CN115746388B - Self-adhesion hemostatic repair gel containing multi-scale pore network, and preparation method and application thereof - Google Patents
Self-adhesion hemostatic repair gel containing multi-scale pore network, and preparation method and application thereof Download PDFInfo
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- CN115746388B CN115746388B CN202211321359.XA CN202211321359A CN115746388B CN 115746388 B CN115746388 B CN 115746388B CN 202211321359 A CN202211321359 A CN 202211321359A CN 115746388 B CN115746388 B CN 115746388B
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Abstract
The invention relates to a self-adhesive hemostatic repair gel containing a multi-scale pore network, a preparation method and application thereof, wherein the hemostatic repair gel comprises a component A and a component B, and the component A is a hydrogel matrix layer of a composite multi-scale pore network formed by mixing microporous hydrogel preparation liquid and nano-porous hydrogel preparation liquid; the component B is a bioadhesive active molecular aqueous solution capable of bridging gel matrix and tissue interface. The island-shaped distributed nano-pore hydrogel is introduced into the micro-pore network hydrogel, so that the rigidity of the gel matrix can be reduced, the conformal contact between the gel matrix and soft tissues is improved, the combination (hydrogen bond, ionic bond and covalent bond) with the surfaces of the soft tissues is accelerated, and the energy dissipation at a pressed interface is promoted; meanwhile, the bioadhesive active molecules can realize bridging of the interface between the nano-pore hydrogel and the soft tissue. The combined action of the nano-pore hydrogel and the bridging adhesive polymer realizes the instant and firm adhesion of the gel and the soft tissue interface, and achieves the rapid hemostasis sealing and repair of wounds.
Description
Technical Field
The invention relates to 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.
Background
Hydrogels have an aqueous network similar to the natural extracellular matrix and have been widely used in biomedical fields such as cell culture, drug delivery, wound dressing and tissue reconstruction. More recently, hydrogels have been further rendered tissue adherent, can form covalent or non-covalent bonds with biological tissue, seal bleeding wounds and promote tissue healing. The application of the material can replace the traditional time-consuming operation sealing mode such as suture, staple and the like, and brings convenience for rapid hemostasis and sealing of wounds. However, for sealing of in vivo gushing dynamic bleeding wounds (e.g., aorta, heart, etc.), current adhesive hydrogels remain undesirable in terms of tissue mechanics match and adhesion strength.
The tissue sealing properties of a viscous hydrogel depend on the self-toughness of the gel matrix and its adhesion to the tissue surface. Clinically useful fibrin sealants and polyethylene glycol-based adhesive hydrogels are easily separated from tissue surfaces due to their brittle matrix and low tissue adhesive strength. Catechol-based hydrogels can adhere to organic and inorganic surfaces, however weak non-covalent adhesion does not allow strong adhesion to wet tissue surfaces. To cope with these problems, related studies have prepared various adhesive hydrogels such as photo-curable adhesive hydrogels, dual-network adhesive hydrogels and double-sided tapes by introducing reactive groups on polymer chains or introducing active ingredients in hydrogels for tissue surface adhesion. However, currently available viscous hydrogels remain to be perfected in terms of both biomechanical match and interfacial adhesion toughness. In particular, mismatched mechanical properties can affect the normal systolic and diastolic function of the target vessel and heart, thereby affecting the therapeutic effect after sealing. Therefore, the invention develops the adhesive hydrogel containing the multi-scale pore canal network, on one hand, the rigidity and flexibility of the gel matrix are regulated through the multi-scale network to promote the conformal contact and biomechanical matching of the gel matrix and the soft tissue, and on the other hand, the adhesive hydrogel endows the gel matrix with strong interfacial adhesion toughness by means of covalent/non-covalent bridging action of bioadhesion molecules and tissue interfaces, and the adhesive hydrogel and the soft tissue interface realize instant and firm adhesion of the gel and the soft tissue interfaces together.
Disclosure of Invention
First, the technical problem to be solved
In order to solve the problems in the prior art, the invention provides a self-adhesive hydrogel containing a multi-scale pore network, a preparation method and application thereof, wherein the self-adhesive hydrogel containing the multi-scale pore network is used for constructing a multi-scale gel matrix, reducing the rigidity of the gel matrix, improving the conformal contact between the gel matrix and soft tissues, and realizing the instant, effective and firm adhesion of gel and soft tissue interfaces based on the bridging effect of bioadhesive molecules.
(II) technical scheme
In order to achieve the above purpose, the main technical scheme adopted by the invention comprises the following steps:
the self-adhesive hemostatic repair gel containing the multi-scale pore network comprises a component A and a component B, wherein the component A is microporous hydrogel preparation liquid and nano-porous hydrogel preparation liquid according to the mass ratio of 1:0.1 to 1 of a hydrogel matrix layer of a composite multi-scale pore network formed by mixing; the component B is a bioadhesive active molecule aqueous solution capable of bridging gel matrix and tissue interface, and the mass concentration of the bioadhesive active molecule is 0.5-5%.
