CN115746388A - Self-adhesion type hemostasis and repair gel containing multi-scale pore network, and preparation method and application thereof - Google Patents
Self-adhesion type hemostasis and repair gel containing multi-scale pore network, and preparation method and application thereof Download PDFInfo
- Publication number
- CN115746388A CN115746388A CN202211321359.XA CN202211321359A CN115746388A CN 115746388 A CN115746388 A CN 115746388A CN 202211321359 A CN202211321359 A CN 202211321359A CN 115746388 A CN115746388 A CN 115746388A
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- Prior art keywords
- hydrogel
- component
- self
- adhesive
- pore network
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Abstract
The invention relates to a self-adhesive hemostasis repair gel containing a multi-scale pore network, a preparation method and application thereof, wherein the hemostasis repair gel comprises a component A and a component B, wherein the component A is a hydrogel matrix layer of a composite multi-scale pore network formed by mixing a micropore hydrogel preparation solution and a nanoporous hydrogel preparation solution; the component B is a biological adhesion active molecule aqueous solution capable of bridging a gel matrix and a tissue interface. The island-shaped nano-pore hydrogel is introduced into the microporous network hydrogel, so that the rigidity of the gel matrix can be reduced, the conformal contact between the gel matrix and soft tissue can be improved, the combination (hydrogen bond, ionic bond and covalent bond) with the soft tissue surface can be accelerated, and the energy dissipation at the pressed interface can be promoted; meanwhile, the biological adhesion active molecules can realize the bridging of the nanoporous hydrogel and the soft tissue interface. The combined action of the nanoporous hydrogel and the bridging adhesive macromolecules realizes the instant and firm adhesion of the gel and the soft tissue interface, and the rapid hemostasis sealing and repairing of the wound are achieved.
Description
Technical Field
The invention relates to a self-adhesion type hemostasis 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 adhesive, which may form covalent or non-covalent bonds with biological tissue, sealing bleeding wounds and promoting tissue healing. The material can replace the traditional time-consuming operation sealing mode such as suture, staple and the like, and brings convenience for the rapid hemostasis and sealing of wounds. However, for sealing of dynamic gushing bleeding wounds (such as aorta, heart, etc.) in vivo, current adhesive hydrogels are still not ideal in terms of tissue mechanical matching and adhesive strength.
The tissue sealing properties of viscous hydrogels depend on the gel matrix's own toughness and its adhesion to the tissue surface. Clinically available fibrin sealants and polyethylene glycol-based adhesive hydrogels are easily separated from the tissue surface due to their brittle matrix and low tissue adhesive strength. Catechol-based hydrogels can adhere to organic and inorganic surfaces, however the weaker non-covalent adhesion does not achieve strong adhesion to wet tissue surfaces. To cope with these problems, related studies have prepared various adhesive hydrogels, such as a photocurable adhesive hydrogel, a double-network adhesive hydrogel and a double-sided adhesive tape, by introducing a reactive group on a polymer chain or introducing an active ingredient into a hydrogel for tissue surface adhesion. However, the viscous hydrogels currently available still remain to be perfected in terms of both biomechanical matching 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 viscous hydrogel containing the multi-scale pore network, on one hand, the rigid and flexible of the gel matrix are regulated through the multi-scale network to promote the conformal contact and biomechanical matching of the gel matrix and soft tissues, on the other hand, the gel matrix is endowed with strong interfacial adhesion toughness by virtue of the covalent/non-covalent bridging action of the biological adhesion molecules and the tissue interface, and the two jointly realize the instant and firm adhesion of the gel and the soft tissue interface.
Disclosure of Invention
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 channel network, and a preparation method and application thereof.
(II) technical scheme
In order to achieve the purpose, the invention adopts the main technical scheme that:
a self-adhesive hemostasis repair gel containing a multi-scale pore network comprises a component A and a component B, wherein the component A is a microporous hydrogel preparation solution and a nano-pore hydrogel preparation solution, and the mass ratio of the component A to the nano-pore hydrogel preparation solution is 1: 0.1-1, mixing to form a hydrogel matrix layer of the composite multi-scale pore channel network; the component B is a biological adhesion active molecule aqueous solution capable of bridging a gel matrix and a tissue interface, and the mass concentration of the biological adhesion 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.
