embodiments of the present invention, based on the total weight of the mixed solution being 100 weight %, the total weight of the acrylic monomer and the zwitterionic monomer is 20-50 weight %, preferably 30-35 weight %. For example, in some embodiments, the total weight of the acrylic monomer and the zwitterionic monomer in the mixed solution can be 20 weight %, 25 weight %, 30 weight %, 35 weight %, 40 weight %, 45 weight %, 50 weight %, or within a range consisting of any two of the foregoing values.

[0064] According to some embodiments of the present invention, the weight ratio of the zwitterionic monomer to the acrylic monomer in the mixed solution is 1:(5-20), preferably 1:(10-15). For example, in some embodiments, the weight ratio of the zwitterionic monomer to the acrylic monomer in the mixed solution can be 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, or within a range consisting of any two of the above values.

[0065] According to some embodiments of the present invention, based on the total amount of the mixed solution as 100 weight%, the amount of the acrylic acid monomer is 15-45 weight%, preferably 25-35 weight%. For example, in some embodiments, the amount of the acrylic acid monomer in the mixed solution can be 15 weight%, 16 weight%, 17 weight%, 18 weight%, 19 weight%, 20 weight%, 21 weight%, 22 weight%, 23 weight%, 24 weight%, 25 weight%, 26 weight%, 27 weight%, 28 weight%, 29 weight%, 30 weight%, 31 weight%, 32 weight%, 33 weight%, 34 weight%, 35 weight%, 36 weight%, 37 weight%, 38 weight%, 39 weight%, 40 weight%, 41 weight%, 42 weight%, 43 weight%, 44 weight%, 45 weight%, or within a range consisting of any two of the above values.

[0066] According to some embodiments of the present invention, based on the total weight of the mixed solution being 100 weight %, the amount of the zwitterionic monomer is 1-8 weight %, preferably 1-6 weight %. For example, in some embodiments, the amount of the zwitterionic monomer in the mixed solution can be 1 weight %, 2 weight %, 3 weight %, 4 weight %, 5 weight %, 6 weight %, 7 weight %, 8 weight %, or within a range consisting of any two of the above values.

[0067] According to some embodiments of the present invention, based on the total weight of the mixed solution as 100 weight%, the amount of the photoinitiator is 0.1-0.5 weight%, preferably 0.2-0.3 weight%. For example, in some embodiments, the amount of the photoinitiator in the mixed solution can be 0.1 weight%, 0.2 weight%, 0.3 weight%, 0.4 weight%, 0.5 weight%, or within a range consisting of any two of the above values.

[0068] According to some embodiments of the present invention, based on the total weight of the mixed solution as 100 weight%, the amount of the cross-linking agent is 0.1-0.5 weight%, preferably 0.2-0.3 weight%. For example, in some embodiments, the amount of the cross-linking agent in the mixed solution can be 0.1 weight%, 0.2 weight%, 0.3 weight%, 0.4 weight%, 0.5 weight%, or within a range consisting of any two of the above values.

[0069] According to some embodiments of the present invention, based on the total amount of the mixed solution as 100 weight%, the amount of the nanoparticles is 3-12.8 weight%, preferably 5-9 weight%. For example, in some embodiments, the amount of nanoparticles in the mixed solution can be 3 weight%, 4 weight%, 5 weight%, 6 weight%, 7 weight%, 8 weight%, 9 weight%, 10 weight%, 11 weight%, 12 weight%, or within a range consisting of any two of the above values.

[0070] According to some embodiments of the present invention, based on the total amount of the mixed solution as 100 weight%, the total amount of the acrylic monomer and the zwitterionic monomer is 20-50 weight%, preferably 30-35 weight%; the weight ratio of the zwitterionic monomer to the acrylic monomer is 1:(5-20), preferably 1:(10-15); the amount of the photoinitiator is 0.1-0.5 weight%, preferably 0.2-0.3 weight%; the amount of the cross-linking agent is 0.1-0.5 weight%, preferably 0.2-0.3 weight%; the amount of the nanoparticles is 3-12.8 weight%, preferably 5-9 weight%; the weight ratio of the nanoparticles to acrylic acid is (10-40):100, preferably (15-30):100; the balance is water.

[0071] According to some embodiments of the present invention, the nanoparticles are biocompatible inorganic nanoparticles, preferably nanoparticles of at least one selected from nano-bioactive glass, silica, zinc oxide, hydroxyapatite, titanium dioxide, and boron nitride, more preferably nanoparticles of nano-bioactive glass, hydroxyapatite and / or silica.

[0072] According to some embodiments of the present invention, the nanoparticles have a particle size of 10-500 nm, preferably 50-500 nm, more preferably 80-300 nm, even more preferably 80-150 nm.

[0073] According to some embodiments of the present invention, the acrylic monomer is selected from at least one of acrylic acid, methacrylic acid, and ethacrylic acid.

[0074] According to some embodiments of the present invention, the zwitterionic monomer is selected from at least one of a methacryloxy-containing zwitterionic monomer and a sulfobetaine zwitterionic monomer; preferably selected from at least one of [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide, sulfobetaine vinylimidazole, and sulfobetaine methacrylate, more preferably sulfobetaine methacrylate and / or [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide.

