WO2021223756A1 - 具有抗炎及促修复功能的可注射水凝胶及其制备方法和在心脏修复中的应用 - Google Patents

具有抗炎及促修复功能的可注射水凝胶及其制备方法和在心脏修复中的应用 Download PDF

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WO2021223756A1
WO2021223756A1 PCT/CN2021/092474 CN2021092474W WO2021223756A1 WO 2021223756 A1 WO2021223756 A1 WO 2021223756A1 CN 2021092474 W CN2021092474 W CN 2021092474W WO 2021223756 A1 WO2021223756 A1 WO 2021223756A1
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injectable hydrogel
hydrogel
inflammatory
repair
acid
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PCT/CN2021/092474
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English (en)
French (fr)
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王云兵
胡成
杨立
刘文琦
邵南
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四川大学
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Priority to CN202180004209.3A priority Critical patent/CN114585396B/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061—Use of materials characterised by their function or physical properties
    • A61L26/008—Hydrogels or hydrocolloids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061—Use of materials characterised by their function or physical properties
    • A61L26/0066—Medicaments; Biocides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/41—Anti-inflammatory agents, e.g. NSAIDs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/62—Encapsulated active agents, e.g. emulsified droplets
    • A61L2300/626—Liposomes, micelles, vesicles

Definitions

  • This application relates to the technical field of biomedical materials, in particular to an injectable hydrogel with anti-inflammatory and repair-promoting functions, its preparation method and its application in cardiac repair.
  • MI Myocardial infarction
  • HF heart failure
  • endanger the life and heart of the patient Failure is one of the main causes of morbidity and mortality worldwide.
  • Heart failure affects approximately 40 million people worldwide.
  • the overall prevalence rate in developed countries is 1-2%, and it rises to more than 10% in people over 65 years of age. Even with the current best treatment, the rate of rehospitalization for heart failure is as high as 24.5%. About 20% of patients with heart failure die within 1 year after diagnosis, and about 50% of patients with heart failure die within 5 years after diagnosis.
  • Acute myocardial infarction is one of the most common critical illnesses in cardiology, which seriously threatens the lives of patients.
  • the main difficulty in the treatment of myocardial infarction lies in the limited ability of the heart tissue to regenerate itself, that is, the irreversibility of heart damage and the extremely short survival time of the heart tissue after ischemia.
  • Myocardial cell death or myocardial tissue necrosis due to insufficient blood flow leading to reduced oxygen supply to the infarcted tissue will destroy the collagen fibers connected between the myocardial cells, weaken the extracellular matrix, and cause the ventricular wall to thin and expand.
  • the granulation tissue formed by fibroblasts, endothelial cells and stem/progenitor cells of the infarcted tissue is gradually replaced by extracellular matrix, and finally scar tissue is formed.
  • the newly created scar tissue lacks the contractile properties required by the heart to pump blood, leading to heart failure.
  • Heart failure can be caused by many factors, but the most common risk factors are high blood pressure, coronary artery disease (blocked heart arteries), diabetes, obesity, smoking and genetics.
  • the three methods for clinical treatment of heart failure include heart transplantation, interventional therapy of medical equipment (including ventricular assist devices), and drug therapy.
  • Heart transplantation is still the only effective treatment for replacing an infarcted heart with a healthy donor heart.
  • injectable hydrogel has attracted attention because it can be injected near the infarcted heart tissue to provide mechanical support for the damaged heart tissue.
  • the injectable hydrogel itself can also be used as a drug carrier to deliver drugs or active therapeutic substances to the infarct site in situ, thereby achieving effective regeneration and repair of the cardiac infarction site.
  • injectable hydrogels have shown great potential in cardiac tissue repair. For example, calcium alginate hydrogel is used for MI treatment by providing mechanical support for the ventricular wall, and has achieved certain therapeutic effects.
  • smart response hydrogels can significantly improve the treatment effect of patients by achieving precise on-demand drug release in diseased sites, and can also reduce the frequency of administration and reduce the side effects of drugs. It is foreseeable that with the maturity of precision drug delivery technology, the clinical transformation of smart response hydrogels will be greatly promoted.
  • multifunctional microenvironment-responsive hydrogels is not only of great significance for improving the treatment of myocardial infarction, but also broadens the way for the application of smart-responsive hydrogels in the field of myocardial infarction treatment.