In use, component B is applied to component a and the side containing component B is applied to the wound tissue interface.
The self-adhesive hemostatic repair gel containing the multi-scale pore network is preferably prepared by mixing a water-soluble synthetic polymer monomer solution with the mass concentration of 10-80% and an initiator;
wherein the water-soluble synthetic high molecular monomer is any one of acrylamide, hydroxyethyl acrylamide or acrylic acid; the initiator is Irgacure 2959 or alpha-ketoglutaric acid as a photoinitiator, or one of ammonium persulfate and tetramethylethylenediamine as a thermal initiator.
Further, preferably, ammonium persulfate and tetramethylethylenediamine are calculated in units of g: the mL ratio is 7:4 was added.
The initiator of the invention refers to a compound which is easily decomposed into free radicals (namely primary free radicals) by light or heat, and is used for initiating the free radical polymerization and copolymerization of vinyl and diene monomers, and can also be used for crosslinking curing and macromolecular crosslinking reaction of unsaturated polyester. 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 preferably comprises a nano-pore hydrogel preparation solution which is a natural polymer aqueous solution with a mass concentration of 1-20%, wherein the natural polymer is a combination of any two or more of agarose, gelatin, chitosan, polylysine and sodium alginate.
In view of the dispersion uniformity of the natural polymer, the mass concentration is preferably 5 to 20%. Wherein, the preferred two-component combination of gelatin and chitosan, agar and chitosan, gelatin and polylysine, sodium alginate and polylysine, and agar and polylysine is 1.
The self-adhesive hemostatic repair gel containing the multi-scale pore network is preferably prepared by reacting biocompatible macromolecules and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC. HCl)/N-hydroxysuccinimide (NHS), wherein the NHS grafting ratio of the bioadhesive active molecules, namely the molar ratio of carboxyl NHS ester to the total number of carboxyl is 10-90%;
the biocompatible polymer is one or the combination of two or more of polyglutamic acid, polyaspartic acid, sodium alginate, hyaluronic acid or polyethylene glycol carboxylic acid.
Wherein EDC & HCl and NHS are further mixed according to a molar ratio of 1 to 10. It should be noted that the grafting ratio is described with respect to the number of carboxyl groups of the biocompatible polymer: namely the number of carboxyl groups of NHS (N-hydroxysuccinimide) on the modification of the biocompatible macromolecule/the total number of carboxyl groups; can pass through 1 H-NMR (hydrogen nuclear magnetic resonance) calculation;
the biocompatible polymer has to carry carboxyl group to modify NHS group, and the modified NHS molecule can react with amino group on the gel matrix and amino group on the tissue surface to form amido bond to realize bridging effect, so the biocompatible polymer is preferably one or the combination of two or more of polyglutamic acid, polyaspartic acid, sodium alginate, hyaluronic acid or polyethylene glycol carboxylic acid.
When preparing the biological adhesion active molecule, the carboxyl of the biological compatibility macromolecule generates NHS active ester under the action of EDC & HCl and NHS, and the activation reaction needs to be carried out in water solution or dimethyl sulfoxide (DMSO) solvent.
Further, the mass ratio of the biocompatible polymer to EDC & HCl/NHS is 1: 10-15 in water or in a mass ratio of 1:5 to 10 react in DMSO, and the concentration of the biocompatible polymer is 5g/L to 50g/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 high-molecular monomer and an initiator in water to obtain a microporous hydrogel preparation solution; mixing the other two natural macromolecules in situ in water to obtain a nanoporous hydrogel preparation solution; mixing the microporous hydrogel preparation solution and the nanoporous hydrogel preparation solution, quickly stirring and uniformly mixing, and pouring into a mold for molding; forming uniformly dispersed nano-pore hydrogel by utilizing the 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-ketoglutaric acid) or thermal crosslinking (the thermal initiator is ammonium persulfate/tetramethylethylenediamine), and polymerizing a water-soluble synthetic high-molecular monomer to form microporous hydrogel; finally, the nano-pore hydrogel is distributed in the microporous hydrogel network in an island form, so that a composite network hydrogel matrix containing micropores and nano-pores is integrally constructed, and the component A is obtained;
(2) Reacting a biocompatible polymer with EDC & HCl and NHS in an aqueous solution (pH 4.5-7.5) or DMSO, adding ethanol or diethyl ether for quenching reaction, centrifugally collecting precipitate, washing the precipitate with glacial ethanol or the glacial diethyl ether, and freeze-drying the precipitate to obtain a biological adhesion active molecule; when in use, the biological adhesion active molecules are dissolved in water to prepare a solution with the mass concentration of 0.5-5 percent, and then the component B is obtained;
(3) The component A and the component B are combined according to the mass ratio of 1.01-0.5 to obtain the self-adhesive hemostatic repair gel containing the multi-scale pore network.
