WO2024087678A1 - 一种含多尺度孔道网络的自粘附型止血修复凝胶、其制备方法及应用 - Google Patents

一种含多尺度孔道网络的自粘附型止血修复凝胶、其制备方法及应用 Download PDF

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WO2024087678A1
WO2024087678A1 PCT/CN2023/101984 CN2023101984W WO2024087678A1 WO 2024087678 A1 WO2024087678 A1 WO 2024087678A1 CN 2023101984 W CN2023101984 W CN 2023101984W WO 2024087678 A1 WO2024087678 A1 WO 2024087678A1
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hydrogel
self
component
pore network
scale pore
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PCT/CN2023/101984
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French (fr)
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朱楚洪
李英豪
谭菊
秦钟梁
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中国人民解放军陆军军医大学
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    • A—HUMAN NECESSITIES
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    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
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    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
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    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
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    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
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    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
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    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/06—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
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    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
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    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
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    • C08L33/00—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides or nitriles thereof; Compositions of derivatives of such polymers
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    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to a self-adhesive hemostatic repair gel containing a multi-scale pore network, a preparation method and application thereof, and belongs to the technical field of biomedical materials.
  • Hydrogels have a water-containing network similar to the natural extracellular matrix and have been widely used in biomedical fields such as cell culture, drug delivery, wound dressings, and tissue reconstruction. Recently, hydrogels have been further endowed with tissue adhesion and can form covalent or non-covalent bonds with biological tissues to seal bleeding wounds and promote tissue healing. The application of this material can replace time-consuming traditional surgical sealing methods such as sutures and staples, bringing convenience to the rapid hemostasis and sealing of wounds. However, for the sealing of gushing dynamic bleeding wounds in the body (such as the aorta, heart, etc.), the current sticky hydrogels are still not ideal in terms of tissue mechanics matching and adhesion strength.
  • the tissue sealing performance of the viscose hydrogel depends on the toughness of the gel matrix itself and its adhesion to the tissue surface.
  • Clinically available fibrin sealants and polyethylene glycol-based viscose hydrogels are easily separated from the tissue surface due to their brittle matrix and low tissue adhesion strength.
  • Catechol-based hydrogels can adhere to organic and inorganic surfaces, but the weak non-covalent adhesion cannot achieve strong adhesion to wet tissue surfaces.
  • related studies have prepared various viscose hydrogels such as photocurable viscose hydrogels, double-network viscose hydrogels and double-sided tapes by introducing reactive groups on polymer chains or active ingredients in hydrogels for tissue surface adhesion.
  • the currently available viscose hydrogels still need to be improved in terms of biomechanical matching and interfacial adhesion toughness.
  • mismatched mechanical properties can affect the normal contraction and relaxation function of the target blood vessels and heart, thereby affecting the therapeutic effect after sealing. Therefore, the present invention develops a viscose hydrogel containing a multi-scale pore network, which, on the one hand, regulates the rigidity and flexibility of the gel matrix through a multi-scale network to promote conformal contact and adhesion between the gel matrix and soft tissue.
  • biomechanical matching and on the other hand, the covalent/non-covalent bridging effect between the bioadhesion molecules and the tissue interface gives the gel matrix strong interfacial adhesion toughness. The two together achieve instant and firm adhesion between the gel and the soft tissue interface.
  • the present invention provides a self-adhesive hydrogel containing a multi-scale pore network and a preparation method and application thereof, which reduces the rigidity of the gel matrix and improves the conformal contact between the gel matrix and the soft tissue by constructing a multi-scale porous gel matrix, and realizes instant, effective and firm adhesion between the gel and the soft tissue interface based on the bridging effect of bioadhesion molecules.
  • the main technical solutions adopted by the present invention include:
  • a self-adhesive hemostatic repair gel containing a multi-scale pore network comprising component A and component B, wherein component A is a hydrogel matrix layer of a composite multi-scale pore network formed by mixing a microporous hydrogel preparation liquid and a nanoporous hydrogel preparation liquid in a mass ratio of 1:0.1-1; and component B is an aqueous solution of bioadhesive active molecules that can bridge the gel matrix and the tissue interface, and the mass concentration of the bioadhesive active molecules is 0.5-5%.
  • the component A and the component B are used in combination at a mass ratio of 1:0.01 to 0.5.
  • component B When in use, component B is applied on component A, and the side containing component B is attached to the wound tissue interface.
  • the self-adhesive hemostatic repair gel containing a multi-scale pore network preferably, the microporous hydrogel preparation solution is obtained by mixing a water-soluble synthetic polymer monomer solution with a mass concentration of 10 to 80% and an initiator;
  • the water-soluble synthetic polymer monomer is any one of acrylamide, hydroxyethyl acrylamide or acrylic acid;
  • the initiator is any one of the photoinitiator Irgacure 2959 or ⁇ -ketoglutaric acid, or the thermal initiator ammonium persulfate and tetramethylethylenediamine.
  • the ratio of ammonium persulfate to tetramethylethylenediamine in units of g:mL is 7: Add in a ratio of 4.
  • the initiator of the present invention refers to a class of compounds that are easily decomposed into free radicals (i.e., primary free radicals) by light or heat, and is used to initiate free radical polymerization and copolymerization reactions of olefinic and diene monomers, and can also be used for crosslinking and curing of unsaturated polyesters and crosslinking reactions of polymers.
  • the mass concentration of the initiator in the microporous hydrogel preparation solution is 0.01-1%.
  • the nanoporous hydrogel preparation solution is a natural polymer aqueous solution with a mass concentration of 1 to 20%, and the natural polymer is any two or more combinations of agarose, gelatin, chitosan, polylysine and sodium alginate.
  • the preferred mass concentration is 5 to 20%.
  • the preferred two-component combinations are gelatin and chitosan, agar and chitosan, gelatin and polylysine, sodium alginate and polylysine, and agar and polylysine, with a mass ratio of 1:0.4 to 2.
  • the bioadhesive hemostatic repair gel containing a multi-scale pore network preferably, the bioadhesive active molecule is formed by the reaction of a biocompatible polymer and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC ⁇ HCl)/N-hydroxysuccinimide (NHS), and the NHS grafting rate of the bioadhesive active molecule, i.e., the molar ratio of carboxyl NHS ester to the total number of carboxyl groups, is 10 to 90%;
  • EDC ⁇ HCl 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • NHS N-hydroxysuccinimide
  • the biocompatible polymer is any one of polyglutamic acid, polyaspartic acid, sodium alginate, hyaluronic acid or polyethylene glycol carboxylic acid or a combination of two or more thereof.