  • the purpose of this application is to provide an anti-inflammatory and repair-promoting function
  • the preparation method of the injectable hydrogel and its application in heart injury repair can effectively solve the problems of poor effect of existing heart failure treatment methods, and the hydrogel provided by the present application has simple preparation methods and low cost advantage.
  • An injectable hydrogel with anti-inflammatory and pro-repair functions forms a gel through the interaction of the functional groups of the polymer and the adjacent hydroxyl groups of the polymer, and responds to acidic conditions and/or Under the condition of active oxygen, the hydrogel will disintegrate after the functional groups of the polymer release the interaction with the adjacent hydroxyl groups of the polymer.
  • the injectable hydrogel is loaded with at least one of a hydrophilic drug, a hydrophobic drug, and an extracellular matrix.
  • the polymer containing functional groups is sodium alginate containing phenylboronic acid groups, chitosan, chitosan quaternary ammonium salt, polylysine, polyethyleneimine, gelatin, sodium alginate, transparent At least one of acid, heparin, carboxymethyl cellulose, dextran, methyl cellulose, starch, and cyclodextrin.
  • the phenylboronic acid group interacts with the o-hydroxy group to form a gel through the boronic ester bond.
  • the boronic ester bond breaks and the gel dissociates.
  • the injectable hydrogel is in a gel state under weakly alkaline conditions. Under acidic conditions and/or active oxygen conditions, the gel dissociates, and the hydrophilic drugs, hydrophobic drugs, and extracellular substances in the gel dissociate. Matrix etc. release.
  • Phenylboronic acid groups and ortho-hydroxyl groups can exist in the same polymer, that is, the same polymer contains multiple phenylboronic acid groups and ortho-hydroxyl groups at the same time. Phenylboronic acid groups and ortho-hydroxyl groups can also exist in different polymers. That is, one polymer contains multiple phenylboronic acid groups, and the other polymer contains multiple ortho-hydroxyl groups.
  • Acidic conditions and weakly alkaline conditions are a relative concept.
  • gel can be formed under neutral conditions.
  • the number of phenylboronic acid groups and o-hydroxyl Gel is formed under alkaline conditions.
  • natural polymers should be understood to include their modified products, that is, chitosan includes unmodified chitosan, and also includes modified products of chitosan.
  • chitosan quaternary ammonium salt, poly Lysine, polyethyleneimine, gelatin, sodium alginate, hyaluronic acid, heparin, carboxymethyl cellulose, dextran, methyl cellulose, starch, and cyclodextrin also include their corresponding modified products , The modified product itself does not adversely affect the formation and dissociation of the gel.
  • the ortho-hydroxy-containing polymer is at least one of sodium alginate, polyvinyl alcohol, sodium alginate, hyaluronic acid, dextran, and starch.
  • the injectable hydrogel is loaded with extracellular matrix
  • hydrophilic drugs and/or hydrophobic drugs are hydrophilic drugs and/or hydrophobic drugs.
  • the injectable hydrogel is loaded with at least an extracellular matrix, and at the same time is loaded with at least one of a hydrophilic drug and a hydrophobic drug.
  • the substances loaded in the injectable hydrogel are selectively loaded in the hydrogel according to actual treatment needs.
  • the extracellular matrix is at least one of collagen, non-collagen, elastin, proteoglycan, and aminoglycan.
  • the extracellular matrix is recombinant humanized collagen.
  • the extracellular matrix is at least one of recombinant type I humanized collagen and recombinant type III humanized collagen.
  • the recombinant type I humanized collagen and the recombinant type III humanized collagen contain amino acid sequence fragments that can be combined with cellular integrins.
  • the recombinant type I humanized collagen and recombinant type III humanized collagen are amino acid sequence fragments that can be combined with cellular integrins encoded by specific type genes of human collagen prepared by DNA recombination technology.
  • the extracellular matrix is recombinant type III humanized collagen.
  • the hydrophobic drug is at least one of naproxen, surivastatin, curcumin, and aspirin.
  • the hydrophobic drug is carried in the injectable hydrogel with an amphiphilic polymer as a carrier.
  • the injectable hydrogel is loaded with curcumin and recombinant humanized collagen.
  • the injectable hydrogel is loaded with curcumin and recombinant type III humanized collagen.