[0075] According to some embodiments of the present invention, the photoinitiator is selected from free radical polymerization photoinitiators, preferably at least one selected from 1-hydroxycyclohexyl phenyl ketone, 2-hydroxy-methylphenylpropane-1-one, 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone benzoin dimethyl ether, and ethyl 4-(N,N-dimethylamino)benzoate, more preferably 2-hydroxy-methylphenylpropane-1-one.

[0076] According to some embodiments of the present invention, the crosslinking agent is selected from compounds having at least two acrylate functional groups, preferably selected from at least one of polyethylene glycol dimethacrylate, polyethylene glycol diacrylate, and trimethylolpropane trimethacrylate, preferably polyethylene glycol dimethacrylate.

[0077] According to some embodiments of the present invention, the number average molecular weight (M n ) is 150-700. For example, in some embodiments, the number average molecular weight (M n ) can be 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, or within a range consisting of any two of the above values. For example, when the cross-linking agent is polyethylene glycol diacrylate, its number average molecular weight can be 150-250. For example, when the cross-linking agent is polyethylene glycol dimethacrylate, its number average molecular weight can be 550-700.

[0078] Exemplary embodiments of the preparation method according to the present invention are as follows:

[0079] Step 1: Weigh an acrylic monomer, a zwitterionic monomer, a crosslinking agent, nanoparticles, a photoinitiator, and water, mix them, and homogenize them to obtain a mixed solution.

[0080] According to some embodiments of the present invention, the homogenization in step 1 is performed by ultrasound, for example, ultrasonic dispersion for 15 minutes, or mechanical stirring, for example, stirring for 1 hour.

[0081] Step 2: Pour the mixed solution into a mold and place it under an ultraviolet lamp for reaction to obtain a double-crosslinked hydrogel composite material.

[0082] According to some embodiments of the present invention, the ultraviolet light irradiation time in step 2 is 5-20 minutes, preferably 8-15 minutes.

[0083] Preferably, the method further comprises step 3: drying the double-crosslinked hydrogel composite material at room temperature, drying it in a vacuum drying oven, and then storing it under refrigerated conditions (about 2-7° C.).

[0084] According to some embodiments of the present invention, the drying time at room temperature in step 3 is 2-8 hours, preferably 3-5 hours; and the vacuum drying time is 12-48 hours, preferably 24-36 hours.

[0085] According to other embodiments of the present invention, the double-crosslinked hydrogel composite material obtained in step 2 can be freeze-dried and then stored.

[0086] In a third aspect, the present invention provides the use of the double-crosslinked hydrogel composite material according to the first aspect, or the double-crosslinked hydrogel composite material obtained by the method according to the second aspect, as a wound repair material, preferably a suture-free wound repair material, and more preferably a tissue patch. The tissue patch can be used on the body surface and / or in the body.

[0087] The present invention also discloses the following embodiments:

[0088] Solution 1: An ultrafine particle hybrid hydrogel composite material, comprising a cross-linked copolymer and ultrafine particles coated in the cross-linked copolymer, wherein the cross-linked copolymer is a copolymer of a cross-linked acrylic monomer and other comonomers;

[0089] Based on the total mass of the hydrogel composite material being 100 wt %, the content of the ultrafine particles in the hydrogel composite material is 3-12 wt %, preferably 5-9 wt %.

[0090] Solution 2: The hydrogel composite material according to Solution 1, characterized in that:

[0091] Taking the total mass of the hydrogel composite material as 100 wt %:

[0092] The content of the cross-linked copolymer in the hydrogel composite material is 20.1-50.5 wt%, preferably 30.2-35.3 wt%;

[0093] Preferably, based on 100 wt% of the total mass of the hydrogel composite material, the total content of structural units derived from acrylic monomers and other comonomers in the cross-linked copolymer is 20-50 wt%, preferably 30-35 wt%; and / or,

[0094] Preferably, the mass ratio of the structural units derived from other comonomers to the structural units derived from acrylic monomers in the cross-linked copolymer is 1:(5-20), preferably 1:(10-15).

[0095] Solution 3: The hydrogel composite material according to Solution 1, characterized in that:

[0096] The ultrafine particles are inorganic ultrafine particles, preferably ultrafine particles of at least one of silicon dioxide, zinc oxide, hydroxyapatite, titanium dioxide, and boron nitride, more preferably ultrafine particles of hydroxyapatite and / or silicon dioxide; and / or,

[0097] The size of the ultrafine particles is between 50-500 nm, preferably between 100-300 nm.

[0098] Solution 4: The hydrogel composite material according to Solution 1, characterized in that:

[0099] The acrylic monomer is selected from water-soluble acrylic acid and its derivatives, preferably at least one selected from acrylic acid, methacrylate, and ethacrylate; and / or,

[0100] The other comonomers are selected from at least one of methacryloyloxy-containing monomers and sulfobetaine monomers; preferably selected from at least one of 2-(methacryloyloxy)ethyl-2-(trimethylamino)ethyl phosphate, [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide, sulfobetaine vinylimidazole, and sulfobetaine methacrylate, more preferably sulfobetaine methacrylate and / or [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide.

[0101] Solution 5: The hydrogel composite material according to any one of Solutions 1 to 4, characterized in that:

[0102] The cross-linked copolymer is obtained by reacting raw materials including the acrylic monomer, other comonomers and a cross-linking agent; preferably,

[0103] The cross-linking agent is selected from acrylate copolymers and / or acrylate compounds, preferably at least one selected from polyethylene glycol dimethacrylate, polyethylene glycol diacrylate, trimethylolpropane trimethacrylate, preferably polyethylene glycol dimethacrylate; and / or,

[0104] Based on the total mass of the hydrogel composite material being 100 wt%, the content of the crosslinking agent in the crosslinked copolymer is 0.1-0.5 wt%, preferably 0.2-0.3 wt%.