  • the EDC ⁇ HCl and NHS are mixed in a molar ratio of 1:1 to 10. It should be noted that the grafting rate is described for the number of carboxyl groups of the biocompatible polymer: that is, the number of carboxyl groups of NHS (N-hydroxysuccinimide) modified on the biocompatible polymer/the total number of carboxyl groups; it can be calculated by 1 H-NMR (nuclear magnetic resonance hydrogen spectrum);
  • Biocompatible polymers must have carboxyl groups before they can be modified with NHS groups. Molecules modified with NHS can react with amino groups on the gel matrix and amino groups on the tissue surface to form amide bonds, thereby achieving a bridging effect. Therefore, the biocompatible polymer is preferably any one of polyglutamic acid, polyaspartic acid, sodium alginate, hyaluronic acid or polyethylene glycol carboxylic acid, or a combination of two or more thereof.
  • the carboxyl groups of biocompatible polymers react with EDC ⁇ HCl and NHS to generate NHS active esters, and the activation reaction needs to be carried out in an aqueous solution or a dimethyl sulfoxide (DMSO) solvent.
  • DMSO dimethyl sulfoxide
  • the biocompatible polymer reacts with EDC ⁇ HCl/NHS in water at a mass ratio of 1:10-15 or in DMSO at a mass ratio of 1:5-10, and the concentration of the biocompatible polymer is 5 g/L-50 g/L.
  • the method for preparing the self-adhesive hemostatic repair gel containing a multi-scale pore network as described above comprises the following steps:
  • Component A and component B are combined in a mass ratio of 1:0.01 to 0.5 to obtain a self-adhesive hemostatic repair gel containing a multi-scale pore network.
  • the thickness of the composite multi-scale pore network hydrogel matrix is 0.1 to 1 mm.
  • step (2) reacting in aqueous solution or DMSO
  • the time is 0.5 to 24 hours, the temperature of ice ethanol or ice ether is -20°C, the number of washing times is 3 to 10 times; the freeze-drying time is 24 to 48 hours.
  • component B When in use, component B is applied to one side of component A for tissue adhesion and wound sealing.
  • the tissues and organs include but are not limited to blood vessels, skin, muscles, heart, stomach tissue, lungs and liver, etc.
  • the present invention provides a self-adhesive hemostatic repair gel with a multi-scale pore network that has soft tissue mechanics matching, instant and strong tissue adhesion. It can quickly, conformably and strongly adhere to the wet tissue interface to achieve rapid hemostatic sealing and repair of wounds, and has good clinical application prospects in the rapid hemostatic sealing of acute massive bleeding.
  • the self-adhesive hemostatic repair gel containing a multi-scale pore network introduces an island-shaped nanoporous hydrogel, which can improve the rigidity and toughness of the double network gel matrix and promote its conformal contact with the target soft tissue interface; at the same time, the nanoporous hydrogel acts as an adhesion anchor point, and under the bridging of bioadhesive active molecules, it interacts with the tissue surface through hydrogen bonds, ionic bonds and covalent bonds to achieve rapid adhesion between the gel and the tissue; moreover, the presence of the nanoporous hydrogel can further optimize the energy dissipation at the adhesion interface and improve the adhesion strength.
  • the self-adhesive hemostatic repair gel containing a multi-scale pore network exhibits good biocompatibility and biodegradability, and can be used in the field of medical hemostatic repair.
  • Fig. 1 is a photo of component A of the present invention
  • Fig. 2 is a photo of component B of the present invention.
  • FIG3 is a stress-strain curve and mechanical stretching photograph of component A of the present invention.
  • FIG4 is the characterization data of mechanical stretching of component A of the present invention.
  • FIG5 is a structural representation of component A of the present invention: i, an optical microscope photograph of nanoporous hydrogel particles dispersed in water; ii, an optical microscope photograph (left) and a scanning electron microscope photograph (right) of a microporous hydrogel matrix; iii, nanoporous hydrogel particles (dashed line portion) dispersed in a microporous hydrogel matrix, the left picture is an optical microscope photograph, and the right picture is a scanning electron microscope photograph;
  • FIG6 is a calculation formula and schematic diagram of hydrogel fracture energy
  • FIG7 is a fracture energy characterization of component A of the present invention: i, a photograph of the composite porous network hydrogel matrix under tensile stress, with the left side being a normal sample and the right side being a notched sample; ii, a stress-strain curve of the composite porous network hydrogel matrix, with the top being a notched sample and the bottom being a normal sample;
  • FIG8 is a nuclear magnetic resonance hydrogen spectrum ( 1 H-NMR) of the bioadhesive polymer HA-NHS;
  • FIG9 is a photograph of the adhesion of the present invention on pig skin
  • FIG10 is a photograph of the adhesion of the present invention to different tissues
  • FIG11 shows the interfacial adhesion strength between the present invention and different biological tissues
  • FIG12 is a photograph showing the hemostatic effect of the present invention on abdominal aorta bleeding in beagle dogs;
  • FIG13 is a photograph showing the repair effect of the present invention on abdominal aorta hemorrhage in beagle dogs;
  • FIG14 is a stress-strain curve of different hydrogels
  • FIG15 is a comparison of the tensile toughness and elastic modulus of different hydrogels
  • FIG16 shows the adhesion strength of different hydrogels to pig skin tissue
  • FIG17 is a comparison of the interfacial adhesion strength of the present invention and commercial bioglue on pig skin tissue
  • Figure 18 is a burst pressure test device
  • FIG19 is a comparison of the bursting pressures of the present invention and commercial bioadhesive for sealing a gap in pig skin tissue;
  • the present invention develops a viscous hydrogel containing a multi-scale pore network.
  • the rigidity and flexibility of the gel matrix are adjusted by introducing a multi-scale pore network to promote the conformity of the gel matrix to the soft tissue.
  • the contact and biomechanical matching on the other hand, with the help of the covalent/non-covalent bridging effect between the bioadhesion molecules and the tissue interface, gives the gel matrix strong interfacial adhesion toughness. The two together achieve instant and firm adhesion between the gel and the soft tissue interface, achieving rapid hemostasis, sealing and repair of the wound.
  • the components and preparation method of a self-adhesive hemostatic repair gel containing a multi-scale pore network include the following steps:
  • the electrostatic and hydrogen bonding interactions between gelatin and chitosan were used to form a uniformly dispersed nanoporous hydrogel.
  • the acrylamide was further cross-linked by 365 nm ultraviolet light (10 W) for 30 min to polymerize the microporous hydrogel.
  • the nanoporous hydrogel was distributed in the microporous hydrogel network in the form of islands, realizing the integrated construction of a composite network hydrogel matrix containing micropores and nanopores with a thickness of 0.5 mm, i.e., component A.
  • component B When in use, 200 mg of component B is applied to one side of 1 g of component A to obtain a self-adhesive hemostatic repair gel containing a multi-scale pore network.
  • Components and preparation method of self-adhesive hemostatic repair gel containing multi-scale pore network The steps include:
  • component B When in use, 500 mg of component B is applied to one side of 1 g of component A to obtain a self-adhesive hemostatic repair gel containing a multi-scale pore network.