Preferably, the component A and the component B are used in combination according to the mass ratio of 1:0.01-0.5.
In use, component B is applied to component A and the side containing component B is applied to the wound tissue interface.
The self-adhesion hemostatic repair gel containing the multi-scale pore network is preferably prepared by mixing a water-soluble synthetic high-molecular monomer solution with the mass concentration of 10-80% with an initiator;
wherein the water-soluble synthetic high molecular monomer is any one of acrylamide, hydroxyethyl acrylamide or acrylic acid; the initiator is any one of a photoinitiator Irgacure 2959 or alpha-ketoglutaric acid, or a thermal initiator ammonium persulfate and tetramethyl ethylenediamine.
Further, preferably, ammonium persulfate and tetramethyl ethylenediamine are in units of g: the mL ratio is 7: 4.
The initiator of the invention refers to a compound which is easy to be decomposed into free radicals (namely primary free radicals) by light or heat, is used for initiating the free radical polymerization and copolymerization reaction of vinyl and diene monomers, and can also be used for the crosslinking curing of unsaturated polyester and the crosslinking reaction of high polymers. The mass concentration of the initiator in the microporous hydrogel preparation solution is 0.01-1%.
The self-adhesive hemostatic repair gel containing the multi-scale pore network as described above, preferably, the nano-pore hydrogel preparation solution is a natural polymer aqueous solution with a mass concentration of 1-20%, and the natural polymer is any two or more of agarose, gelatin, chitosan, polylysine and sodium alginate.
In view of the uniformity of dispersion of natural polymers, the mass concentration is preferably 5 to 20%. Wherein, the weight ratio of the two components of gelatin and chitosan, agar and chitosan, gelatin and polylysine, sodium alginate and polylysine and agar and polylysine is preferably 1:0.4-2.
Preferably, the self-adhesion hemostatic repair gel containing the multi-scale pore network is characterized in that the bioadhesive active molecules are prepared by reacting biocompatible polymers with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC.HCl)/N-hydroxysuccinimide (NHS), and the NHS grafting ratio of the bioadhesive active molecules, namely the molar ratio of carboxyl NHS ester to the total number of carboxyl groups, is 10-90%;
the biocompatible polymer is any one or the combination of two or more of polyglutamic acid, polyaspartic acid, sodium alginate, hyaluronic acid or polyethylene glycol carboxylic acid.
Wherein, further, the EDC & HCl and NHS are mixed according to the mol ratio of 1:1-10. The grafting ratio is described with respect to the number of carboxyl groups of the biocompatible polymer: i.e., the number of carboxyl groups/total number of carboxyl groups of NHS (N-hydroxysuccinimide) modified by the biocompatible polymer; can pass through 1 H-NMR (nuclear magnetic resonance hydrogen spectrum) calculation;
the biocompatible polymer must have carboxyl to modify NHS group, and the modified NHS molecule can react with amino groups on gel matrix and amino groups on tissue surface to form amide bond, so as to implement bridging action, so that the biocompatible polymer is preferably any one or two or more of polyglutamic acid, polyaspartic acid, sodium alginate, hyaluronic acid or polyethylene glycol carboxylic acid.
When preparing the bioadhesive active molecules, carboxyl groups of the biocompatible polymers generate NHS active esters under the action of EDC and HCl and NHS, and the activation reaction is required to be carried out in an aqueous solution or a dimethyl sulfoxide (DMSO) solvent.
Further, the mass ratio of the biocompatible polymer to EDC/HCl/NHS is 1:10 to 15 in water or with a mass ratio of 1: 5-10 in DMSO, the concentration of biocompatible polymer is 5 g/L-50 g/L.
The preparation method of the self-adhesive hemostatic repair gel containing the multi-scale pore network comprises the following steps:
(1) Dissolving a water-soluble synthetic polymer monomer and an initiator in water to obtain a microporous hydrogel preparation solution; mixing the other two natural polymers in situ in water to obtain a nano-pore hydrogel preparation solution; mixing the microporous hydrogel preparation solution and the nano-porous hydrogel preparation solution, rapidly stirring, uniformly mixing, pouring into a mold, and molding; forming uniformly dispersed nano-pore hydrogel by utilizing electrostatic, hydrogen bond, hydrophobic, coordination or cation-pi bond interaction among natural macromolecules; further carrying out ultraviolet crosslinking (the photoinitiator is Irgacure 2959 or alpha-ketoglutarate) or thermal crosslinking (the thermal initiator is ammonium persulfate/tetramethyl ethylenediamine), and polymerizing the water-soluble synthetic high molecular monomer to form microporous hydrogel; finally, the nano-pore hydrogel is distributed in a microporous hydrogel network in an island-shaped form, so that a composite network hydrogel matrix containing micropores and nano-pores is integrally constructed, and the component A is obtained;
(2) Reacting biocompatible polymer with EDC, HCl and NHS in water solution (pH 4.5-7.5) or DMSO, adding ethanol or diethyl ether for quenching reaction, centrifuging to collect precipitate, washing with glacial ethanol or glacial diethyl ether, and freeze-drying the precipitate to obtain bioactive adhesion molecules; when in use, the bioadhesive active molecules are dissolved in water to prepare a solution with the mass concentration of 0.5-5%, so as to obtain the component B;
(3) The component A and the component B are combined according to the mass ratio of 1:0.01-0.5 to obtain the self-adhesive hemostatic repair gel containing the multi-scale pore network.