[0105] Solution 6: The hydrogel composite material according to Solution 5, characterized in that:

[0106] The mechanical strength of the hydrogel composite material is 80-130 kPa; and / or,

[0107] The adhesion strength of the hydrogel composite material is 25-50 kPa;

[0108] Preferably, the hydrogel composite material is prepared by a method comprising the following steps:

[0109] A mixed solution containing acrylic monomers, other comonomers, a photoinitiator, a crosslinking agent, ultrafine particles and water is reacted under light conditions to obtain the hydrogel composite material.

[0110] Scheme 7. A method for preparing a hydrogel composite material, preferably used for the method for preparing the hydrogel composite material according to any one of Schemes 1 to 6, comprising:

[0111] reacting a mixture of acrylic monomers, other comonomers, a photoinitiator, a crosslinking agent, ultrafine particles and water under light conditions to obtain the ultrafine particle hybrid hydrogel composite material;

[0112] The mass ratio of the ultrafine particles to the acrylic monomer is (10-40):100, preferably (15-30):100.

[0113] Scheme 8: The preparation method according to Scheme 7, characterized in that:

[0114] The reaction conditions include:

[0115] Under ultraviolet light, and / or, the illumination time is 5-20 minutes, preferably 8-15 minutes; and / or,

[0116] Taking the total mass of the mixed solution as 100wt%:

[0117] The total amount of the acrylic monomer and other comonomers is 20-50 wt%, preferably 30-35 wt%; and / or,

[0118] The mass ratio of the other comonomers to the acrylic monomers is 1:(5-20), preferably 1:(10-15); and / or,

[0119] The amount of the photoinitiator is 0.1-0.5 wt%, preferably 0.2-0.3 wt%; and / or,

[0120] The amount of the cross-linking agent is 0.1-0.5 wt%, preferably 0.2-0.3 wt%.

[0121] Scheme 9: The preparation method according to Scheme 7 or 8, characterized in that:

[0122] The ultrafine particles are inorganic ultrafine particles, preferably ultrafine particles of at least one of silicon dioxide, zinc oxide, hydroxyapatite, titanium dioxide, and boron nitride, more preferably ultrafine particles of hydroxyapatite and / or silicon dioxide; and / or,

[0123] The size of the ultrafine particles is between 50-500 nm, preferably between 100-300 nm; and / or,

[0124] The acrylic monomer is selected from water-soluble acrylic acid and its derivatives, preferably at least one selected from acrylic acid, methacrylate, and ethacrylate; and / or,

[0125] The other comonomers are selected from at least one of methacryloyloxy-containing monomers and sulfobetaine monomers; preferably selected from at least one of 2-(methacryloyloxy)ethyl-2-(trimethylamino)ethyl phosphate, [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide, sulfobetaine vinylimidazole, and sulfobetaine methacrylate, more preferably sulfobetaine methacrylate and / or [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide.

[0126] Scheme 10: The preparation method according to Scheme 7 or 8, characterized in that:

[0127] The photoinitiator is selected from free radical polymerization photoinitiators, preferably at least one selected from 1-hydroxycyclohexyl phenyl ketone, 2-hydroxy-methylphenylpropane-1-one, 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone benzoin dimethyl ether, and ethyl 4-(N,N-dimethylamino)benzoate, more preferably 2-hydroxy-methylphenylpropane-1-one; and / or,

[0128] The cross-linking agent is selected from acrylate copolymers and / or acrylate compounds, preferably at least one selected from polyethylene glycol dimethacrylate, polyethylene glycol diacrylate, and trimethylolpropane trimethacrylate, more preferably polyethylene glycol dimethacrylate.

[0129] Scheme 11. An ultrafine particle hybrid tissue patch, wherein the material of the ultrafine particle hybrid tissue patch comprises the hydrogel composite material according to any one of Schemes 1-6 or the hydrogel composite material obtained by the preparation method according to any one of Schemes 7-10;

[0130] Preferably, the thickness of the ultrafine particle hybrid tissue patch is between 0.5-5 mm, preferably 1-2 mm.

[0131] Solution 12: A method for preparing the ultrafine particle hybrid tissue patch of Solution 11, comprising: reacting the mixed solution under light conditions to prepare the hydrogel composite material using the preparation method of any one of Solutions 7-10, and performing the reaction in a patch mold;

[0132] Preferably, the reaction is carried out in a mould having a thickness between 0.5 and 5 mm, preferably 1 and 2 mm.

[0133] Scheme 13. Use of the hydrogel composite material according to any one of Schemes 1-6, or the hydrogel composite material obtained by the preparation method according to any one of Schemes 7-10, or the ultrafine particle hybrid tissue patch according to Scheme 11, or the ultrafine particle hybrid tissue patch obtained by the preparation method according to Scheme 12, as a wound repair material;

[0134] It is preferably used as a suture-free wound repair material.

[0135] Example

[0136] The present invention will be described in detail below with reference to specific embodiments. It is necessary to point out that the following embodiments are only used to further illustrate the present invention and are not to be construed as limiting the scope of protection of the present invention. Non-essential improvements and adjustments made by those skilled in the art to the present invention based on the contents of the present invention still fall within the scope of protection of the present invention.