  • the application also provides a hydrogel for repairing heart damage, and the hydrogel is the above-mentioned injectable hydrogel that acts on the damaged part of the heart.
  • the curcumin is used to reduce inflammation at the injured site, and the recombinant human-derived type III collagen promotes the regeneration of cardiomyocytes.
  • the interaction between the two can effectively promote the proliferation and growth of cardiomyocytes and repair heart damage.
  • the application also provides a hydrogel for treating heart failure, the hydrogel being the above-mentioned injectable hydrogel acting on the heart disease site.
  • the application also provides a hydrogel for treating myocardial infarction, and the hydrogel is the injectable hydrogel that acts on the site of myocardial infarction.
  • the application also provides the application of the injectable hydrogel with anti-inflammatory and repair-promoting functions in the repair of heart damage.
  • the application also provides the application of the injectable hydrogel with anti-inflammatory and repair promoting functions in the treatment of heart failure.
  • the application also provides the application of the injectable hydrogel with anti-inflammatory and promoting repair functions in the treatment of myocardial infarction.
  • the present application also provides a method for repairing heart damage, which applies the injectable hydrogel to the damaged part of the heart.
  • the application also provides a method for treating heart failure, which applies the injectable hydrogel to the heart disease site.
  • the application also provides a method for repairing heart damage, in which the injectable hydrogel is injected into the heart disease site.
  • This application also provides a method for treating heart failure, in which the injectable hydrogel is injected into the site of myocardial infarction.
  • This application also provides a method for treating myocardial infarction, in which the injectable hydrogel is injected into the site of myocardial infarction.
  • the application also provides a method for preparing the injectable hydrogel, including:
  • At least one of a hydrophilic drug, an extracellular matrix, and a hydrophobic drug, a first polymer, and an ortho-hydroxy-containing polymer are mixed to prepare the injectable hydrogel.
  • the ortho-hydroxyl-containing polymer contains multiple ortho-hydroxyl groups, and after the first polymer is mixed with the ortho-hydroxyl-containing polymer, a gel can be formed without additional pH adjustment.
  • the first polymer is prepared by reacting in the presence of a condensing agent and a catalyst using any one of the following combinations of raw materials:
  • phenylboronic acid groups in the polymer can be carried out through the amidation reaction of amino and carboxyl groups, or the esterification reaction of hydroxyl and carboxyl groups. Therefore, one of the polymers and phenylboronic acid contains amino or hydroxyl groups, and the other Those containing carboxyl groups can introduce phenylboronic acid groups into the polymer.
  • Condensing agent is 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, O-benzotriazole-tetramethylurea hexafluorophosphate, benzotriazole hexafluorophosphate At least one of -1-yl-oxytripyrrolidinyl phosphorus and dicyclohexylcarbodiimide, the catalyst is 4-dimethylaminopyridine, N-hydroxysuccinimide, 1-hydroxybenzotriazide At least one of azoles.
  • the preparation method of the first polymer is as follows:
  • the side chain of the first polymer contains phenylboronic acid groups.
  • the number of phenylboronic acid groups in the polymer will affect the formation and dissociation of the gel, and the amount of phenylboronic acid groups introduced should be appropriate.
  • the mass ratio of the amino or hydroxyl-containing polymer, the carboxyl-containing phenylboronic acid, the condensing agent, and the catalyst is 7:(4-5):(2-3):1; or the carboxyl-containing polymer,
  • the mass ratio of amino or hydroxyl phenylboronic acid, condensing agent, and catalyst is 7:(4-5):(2-3):1.
  • the preparation method of the first polymer is as follows:
  • Hydrophilic drugs, extracellular matrix and other substances with better water solubility can be directly mixed with the first polymer and polymers containing ortho-hydroxy groups to obtain injectable hydrogels. After special treatment is required for hydrophobic drugs, A polymer and a polymer containing ortho-hydroxyl groups are mixed.
  • the hydrophobic drug uses an amphiphilic polymer as a carrier to prepare drug-loaded nanomicelles, and the drug-loaded nanomicelles are mixed with the first polymer and the polymer containing ortho-hydroxy groups to prepare the hydrophobic drug.