  • the components and preparation method of a self-adhesive hemostatic repair gel containing a multi-scale pore network include the following steps:
  • nanoporous hydrogel preparation solution for 30 min, and cooled to room temperature to obtain a nanoporous hydrogel preparation solution; the above microporous hydrogel preparation solution and nanoporous hydrogel preparation solution were continued to be rapidly stirred and mixed at 60° C., and then poured into a cooled mold; the electrostatic and hydrogen bonding interactions between gelatin and polylysine were used to form a nanoporous hydrogel preparation solution.
  • the uniformly dispersed nanoporous hydrogel was formed by the action of 284 nm ultraviolet light (10 W) for crosslinking for 30 min, and the acrylic acid was polymerized to form a microporous hydrogel.
  • the nanoporous hydrogel was distributed in the microporous hydrogel network in the form of islands, realizing the integrated construction of a composite network hydrogel matrix containing micropores and nanopores with a thickness of 0.5 mm, namely component A.
  • the components and preparation method of a self-adhesive hemostatic repair gel containing a multi-scale pore network include the following steps:
  • the components and preparation method of a self-adhesive hemostatic repair gel containing a multi-scale pore network include the following steps:
  • the electrostatic and hydrogen bonding interactions between agar and chitosan were used to form a uniformly dispersed nanoporous hydrogel.
  • the hydroxyethyl acrylamide was further cross-linked by 365 nm ultraviolet light (10 W) for 30 min to polymerize the microporous hydrogel.
  • the nanoporous hydrogel was distributed in the microporous hydrogel network in the form of islands, realizing the integrated construction of a composite network hydrogel matrix containing micropores and nanopores with a thickness of 0.5 mm, i.e., component A.
  • component B When in use, 0.5 g of component B is applied to one side of 1 g of component A to obtain a self-adhesive hemostatic repair gel containing a multi-scale pore network.
  • the self-adhesive hemostatic repair gel containing a multi-scale pore network prepared in Example 5 was selected to characterize the structure and properties of its components.
  • the photo of component A is shown in Figure 1, and the photo of component B is shown in Figure 2.
  • the mechanical characterization results obtained by further calculation are shown in Figure 4. Its elastic modulus is 106.3 ⁇ 1.7kPa, and the tensile toughness reaches 3.6 ⁇ 0.2MJ/m 3 , indicating that component A has good flexibility and toughness, which meets the requirements of soft tissue interface adhesion.
  • component A was further characterized, and the results showed that the nanoporous hydrogel was dispersed in the microporous hydrogel matrix, and together formed a composite multi-scale pore network hydrogel containing micropores and nanopores.
  • i optical microscope photo of nanoporous hydrogel particles dispersed in water
  • ii optical microscope photo (left) and scanning electron microscope photo (right) of the microporous hydrogel matrix
  • iii nanoporous hydrogel particles (dashed part) dispersed in the microporous hydrogel matrix
  • the left picture is an optical microscope photo
  • the right picture is a scanning electron microscope photo.
  • This special hydrogel structure has high fracture energy.
  • the calculated fracture energy of component A is as high as 9170J/ m2 ( Figure 7), indicating that component A is a high-strength adhesion hydrogel matrix.
  • Proton nuclear magnetic resonance ( 1 H-NMR) was used to characterize the molecular structure of component B.
  • the NHS grafting rate of HA in HA-NHS was calculated to be 18.8%.
  • FIG9 shows the preparation steps of the adhesive tissue sample
  • FIG10 is a diagram of the adhesion effect of the present invention with different tissues (skin, heart, stomach, muscle, liver), which preliminarily shows that it has good tissue adhesion.
  • the final adhesion strength was calculated according to i and ii in FIG11, and the results are shown in iii of FIG11, specifically skin: >1000J/m 2 ; heart: 570J/m 2 ; stomach: 450J/m 2 ; muscle: 340J/m 2 ; liver: 190J/m 2 .
  • Beagle dogs were selected and anesthetized by intravenous injection of pentobarbital solution (3%). The abdomen was shaved and disinfected to expose the abdominal aorta. Hemostatic forceps were used to stop bleeding. A 5 mm long incision was made in the abdominal aorta, as shown in A in FIG. 12 . The hemostatic forceps were released, and the bleeding at the incision was observed. The incision site was blocked with the hemostatic repair gel of Example 5 of the present invention (as shown in A in FIG. 12 ) and pressed for 0.5 to 1 min before the hemostatic forceps were released. The result was shown in B in FIG. 12 .
  • a single-component microporous network hydrogel (single network: polyhydroxyethyl acrylamide replaces polyhydroxyethyl acrylamide/agar/polylysine), a two-component microporous network hydrogel (two-component network: polyhydroxyethyl acrylamide/agar replaces polyhydroxyethyl acrylamide/agar/polylysine) and a composite porous network hydrogel containing micropores and nanopores of the present invention (the material obtained in Example 5) were prepared respectively, and then subjected to tensile tests, the experimental method was the same as above, and the tensile stress-strain curves thereof were shown in FIG14.
  • the tensile toughness and elastic modulus were further calculated based on the stress-strain curve, and the results are shown in FIG15 , which indicate that the composite porous network hydrogel containing micropores and nanopores of the present invention has the highest tensile toughness (3.6 ⁇ 0.2 MJ/m 3 ) and tissue-matching elastic modulus (106.3 ⁇ 1.7 kPa).
  • the adhesion strength of the single-component microporous network hydrogel (single network: poly(hydroxyethyl acrylamide), the double-component microporous network hydrogel (double network: poly(hydroxyethyl acrylamide/agar)) and the composite porous network hydrogel containing micropores and nanopores of the present invention at the pig skin tissue interface was further studied ( FIG. 16 ):
  • the three types of hydrogels have low adhesion to pig skin; when HA or HA-NHS is selected as the adhesive layer, the interface toughness of the single-component microporous network hydrogel or the two-component microporous network hydrogel to the skin tissue is still not improved; only the composite porous network hydrogel containing micropores and nanopores of the present invention combined with HA-NHS as an adhesive layer and covalently bonded with the tissue interface can show high interface adhesion strength (>1000 J/m 2 ).
  • the sealing ability of the self-adhesive hemostatic repair gel component prepared by the present invention and clinically available bioadhesives (such as cyanoacrylate CA and fibrin glue Bioseal) for soft tissue wounds was compared through a bursting pressure test.
  • bioadhesives such as cyanoacrylate CA and fibrin glue Bioseal
  • a phosphate buffer solution (PBS) was injected into the closed system, and the hydraulic pressure in the system gradually increased.
  • PBS phosphate buffer solution
  • the bursting pressure of the hemostatic repair gel component is 694 ⁇ 71 mmHg, which is much higher than the normal human systolic blood pressure of 120 mmHg; and much higher than the bursting pressure of clinically used biological adhesives (cyanoacrylate CA: 66 ⁇ 8 mmHg and fibrin glue Bioseal: 56 ⁇ 28 mmHg).