[0137] The reagents involved in the following examples are all commercially available, and their commercial information is listed in the following Table 1:

[0138] Table 1

[0139] Preparation procedure

[0140] In the following examples, unless otherwise specified, the temperature condition is room temperature.

[0141] Example 1

[0142] Step 1: Weigh 10 g of acrylic acid, 1 g of sulfobetaine methacrylate, 20 g of water, 2 g of hydroxyapatite nanoparticles, 0.07 g of 2-hydroxy-methylphenylpropane-1-one, and 0.07 g of polyethylene glycol dimethacrylate, mix and homogenize to obtain a mixed solution.

[0143] Step 2: Pour the mixed solution into a mold with a thickness of 1 mm and place it under a UV lamp to react for 10 minutes to obtain a hydrogel composite material.

[0144] Step 3: Dry the hydrogel composite material at room temperature for 3 hours, then place it in a vacuum drying oven to dry for 24 hours, and then store it under refrigerated conditions.

[0145] Example 2

[0146] Step 1: Weigh 10 g of acrylic acid, 1 g of sulfobetaine methacrylate, 20 g of water, 2 g of silica nanoparticles, 0.07 g of 2-hydroxy-methylphenylpropane-1-one, and 0.07 g of polyethylene glycol dimethacrylate, mix and homogenize to obtain a mixed solution.

[0147] Step 2: Pour the mixed solution into a mold with a thickness of 1 mm and place it under a UV lamp to react for 10 minutes to obtain a hydrogel composite material.

[0148] Step 3: Dry the hydrogel composite material at room temperature for 3 hours, then place it in a vacuum drying oven to dry for 24 hours, and then store it under refrigerated conditions.

[0149] Example 3

[0150] Step 1: Weigh 10 g of acrylic acid, 1 g of sulfobetaine methacrylate, 20 g of water, 3 g of hydroxyapatite nanoparticles, 0.07 g of 2-hydroxy-methylphenylpropane-1-one, and 0.07 g of polyethylene glycol dimethacrylate, mix and homogenize to obtain a mixed solution.

[0151] Step 2: Pour the mixed solution into a mold with a thickness of 1 mm and place it under a UV lamp to react for 10 minutes to obtain a hydrogel composite material.

[0152] Step 3: Dry the hydrogel composite material at room temperature for 3 hours, then place it in a vacuum drying oven to dry for 24 hours, and then store it under refrigerated conditions.

[0153] Example 4

[0154] Step 1: Weigh 10 g of acrylic acid, 1 g of sulfobetaine methacrylate, 20 g of water, 3 g of silica nanoparticles, 0.07 g of 2-hydroxy-methylphenylpropane-1-one, and 0.07 g of polyethylene glycol dimethacrylate, mix and homogenize to obtain a mixed solution.

[0155] Step 2: Pour the mixed solution into a mold with a thickness of 1 mm and place it under a UV lamp to react for 10 minutes to obtain a hydrogel composite material.

[0156] Step 3: Dry the hydrogel composite material at room temperature for 3 hours, then place it in a vacuum drying oven to dry for 24 hours, and then store it under refrigerated conditions.

[0157] Example 5

[0158] Step 1: Weigh 10 g of acrylic acid, 0.67 g of [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide, 18 g of water, 2 g of hydroxyapatite nanoparticles, 0.07 g of 2-hydroxy-methylphenylpropane-1-one, and 0.07 g of polyethylene glycol dimethacrylate, mix and homogenize to obtain a mixed solution.

[0159] Step 2: Pour the mixed solution into a mold with a thickness of 1 mm and place it under a UV lamp to react for 10 minutes to obtain a hydrogel composite material.

[0160] Step 3: Dry the hydrogel composite material at room temperature for 3 hours, then place it in a vacuum drying oven to dry for 24 hours, and then store it under refrigerated conditions.

[0161] Example 6

[0162] Step 1: Weigh 10 g of acrylic acid, 1 g of sulfobetaine methacrylate, 20 g of water, 2 g of hydroxyapatite nanoparticles, 0.07 g of 2-hydroxy-methylphenylpropane-1-one, and 0.08 g of trimethylolpropane trimethacrylate, mix and homogenize to obtain a mixed solution.

[0163] Step 2: Pour the mixed solution into a mold with a thickness of 1 mm and place it under a UV lamp to react for 10 minutes to obtain a hydrogel composite material.

[0164] Step 3: Dry the hydrogel composite material at room temperature for 3 hours, then place it in a vacuum drying oven to dry for 24 hours, and then store it under refrigerated conditions.

[0165] Example 7

[0166] Step 1: Weigh 10 g of acrylic acid, 1 g of sulfobetaine methacrylate, 20 g of water, 2 g of hydroxyapatite nanoparticles, 0.07 g of 2-hydroxy-methylphenylpropane-1-one, and 0.07 g of polyethylene glycol dimethacrylate, mix and homogenize to obtain a mixed solution.

[0167] Step 2: Pour the mixed solution into a mold with a thickness of 1 mm and place it under a UV lamp to react for 20 minutes to obtain a hydrogel composite material.

[0168] Step 3: Dry the hydrogel composite material at room temperature for 3 hours, then place it in a vacuum drying oven to dry for 24 hours, and then store it under refrigerated conditions.