According to 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 aqueous solution or DMSO is 0.5 to 24 hours, the temperature of the glacial ethanol or the glacial ethyl ether is-20 ℃, and the washing times are 3 to 10 times; the freeze drying time is 24-48 h.
In use, component B is applied to one side of component a for tissue adhesion and wound sealing.
The application of 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 in preparing a hemostatic and repair material or an adhesive and wound sealing material of a tissue organ.
For the above applications, preferably, the tissue organ includes, but is 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 is applied to preparation of hemostatic materials, wound dressings and tissue adhesives.
(III) advantageous effects
The beneficial effects of the invention are:
the invention provides a self-adhesive hemostatic repair gel containing a multi-scale pore canal network, which has the advantages of soft tissue mechanics matching, instant and strong tissue adhesion. Can be quickly, conformally and strongly adhered to a moist tissue interface, realizes quick hemostasis sealing and repair of wounds, and has good clinical application prospect in the quick hemostasis sealing of acute major 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 introduces the island-shaped nano-pore hydrogel, so that the rigidity of the double-network gel matrix can be improved, the toughness can be improved, and the conformal contact between the double-network gel matrix and a target soft tissue interface can be promoted; meanwhile, the nanoporous hydrogel is used as an adhesion anchor point, and is interacted with the tissue surface through hydrogen bonds, ionic bonds and covalent bonds under the bridging of biological adhesion active molecules to realize the rapid adhesion of the gel and the tissue; moreover, the presence of the nanoporous hydrogel may further optimize energy dissipation at the adhesion interface, increasing 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 graph of stress-strain curves and mechanical tensile photographs of component A of the present invention;
FIG. 4 is data representative of mechanical stretching for component A of the present invention;
FIG. 5 is a structural characterization of inventive component A: i, light microscopy of nanoporous hydrogel particles dispersed in water; ii, optical microscopy (left) and scanning electron microscopy (right) of the microporous hydrogel matrix; iii, the nanoporous hydrogel particles (dotted line portions) 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 of the breaking energy of hydrogel and a schematic diagram;
FIG. 7 is a fracture energy characterization of inventive component A: i, taking a picture 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, the 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 the NMR spectrum of the bioadhesive polymer HA-NHS ( 1 H-NMR)；
FIG. 9 is a photograph of the adhesion of the present invention to pigskin;
FIG. 10 is a photograph of an adhesion of the present invention to different tissues;
FIG. 11 is a graph of interfacial adhesion strength with different biological tissues according to the invention;
FIG. 12 is a photograph showing the hemostatic effect of the present invention on abdominal aortic hemorrhage of beagle dogs;
FIG. 13 is a photograph showing the repairing effect of the present invention on the hemorrhaging of abdominal aorta of beagle dog;
FIG. 14 is a stress-strain curve for various hydrogels;
FIG. 15 is a comparison of tensile toughness and elastic modulus of different hydrogels;
FIG. 16 is a graph of the adhesion strength of different hydrogels to porcine dermal tissue;
FIG. 17 is a comparison of the interfacial adhesion strength of the present invention and commercial biogel on porcine skin tissue.
Detailed Description
The invention develops a viscous hydrogel containing a multi-scale pore network, on one hand, the rigid flexibility of the gel matrix is regulated by introducing the multi-scale pore network to promote the conformal contact and biomechanical matching of the gel matrix and soft tissues, on the other hand, the gel matrix is endowed with strong interface adhesion toughness by virtue of the covalent/non-covalent bridging action of biological adhesion molecules and tissue interfaces, and the two jointly realize the instant and firm adhesion of the gel and the soft tissue interfaces, thereby achieving the rapid hemostasis sealing and repair of wounds.