  • the results are shown in Figure 19.

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Abstract

本发明涉及一种含多尺度孔道网络的自粘附型止血修复凝胶、其制备方法及应用，其止血修复凝胶包括组分A和组分B，所述组分A为微孔水凝胶制备液和纳孔水凝胶制备液混合形成的复合多尺度孔道网络的水凝胶基质层；所述组分B为一种可桥联凝胶基质和组织界面的生物粘附活性分子水溶液。其在微孔网络水凝胶中引入岛状分布的纳孔水凝胶可以降低凝胶基质的刚性，改善凝胶基质与软组织的适形接触，加速与软组织表面的结合(氢键、离子键和共价键)，并促进受压界面处的能量耗散；同时，生物粘附活性分子可以实现纳孔水凝胶与软组织界面的桥联。纳孔水凝胶和桥联型粘附高分子的共同作用实现凝胶与软组织界面的即时和牢固的粘合，达到伤口的快速止血封合和修复。

Description

一种含多尺度孔道网络的自粘附型止血修复凝胶、其制备方法及应用 技术领域
本发明涉及一种含多尺度孔道网络的自粘附型止血修复凝胶、其制备方法及应用，属于生物医用材料技术领域。
背景技术
水凝胶具有类似于天然细胞外基质的含水网络，已被广泛用于细胞培养、药物输送、伤口敷料和组织重建等生物医学领域。最近，水凝胶被进一步赋予组织粘附性，可以与生物组织形成共价或非共价键，密封出血性伤口并促进组织愈合。该材料的应用可以替代使用缝线和订书钉等耗时的传统手术密封方式，为伤口的快速止血封合带来了方便。然而，对于体内喷涌性动态出血创面(如主动脉、心脏等)的密封，目前的粘性水凝胶在组织力学匹配度和粘附强度方面仍然不理想。
粘性水凝胶的组织密封性能依赖于凝胶基质的自身韧性以及其对组织表面的粘附性。临床上可用的纤维蛋白密封胶和基于聚乙二醇的粘性水凝胶，由于其脆性基质和低组织粘合强度，很容易与组织表面分离。基于儿茶酚的水凝胶可以粘附在有机和无机表面上，然而较弱的非共价粘附作用无法实现对湿组织表面的强粘附。为了应对这些难题，相关研究通过在聚合物链上引入反应性基团或在水凝胶中引入活性成分用于组织表面粘合，制备了各种粘性水凝胶，如光固化粘性水凝胶，双网络粘性水凝胶和双面胶带。然而，目前可获得的粘性水凝胶在生物力学匹配度和界面粘附韧性两方面仍然有待完善。特别是，不匹配的力学性能会影响目标血管和心脏的正常收缩和舒张功能，从而影响密封后的治疗效果。因此本发明开发一种含多尺度孔道网络的粘性水凝胶，一方面通过多尺度网络调节凝胶基质的刚柔性促进凝胶基质与软组织的适形接触和 生物力学匹配，另一方面借助生物粘附分子与组织界面的共价/非共价桥联作用赋予凝胶基质强的界面粘附韧性，两者共同实现凝胶与软组织界面的即时和牢固的粘合。
发明内容
(一)要解决的技术问题
为了解决现有技术的上述问题，本发明提供一种含多尺度孔道网络的自粘附型水凝胶及其制备方法和应用，通过构建多孔尺度的凝胶基质，降低凝胶基质的刚性，改善凝胶基质与软组织的适形接触，并基于生物粘附分子的桥联作用，实现凝胶与软组织界面的即时、有效和牢固的粘合。
(二)技术方案
为了达到上述目的，本发明采用的主要技术方案包括：
一种含多尺度孔道网络的自粘附型止血修复凝胶，其包括组分A和组分B，所述组分A为微孔水凝胶制备液和纳孔水凝胶制备液按质量比1：0.1～1混合形成的复合多尺度孔道网络的水凝胶基质层；所述组分B为一种可桥联凝胶基质和组织界面的生物粘附活性分子水溶液，生物粘附活性分子的质量浓度为0.5～5％。
优选地，所述组分A和组分B按质量比为1:0.01～0.5进行组合使用。
使用时，将组分B涂覆于组分A上，将含组分B的一面贴合在创伤组织界面上。
如上所述的含多尺度孔道网络的自粘附型止血修复凝胶，优选地，所述微孔水凝胶制备液由质量浓度为10～80％的水溶性合成高分子单体溶液和引发剂混合得到；
其中，水溶性合成高分子单体为丙烯酰胺、羟乙基丙烯酰胺或丙烯酸中的任一种；所述引发剂为光引发剂Irgacure 2959或α-酮戊二酸、或热引发剂过硫酸铵和四甲基乙二胺中的任一种。
进一步，优选地，过硫酸铵和四甲基乙二胺按单位为g：mL比为7： 4的比例进行添加。
本发明的引发剂指一类容易受光或热分解成自由基(即初级自由基)的化合物，用于引发烯类、双烯类单体的自由基聚合和共聚合反应，也可用于不饱和聚酯的交联固化和高分子交联反应。引发剂在微孔水凝胶制备液中的质量浓度为0.01～1％。
如上所述的含多尺度孔道网络的自粘附型止血修复凝胶，优选地，所述纳孔水凝胶制备液为质量浓度为1～20％的天然高分子水溶液，天然高分子为琼脂糖、明胶、壳聚糖、聚赖氨酸和海藻酸钠中的任两种或多种组合。
考虑天然高分子的分散均匀性，优选质量浓度为5～20％。其中，优选明胶与壳聚糖、琼脂与壳聚糖、明胶与聚赖氨酸、海藻酸钠与聚赖氨酸、琼脂与聚赖氨酸间的双组分组合，质量比为1:0.4～2。
如上所述的含多尺度孔道网络的自粘附型止血修复凝胶，优选地，所述生物粘附活性分子由生物相容性高分子与1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC·HCl)/N-羟基琥珀酰亚胺(NHS)反应而成，生物粘附活性分子的NHS接枝率，即羧基NHS酯与羧基总数的摩尔比，为10～90％；
生物相容性高分子为聚谷氨酸、聚天冬氨酸、海藻酸钠、透明质酸或聚乙二醇羧酸中的任一种或两种或多种的组合。
其中，进一步地，所述EDC·HCl和NHS按摩尔比为1:1～10进行混合。需要说明的是，所述接枝率是针对生物相容性高分子的羧基数量来阐述的：即生物相容性高分子修饰上NHS(N-羟基琥珀酰亚胺)的羧基个数/总羧基数；可以通过1H-NMR(核磁共振氢谱)计算得到；