[0169] Example 8

[0170] Step 1: Weigh 10 g of acrylic acid, 0.8 g of sulfobetaine vinylimidazole, 20 g of water, 2 g of hydroxyapatite nanoparticles, 0.07 g of 2-hydroxy-methylphenylpropane-1-one, and 0.07 g of polyethylene glycol dimethacrylate, mix and homogenize to obtain a mixed solution.

[0171] Step 2: Pour the mixed solution into a mold with a thickness of 1 mm and place it under a UV lamp to react for 10 minutes to obtain a hydrogel composite material.

[0172] Step 3: Dry the hydrogel composite material at room temperature for 3 hours, then place it in a vacuum drying oven to dry for 24 hours, and then store it under refrigerated conditions.

[0173] Example 9

[0174] Step 1: Weigh 10 g of acrylic acid, 1 g of sulfobetaine methacrylate, 20 g of water, 2 g of hydroxyapatite nanoparticles, 0.07 g of 2-hydroxy-methylphenylpropane-1-one, and 0.07 g of polyethylene glycol dimethacrylate, mix and homogenize to obtain a mixed solution.

[0175] Step 2: Pour the mixed solution into a mold with a thickness of 1 mm and place it under a UV lamp to react for 15 minutes to obtain a hydrogel composite material.

[0176] Step 3: Dry the hydrogel composite material at room temperature for 3 hours, then place it in a vacuum drying oven to dry for 24 hours, and then store it under refrigerated conditions.

[0177] Example 10

[0178] Step 1: Weigh 10 g of acrylic acid, 1 g of sulfobetaine methacrylate, 20 g of water, 2 g of hydroxyapatite nanoparticles, 0.07 g of 2-hydroxy-methylphenylpropane-1-one, and 0.08 g of trimethylolpropane trimethacrylate, mix and homogenize to obtain a mixed solution.

[0179] Step 2: Pour the mixed solution into a mold with a thickness of 1 mm and place it under a UV lamp to react for 15 minutes to obtain a hydrogel composite material.

[0180] Step 3: Dry the hydrogel composite material at room temperature for 3 hours, then place it in a vacuum drying oven to dry for 24 hours, and then store it under refrigerated conditions.

[0181] Example 11

[0182] Step 1: Weigh 10 g of acrylic acid, 2 g of sulfobetaine methacrylate, 20 g of water, 2 g of hydroxyapatite nanoparticles, 0.07 g of 2-hydroxy-methylphenylpropane-1-one, and 0.07 g of polyethylene glycol dimethacrylate, mix and homogenize to obtain a mixed solution.

[0183] Step 2: Pour the mixed solution into a mold with a thickness of 1 mm and place it under a UV lamp to react for 10 minutes to obtain a hydrogel composite material.

[0184] Step 3: Dry the hydrogel composite material at room temperature for 3 hours, then place it in a vacuum drying oven to dry for 24 hours, and then store it under refrigerated conditions.

[0185] Example 12

[0186] Step 1: Weigh 10 g of acrylic acid, 0.67 g of sulfobetaine methacrylate, 20 g of water, 2 g of hydroxyapatite nanoparticles, 0.07 g of 2-hydroxy-methylphenylpropane-1-one, and 0.07 g of polyethylene glycol dimethacrylate, mix and homogenize to obtain a mixed solution.

[0187] Step 2: Pour the mixed solution into a mold with a thickness of 1 mm and place it under a UV lamp to react for 10 minutes to obtain a hydrogel composite material.

[0188] Step 3: Dry the hydrogel composite material at room temperature for 3 hours, then place it in a vacuum drying oven to dry for 24 hours, and then store it under refrigerated conditions.

[0189] Example 13

[0190] Step 1: Weigh 10 g of acrylic acid, 0.5 g of sulfobetaine methacrylate, 20 g of water, 2 g of hydroxyapatite nanoparticles, 0.07 g of 2-hydroxy-methylphenylpropane-1-one, and 0.07 g of polyethylene glycol dimethacrylate, mix and homogenize to obtain a mixed solution.

[0191] Step 2: Pour the mixed solution into a mold with a thickness of 1 mm and place it under a UV lamp to react for 10 minutes to obtain a hydrogel composite material.

[0192] Step 3: Dry the hydrogel composite material at room temperature for 3 hours, then place it in a vacuum drying oven to dry for 24 hours, and then store it under refrigerated conditions.

[0193] Example 14

[0194] Step 1: Weigh 10 g of acrylic acid, 0.5 g of sulfobetaine methacrylate, 20 g of water, 1 g of hydroxyapatite nanoparticles, 0.07 g of 2-hydroxy-methylphenylpropane-1-one, and 0.07 g of polyethylene glycol dimethacrylate, mix and homogenize to obtain a mixed solution.

[0195] Step 2: Pour the mixed solution into a mold with a thickness of 1 mm and place it under a UV lamp to react for 10 minutes to obtain a hydrogel composite material.

[0196] Step 3: Dry the hydrogel composite material at room temperature for 3 hours, then place it in a vacuum drying oven to dry for 24 hours, and then store it under refrigerated conditions.

[0197] Example 15

[0198] Step 1: Weigh 10 g of acrylic acid, 0.5 g of sulfobetaine methacrylate, 20 g of water, 4.5 g of hydroxyapatite nanoparticles, 0.07 g of 2-hydroxy-methylphenylpropane-1-one, and 0.07 g of polyethylene glycol dimethacrylate, mix and homogenize to obtain a mixed solution.