  • the injectable hydrogel of the drug uses an amphiphilic polymer as a carrier to prepare drug-loaded nanomicelles, and the drug-loaded nanomicelles are mixed with the first polymer and the polymer containing ortho-hydroxy groups to prepare the hydrophobic drug.
  • amphiphilic polymer and the hydrophobic drug are self-assembled to prepare drug-loaded nanomicelles, the amphiphilic polymer is the drug carrier, and the hydrophobic drug is the encapsulated drug.
  • the amphiphilic polymer is composed of a hydrophilic segment and a hydrophobic segment.
  • the hydrophilic segment is polyethylene glycol, polyvinyl ether, polyvinyl alcohol, polyethylene imine, polyvinylpyrrolidone, and polypropylene phthalamide.
  • the hydrophobic segment is at least one of polypropylene oxide, polystyrene, polysiloxane, polybutadiene, polymethyl methacrylate, polymethyl acrylate, and polybutyl acrylate.
  • the preparation of the drug-loaded nanomicelles includes:
  • amphiphilic polymer and the hydrophobic drug are dissolved in a benign solvent and slowly added dropwise to water under continuous stirring. After dialysis, a drug-loaded nanomicelle solution with a concentration of 1-2 mg/mL is obtained.
  • the benign solvent is at least one of DMSO, DMF, methanol, and acetone. Further preferably, the benign solvent is DMSO and/or acetone.
  • amphiphilic polymer and the hydrophobic drug are dissolved in a benign solvent, slowly added dropwise to deionized water under continuous stirring, stirred for 3-6 hours, and dialyzed in deionized water to prepare drug-loaded nanometers.
  • Micelles are dissolved in a benign solvent, slowly added dropwise to deionized water under continuous stirring, stirred for 3-6 hours, and dialyzed in deionized water to prepare drug-loaded nanometers.
  • the mass ratio of the amphiphilic polymer to the hydrophobic drug is 4-8:1.
  • amphiphilic polymer and the hydrophobic drug are dissolved in a benign solvent, slowly added dropwise to deionized water under continuous stirring, stirred for 4 hours, and dialyzed in deionized water to prepare drug-loaded nanomicelles ,
  • the mass ratio of amphiphilic polymer and hydrophobic drug is 5:1.
  • the aqueous solution of the first polymer is mixed with the aqueous solution of the ortho-hydroxy-containing polymer to obtain the injectable hydrogel, and the aqueous solution of the first polymer contains a hydrophilic drug, an extracellular matrix, and a drug-carrying agent.
  • the mass concentration of the first polymer is 0.5-10% w/v.
  • the aqueous solution of the first polymer is mixed with the aqueous solution of the ortho-hydroxy-containing polymer to obtain the injectable hydrogel, and the aqueous solution of the first polymer contains a hydrophilic drug, an extracellular matrix, and a drug-carrying agent.
  • the mass concentration of the first polymer is 0.5 to 5% w/v.
  • the aqueous solution of the first polymer is mixed with the aqueous solution of the ortho-hydroxy-containing polymer to obtain the injectable hydrogel, and the aqueous solution of the first polymer contains a hydrophilic drug, an extracellular matrix, and a drug-carrying agent.
  • the mass concentration of the first polymer is 0.5-3% w/v.
  • the mass concentration of the hydrophilic drug in the first polymer aqueous solution is 1 to 1000 ⁇ g mg/mL.
  • the mass concentration of the hydrophilic drug in the first polymer aqueous solution is 1 to 500 ⁇ g mg/mL.
  • the mass concentration of the extracellular matrix in the first polymer aqueous solution is 1 to 6 mg/mL.
  • the mass concentration of the extracellular matrix in the first polymer aqueous solution is 1 to 3 mg/mL.
  • the mass concentration of the drug-loaded nanomicelles in the first polymer aqueous solution is 30-200 ⁇ g/mL.
  • the mass concentration of the drug-loaded nanomicelles in the first polymer aqueous solution is 50-150 ⁇ g/mL.
  • the mass concentration of the ortho-hydroxyl-containing polymer is 0.5-10% w/v.
  • the mass concentration of the ortho-hydroxy-containing polymer is 0.5 to 5% w/v.
  • the mass concentration of the ortho-hydroxy-containing polymer is 0.5-3% w/v.
  • the volume ratio of the first polymer aqueous solution to the ortho-hydroxy-containing polymer aqueous solution is 1:0.5-1.5.