生物相容性高分子必须带有羧基才可以修饰上NHS基团，修饰上NHS的分子可以与凝胶基质上的氨基以及组织表面的氨基反应形成酰胺键，实现桥联作用，所以生物相容性高分子优选为聚谷氨酸、聚天冬氨酸、海藻酸钠、透明质酸或聚乙二醇羧酸中的任一种或两种或多种组合。
制备生物粘附活性分子时，生物相容性高分子的羧基在EDC·HCl与NHS作用下生成NHS活性酯，活化反应需要在水溶液或者二甲基亚砜(DMSO)溶剂中进行。
进一步地，生物相容性高分子与EDC·HCl/NHS以质量比为1：10～15在水中进行反应或以质量比为1：5～10在DMSO中进行反应，生物相容性高分子浓度为5g/L～50g/L。
如上所述的含多尺度孔道网络的自粘附型止血修复凝胶的制备方法，其包括如下步骤：
(1)将水溶性合成高分子单体和引发剂溶于水，得到微孔水凝胶制备液；将另外两种天然高分子在水中原位混合，得到纳孔水凝胶制备液；将微孔水凝胶制备液和纳孔水凝胶制备液混合并快速搅拌混匀，倒入模子中成型；利用天然高分子间的静电、氢键、憎水、配位或者阳离子-π键相互作用形成分散均匀的纳孔水凝胶；进一步经紫外光交联(光引发剂为Irgacure 2959或α-酮戊二酸)或者热交联(热引发剂为过硫酸铵/四甲基乙二胺)，水溶性合成高分子单体聚合形成微孔水凝胶；最终，纳孔水凝胶以岛状形式分布在微孔水凝胶网络中，实现一体构建含微孔和纳孔的复合网络水凝胶基质，即得组分A；
(2)将生物相容性高分子与EDC·HCl、NHS在水溶液(pH 4.5～7.5)或DMSO中反应，之后加入乙醇或乙醚淬灭反应，离心收集沉淀并用冰乙醇或冰乙醚洗涤，然后将沉淀冷冻干燥，得到生物粘附活性分子；使用时，将生物粘附活性分子溶于水配置成质量浓度为0.5～5％的溶液，即得组分B；
(3)组分A与组分B按质量比1:0.01～0.5进行组合使用，即得一种含多尺度孔道网络的自粘附型止血修复凝胶。
如上所述的制备方法，在步骤(1)中，所述复合多尺度孔道网络水凝胶基质的厚度为0.1～1mm。
如上所述的制备方法，在步骤(2)中，在水溶液或DMSO中反应的 时间为0.5～24h，冰乙醇或冰乙醚为-20℃，洗涤的次数为3～10次；冷冻干燥的时间为24～48h。
使用时，将组分B涂覆于组分A的其中一面用于组织粘附和创伤封合。
如上所述的含多尺度孔道网络的自粘附型止血修复凝胶或由上述制备方法获得的含多尺度孔道网络的自粘附型止血修复凝胶在制备止血和修复材料或组织器官的粘附和创伤封合材料中的应用。
如上所述的应用，优选地，所述组织器官包括但不限于血管、皮肤、肌肉、心脏、胃组织、肺和肝脏等。
如上所述的含多尺度孔道网络的自粘附型止血修复凝胶或由上述制备方法获得的含多尺度孔道网络的自粘附型止血修复凝胶在制备止血材料、伤口敷料、组织粘合剂中的应用。
(三)有益效果
本发明的有益效果是：
本发明提供了一种具有软组织力学匹配的、即时和强大组织粘附力的含多尺度孔道网络的自粘附型止血修复凝胶。可快速、适形且强粘附于湿润组织界面，实现伤口的快速止血封合和修复，其在急性大出血的快速止血封合方面具有很好的临床应用前景。
与传统的双网络粘合型水凝胶相比，本发明提供的含多尺度孔道网络的自粘附型止血修复凝胶引入岛状分布的纳孔水凝胶，既可以改善双网络凝胶基质的刚性并提高韧性，促进其与目标软组织界面的适形接触；同时纳孔水凝胶作为粘附锚点，在生物粘附活性分子桥联下，通过氢键、离子键和共价键与组织表面相互作用，实现凝胶与组织的快速粘合；而且，纳孔水凝胶的存在可以进一步优化粘附界面处的能量耗散，提高粘附强度。含多尺度孔道网络的自粘附型止血修复凝胶表现出良好的生物相容性和生物降解性，可用于医用止血修复领域。
附图说明
图1为本发明组分A的照片；
图2为本发明组分B的照片；
图3为本发明组分A的应力-应变曲线以及力学拉伸照片；
图4为本发明组分A的力学拉伸的表征数据；
图5为本发明组分A的结构表征：i，纳孔水凝胶颗粒分散在水中的光学显微镜照片；ii，微孔水凝胶基质的光学显微镜照片(左)和扫描电镜照片(右)；iii，纳孔水凝胶颗粒(虚线部分)分散在微孔水凝胶基质中，左图为光学显微镜照片，右图为扫描电镜照片；
图6为水凝胶断裂能的计算公式以及示意图；
图7为本发明组分A的断裂能表征：i，复合多孔网络水凝胶基质在拉伸应力下的照片，左边为正常样本，右边为缺口样本；ii，复合多孔网络水凝胶基质的应力应变曲线，上边为缺口样本，下边为正常样本；
图8为生物粘附高分子HA-NHS的核磁共振氢谱(1H-NMR)；
图9为本发明在猪皮上的粘附照片；
图10为本发明用于不同组织的粘附照片；
图11为本发明与不同生物组织的界面粘附强度；
图12为本发明用于比格犬腹主动脉出血的止血效果照片；
图13为本发明用于比格犬腹主动脉出血的修复效果照片；
图14为不同水凝胶的应力-应变曲线；
图15为不同水凝胶的拉伸韧性和弹性模量对比结果；
图16为不同水凝胶对猪皮组织的粘附强度；
图17为本发明与商业化生物胶在猪皮组织的界面粘附强度对比；
图18为爆破压测试装置；
图19为本发明与商业化生物胶封合猪皮组织缺口的爆破压对比；
具体实施方式
本发明开发了一种含多尺度孔道网络的粘性水凝胶，一方面通过引入多尺度孔道网络调节凝胶基质的刚柔性促进凝胶基质与软组织的适形 接触和生物力学匹配，另一方面借助生物粘附分子与组织界面的共价/非共价桥联作用赋予凝胶基质强的界面粘附韧性，两者共同实现凝胶与软组织界面的即时和牢固的粘合，达到伤口的快速止血封合和修复。
为了更好的解释本发明，以便于理解，下面结合附图，通过具体实施方式，对本发明作详细描述。
实施例1
含多尺度孔道网络的自粘附型止血修复凝胶的组分和制备方法，其包括如下步骤：