In the preparation method, in the step (1), the thickness of the composite multi-scale pore network hydrogel matrix is 0.1-1 mm.
In the preparation method, in the step (2), the reaction time in the water solution or DMSO is 0.5-24 h, the temperature of the glacial ethanol or the glacial diethyl ether is-20 ℃, and the washing times are 3-10 times; the freeze drying time is 24-48 h.
In use, component B is applied to one of the sides of component a for tissue adhesion and wound closure.
The self-adhesive hemostatic repair gel containing the multi-scale pore network or the self-adhesive hemostatic repair gel containing the multi-scale pore network obtained by the preparation method is applied to the preparation of hemostatic and repair materials or adhesion and wound sealing materials of tissues and organs.
For the applications described above, preferably, the tissue organs include, but are not limited to, blood vessels, skin, muscle, heart, stomach tissue, lung, liver, and the like.
The self-adhesive hemostatic repair gel containing the multi-scale pore network or the self-adhesive hemostatic repair gel containing the multi-scale pore network obtained by the preparation method can be applied to the preparation of hemostatic materials, wound dressings and tissue adhesives.
(III) beneficial effects
The beneficial effects of the invention are as follows:
the invention provides a self-adhesive hemostatic repair gel containing a multi-scale pore network, which has the advantages of soft tissue mechanical matching, instant and strong tissue adhesion. Can be quickly and conformally adhered to a moist tissue interface, realizes quick hemostasis sealing and repair of wounds, and has good clinical application prospect in the aspect of quick hemostasis sealing of acute massive hemorrhage.
Compared with the traditional double-network adhesive hydrogel, the self-adhesive hemostatic repair gel containing the multi-scale pore network provided by the invention is introduced into the island-shaped distributed nano-pore hydrogel, so that the rigidity and toughness of the double-network gel matrix can be improved, and the conformal contact between the self-adhesive hemostatic repair gel and a target soft tissue interface can be promoted; meanwhile, the nano-pore hydrogel is used as an adhesion anchor point, and under the bridging of bioadhesive active molecules, the gel and the tissue are quickly adhered through the interaction of hydrogen bonds, ionic bonds and covalent bonds with the tissue surface; moreover, the existence of the nano-pore hydrogel can further optimize the energy dissipation at the adhesion interface and improve the adhesion strength. The self-adhesive hemostatic repair gel containing the multi-scale pore network has good biocompatibility and biodegradability, and can be used in the field of medical hemostatic repair.
Drawings
FIG. 1 is a photograph of component A of the present invention;
FIG. 2 is a photograph of component B of the present invention;
FIG. 3 is a photograph of stress-strain curves and mechanical stretching of component A of the present invention;
FIG. 4 is data representing the mechanical stretching of component A of the present invention;
FIG. 5 is a structural representation of component A of the present invention: i, optical microscopy pictures of nano-porous hydrogel particles dispersed in water; ii, optical microscopy (left) and scanning electron microscopy (right) of the microporous hydrogel matrix; iii, the nano-porous hydrogel particles (dotted line part) are dispersed in the microporous hydrogel matrix, the left image is an optical microscope photograph, and the right image is a scanning electron microscope photograph;
FIG. 6 is a calculation formula and schematic diagram of the breaking energy of hydrogel;
FIG. 7 is a representation of the break energy of component A according to the invention: i, a photograph of the composite porous network hydrogel matrix under tensile stress, wherein the left side is a normal sample, and the right side is a notch sample; ii, a stress-strain curve of the composite porous network hydrogel matrix, wherein the upper side is a notch sample, and the lower side is a normal sample;
FIG. 8 shows hydrogen nuclear magnetic resonance spectrum of bioadhesive polymer HA-NHS 1 H-NMR)；
FIG. 9 is a photograph showing the adhesion of the present invention to pigskin;
FIG. 10 is a photograph of an adhesive of the present invention for different tissues;
FIG. 11 is a graph of interfacial adhesion strength of the present invention with different biological tissues;
FIG. 12 is a photograph showing the hemostatic effect of the present invention for abdominal aortic hemorrhage in beagle dogs;
FIG. 13 is a photograph showing the effect of the present invention on restoration of abdominal aortic hemorrhage in beagle dogs;
FIG. 14 is a stress-strain curve for different hydrogels;
FIG. 15 is a graph showing the tensile toughness and elastic modulus comparison results for different hydrogels;
FIG. 16 is a graph showing the adhesion strength of various hydrogels to pigskin tissue;
FIG. 17 is a comparison of interfacial adhesion strength of the present invention with commercial bio-gels in pigskin tissue.