  • the volume ratio of the first polymer aqueous solution to the ortho-hydroxy-containing polymer aqueous solution is 1:0.8 to 1.2.
  • the volume ratio of the first polymer aqueous solution to the ortho-hydroxy-containing polymer aqueous solution is 1:1.
  • the aqueous solution of the first polymer is mixed with the aqueous solution of the ortho-hydroxy-containing polymer to obtain the injectable hydrogel, and the aqueous solution of the first polymer contains a hydrophilic drug, an extracellular matrix, and a drug-carrying agent. At least one of the nanomicelles.
  • the mass concentration of the first polymer is 1% w/v
  • the mass concentration of polyvinyl alcohol is 1% w/v.
  • An aqueous polymer solution and an aqueous polyvinyl alcohol solution are mixed in equal volumes to obtain a hydrogel.
  • the amino group-containing polymer is at least one of chitosan, chitosan quaternary ammonium salt, polylysine, polyethyleneimine, and gelatin.
  • the carboxyl group-containing polymer is at least one of sodium alginate, hyaluronic acid, heparin, and carboxymethyl cellulose.
  • the hydroxyl-containing polymer is at least one of starch, cellulose (methyl cellulose), dragon gum, konjac gum, gum arabic, lignin, dextran, and cyclodextrin.
  • the ortho-hydroxyl-containing polymer is at least one of polyvinyl alcohol, sodium alginate, hyaluronic acid, dextran, and starch.
  • the ortho-hydroxyl-containing polymer is polyvinyl alcohol.
  • the carboxyl-containing phenylboronic acid is 4-carboxyphenylboronic acid, 2-carboxyphenylboronic acid, 3-carboxyphenylboronic acid, 4-carboxy-3-fluorophenylboronic acid, 3-carboxy-4-fluorophenylboronic acid, 5- At least one of carboxy-2-chlorophenylboronic acid and 4-carboxy-2-chlorophenylboronic acid;
  • the amino-containing phenylboronic acid is 4-aminophenylboronic acid, 2-aminophenylboronic acid, 3-aminophenylboronic acid, 3-carbamoylphenylboronic acid, 3-amino-4-fluorophenylboronic acid, 3-amino-4-methyl At least one of phenylboronic acid;
  • the hydroxyl-containing phenylboronic acid is 4-hydroxyphenylboronic acid, 3-fluoro-4-hydroxyphenylboronic acid, 2-fluoro-3-hydroxyphenylboronic acid, 2-fluoro-5-hydroxyphenylboronic acid, 3-hydroxy-4-chlorobenzene At least one of boric acid and 3-fluoro-4-hydroxyphenylboronic acid.
  • the extracellular matrix is at least one of collagen, non-collagen, elastin, proteoglycan, and aminoglycan.
  • Extracellular matrix is different from drugs, as long as the function is to promote cell proliferation, growth, and speed up the repair process.
  • the extracellular matrix is at least one of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), recombinant humanized collagen, and deferoxamine (DFO).
  • bFGF basic fibroblast growth factor
  • VEGF vascular endothelial growth factor
  • DFO deferoxamine
  • the extracellular matrix is recombinant humanized collagen.
  • the hydrophobic drugs are anti-inflammatory drugs, analgesics, angiogenesis drugs, diuretics, angiotensin-converting enzyme inhibitors, ⁇ -receptor blockers, digitalis drugs, aldosterone antagonists, At least one of angiotensin direceptor antagonists, anticoagulants, and antiplatelet drugs.
  • the hydrophobic drug is at least one of naproxen, surivastatin, curcumin, and aspirin.
  • the application also provides an injectable hydrogel with anti-inflammatory and repair-promoting functions prepared by the preparation method.
  • the application also provides a hydrogel for repairing heart damage, and the hydrogel is the above-mentioned injectable hydrogel that acts on the damaged part of the heart.
  • the application also provides a hydrogel for treating heart failure, the hydrogel being the above-mentioned injectable hydrogel acting on the heart disease site.
  • the application also provides a hydrogel for treating myocardial infarction, and the hydrogel is the injectable hydrogel that acts on the site of myocardial infarction.
  • the application also provides the application of the injectable hydrogel with anti-inflammatory and repair-promoting functions in the repair of heart damage.