[0199] Step 2: Pour the mixed solution into a mold with a thickness of 1 mm and place it under a UV lamp to react for 10 minutes to obtain a hydrogel composite material.

[0200] Step 3: Dry the hydrogel composite material at room temperature for 3 hours, then place it in a vacuum drying oven to dry for 24 hours, and then store it under refrigerated conditions.

[0201] Comparative Example 1

[0202] Step 1: Weigh 10 g of acrylic acid, 1 g of sulfobetaine methacrylate, 20 g of water, 0.07 g of 2-hydroxy-methylphenylpropane-1-one, and 0.07 g of polyethylene glycol dimethacrylate, mix and homogenize to obtain a mixed solution.

[0203] Step 2: Pour the mixed solution into a mold with a thickness of 1 mm and place it under a UV lamp to react for 10 minutes to obtain a hydrogel material.

[0204] Step 3: Dry the hydrogel material at room temperature for 3 hours, then place it in a vacuum drying oven to dry for 24 hours, and then store it under refrigerated conditions.

[0205] Comparative Example 2

[0206] Step 1: Weigh 10 g of acrylic acid, 1 g of sulfobetaine methacrylate, 20 g of water, 0.3 g of hydroxyapatite nanoparticles, 0.07 g of 2-hydroxy-methylphenylpropane-1-one, and 0.07 g of polyethylene glycol dimethacrylate, mix and homogenize to obtain a mixed solution.

[0207] Step 2: Pour the mixed solution into a mold with a thickness of 1 mm and place it under a UV lamp to react for 10 minutes to obtain a hydrogel composite material.

[0208] Step 3: Dry the hydrogel composite material at room temperature for 3 hours, then place it in a vacuum drying oven to dry for 24 hours, and then store it under refrigerated conditions.

[0209] Comparative Example 3

[0210] Step 1: Weigh 10 g of methyl acrylate, 1 g of sulfobetaine methacrylate, 20 g of water, 2 g of hydroxyapatite nanoparticles, 0.07 g of 2-hydroxy-methylphenylpropane-1-one, and 0.07 g of polyethylene glycol dimethacrylate, mix and homogenize to obtain a mixed solution.

[0211] Step 2: Pour the mixed solution into a mold with a thickness of 1 mm and place it under a UV lamp to react for 10 minutes to obtain a hydrogel composite material.

[0212] Step 3: Dry the hydrogel composite material at room temperature for 3 hours, then place it in a vacuum drying oven to dry for 24 hours, and then store it under refrigerated conditions.

[0213] Comparative Example 4

[0214] Step 1: Weigh 10 g of acrylic acid, 0.8 g of 2-(methacryloyloxy)ethyl-2-(trimethylamino)ethyl phosphate, 20 g of water, 2 g of hydroxyapatite nanoparticles, 0.07 g of 2-hydroxy-methylphenylpropane-1-one, and 0.07 g of polyethylene glycol dimethacrylate, mix and homogenize to obtain a mixed solution.

[0215] Step 2: Pour the mixed solution into a mold with a thickness of 1 mm and place it under a UV lamp to react for 10 minutes to obtain a hydrogel composite material.

[0216] Step 3: Dry the hydrogel composite material at room temperature for 3 hours, then place it in a vacuum drying oven to dry for 24 hours, and then store it under refrigerated conditions.

[0217] Comparative Example 5

[0218] Step 1: Weigh 11 g of acrylic acid, 20 g of water, 2 g of hydroxyapatite nanoparticles, 0.07 g of 2-hydroxy-methylphenylpropane-1-one, and 0.07 g of polyethylene glycol dimethacrylate, mix and homogenize to obtain a mixed solution.

[0219] Step 2: Pour the mixed solution into a mold with a thickness of 1 mm and place it under a UV lamp to react for 10 minutes to obtain a hydrogel composite material.

[0220] Step 3: Dry the hydrogel composite material at room temperature for 3 hours, then place it in a vacuum drying oven to dry for 24 hours, and then store it under refrigerated conditions.

[0221] Comparative Example 6

[0222] Step 1: Weigh 10 g of acrylic acid, 1 g of sulfobetaine methacrylate, 20 g of water, 2 g of hydroxyapatite nanoparticles, and 0.07 g of 2-hydroxy-methylphenylpropane-1-one, mix and homogenize to obtain a mixed solution.

[0223] Step 2: Pour the mixed solution into a mold with a thickness of 1 mm and place it under a UV lamp to react for 10 minutes to obtain a hydrogel composite material.

[0224] Step 3: Dry the hydrogel composite material at room temperature for 3 hours, then place it in a vacuum drying oven to dry for 24 hours, and then store it under refrigerated conditions.

[0225] Comparative Example 7

[0226] Step 1: Weigh 10 g of acrylic acid, 0.67 g of [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide, 20 g of water, 2 g of hydroxyapatite nanoparticles, and 0.07 g of 2-hydroxy-methylphenylpropane-1-one, mix and homogenize to obtain a mixed solution.

[0227] Step 2: Pour the mixed solution into a mold with a thickness of 1 mm and place it under a UV lamp to react for 10 minutes to obtain a hydrogel composite material.

[0228] Step 3: Dry the hydrogel composite material at room temperature for 3 hours, then place it in a vacuum drying oven to dry for 24 hours, and then store it under refrigerated conditions.