Detailed Description
The invention develops a viscous hydrogel containing a multi-scale pore network, which on one hand promotes the conformal contact and biomechanical matching of a gel matrix and soft tissues by introducing the multi-scale pore network to regulate the rigidity and flexibility of the gel matrix, and on the other hand, endows the gel matrix with strong interface adhesion toughness by means of covalent/non-covalent bridging action of bioadhesive molecules and tissue interfaces, and the two realize instant and firm adhesion of the gel and the soft tissue interfaces together so as to achieve rapid hemostatic sealing and repairing of wounds.
The invention will be better explained by the following detailed description of the embodiments with reference to the drawings.
Example 1
The components and the preparation method of the self-adhesive hemostatic repair gel containing the multi-scale pore network comprise the following steps:
(1) Dissolving 3g of acrylamide in 3mL of deionized water to prepare a solution with the mass concentration of 50%, stirring at room temperature until the solution is completely dissolved, adding 30mg of polysiloxane resin (Irgacure 2959), and continuously stirring until the solution is completely dissolved to obtain a microporous hydrogel preparation solution; adding 300mg of gelatin and 200mg of chitosan into 3.5mL of deionized water, stirring and dissolving at 60 ℃ for 30min to obtain a nano-pore hydrogel preparation solution; the microporous hydrogel preparation solution and the nano-porous hydrogel preparation solution are continuously and rapidly stirred and uniformly mixed at 60 ℃, and then poured into a cooled mold; forming uniformly dispersed nano-pore hydrogel by utilizing interactions such as static electricity, hydrogen bonds and the like between gelatin and chitosan; further crosslinking by 365nm ultraviolet light (10W) for 30min, and polymerizing acrylamide to form microporous hydrogel; finally, the nano-pore hydrogel is distributed in a microporous hydrogel network in an island-shaped form, so that a composite network hydrogel matrix containing micropores and nano-pores is integrally constructed, and the thickness of the composite network hydrogel matrix is 0.5mm, namely the component A;
(2) 1g of sodium alginate was reacted with EDC. HCl (10 mmol,1.92 g), NHS (100 mmol,11.5 g) in 200mL of aqueous solution (pH 6.0) for 2h, quenched with 800mL of ethanol, collected by centrifugation and washed 3 times with ethanol at-20℃and then freeze-dried for 24h to give sodium alginate-NHS ester; when in use, 20mg of sodium alginate-NHS ester is dissolved in deionized water to prepare a solution with the mass concentration of 2%, namely a component B;
(3) When in use, 200mg of component B is coated on one surface of 1g of component A, thus obtaining the self-adhesive hemostatic repair gel containing the multi-scale pore network.
Example 2
The components and the preparation method of the self-adhesive hemostatic repair gel containing the multi-scale pore network comprise the following steps:
(1) Dissolving 4g of hydroxyethyl acrylamide in 2mL of deionized water to prepare a solution with the mass concentration of 66.7%, stirring at room temperature until the solution is completely dissolved, adding 40mg Irgacure 2959, and continuously stirring until the solution is completely dissolved to obtain a microporous hydrogel preparation solution; adding 500mg of agar and 200mg of chitosan into 3.3mL of deionized water, stirring and dissolving at 95 ℃ for 20min to obtain a nano-pore hydrogel preparation solution; the microporous hydrogel preparation solution and the nano-porous hydrogel preparation solution are continuously and rapidly stirred and uniformly mixed at 95 ℃, and then poured into a cooled mold; forming uniformly dispersed nano-pore hydrogel by utilizing interactions such as static electricity, hydrogen bonds and the like between agar-chitosan; further crosslinking by 365nm ultraviolet light (10W) for 30min, and polymerizing hydroxyethyl acrylamide to form microporous hydrogel; finally, the nano-pore hydrogel is distributed in a microporous hydrogel network in an island-shaped form, so that a composite network hydrogel matrix containing micropores and nano-pores is integrally constructed, and the thickness of the composite network hydrogel matrix is 0.5mm, namely the component A;
(2) 2g of polyethylene glycol carboxylic acid was reacted with EDC. HCl (10 mmol,1.92 g), NHS (10 mmol,1.15 g) in 40mL of DMSO for 24 hours, quenched with 40mL of diethyl ether, collected by centrifugation and washed 3 times with diethyl ether at-20℃and then the precipitate was freeze-dried for 48 hours to give polyethylene glycol carboxylic acid-NHS ester; when in use, 200mg of polyethylene glycol carboxylic acid-NHS ester is dissolved in deionized water to prepare a solution with the mass concentration of 20%, namely a component B;
(3) When in use, 500mg of component B is coated on one surface of 1g of component A, thus obtaining the self-adhesive hemostatic repair gel containing the multi-scale pore network.