  • the application also provides the application of the injectable hydrogel with anti-inflammatory and repair promoting functions in the treatment of heart failure.
  • the application also provides the application of the injectable hydrogel with anti-inflammatory and promoting repair functions in the treatment of myocardial infarction.
  • the application also provides a method for repairing heart damage, which applies the injectable hydrogel to the damaged part of the heart.
  • the application also provides a method for treating heart failure, which applies the injectable hydrogel to the heart disease site.
  • This application also provides a method for repairing heart damage, in which the injectable hydrogel is injected into the heart disease site.
  • This application also provides a method for treating heart failure, in which the injectable hydrogel is injected into the site of myocardial infarction.
  • This application also provides a method for treating myocardial infarction, in which the injectable hydrogel is injected into the site of myocardial infarction.
  • the materials used to prepare hydrogel carriers with anti-inflammatory and repair-promoting functions are natural polymer materials with a wide range of sources and low cost, and at the same time have good biocompatibility;
  • hydrophilic extracellular matrix used has small immune and rejection reactions and good solubility, which is a very safe biological extracellular matrix
  • the preparation process of the dual-response hydrogel is simple and has excellent physical and chemical properties, such as short gelation time and good injectability;
  • the dual-response hydrogel has both pH and ROS response properties, which can realize the on-demand release of hydrophobic drugs and hydrophilic extracellular matrix in response;
  • the dual-response hydrogel promotes the rapid repair of the damaged heart through anti-oxidation, anti-inflammatory and pro-angiogenesis mechanisms.
  • microenvironmental response strategy of dual-response hydrogels to stimulate drug release on demand and its good biocompatibility will achieve rapid repair of myocardial infarction sites.
  • This application also provides an injectable hydrogel with anti-inflammatory and repair-promoting functions, including the following raw materials: biological macromolecules containing amino and ortho-hydroxyl groups, biological macromolecules containing carboxyl and ortho-hydroxyl groups, and amino, hydroxyl, or Carboxyl phenylboronic acid.
  • hydrophilic drugs and/or hydrophobic drugs are examples of hydrophilic drugs and/or hydrophobic drugs.
  • This application also provides an injectable hydrogel with anti-inflammatory and repair-promoting functions, including the following raw materials: hydrophilic drugs, hydrophobic drugs, biological macromolecules containing amino groups and ortho hydroxyl groups, and carboxyl groups and ortho hydroxyl groups. Of biological macromolecules and phenylboronic acid containing amino, hydroxyl or carboxyl groups.
  • hydrophilic drugs include growth factors, polypeptide drugs, gene drugs and water-soluble protein drugs.
  • hydrophobic drugs include anti-inflammatory drugs, pro-angiogenesis drugs, pro-cell proliferation drugs, and pro-cell migration drugs.
  • anti-inflammatory drugs include fat-soluble drugs such as aspirin, paracetamol, amoxicillin, and phenylbutazone.
  • the biological macromolecules containing amino groups and ortho-hydroxy groups include at least one of chitosan, modified products of sodium alginate, and modified products of hyaluronic acid.
  • the modified product of sodium alginate and the modified product of hyaluronic acid are based on sodium alginate and hyaluronic acid.
  • the amino group is mainly introduced into sodium alginate and hyaluronic acid.
  • the natural polymer can be introduced into the supply through chemical reaction
  • the reacted amino group, carboxyl group or ortho-hydroxy group can theoretically be used as the raw material of injectable hydrogel.
  • the biological macromolecules containing carboxyl groups and ortho-hydroxyl groups include sodium alginate, hyaluronic acid and modified products thereof, carboxymethyl cellulose, or modified products of carboxymethyl cellulose.
  • the phenylboronic acid containing an amino group, a hydroxyl group or a carboxyl group is ortho-aminophenylboronic acid, meta-aminophenylboronic acid, para-aminophenylboronic acid, ortho-hydroxyphenylboronic acid, meta-hydroxyphenylboronic acid, and para-hydroxyphenylboronic acid , Ortho-carboxyphenylboronic acid, meta-carboxyphenylboronic acid, or para-carboxyphenylboronic acid.
  • the application also provides a hydrogel for repairing heart damage, and the hydrogel is the above-mentioned injectable hydrogel that acts on the damaged part of the heart.