[0229] Comparative Example 8

[0230] Step 1: Weigh 10 g of acrylic acid, 1 g of sulfobetaine methacrylate, 20 g of water, 6 g of silica nanoparticles, 0.07 g of 2-hydroxy-methylphenylpropane-1-one, and 0.07 g of polyethylene glycol dimethacrylate, mix and homogenize to obtain a mixed solution.

[0231] Step 2: Pour the mixed solution into a mold with a thickness of 1 mm and place it under a UV lamp to react for 10 minutes to obtain a hydrogel composite material.

[0232] Step 3: Dry the hydrogel composite material at room temperature for 3 hours, then place it in a vacuum drying oven to dry for 24 hours, and then store it under refrigerated conditions.

[0233] Test Procedure

[0234] Anti-swelling performance test of gel materials: The swelling performance curve of the gel material is tested under a constant temperature of 25°C. After weighing the gel sample, immerse it in a beaker filled with ultrapure water to allow it to fully absorb water and swell. Weigh the swollen hydrogel every 1 hour. Before each weighing, gently wipe it with filter paper to remove excess water on the surface and surrounding area of ​​the hydrogel. Stop weighing when the mass of the swollen hydrogel tends to be stable or after 48 hours. The calculation formula of the swelling rate (S) is as follows:

[0235] S=(W t -W0) / W0×100(where W t is the weight of the swollen hydrogel at different time t, and W0 is the initial weight of the gel).

[0236] Mechanical properties of gel materials were tested at room temperature using a WDW-05 electronic universal testing machine (Time Group Inc., China) in accordance with GB / T 16491-2008. At least three samples were tested for each mechanical property.

[0237] The tensile strength of the gel material was tested with reference to the national standard GB / T 528-2009.

[0238] The adhesion strength of the gel material was tested with reference to the pharmaceutical industry standard YY / T 0729.2-2009: Test method for adhesion performance of tissue adhesives Part 2: T-peel tensile bearing strength.

[0239] The performance of each sample was tested three times and the average value was obtained. The results are shown in Table 2.

[0240] Table 2

[0241] As shown in Table 2, the double-crosslinked hydrogel composite materials of Examples 1-15 exhibited an adhesion strength greater than 25 kPa, exceeding the adhesion strength of commercially available tissue patches (e.g., 20 kPa). They also exhibited a tensile strength greater than 80 kPa, and a 48-hour swelling ratio less than 100% tested at a constant temperature of 25°C, making them suitable for both on-body and in-vivo tissue patches. Hydrogel materials with both high mechanical strength, high adhesion strength, and good anti-swelling properties were not obtained when the composite materials did not contain nanoparticles (Comparative Example 1), when the ratio of nanoparticles to polymerizable monomers was too low (Comparative Example 2) or too high (Comparative Example 8), when acrylic monomers not specified in the present invention were used (Comparative Example 3) or non-zwitterionic monomers (Comparative Example 4), when zwitterionic monomers were not used (Comparative Example 5), or when a crosslinking agent was not used (Comparative Examples 6-7).

[0242] A peel-adhesion cycle test was also conducted, and the results are shown in Table 3. As can be seen from Table 3, after 6 cycles of adhesion-peel-re-adhesion, the adhesion strength of the hydrogel composite materials of Examples 1-4 was stably maintained above 30 kPa.

[0243] Table 3

[0244] In summary, the double-crosslinked hydrogel composite material according to the present invention has high adhesion strength and cyclic adhesion stability, as well as high anti-swelling and mechanical stability, and is suitable for use as a suture-free tissue patch to promote wound healing and repair on the body surface and in the body.

[0245] The preferred embodiments of the present application are described in detail above. However, the present application is not limited to the specific details of the above embodiments. Within the technical concept of the present application, various simple modifications can be made to the technical solution of the present application, and these simple modifications all fall within the scope of protection of the present application.

[0246] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. To avoid unnecessary repetition, this application will not further describe various possible combinations.

[0247] In addition, the various implementation methods of the present application may be arbitrarily combined, and as long as they do not violate the concept of the present application, they should also be regarded as the contents disclosed in the present application.

Claims

1. A double-crosslinked hydrogel composite material, characterized in that The invention relates to a physical-chemical double cross-linked copolymer formed by reacting at least one acrylic monomer and at least one zwitterionic monomer in the presence of nanoparticles and a cross-linking agent, wherein the weight ratio of the nanoparticles to the structural units derived from the acrylic monomer is 1:(2-15), preferably 1:(3-10).

2. The double-crosslinked hydrogel composite material according to claim 1, characterized in that: Taking the total amount of the double-crosslinked hydrogel composite material as 100 wt %: The total content of the structural units derived from acrylic monomers and zwitterionic monomers in the double-crosslinked hydrogel composite material is 20-50% by weight, preferably 30-35% by weight; and / or, The content of the structural units derived from the crosslinking agent in the double-crosslinked hydrogel composite material is 0.1-0.5 wt %, preferably 0.2-0.3 wt %; and / or, The content of nanoparticles in the double-crosslinked hydrogel composite material is 3-12.8 wt%, preferably 5-9 wt%; and / or, The weight ratio of the structural units derived from zwitterionic monomers to the structural units derived from acrylic monomers in the double-crosslinked hydrogel composite material is 1:(5-20), preferably 1:(10-15).