For a better understanding of the present invention, reference will now be made in detail to the present embodiments of the invention, which are illustrated in the accompanying drawings.
Example 1
The self-adhesive hemostatic repairing gel containing the multi-scale pore network comprises the following components:
(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 acrylamide is completely dissolved, adding 30mg of polysiloxane resin (Irgacure 2959), and continuously stirring until the acrylamide 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 for 30min at 60 ℃ to obtain a nano-pore hydrogel preparation solution; continuously and rapidly stirring and uniformly mixing the microporous hydrogel preparation solution and the nanoporous hydrogel preparation solution at 60 ℃, and then pouring the mixture into a cooled mold; forming uniformly dispersed nano-pore hydrogel by utilizing the interaction of static electricity, hydrogen bond and the like between the gelatin and the chitosan; further crosslinking for 30min by 365nm ultraviolet light (10W), and polymerizing acrylamide to form microporous hydrogel; finally, the nano-pore hydrogel is distributed in the microporous hydrogel network in an island form, so that a composite network hydrogel matrix containing micropores and nano-pores is integrally constructed, wherein the thickness of the composite network hydrogel matrix is 0.5mm, namely the component A;
(2) Reacting 1g of sodium alginate with EDC & HCl (10mmol, 1.92g) and NHS (100 mmol,11.5 g) in 200mL of aqueous solution (pH 6.0) for 2h, adding 800mL of ethanol to quench the reaction, centrifuging, collecting precipitate, washing the precipitate with ethanol at the temperature of-20 ℃ for 3 times, and freeze-drying the precipitate for 24h to obtain 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 percent, namely a component B;
(3) When in use, 200mg of the component B is coated on one surface of 1g of the component A, and the self-adhesive hemostatic repair gel containing the multi-scale pore network is obtained.
Example 2
The self-adhesive hemostatic repairing gel containing the multi-scale pore network comprises the following components:
(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 of 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, and stirring and dissolving at 95 ℃ for 20min to obtain a nano-pore hydrogel preparation solution; continuously rapidly stirring and uniformly mixing the microporous hydrogel preparation solution and the nanoporous hydrogel preparation solution at 95 ℃, and then pouring the mixture into a cooled mold; forming uniformly dispersed nano-pore hydrogel by utilizing the interaction of static electricity, hydrogen bonds and the like between agar and chitosan; further crosslinking for 30min by 365nm ultraviolet light (10W), and polymerizing hydroxyethyl acrylamide to form microporous hydrogel; finally, the nano-pore hydrogel is distributed in the microporous hydrogel network in an island form, so that a composite network hydrogel matrix containing micropores and nano-pores is integrally constructed, wherein the thickness of the composite network hydrogel matrix is 0.5mm, namely the component A;
(2) Reacting 2g of polyethylene glycol carboxylic acid with EDC & HCl (10mmol, 1.92g) and NHS (10 mmol, 1.15g) in 40mL of DMSO for 24h, adding 40mL of diethyl ether to quench the reaction, centrifuging, collecting the precipitate, washing the precipitate with diethyl ether at the temperature of-20 ℃ for 3 times, and then freezing and drying the precipitate for 48h to obtain 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 the component B is coated on one surface of 1g of the component A, thus obtaining the self-adhesive hemostatic repair gel containing the multi-scale pore network.