  • the application also provides a hydrogel for treating heart failure, the hydrogel being the above-mentioned injectable hydrogel acting on the heart disease site.
  • the application also provides a hydrogel for treating myocardial infarction, and the hydrogel is the injectable hydrogel that acts on the site of myocardial infarction.
  • the application also provides the application of the injectable hydrogel with anti-inflammatory and repair-promoting functions in the repair of heart damage.
  • the application also provides the application of the injectable hydrogel with anti-inflammatory and repair promoting functions in the treatment of heart failure.
  • the application also provides the application of the injectable hydrogel with anti-inflammatory and promoting repair functions in the treatment of myocardial infarction.
  • the application also provides a method for repairing heart damage, which applies the injectable hydrogel to the damaged part of the heart.
  • the application also provides a method for treating heart failure, which applies the injectable hydrogel to the heart disease site.
  • This application also provides a method for repairing heart damage, in which the injectable hydrogel is injected into the heart disease site.
  • This application also provides a method for treating heart failure, in which the injectable hydrogel is injected into the site of myocardial infarction.
  • This application also provides a method for treating myocardial infarction, in which the injectable hydrogel is injected into the site of myocardial infarction.
  • the method for preparing the above-mentioned injectable hydrogel with anti-inflammatory and repair-promoting functions includes the following steps:
  • the drug-loaded nanomicelles are spherical, uniform in particle size, and have high drug loading rate and encapsulation rate.
  • the carrier of the drug-loaded nanomicelle is an amphiphilic polymer.
  • step (2) the drug-loaded nanomicelles are used to encapsulate hydrophobic drugs.
  • step (2) the drug-loaded nanomicelles will disintegrate in the structure of the inflammation site to accelerate the release of the drug.
  • the above-mentioned injectable hydrogel with anti-inflammatory and repair promoting functions can be prepared only by changing the pH value of the solution.
  • injectable hydrogels with anti-inflammatory and repair promoting functions have multiple dynamic functions such as self-healing, remodeling, and injectability.
  • injectable hydrogels with anti-inflammatory and repair-promoting functions can work through a controlled drug release system mediated by pH and reactive oxygen species (ROS) responses.
  • ROS reactive oxygen species
  • the above-mentioned injectable hydrogel with anti-inflammatory and repair promoting functions has good cell compatibility and no adverse reactions in the body.
  • the above-mentioned injectable hydrogel with anti-inflammatory and promoting repair functions is used in the preparation or application of cardiac repair.
  • the multi-responsive hydrogel is prepared from a single and defined polymer composition.
  • the multi-responsive hydrogel is successfully prepared through a minimum of synthesis steps and operating procedures
  • the injectable hydrogel formulation still has good rheological properties and structure retention after loading two different drugs
  • the injectable hydrogel formula has multiple dynamic functions such as self-healing, reshaping, injection, etc.;
  • the injectable hydrogel formula has super responsive drug release characteristics in the area of inflammation
  • the injectable hydrogel formula has good cell compatibility and no adverse reactions in the body.
  • the injectable hydrogel with anti-inflammatory and repair promoting functions produced by this method can increase the drug loading and drug loading types in the hydrogel dressing Wait. Not only can different polymers be replaced to form various types of hydrogels, but also different drugs, including hydrophilic drugs or hydrophobic drugs, can be replaced to give hydrogels different active functions.
  • the hydrogel provided by this application has good injectability. It is injected into the damaged part of the heart, and the immune and rejection reaction is small. Oxidation, anti-inflammatory and promoting angiogenesis promote the rapid repair of damaged heart.
  • This application also provides a method for preparing an injectable hydrogel with anti-inflammatory and repair-promoting functions, including the following steps:
  • Step 1 Use a functional polymer containing ortho hydroxyl groups to react with amino, hydroxyl or carboxyl-containing phenylboronic acid to prepare side-linked branched phenylboronic acid polymers; the ortho hydroxyl functional polymer contains amino and ortho hydroxyl groups Biomacromolecules or biomacromolecules containing carboxyl and ortho-hydroxyl groups;
  • Step 2 Dissolve the phenylboronic acid polymer in water, and adjust the pH value of the mixed solution to 8-9 to prepare a hydrogel.
  • the hydrophilic drug and/or the micelle containing the hydrophobic drug are mixed with the aqueous solution of phenylboronic acid polymer, and the pH value of the mixed solution is adjusted to 8-9.