3. The double-crosslinked hydrogel composite material according to any one of the preceding claims, characterized in that: The nanoparticles are biocompatible inorganic nanoparticles, preferably nanoparticles of at least one selected from the group consisting of nano-bioactive glass, silicon dioxide, zinc oxide, hydroxyapatite, titanium dioxide, and boron nitride, more preferably nanoparticles of nano-bioactive glass, hydroxyapatite, and / or silicon dioxide; and / or, The particle size of the nanoparticles is 10-500 nm, preferably 50-500 nm, more preferably 80-300 nm, and even more preferably 80-150 nm.

4. The double-crosslinked hydrogel composite material according to any one of the preceding claims, characterized in that: The acrylic monomer is selected from at least one of acrylic acid, methacrylic acid, and ethacrylic acid; and / or, The zwitterionic monomer is selected from at least one of a methacryloxy-containing zwitterionic monomer and a sulfobetaine zwitterionic monomer; preferably selected from at least one of [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide, sulfobetaine vinylimidazole, and sulfobetaine methacrylate, more preferably sulfobetaine methacrylate and / or [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide.

5. The double-crosslinked hydrogel composite material according to any one of the preceding claims, characterized in that: The crosslinking agent is selected from compounds having at least two acrylate functional groups, preferably at least one selected from polyethylene glycol dimethacrylate, polypropylene glycol dimethacrylate, polyethylene glycol diacrylate, trimethylolpropane trimethacrylate, more preferably polyethylene glycol dimethacrylate.

6. The double-crosslinked hydrogel composite material according to any one of the preceding claims, characterized in that: The tensile strength of the double-crosslinked hydrogel composite material is 80-130 kPa; and / or, The double-crosslinked hydrogel composite material has an adhesion strength of 25-50 kPa; and / or, The swelling rate of the double-crosslinked hydrogel composite material tested at a constant temperature of 25° C. for 48 hours is less than 100%; and / or, The thickness of the double-crosslinked hydrogel composite material is 0.5-5 mm, preferably 1-2 mm.

7. A method for preparing a double-crosslinked hydrogel composite material, preferably a double-crosslinked hydrogel composite material according to any one of claims 1 to 6, characterized in that The following steps are involved: A mixture comprising at least one acrylic monomer, at least one zwitterionic monomer, a photoinitiator, nanoparticles, a crosslinking agent, and water is reacted under light conditions to obtain the double-crosslinked hydrogel composite material, wherein the weight ratio of the nanoparticles to the acrylic monomer is 1:(2-15), preferably 1:(3-10).

8. The method according to claim 7, wherein: The reaction conditions include: The reaction is carried out at room temperature; and / or, The reaction is carried out under ultraviolet light; and / or, The illumination time is 5-20 minutes, preferably 8-15 minutes; and / or, The reaction is carried out in a mold with a thickness of 0.5-5 mm, preferably 1-2 mm.

9. The method according to claim 7 or 8, characterized in that: Taking the total amount of the mixed solution as 100% by weight: The total amount of the acrylic monomer and the zwitterionic monomer is 20-50 wt%, preferably 30-35 wt%; and / or, The amount of the photoinitiator is 0.1-0.5 wt%, preferably 0.2-0.3 wt%; and / or, The amount of the cross-linking agent is 0.1-0.5 wt%, preferably 0.2-0.3 wt%; and / or, The amount of the nanoparticles is 3-12.8 wt%, preferably 5-9 wt%; and / or, The weight ratio of the zwitterionic monomer to the acrylic monomer is 1:(5-20), preferably 1:(10-15).

10. The method according to any one of claims 7 to 9, characterized in that: The nanoparticles are biocompatible inorganic nanoparticles, preferably nanoparticles of at least one selected from the group consisting of nano-bioactive glass, silicon dioxide, zinc oxide, hydroxyapatite, titanium dioxide, and boron nitride, more preferably nanoparticles of nano-bioactive glass, hydroxyapatite, and / or silicon dioxide; and / or, The particle size of the nanoparticles is 10-500 nm, preferably 50-500 nm, more preferably 80-300 nm, even more preferably 80-150 nm.

11. The method according to any one of claims 7 to 10, characterized in that: The acrylic monomer is selected from at least one of acrylic acid, methacrylic acid, and ethacrylic acid; and / or, The zwitterionic monomer is selected from at least one of a methacryloxy-containing zwitterionic monomer and a sulfobetaine zwitterionic monomer; preferably selected from at least one of [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide, sulfobetaine vinylimidazole, and sulfobetaine methacrylate, more preferably sulfobetaine methacrylate and / or [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide.

12. The method according to any one of claims 7 to 11, characterized in that: The photoinitiator is selected from free radical polymerization photoinitiators, preferably at least one selected from 1-hydroxycyclohexyl phenyl ketone, 2-hydroxy-methylphenylpropane-1-one, 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone benzoin dimethyl ether, and ethyl 4-(N,N-dimethylamino)benzoate, more preferably 2-hydroxy-methylphenylpropane-1-one; and / or, The crosslinking agent is selected from compounds having at least two acrylate functional groups, preferably at least one selected from polyethylene glycol dimethacrylate, polypropylene glycol dimethacrylate, polyethylene glycol diacrylate, trimethylolpropane trimethacrylate, more preferably polyethylene glycol dimethacrylate.

13. The double-crosslinked hydrogel composite material according to any one of claims 1-6 or the double-crosslinked hydrogel composite material obtained by the method according to any one of claims 7-12 is used as a wound repair material, preferably a suture-free wound repair material, more preferably an application as a tissue patch.

Images