Example 3
The components of the self-adhesive hemostatic repair gel containing the multi-scale pore network and the preparation method thereof comprise the following steps:
(1) Dissolving 3g of acrylic acid in 4mL of deionized water to prepare a solution with the mass concentration of 43%, stirring at room temperature until the solution is completely dissolved, adding 20mg of alpha-ketoglutaric acid, and continuously stirring until the solution is completely dissolved to obtain a 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; continuously rapidly stirring and uniformly mixing the microporous hydrogel preparation solution and the nanoporous hydrogel preparation solution at 60 ℃, and then pouring the mixture into a cooled mold; forming uniformly dispersed nano-pore hydrogel by utilizing the interaction of static electricity, hydrogen bonds and the like between the gelatin and the polylysine; further crosslinking for 30min by 284nm ultraviolet light (10W), and polymerizing acrylic acid to form microporous hydrogel; finally, the nano-pore hydrogel is distributed in the microporous hydrogel network in an island form, so that a composite network hydrogel matrix containing micropores and nano-pores is integrally constructed, wherein the thickness of the composite network hydrogel matrix is 0.5mm, namely the component A;
(2) Reacting 0.5g of polyglutamic acid with EDC & HCl (10mmol, 1.92g) and NHS (10 mmol,1.15 g) in 10mL of DMSO for 24 hours, adding 40mL of ethanol to quench the reaction, centrifuging, collecting the precipitate, washing the precipitate with ethanol at the temperature of-20 ℃ for 3 times, and then freeze-drying the precipitate for 24 hours 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 percent, namely a component B;
(3) When in use, 1g of the component B is coated on one surface of 1g of the component A, and the self-adhesive hemostatic repair gel containing the multi-scale pore network is obtained.
Example 4
The self-adhesive hemostatic repairing gel containing the multi-scale pore network comprises the following components:
(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 tetramethylethylenediamine in ice bath, and continuously stirring until the solution is completely dissolved to obtain a microporous hydrogel preparation solution; adding 200mg of polylysine and 100mg of sodium alginate into 5.7mL of deionized water, and stirring at room temperature to dissolve to obtain a nano-pore hydrogel preparation solution; continuously and rapidly stirring and uniformly mixing the microporous hydrogel preparation liquid and the nanoporous hydrogel preparation liquid in an ice bath, and then pouring the mixture into a mold; forming uniformly dispersed nano-pore hydrogel by utilizing the interaction of static electricity, hydrogen bonds and the like between polylysine and sodium alginate; further carrying out thermal crosslinking and hydroxyethyl acrylamide polymerization to form microporous hydrogel; finally, the nano-pore hydrogel is distributed in the microporous hydrogel network in an island form, so that a composite network hydrogel matrix containing micropores and nano-pores is integrally constructed, wherein the thickness of the composite network hydrogel matrix is 0.5mm, namely the component A;
(2) Reacting 0.4g of polyaspartic acid with EDC & HCl (10mmol, 1.92g) and NHS (10 mmol, 1.15g) in 10mL of DMSO for 24 hours, adding 40mL of ethanol to quench the reaction, centrifuging, collecting precipitates, washing the precipitates for 3 times with ethanol at the temperature of-20 ℃, and then freezing and drying the precipitates for 24 hours 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 percent, namely a component B;
(3) When in use, 1g of the component B is coated on one surface of 1g of the component A, and the self-adhesive hemostatic repair gel containing the multi-scale pore network is obtained.
Example 5
The self-adhesive hemostatic repairing gel containing the multi-scale pore network comprises the following components:
(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 of 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, and stirring and dissolving at 95 ℃ for 20min to obtain a nano-pore hydrogel preparation solution; continuously and rapidly stirring and uniformly mixing the microporous hydrogel preparation solution and the nanoporous hydrogel preparation solution at 95 ℃, and then pouring the mixture into a cooled mold; forming uniformly dispersed nano-pore hydrogel by utilizing the interaction of static electricity, hydrogen bonds and the like between the agar and the chitosan; further crosslinking for 30min by 365nm ultraviolet light (10W), and polymerizing hydroxyethyl acrylamide to form microporous hydrogel; finally, the nano-pore hydrogel is distributed in the microporous hydrogel network in an island form, so that a composite network hydrogel matrix containing micropores and nano-pores is integrally constructed, wherein the thickness of the composite network hydrogel matrix is 0.5mm, namely the component A;
(2) Reacting 1g hyaluronic acid with EDC & HCl (10mmol, 1.92g) and NHS (100mmol, 11.5 g) in 200mL aqueous solution (pH 5.0) for 2h, adding 800mL ethanol to quench the reaction, centrifuging to collect precipitate, washing the precipitate with ethanol at the temperature of-20 ℃ for 3 times, and freeze-drying the precipitate for 48h 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 percent, namely a component B;
(3) When in use, 0.5g of the component B is coated on one surface of 1g of the component A, and the self-adhesive hemostatic repair gel containing the multi-scale pore network is obtained.