(1)将3g丙烯酰胺溶于3mL去离子水中配置成质量浓度为50％的溶液，室温搅拌至完全溶解后，加入30mg聚硅氧烷树脂(Irgacure 2959)，继续搅拌直至完全溶解，得到微孔水凝胶制备液；将300mg明胶和200mg壳聚糖加入3.5mL去离子水中，60℃搅拌溶解30min，得到纳孔水凝胶制备液；将以上微孔水凝胶制备液和纳孔水凝胶制备液继续在60℃快速搅拌混匀，然后倒入冷却的模子中；利用明胶-壳聚糖间的静电、氢键等相互作用形成分散均匀的纳孔水凝胶；进一步经365nm紫外光(10W)交联30min，丙烯酰胺聚合形成微孔水凝胶；最终，纳孔水凝胶以岛状形式分布在微孔水凝胶网络中，实现一体构建含微孔和纳孔的复合网络水凝胶基质，厚度为0.5mm，即组分A；
(2)将1g海藻酸钠与EDC·HCl(10mmol，1.92g)、NHS(100mmol，11.5g)在200mL水溶液(pH 6.0)中反应2h，加入800mL乙醇淬灭反应，离心收集沉淀并用-20℃乙醇洗涤3次，然后将沉淀冷冻干燥24h，得到海藻酸钠-NHS酯；使用时，将20mg海藻酸钠-NHS酯溶于去离子水配置成质量浓度为2％的溶液，即组分B；
(3)使用时，将200mg组分B涂覆于1g组分A的其中一面，即得一种含多尺度孔道网络的自粘附型止血修复凝胶。
实施例2
含多尺度孔道网络的自粘附型止血修复凝胶的组分和制备方法，其 包括如下步骤：
(1)将4g羟乙基丙烯酰胺溶于2mL去离子水中配置成质量浓度66.7％的溶液，室温搅拌至完全溶解后，加入40mg Irgacure 2959，继续搅拌直至完全溶解，得到微孔水凝胶制备液；将500mg琼脂和200mg壳聚糖加入3.3mL去离子水中，95℃搅拌溶解20min，得到纳孔水凝胶制备液；将以上微孔水凝胶制备液和纳孔水凝胶制备液继续在95℃快速搅拌混匀，然后倒入冷却的模子中；利用琼脂-壳聚糖间的静电、氢键等相互作用形成分散均匀的纳孔水凝胶；进一步经365nm紫外光(10W)交联30min，羟乙基丙烯酰胺聚合形成微孔水凝胶；最终，纳孔水凝胶以岛状形式分布在微孔水凝胶网络中，实现一体构建含微孔和纳孔的复合网络水凝胶基质，厚度为0.5mm，即组分A；
(2)将2g聚乙二醇羧酸与EDC·HCl(10mmol，1.92g)、NHS(10mmol，1.15g)在40mL DMSO中反应24h，加入40mL乙醚淬灭反应，离心收集沉淀并用-20℃乙醚洗涤3次，然后将沉淀冷冻干燥48h，得到聚乙二醇羧酸-NHS酯；使用时，将200mg聚乙二醇羧酸-NHS酯溶于去离子水配置成质量浓度为20％的溶液，即组分B；
(3)使用时，将500mg组分B涂覆于1g组分A的其中一面，即得一种含多尺度孔道网络的自粘附型止血修复凝胶。
实施例3
含多尺度孔道网络的自粘附型止血修复凝胶的组分和制备方法，其包括如下步骤：
(1)将3g丙烯酸溶于4mL去离子水中配置成质量浓度43％的溶液，室温搅拌至完全溶解后，加入20mgα-酮戊二酸，继续搅拌直至完全溶解，得到微孔水凝胶制备液；将200mg明胶和300mg聚赖氨酸加入2.5mL去离子水中，60℃搅拌溶解30min，冷却至室温得到纳孔水凝胶制备液；将以上微孔水凝胶制备液和纳孔水凝胶制备液继续在60℃快速搅拌混匀，然后倒入冷却的模子中；利用明胶-聚赖氨酸间的静电、氢键等相互 作用形成分散均匀的纳孔水凝胶；进一步经284nm紫外光(10W)交联30min，丙烯酸聚合形成微孔水凝胶；最终，纳孔水凝胶以岛状形式分布在微孔水凝胶网络中，实现一体构建含微孔和纳孔的复合网络水凝胶基质，厚度为0.5mm，即组分A；
(2)将0.5g聚谷氨酸与EDC·HCl(10mmol，1.92g)、NHS(10mmol，1.15g)在10mL DMSO中反应24h，加入40mL乙醇淬灭反应，离心收集沉淀并用-20℃乙醇洗涤3次，然后将沉淀冷冻干燥24h，得到聚谷氨酸-NHS酯；使用时，将100mg聚谷氨酸-NHS酯溶于去离子水配置成质量浓度为10％的溶液，即组分B；
(3)使用时，将1g组分B涂覆于1g组分A的其中一面，即得一种含多尺度孔道网络的自粘附型止血修复凝胶。
实施例4
含多尺度孔道网络的自粘附型止血修复凝胶的组分和制备方法，其包括如下步骤：
(1)将3g羟乙基丙烯酰胺溶于1mL去离子水中配置成质量浓度75％的溶液，室温搅拌至完全溶解后，冰浴下加入14mg过硫酸铵和8μL四甲基乙二胺，继续搅拌直至完全溶解，得到微孔水凝胶制备液；将200mg聚赖氨酸和100mg海藻酸钠加入5.7mL去离子水中，室温搅拌溶解得到纳孔水凝胶制备液；将以上微孔水凝胶制备液和纳孔水凝胶制备液继续在冰浴下快速搅拌混匀，然后倒入模子中；利用聚赖氨酸-海藻酸钠间的静电、氢键等相互作用形成分散均匀的纳孔水凝胶；进一步经热交联，羟乙基丙烯酰胺聚合形成微孔水凝胶；最终，纳孔水凝胶以岛状形式分布在微孔水凝胶网络中，实现一体构建含微孔和纳孔的复合网络水凝胶基质，厚度为0.5mm，即组分A；
(2)将0.4g聚天冬氨酸与EDC·HCl(10mmol，1.92g)、NHS(10mmol，1.15g)在10mL DMSO中反应24h，加入40mL乙醇淬灭反应，离心收集沉淀并用-20℃乙醇洗涤3次，然后将沉淀冷冻干燥24h，得到 聚天冬氨酸-NHS酯；使用时，将100mg聚天冬氨酸-NHS酯溶于去离子水配置成质量浓度为10％的溶液，即组分B；
(3)使用时，将1g组分B涂覆于1g组分A的其中一面，即得一种含多尺度孔道网络的自粘附型止血修复凝胶。
实施例5
含多尺度孔道网络的自粘附型止血修复凝胶的组分和制备方法，其包括如下步骤：
(1)将3g羟乙基丙烯酰胺溶于3mL去离子水中配置成质量浓度50％的溶液，室温搅拌至完全溶解后，加入30mg Irgacure 2959，继续搅拌直至完全溶解，得到微孔水凝胶制备液；将500mg琼脂和200mg聚赖氨酸加入3.3mL去离子水中，95℃搅拌溶解20min，得到纳孔水凝胶制备液；将以上微孔水凝胶制备液和纳孔水凝胶制备液继续在95℃快速搅拌混匀，然后倒入冷却的模子中；利用琼脂-壳聚糖间的静电、氢键等相互作用形成分散均匀的纳孔水凝胶；进一步经365nm紫外光(10W)交联30min，羟乙基丙烯酰胺聚合形成微孔水凝胶；最终，纳孔水凝胶以岛状形式分布在微孔水凝胶网络中，实现一体构建含微孔和纳孔的复合网络水凝胶基质，厚度为0.5mm，即组分A；