Example 3
The components and the preparation method of the self-adhesive hemostatic repair gel containing the multi-scale pore network comprise the following steps:
(1) 3g of acrylic acid is dissolved in 4mL of deionized water to prepare a solution with the mass concentration of 43%, after the solution is stirred at room temperature until the solution is completely dissolved, 20mg of alpha-ketoglutaric acid is added, and the stirring is continued until the solution is completely dissolved, so as to obtain microporous hydrogel preparation solution; adding 200mg of gelatin and 300mg of polylysine into 2.5mL of deionized water, stirring and dissolving at 60 ℃ for 30min, and cooling to room temperature to obtain a nano-pore hydrogel preparation solution; the microporous hydrogel preparation solution and the nano-porous hydrogel preparation solution are continuously and rapidly stirred and uniformly mixed at 60 ℃, and then poured into a cooled mold; forming uniformly dispersed nano-pore hydrogel by utilizing interactions such as static electricity, hydrogen bonds and the like between gelatin and polylysine; further crosslinking by 284nm ultraviolet light (10W) for 30min, and polymerizing acrylic acid to form microporous hydrogel; finally, the nano-pore hydrogel is distributed in a microporous hydrogel network in an island-shaped form, so that a composite network hydrogel matrix containing micropores and nano-pores is integrally constructed, and the thickness of the composite network hydrogel matrix is 0.5mm, namely the component A;
(2) 0.5g of polyglutamic acid is reacted with EDC.HCl (10 mmol,1.92 g) and NHS (10 mmol,1.15 g) in 10mL of DMSO for 24h, the reaction is quenched by adding 40mL of ethanol, the precipitate is collected by centrifugation and washed 3 times with ethanol at-20 ℃, and then the precipitate is freeze-dried for 24h to obtain polyglutamic acid-NHS ester; when in use, 100mg of polyglutamic acid-NHS ester is dissolved in deionized water to prepare a solution with the mass concentration of 10%, namely a component B;
(3) When in use, 1g of component B is coated on one surface of 1g of component A, thus obtaining the self-adhesive hemostatic repair gel containing the multi-scale pore network.
Example 4
The components and the preparation method of the self-adhesive hemostatic repair gel containing the multi-scale pore network comprise the following steps:
(1) Dissolving 3g of hydroxyethyl acrylamide in 1mL of deionized water to prepare a solution with the mass concentration of 75%, stirring at room temperature until the solution is completely dissolved, adding 14mg of ammonium persulfate and 8 mu L of tetramethyl ethylenediamine in ice bath, and continuously stirring until the solution is completely dissolved to obtain a microporous hydrogel preparation solution; adding 200. 200mg polylysine and 100mg sodium alginate into 5.7mL of deionized water, and stirring and dissolving at room temperature to obtain a nano-pore hydrogel preparation solution; the microporous hydrogel preparation liquid and the nano-porous hydrogel preparation liquid are continuously and rapidly stirred and uniformly mixed under ice bath, and then poured into a mold; forming uniformly dispersed nano-pore hydrogel by utilizing interactions such as static electricity, hydrogen bonds and the like between polylysine and sodium alginate; further thermally crosslinking, and polymerizing hydroxyethyl acrylamide to form microporous hydrogel; finally, the nano-pore hydrogel is distributed in a microporous hydrogel network in an island-shaped form, so that a composite network hydrogel matrix containing micropores and nano-pores is integrally constructed, and the thickness of the composite network hydrogel matrix is 0.5mm, namely the component A;
(2) 0.4g of polyaspartic acid is reacted with EDC.HCl (10 mmol,1.92 g) and NHS (10 mmol,1.15 g) in 10mL of DMSO for 24h, the reaction is quenched by adding 40mL of ethanol, the precipitate is collected by centrifugation and washed 3 times with ethanol at-20 ℃, and then the precipitate is freeze-dried for 24h to obtain polyaspartic acid-NHS ester; when in use, 100mg of polyaspartic acid-NHS ester is dissolved in deionized water to prepare a solution with the mass concentration of 10%, namely a component B;
(3) When in use, 1g of component B is coated on one surface of 1g of component A, thus obtaining the self-adhesive hemostatic repair gel containing the multi-scale pore network.