Example 6
The self-adhesive hemostatic repair gel containing the multi-scale pore network prepared in example 5 was selected, and the structure and properties of the components were characterized.
The photograph of component A is shown in FIG. 1, the photograph of component B is shown in FIG. 2, and the obtained component A was subjected to a tensile test in accordance with ASTM D-638. The tensile effect and the stress-strain curve are shown in fig. 3, the elongation at break is lambda =12, and the tensile strength at break is 544.0 ± 43.5kPa, which indicates that the obtained component a has better tensile effect. The mechanical characterization results obtained by further calculation are shown in FIG. 4, and the elastic modulus is106.3 +/-1.7 kPa, and the tensile toughness reaches 3.6 +/-0.2 MJ/m 3 The component A is proved to have good flexibility and toughness, and the requirements of soft tissue interface adhesion are met.
The structure of the component A is further characterized, and the result shows that the nano-pore hydrogel is dispersed in the microporous hydrogel matrix to jointly form the composite multi-scale pore network hydrogel containing micropores and nano pores. As shown in fig. 5, i, light micrograph of nanoporous hydrogel particles dispersed in water; ii, optical microscopy (left) and scanning electron microscopy (right) of the microporous hydrogel matrix; iii, nanoporous hydrogel particles (dotted line portions) 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. This particular hydrogel structure has a high energy to break. With reference to the fracture energy characterization method of FIG. 6, the fracture energy of component A is calculated to be as high as 9170J/m 2 (FIG. 7), showing that component A is a high strength adhesive hydrogel matrix. Nuclear magnetic resonance hydrogen spectrum ( 1 H-NMR) was used to characterize the molecular structure of component B, and as shown in fig. 8, the NHS grafting ratio of HA in HA-NHS was calculated to be 18.8% based on the integration of the methyl peak of HA amide bond (δ =1.98,3h) and the methylene peak of NHS (δ =2.75,4h).
Example 6
Interfacial adhesion strength between the self-adhesive haemostatic repair gel of example 5 of the invention and different tissues (skin, heart, stomach, muscle, liver) was measured according to the test standards for tissue adhesives (180 ° peel test, ASTM F2256). Fig. 9 shows the preparation steps of the adherent tissue sample, and fig. 10 is a graph of the effect of the invention on adhesion to different tissues (skin, heart, stomach, muscle, liver), which was shown primarily to have better 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 (ii) a Heart: 570J/m 2 (ii) a Stomach: 450J/m 2 (ii) a Muscle: 340J/m 2 (ii) a Liver: 190J/m 2 。
Example 7
Hemostatic repair for biger dog abdominal aortic hemorrhage
Selecting a beagle dog, performing intravenous injection of a pentobarbital solution (3%) for anesthesia, shaving and disinfecting the abdomen, exposing the abdominal aorta, stopping bleeding by using a hemostatic forceps, cutting a 5 mm-long incision at the abdominal aorta, loosening the hemostatic forceps as shown in A in figure 12, observing the blood spraying condition at the incision, plugging the incision part (as shown in A in figure 12) by using the hemostatic repair gel of the embodiment 5 of the invention, and loosening the hemostatic forceps after pressing for 0.5-1 min, wherein the result is shown in B in figure 12, the abdominal aorta has no blood leakage, and the gel material is well adhered to the surface of a blood vessel; the blood flow is detected by Doppler ultrasonic after the operation, which shows that the blood vessel is smooth; histological section staining showed no significant inflammatory response after surgery, gradual degradation of the gel, and gradual repair of the vessels, as shown in fig. 13.
Comparative example 1
Referring to example 5, a one-component microporous network hydrogel (single network: polyhydroxyethylacrylamide instead of polyhydroxyethylacrylamide/agar/polylysine), a two-component microporous network hydrogel (double network: polyhydroxyethylacrylamide/agar instead of polyhydroxyethylacrylamide/agar/polylysine), and a composite porous network hydrogel containing micropores and nanopores according to the present invention (the material obtained in example 5) were prepared, respectively, and then subjected to a tensile test, which was performed as above, and the tensile stress-strain curve thereof is shown in fig. 14. The single component microporous network hydrogel (single network) had an elongation at break of λ =22, but had a tensile strength at break of only 94.6 ± 13.9kPa. In contrast, the bicomponent microporous network hydrogel (double network) has a high tensile strength at break (721.1 ± 14.8 kPa), but its elongation at break is only λ =3; the composite porous network hydrogel containing micropores and nanopores has high breaking tensile strength (544.0 +/-43.5 kPa) and breaking elongation (lambda = 12) at the same time. The tensile toughness and elastic modulus were further calculated based on the stress-strain curve, and the results are shown in FIG. 15, which shows that the composite porous network hydrogel containing micropores and nanopores according to the present invention has the highest tensile toughness (3.6. + -. 0.2 MJ/m) 3 ) And tissue-matched elastic modulus (106.3. + -. 1.7 kPa).