(2)将1g透明质酸与EDC·HCl(10mmol，1.92g)、NHS(100mmol，11.5g)在200mL水溶液(pH 5.0)中反应2h，加入800mL乙醇淬灭反应，离心收集沉淀并用-20℃乙醇洗涤3次，然后将沉淀冷冻干燥48h，得到透明质酸-NHS酯；使用时，将50mg透明质酸NHS酯溶于去离子水配置成质量浓度为5％的溶液，即组分B；
(3)使用时，将0.5g组分B涂覆于1g组分A的其中一面，即得一种含多尺度孔道网络的自粘附型止血修复凝胶。
实施例6
选取实施例5中制备的含多尺度孔道网络的自粘附型止血修复凝胶，对其组分的结构和性能进行表征。
组分A的照片如图1所示，组分B的照片如图2所示，将获得的组分A按ASTM D-638标准进行拉伸实验。其拉伸效果和应力-应变曲线如图3所示，断裂伸长率为λ＝12，断裂拉伸强度为544.0±43.5kPa，说明获得的组分A具有较好的抗拉伸效果。进一步计算得到的力学表征结果如图4所示，其弹性模量为106.3±1.7kPa，拉伸韧性达到3.6±0.2MJ/m3，说明组分A具有好的柔性和韧性，契合软组织界面粘附的要求。
进一步对组分A的结构进行表征，结果表明纳孔水凝胶分散在微孔水凝胶基质中，共同形成了含微孔和纳孔的复合多尺度孔道网络水凝胶。如图5所示，i，纳孔水凝胶颗粒分散在水中的光学显微镜照片；ii，微孔水凝胶基质的光学显微镜照片(左)和扫描电镜照片(右)；iii，纳孔水凝胶颗粒(虚线部分)分散在微孔水凝胶基质中，左图为光学显微镜照片，右图为扫描电镜照片。这种特殊的水凝胶结构具有高的断裂能。参照图6的断裂能表征方法，计算得到组分A的断裂能高达9170J/m2(图7)，表明组分A是一种高强度的粘附水凝胶基质。核磁共振氢谱(1H-NMR)用于表征组分B的分子结构，如图8所示，基于HA酰胺键的甲基峰(δ＝1.98，3H)和NHS的亚甲基峰(δ＝2.75，4H)的积分结果，计算得到HA-NHS中HA的NHS接枝率为18.8％。
实施例6
按照组织粘合剂的测试标准(180°剥离测试，ASTM F2256)，测量了本发明实施例5的自粘附型止血修复凝胶与不同组织(皮肤、心脏、胃部、肌肉、肝脏)之间的界面粘附强度。图9呈现的是粘附组织样品的制备步骤，图10为本发明与不同组织(皮肤、心脏、胃、肌肉、肝脏)的粘附效果图，初步表明其具有较好的组织粘附性。进一步，按照图11中i和ii计算最终的粘附强度，结果见图11的iii，具体为皮肤：>1000J/m2；心脏：570J/m2；胃部：450J/m2；肌肉：340J/m2；肝脏：190J/m2。
实施例7
用于比格犬腹主动脉出血的止血修复
选取比格犬，静脉注射戊巴比妥溶液(3％)进行麻醉，腹部剃毛消毒并暴露出腹主动脉，止血钳止血，在腹主动脉处切一个5mm长的切口，如图12中A所示，松开止血钳，观察切口处喷血情况，用本发明实施例5的止血修复凝胶封堵切口部位(如图12中的A)并按压0.5～1min后松开止血钳，结果如图12中B所示，腹主动脉无血液渗漏，凝胶材料与血管表面粘附良好；术后用多普勒超声检测血流表明血管通畅良好；组织学切片染色显示术后无明显炎症反应，凝胶逐渐降解，血管逐渐修复，如图13所示。
对比例1
参照实施例5，分别制备单组分微孔网络水凝胶(单网络：聚羟乙基丙烯酰胺替代聚羟乙基丙烯酰胺/琼脂/聚赖氨酸)、双组分微孔网络水凝胶(双网络：聚羟乙基丙烯酰胺/琼脂替代聚羟乙基丙烯酰胺/琼脂/聚赖氨酸)和本发明的含微孔和纳孔的复合多孔网络水凝胶(按实施例5中获得的材料)，然后对其进行拉伸实验，实验方法同上，其拉伸的应力-应变曲线如图14所示。单组分微孔网络水凝胶(单网络)的断裂伸长率为λ＝22，但其断裂拉伸强度仅为94.6±13.9kPa。相反的，双组分微孔网络水凝胶(双网络)具有高的断裂拉伸强度(721.1±14.8kPa)，但其断裂伸长率仅为λ＝3；本发明的含微孔和纳孔的复合多孔网络水凝胶则同时具有高的断裂拉伸强度(544.0±43.5kPa)和断裂伸长率(λ＝12)。进一步基于应力-应变曲线计算得到拉伸韧性和弹性模量，结果如图15所示，结果说明本发明的含微孔和纳孔的复合多孔网络水凝胶具有最高的拉伸韧性(3.6±0.2MJ/m3)和组织匹配的弹性模量(106.3±1.7kPa)。
对比例2
进一步研究了单组分微孔网络水凝胶(单网络：聚羟乙基丙烯酰胺)、双组分微孔网络水凝胶(双网络：聚羟乙基丙烯酰胺/琼脂)和本发明的含微孔和纳孔的复合多孔网络水凝胶在猪皮组织界面的粘附强度(图16)：
在没有粘合层的情况下，三类水凝胶对猪皮肤的附着力较低；选择HA或HA-NHS作为粘合层，单组分微孔网络水凝胶或双组分微孔网络水凝胶对皮肤组织的界面韧性仍然没有得到改善；只有本发明的含微孔和纳孔的复合多孔网络水凝胶结合HA-NHS作为粘合层，与组织界面形成共价键合才表现出高的界面粘附强度(>1000J/m2)。
对比例3
进一步比较了本发明与临床可用的生物粘合剂(如氰基丙烯酸酯CA和纤维蛋白胶Bioseal)的粘合性能(图17)。众所周知，CA暴露在空气中会立即固化。然而，在界面水存在的情况下，它对猪皮肤的附着力明显降低。一方面，当粘合剂界面受到应力时，CA的刚性结构不能有效地耗散能量。此外，界面水会影响CA与组织界面之间的化学键合。Bioseal是一种基于纤维蛋白的密封剂，由纤维蛋白原和凝血酶以及微量的钙和因子XIII组成，由于其水凝胶基质的低韧性和非共价界面结合，它也表现出非常低的粘附能，对猪皮肤的粘附力较弱。进一步研究了它们在界面血液存在下的组织粘附性能，CA的界面粘附强度明显下降，而Bioseal略有增强。对于本发明，无论是否接触血液，它都表现出高的组织界面粘附性能。