Example 5
The components and the preparation method of the self-adhesive hemostatic repair gel containing the multi-scale pore network comprise the following steps:
(1) Dissolving 3g of hydroxyethyl acrylamide in 3mL of deionized water to prepare a solution with the mass concentration of 50%, stirring at room temperature until the solution is completely dissolved, adding 30mg Irgacure 2959, and continuously stirring until the solution is completely dissolved to obtain a microporous hydrogel preparation solution; adding 500mg of agar and 200mg of polylysine into 3.3mL of deionized water, stirring and dissolving at 95 ℃ for 20min to obtain a nano-pore hydrogel preparation solution; the microporous hydrogel preparation solution and the nano-porous hydrogel preparation solution are continuously and rapidly stirred and uniformly mixed at 95 ℃, and then poured into a cooled mold; forming uniformly dispersed nano-pore hydrogel by utilizing interactions such as static electricity, hydrogen bonds and the like between agar-chitosan; further crosslinking by 365nm ultraviolet light (10W) for 30min, and polymerizing hydroxyethyl acrylamide to form microporous hydrogel; finally, the nano-pore hydrogel is distributed in a microporous hydrogel network in an island-shaped form, so that a composite network hydrogel matrix containing micropores and nano-pores is integrally constructed, and the thickness of the composite network hydrogel matrix is 0.5mm, namely the component A;
(2) 1g of hyaluronic acid was reacted with EDC. HCl (10 mmol,1.92 g), NHS (100 mmol,11.5 g) in 200mL of aqueous solution (pH 5.0) for 2 hours, quenched by adding 800mL of ethanol, collected by centrifugation and washed 3 times with ethanol at-20 ℃, and then the precipitate was freeze-dried for 48 hours to obtain hyaluronic acid-NHS ester; when in use, 50mg of hyaluronic acid NHS ester is dissolved in deionized water to prepare a solution with the mass concentration of 5%, namely a component B;
(3) When in use, 0.5g of component B is coated on one surface of 1g of component A, thus obtaining the self-adhesive hemostatic repair gel containing the multi-scale pore network.
Example 6
The self-adhesive hemostatic repair gel containing the multi-scale pore network prepared in example 5 was selected and its components were characterized for structure and performance.
A photograph of the component A is shown in FIG. 1, a photograph of the component B is shown in FIG. 2, and the obtained component A is subjected to a tensile test according to ASTM D-638. The tensile effect and the stress-strain curve are shown in fig. 3, the elongation at break is lambda=12, the tensile strength at break is 544.0 +/-43.5 kPa, and the obtained component A has better tensile effect. The further calculated mechanical characterization result is shown in figure 4, the elastic modulus is 106.3+/-1.7 kPa, and the tensile toughness reaches 3.6+/-0.2 MJ/m 3 The component A has good flexibility and toughness, and meets the requirement of soft tissue interface adhesion.
Further characterizing the structure of the component A, the result shows that the nano-pore hydrogel is dispersed in the micro-pore hydrogel matrix to jointly form the composite multi-scale pore channel network hydrogel containing micro-pores and nano-pores. As shown in fig. 5, i, an optical micrograph of the nanoporous hydrogel particles dispersed in water; ii, optical microscopy (left) and scanning electron microscopy (right) of the microporous hydrogel matrix; iii, the nano-porous hydrogel particles (dotted line part) are dispersed in the microporous hydrogel matrix, the left image is an optical micrograph, and the right image is a scanning electron micrograph. This particular hydrogel structure has a high energy to break. Referring to the method of characterization of the break energy of FIG. 6, the break energy of component A was calculated to be as high as 9170J/m 2 (FIG. 7) shows that component A is a high strength adhesive hydrogel matrix. Nuclear magnetic resonance hydrogen spectrum [ ] 1 H-NMR) for characterizing the molecular structure of component B, as shown in FIG. 8, a radicalThe integration of the methyl peak of HA amide bond (δ= 1.98,3H) and the methylene peak of NHS (δ= 2.75,4H) gives a calculated NHS grafting of HA in HA-NHS of 18.8%.
Example 6
The interfacial adhesion strength between the self-adhesive hemostatic repair gel of example 5 of the present invention and different tissues (skin, heart, stomach, muscle, liver) was measured according to the tissue adhesive test standard (180 ° peel test, ASTM F2256). Fig. 9 shows the preparation steps of the adhered tissue samples, and fig. 10 is a graph showing the adhesion effect of the present invention to different tissues (skin, heart, stomach, muscle, liver), which shows primarily that the present invention has good tissue adhesion. Further, the final adhesion strength was calculated according to i and ii in fig. 11, and the result is shown in iii of fig. 11, specifically skin:>1000J/m 2 the method comprises the steps of carrying out a first treatment on the surface of the And (3) heart: 570J/m 2 The method comprises the steps of carrying out a first treatment on the surface of the Stomach: 450J/m 2 The method comprises the steps of carrying out a first treatment on the surface of the Muscle: 340J/m 2 The method comprises the steps of carrying out a first treatment on the surface of the Liver: 190J/m 2 。
Example 7
Hemostatic repair for abdominal aortic hemorrhage of beagle dogs
Selecting beagle dogs, intravenous injection of pentobarbital solution (3%) for anesthesia, shaving and sterilizing the abdomen and exposing the abdominal aorta, hemostat hemostasis, cutting a 5mm long incision at the abdominal aorta, as shown in a in fig. 12A, loosening the hemostat, observing the blood spraying condition at the incision, plugging the incision part (as shown in a in fig. 12A) by using the hemostatic repairing gel of the embodiment 5 of the invention, and loosening the hemostat after pressing for 0.5-1 min, wherein as shown in a result in a fig. 12B, the abdominal aorta has no blood leakage, and the gel material has good adhesion with the surface of a blood vessel; the blood flow is detected by Doppler ultrasound after operation, which shows that the blood vessel is smooth; histological section staining showed no apparent inflammatory reaction after surgery, gradual degradation of the gel and gradual repair of the blood vessels, as shown in fig. 13.