Comparative example 2
The adhesion strength of the single-component microporous network hydrogel (single network: polyhydroxyethylacrylamide), the two-component microporous network hydrogel (double network: polyhydroxyethylacrylamide/agar) and the composite porous network hydrogel containing micropores and nanopores of the present invention at the interface of the pigskin tissue was further investigated (fig. 16):
under the condition of no adhesive layer, the three types of hydrogel have low adhesion to the pigskin; HA or HA-NHS is selected as an adhesive layer, and the interfacial toughness of the single-component microporous network hydrogel or the double-component microporous network hydrogel to skin tissues is still not improved; only if 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, the high interface adhesion strength is shown (>1000J/m 2 )。
Comparative example 3
The adhesion performance of the present invention was further compared to clinically available bioadhesives (e.g. cyanoacrylate CA and fibrin glue Bioseal), fig. 17). It is well known that CA cures immediately upon exposure to air. However, in the presence of interfacial water, its adhesion to swine skin is significantly reduced. On the one hand, the rigid structure of the CA is not able to dissipate energy efficiently 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 with trace amounts of calcium and factor XIII, which also exhibits very low adhesion energy and weak adhesion to porcine skin due to the low toughness and non-covalent interfacial bonding of its hydrogel matrix. Further study on their tissue adhesion properties in the presence of interfacial blood, the interfacial adhesion strength of CA is significantly reduced, while Bioseal is slightly enhanced. For the present invention, it exhibits high tissue interface adhesion properties whether or not in contact with blood.
While the invention has been described with reference to a preferred embodiment, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. However, any simple modification, equivalent change and modification of the above embodiments according to the technical essence of the present invention are within the protection scope of the technical solution of the present invention.
Claims (10)
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 a microporous hydrogel preparation liquid and a nanoporous hydrogel preparation liquid in a mass ratio of 1: 0.1-1, mixing to form a hydrogel matrix layer of the composite multi-scale pore channel network; the component B is a biological adhesion active molecule aqueous solution capable of bridging a gel matrix and a tissue interface, and the mass concentration of the biological adhesion active molecule is 0.5-5%.
2. The self-adhesive hemostatic repair gel containing the multi-scale pore network according to claim 1, wherein the microporous hydrogel preparation solution is prepared by mixing a water-soluble synthetic polymer monomer solution with a 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 alpha-ketoglutaric acid; the thermal initiator is ammonium persulfate and tetramethyl ethylene diamine.
3. The self-adhesive hemostatic repair gel comprising a multiscale pore network according to claim 2, wherein ammonium persulfate and tetramethylethylenediamine are present in the unit of g: the mL ratio was 7.
4. The self-adhesive hemostatic repair gel containing the multi-scale pore network according to claim 1, wherein the nanoporous hydrogel preparation solution is a natural polymer aqueous solution with a mass concentration of 1-20%, and the natural polymer is a combination of any two or more of agarose, gelatin, chitosan, polylysine and sodium alginate.
5. The self-adhesive hemostatic repair gel with a multi-scale pore network according to claim 1, wherein the bioadhesive active molecules are formed by the reaction of biocompatible macromolecules and EDC. HCl and NHS, and the NHS grafting ratio of the bioadhesive active molecules, i.e. the molar ratio of carboxyl NHS ester to the total number of carboxyl, is 10-90%;
the biocompatible polymer is one or the combination of two or more of polyglutamic acid, polyaspartic acid, sodium alginate, hyaluronic acid or polyethylene glycol carboxylic acid.