对比例4
进一步，通过爆破压测试比较本发明制备的自粘附型止血修复凝胶组分与临床可用的生物粘合剂(如氰基丙烯酸酯CA和纤维蛋白胶Bioseal)对软组织伤口的封合能力。根据测试标准(ASTM F2392-04)，取猪皮组织并在中心部位制造穿孔(孔径为2mm)，将其作为封合目标组织安装在现有的爆破压测试设备上(如图18)。然后用不同的生物粘合剂粘附密封缺口。当生物粘合剂和组织在短时间内达到牢固粘合，立即进行爆破压力测量。封闭体系中注入磷酸盐缓存溶液(PBS)，体系中的液压逐渐增加。当粘附密封区域出现液体泄漏，压力达到峰值并下降，记录此时的峰值压力为爆破压。结果为本发明实施例5制备的自粘附型 止血修复凝胶组分的爆破压力为694±71mmHg，远高于人类正常收缩压120mmHg；大大高于临床用的生物粘合剂(氰基丙烯酸酯CA：66±8mmHg和纤维蛋白胶Bioseal：56±28mmHg)的爆破压力，结果如图19所示。
以上所述，仅是本发明的较佳实施例而已，并非是对本发明做其它形式的限制，任何本领域技术人员可以利用上述公开的技术内容加以变更或改型为等同变化的等效实施例。但是凡是未脱离本发明技术方案内容，依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与改型，仍属于本发明技术方案的保护范围。

Claims (10)

  1. 一种含多尺度孔道网络的自粘附型止血修复凝胶，其特征在于，其包括组分A和组分B，所述组分A为微孔水凝胶制备液和纳孔水凝胶制备液按质量比1：0.1～1混合形成的复合多尺度孔道网络的水凝胶基质层；所述组分B为一种可桥联凝胶基质和组织界面的生物粘附活性分子水溶液，生物粘附活性分子的质量浓度为0.5～5％。
  2. 如权利要求1所述的含多尺度孔道网络的自粘附型止血修复凝胶，其特征在于，所述微孔水凝胶制备液由质量浓度为10～80％的水溶性合成高分子单体溶液和0.01～1％引发剂混合得到；
    其中，水溶性合成高分子单体为丙烯酰胺、羟乙基丙烯酰胺或丙烯酸中的任一种；所述引发剂为光引发剂或热引发剂，其中光引发剂为Irgacure 2959或α-酮戊二酸；热引发剂为过硫酸铵和四甲基乙二胺。
  3. 如权利要求2所述的含多尺度孔道网络的自粘附型止血修复凝胶，其特征在于，过硫酸铵和四甲基乙二胺按单位为g：mL比为7:4的比例进行添加。
  4. 如权利要求1所述的含多尺度孔道网络的自粘附型止血修复凝胶，其特征在于，所述纳孔水凝胶制备液为质量浓度为1～20％的天然高分子水溶液，天然高分子为琼脂糖、明胶、壳聚糖、聚赖氨酸和海藻酸钠中的任两种或多种组合。
  5. 如权利要求1所述的含多尺度孔道网络的自粘附型止血修复凝胶，其特征在于，所述生物粘附活性分子由生物相容性高分子与EDC·HCl和NHS反应而成，生物粘附活性分子的NHS接枝率，即羧基NHS酯与羧基总数的摩尔比，为10～90％；
    生物相容性高分子为聚谷氨酸、聚天冬氨酸、海藻酸钠、透明质酸或聚乙二醇羧酸中的任一种或两种或多种组合。
  6. 如权利要求5所述的含多尺度孔道网络的自粘附型止血修复凝胶，其特征在于，制备生物粘附活性分子时，生物相容性高分子与EDC·HCl/NHS以质量比为1：10～15在水中进行反应或以质量比为1：5～10 在DMSO中进行反应，生物相容性高分子浓度为5g/L～50g/L。
  7. 如权利要求1-6中任一项所述的含多尺度孔道网络的自粘附型止血修复凝胶的制备方法，其特征在于，其包括如下步骤：
    (1)将水溶性合成高分子单体和引发剂溶于水，得到微孔水凝胶制备液；将另外两种天然高分子在水中原位混合，得到纳孔水凝胶制备液；将微孔水凝胶制备液和纳孔水凝胶制备液混合并快速搅拌混匀，倒入模子中成型；利用天然高分子间的静电、氢键、憎水、配位或者阳离子-π键相互作用形成分散均匀的纳孔水凝胶；进一步经紫外光交联或者热交联，水溶性合成高分子单体聚合形成微孔水凝胶；最终，纳孔水凝胶以岛状形式分布在微孔水凝胶网络中，实现一体构建含微孔和纳孔的复合网络水凝胶基质，即得组分A；
    (2)将生物相容性高分子与EDC·HCl、NHS在水溶液或DMSO中反应，之后加入乙醇或乙醚淬灭反应，离心收集沉淀并用冰乙醇或冰乙醚洗涤，然后将沉淀冷冻干燥，得到生物粘附活性分子；使用时，将生物粘附活性分子溶于水配置成质量浓度为0.5～5％的溶液，即得组分B；
    (3)组分A与组分B按质量比1:0.01～0.5进行组合使用，即得一种含多尺度孔道网络的自粘附型止血修复凝胶。
  8. 如权利要求7所述的制备方法，其特征在于，在步骤(1)中，所述复合多尺度孔道网络水凝胶基质的厚度为0.1～1mm；
    在步骤(2)中，在水溶液或DMSO中反应的时间为0.5～24h，冰乙醇或冰乙醚为-20℃，洗涤的次数为3～10次；冷冻干燥的时间为24～48h。
  9. 如权利要求1-6中任一项所述的含多尺度孔道网络的自粘附型止血修复凝胶或如权利要求7或8所述制备方法制备的含多尺度孔道网络的自粘附型止血修复凝胶在制备止血和修复材料或组织器官的粘附和创伤封合材料中的应用。
  10. 如权利要求1-6中任一项所述的含多尺度孔道网络的自粘附型止血修复凝胶或如权利要求7或8所述制备方法制备的含多尺度孔道网络 的自粘附型止血修复凝胶在制备止血材料、伤口敷料、组织粘合剂中的应用。
PCT/CN2023/101984 2022-10-26 2023-06-21 一种含多尺度孔道网络的自粘附型止血修复凝胶、其制备方法及应用 WO2024087678A1 (zh)

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