Comparative example 1
Referring to example 5, a single-component microporous network hydrogel (single network: polyhydroxyethyl acrylamide instead of polyhydroxyethyl acrylamide/agar/polylysine) and a two-component microporous network hydrogel (double network: polyhydroxyethyl acrylamide/agar instead of polyhydroxyethyl acrylamide/agar) were prepared, respectivelyPolylysine) and the microporous and nanoporous composite porous network hydrogel of the present invention (material obtained as in example 5) were then subjected to a tensile test, the tensile stress-strain curves of which are shown in fig. 14, as described above. The elongation at break of the monocomponent microporous network hydrogel (monocomponent network) is λ=22, but its tensile strength at break is only 94.6±13.9kPa. In contrast, a two-component microporous network hydrogel (dual network) has a high tensile strength at break (721.1 ±14.8 kPa), but an elongation at break of only λ=3; the composite porous network hydrogel containing micropores and nanopores has high tensile strength at break (544.0 +/-43.5 kPa) and elongation at break (lambda=12). Further, the tensile toughness and the elastic modulus are calculated based on the stress-strain curve, and the result is shown in FIG. 15, which shows that the microporous and nanoporous composite porous network hydrogel of the invention has the highest tensile toughness (3.6+ -0.2 MJ/m) 3 ) Modulus of elasticity (106.3.+ -. 1.7 kPa) matched to tissue.
Comparative example 2
The adhesion strength of the single-component microporous network hydrogel (single network: polyhydroxyethyl acrylamide), the two-component microporous network hydrogel (dual network: polyhydroxyethyl acrylamide/agar) and the microporous and nanoporous composite porous network hydrogel of the invention at pigskin tissue interface was further studied (fig. 16):
in the absence of an adhesive layer, the three types of hydrogels have low adhesion to pigskin; the HA or the HA-NHS is selected as an adhesive layer, and the interface toughness of the single-component microporous network hydrogel or the two-component microporous network hydrogel on skin tissues is not improved yet; only the composite porous network hydrogel containing micropores and nanopores of the invention is combined with HA-NHS as an adhesive layer to form covalent bonding with a tissue interface, so that the composite porous network hydrogel shows high interfacial adhesion strength [ (]>1000J/m 2 )。
Comparative example 3
The adhesive properties of the present invention were further compared to clinically useful bioadhesives (e.g., cyanoacrylate CA and fibrin glue Bioseal), FIG. 17. It is well known that CA immediately cures upon exposure to air. However, in the presence of interfacial water, its adhesion to porcine skin is significantly reduced. On the one hand, the rigid structure of CA is not able to effectively dissipate energy when the adhesive interface is stressed. In addition, interfacial water can affect the chemical bonding between CA and the tissue interface. Bioseal is a fibrin-based sealant consisting of fibrinogen and thrombin and trace amounts of calcium and factor XIII, which also exhibits very low adhesion to porcine skin due to its low toughness and non-covalent interfacial bonding of the hydrogel matrix. Further studies were made on their tissue adhesion properties in the presence of interfacial blood, with a marked decrease in the interfacial adhesion strength of CA, while Bioseal was slightly enhanced. For the present invention, it exhibits high tissue interfacial adhesion performance, whether or not in contact with blood.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention in any way, and any person skilled in the art may make modifications or alterations to the above disclosed technical content to equivalent embodiments. However, any simple modification, equivalent variation and variation of the above embodiments according to the technical substance of the present invention still fall within the protection scope of the technical solution of the present invention.