6. The self-adhesive hemostatic repair gel comprising a multi-scale pore network according to claim 5, wherein when preparing the bioadhesive active molecules, the mass ratio of the biocompatible polymer to EDC. HCl/NHS is 1: 10-15 in water or in a mass ratio of 1: 5-10 react in DMSO, and the concentration of the biocompatible polymer is 5-50 g/L.
7. The method for preparing the self-adhesive hemostatic repair gel containing the multiscale pore network according to any one of claims 1-6, comprising the steps of:
(1) Dissolving a water-soluble synthetic high-molecular monomer and an initiator in water to obtain a microporous hydrogel preparation solution; mixing the other two natural macromolecules in situ in water to obtain a nanoporous hydrogel preparation solution; mixing the microporous hydrogel preparation solution and the nanoporous hydrogel preparation solution, quickly stirring and uniformly mixing, and pouring into a mold for molding; forming uniformly dispersed nano-pore hydrogel by utilizing the electrostatic, hydrogen bond, hydrophobic, coordination or cation-pi bond interaction among natural macromolecules; further carrying out ultraviolet crosslinking or thermal crosslinking, and polymerizing the water-soluble synthetic high-molecular monomer to form the microporous hydrogel; finally, the nano-pore hydrogel is distributed in the microporous hydrogel network in an island form, so that a composite network hydrogel matrix containing micropores and nano-pores is integrally constructed, and the component A is obtained;
(2) Reacting a biocompatible polymer with EDC & HCl and NHS in an aqueous solution or DMSO, adding ethanol or diethyl ether for quenching reaction, centrifugally collecting precipitate, washing the precipitate with glacial ethanol or glacial diethyl ether, and freeze-drying the precipitate to obtain a biological adhesion active molecule; when in use, the biological adhesion active molecules are dissolved in water to prepare a solution with the mass concentration of 0.5-5 percent, and then the component B is obtained;
(3) The component A and the component B are combined according to the mass ratio of 1.01-0.5 to obtain the self-adhesive hemostatic repair gel containing the multi-scale pore network.
8. The method of claim 7, wherein in step (1), the thickness of the composite multi-scale pore network hydrogel matrix is 0.1 to 1mm;
in the step (2), the reaction time in aqueous solution or DMSO is 0.5 to 24 hours, the temperature of the glacial ethanol or the glacial ethyl ether is minus 20 ℃, and the washing times are 3 to 10 times; the freeze drying time is 24-48 h.
9. Use of the self-adhesive haemostatic repair gel comprising a multi-scale pore network according to any of claims 1-6 or the self-adhesive haemostatic repair gel comprising a multi-scale pore network prepared by the method of claim 7 or 8 in the preparation of a haemostatic and repair material or an adhesive and wound sealing material for a tissue or organ.
10. Use of the self-adhesive haemostatic repair gel comprising a multi-scale pore network according to any of claims 1-6 or the self-adhesive haemostatic repair gel comprising a multi-scale pore network prepared by the preparation method according to claim 7 or 8 for preparing haemostatic 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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| US20120156164A1 (en) * | 2009-09-04 | 2012-06-21 | Ajou University Industry-Academic Cooperation Foundation | In situ-forming hydrogel for tissue adhesives and biomedical use thereof |
| CN108714241A (en) * | 2018-06-22 | 2018-10-30 | 中国人民解放军陆军军医大学第附属医院 | Application of the SIS epoxy resins in preparing hemostatic material |
| CN113599566A (en) * | 2021-08-30 | 2021-11-05 | 重庆市沙坪坝区中智医谷研究院 | Hydrophobic polymer hemostatic repair material, preparation method and application thereof |
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| US20120156164A1 (en) * | 2009-09-04 | 2012-06-21 | Ajou University Industry-Academic Cooperation Foundation | In situ-forming hydrogel for tissue adhesives and biomedical use thereof |
| CN108714241A (en) * | 2018-06-22 | 2018-10-30 | 中国人民解放军陆军军医大学第附属医院 | Application of the SIS epoxy resins in preparing hemostatic material |
| CN113599566A (en) * | 2021-08-30 | 2021-11-05 | 重庆市沙坪坝区中智医谷研究院 | Hydrophobic polymer hemostatic repair material, preparation method and application thereof |
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