Claims (7)
1. The self-adhesive hemostatic repair gel containing the multi-scale pore network is characterized by comprising a component A and a component B, wherein the component A is microporous hydrogel preparation liquid and nano-porous hydrogel preparation liquid according to the mass ratio of 1: 0.1-1 of a hydrogel matrix layer of a composite multi-scale pore network formed by mixing; the component B is a bioadhesive active molecule aqueous solution capable of bridging gel matrix and tissue interface, and the mass concentration of the bioadhesive active molecule is 0.5-5%;
the microporous hydrogel preparation solution is prepared by mixing a water-soluble synthetic high polymer monomer solution with the mass concentration of 10-80% and 0.01-1% of an initiator;
wherein the water-soluble synthetic high molecular monomer is any one of acrylamide, hydroxyethyl acrylamide or acrylic acid; the initiator is a photoinitiator or a thermal initiator, wherein the photoinitiator is Irgacure 2959 or a-ketoglutaric acid; the thermal initiator is ammonium persulfate and tetramethyl ethylenediamine;
the nano-pore hydrogel preparation liquid is a natural polymer aqueous solution with the mass concentration of 1-20%, and the natural polymer is any two or more of agarose, gelatin, chitosan, polylysine and sodium alginate;
the bioadhesive active molecules are formed by reacting biocompatible polymers with EDC, HCl and NHS, and the NHS grafting rate of the bioadhesive active molecules, namely the molar ratio of carboxyl NHS ester to the total number of carboxyl groups, is 10-90%;
the biocompatible polymer is any one or two or more of polyglutamic acid, polyaspartic acid, sodium alginate, hyaluronic acid or polyethylene glycol carboxylic acid.
2. The self-adhesive hemostatic repair gel containing a network of multi-scale tunnels of claim 1, wherein ammonium persulfate and tetramethyl ethylenediamine are in units of g: the addition was made at a ratio of 7:4 mL.
3. The self-adhesive hemostatic repair gel containing a network of multi-scale channels according to claim 1, wherein the mass ratio of biocompatible polymer to edc.hcl/NHS is 1: 10-15 in water or with a mass ratio of 1: 5-10 in DMSO, the concentration of the biocompatible polymer is 5 g/L-50 g/L.
4. A method of preparing a self-adhesive hemostatic repair gel comprising a network of multi-scale tunnels according to any one of claims 1-3, comprising the steps of:
(1) Dissolving a water-soluble synthetic polymer monomer and an initiator in water to obtain a microporous hydrogel preparation solution; mixing the other two natural polymers in situ in water to obtain a nano-pore hydrogel preparation solution; mixing the microporous hydrogel preparation solution and the nano-porous hydrogel preparation solution, rapidly stirring, uniformly mixing, pouring into a mold, and molding; forming uniformly dispersed nano-pore hydrogel by utilizing electrostatic, hydrogen bond, hydrophobic, coordination or cation-p bond interaction among natural macromolecules; further ultraviolet light crosslinking or thermal crosslinking, and polymerizing the water-soluble synthetic high molecular monomer to form microporous hydrogel; finally, the nano-pore hydrogel is distributed in a microporous hydrogel network in an island-shaped form, so that a composite network hydrogel matrix containing micropores and nano-pores is integrally constructed, and the component A is obtained;
(2) Reacting biocompatible polymer with EDC, HCl and NHS in water solution or DMSO, adding ethanol or diethyl ether for quenching reaction, centrifuging to collect precipitate, washing with glacial ethanol or diethyl ether, and freeze drying to obtain bioactive molecule; when in use, the bioadhesive active molecules are dissolved in water to prepare a solution with the mass concentration of 0.5-5%, so that the component B is obtained;
(3) The component A and the component B are combined according to the mass ratio of 1:0.01-0.5 to obtain the self-adhesive hemostatic repair gel containing the multi-scale pore network.
5. The method according to claim 4, wherein in the step (1), the thickness of the composite multi-scale channel network hydrogel matrix is 0.1-1 mm;
in the step (2), the reaction time in aqueous solution or DMSO is 0.5-24 h, the temperature of the glacial ethanol or the glacial diethyl ether is-20 ℃, and the washing times are 3-10 times; the freeze drying time is 24-48 h.
6. Use of a self-adhesive hemostatic repair gel comprising a network of multi-scale channels according to any one of claims 1-3 or a self-adhesive hemostatic repair gel comprising a network of multi-scale channels prepared according to the method of preparation of claim 4 or 5 for the preparation of hemostatic and repair materials or adhesion and wound closure materials for tissue and organs.
7. Use of a self-adhesive hemostatic repair gel comprising a network of multi-scale channels according to any one of claims 1-3 or prepared according to the preparation method of claims 4 or 5 for preparing hemostatic materials, wound dressings, tissue adhesives.
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| PCT/CN2023/101984 WO2024087678A1 (en) | 2022-10-26 | 2023-06-21 | Self-adhesive hemostatic repair gel with multi-scale pore network, and preparation method therefor and use thereof |
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| CN113599566A (en) * | 2021-08-30 | 2021-11-05 | 重庆市沙坪坝区中智医谷研究院 | A kind of hydrophobic polymer hemostatic repair material, its preparation method and application |
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