  • a benign solvent to dissolve the amphiphilic drug carrier and the hydrophobic drug, slowly add water to them under stirring to prepare a drug-loaded micelle solution, and combine the hydrophilic drug and/or drug-loaded micelle solution with The phenylboronic acid polymer aqueous solution is mixed, and the pH value of the mixed solution is adjusted to 8-9 to prepare.
  • This application also provides a method for preparing an injectable hydrogel with anti-inflammatory and repair-promoting functions, including the following steps:
  • a phenylboronic acid polymer is prepared by reacting a functional polymer containing ortho hydroxyl and phenylboronic acid containing amino, hydroxyl or carboxyl groups;
  • step (3) Use a benign solvent to dissolve the amphiphilic drug carrier and the hydrophobic drug prepared in step (2), and then add water to them under stirring to prepare a drug-loaded micelle solution;
  • Phenylboronic acid polymers contain both phenylboronic acid groups and ortho-hydroxyl groups. Due to the limitation of the number of ortho-hydroxyl and phenylboronic acid groups and steric hindrance, the pH value needs to be adjusted to form a gel.
  • step (1) dissolving the functional polymer containing ortho hydroxyl to obtain a functional polymer solution containing ortho hydroxyl, and adding a condensing agent and an amino, hydroxyl or carboxyl containing functional polymer to the solution.
  • the phenylboronic acid is stirred at 30-40°C for 20-30h, then dialyzed in deionized water, and then freeze-dried to obtain a purified phenylboronic acid polymer.
  • the mass ratio of the functional polymer of the ortho hydroxyl group, the condensing agent and the phenylboronic acid of the amino group, the hydroxyl group or the carboxyl group is 4-6:4-6:1-2.
  • step (1) dissolving the functional polymer containing ortho hydroxyl to obtain a functional polymer solution containing ortho hydroxyl, and adding a condensing agent and an amino, hydroxyl or carboxyl containing functional polymer to the solution.
  • Phenylboronic acid stirred at 37°C for 24h, dialyzed in deionized water for 3 days, and then freeze-dried to obtain purified phenylboronic acid polymer.
  • the functional polymer of ortho hydroxyl group, condensation agent and amino, hydroxyl or carboxyl group The mass ratio of phenylboronic acid is 5:4.8:1.95.
  • the condensing agent includes 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-hydroxysuccinimide.
  • step (2) is: completely dissolving the hydrophilic polymer and hydrophobic molecules in dimethyl sulfoxide at 80°C, and adding N,N'-di Cyclohexylcarbodiimide and 4-dimethylaminopyridine were continuously stirred at 80°C for 48 hours.
  • the reactants were dialyzed in water for 2 days to remove unreacted hydrophobic molecules, and finally lyophilized for use.
  • the hydrophilicity is high.
  • the mass ratio of molecule, hydrophobic molecule, N,N'-dicyclohexylcarbodiimide and 4-dimethylaminopyridine is 2:1.5:1:0.5.
  • hydrophilic polymer includes hyaluronic acid, starch, cellulose, polyacrylic acid, polyacrylamide, polyvinyl alcohol, glycolic acid, and polylysine.
  • hydrophobic molecules include cholesterol, polyolefin, polycarbonate, polyamide, polyacrylonitrile, polyester, polylactic acid, and acrylate.
  • step (3) dissolving the amphiphilic drug carrier and the hydrophobic drug prepared in step (2) in a benign solvent, and then heating at 70-90°C, and under stirring conditions Among them, water was added drop by drop, and after dialysis, a drug-loaded micelle solution with a concentration of 0.5-1.5 mg/mL was prepared.
  • step (3) dissolving 0.04 parts of the amphiphilic drug carrier prepared in step (2) and 0.008 parts of the hydrophobic drug in a benign solvent, and then heating at 80°C under stirring conditions Water was added dropwise to it, and a drug-loaded micelle solution with a concentration of 1 mg/mL was prepared after dialysis.
  • the benign solvent in step (3) includes DMSO, DMF, methanol and acetone.
  • step (4) dissolving the hydrophilic drug and the phenylboronic acid polymer prepared in step (1) in the drug-loaded micelle solution prepared in step (3), so that The concentration of the phenylboronic acid polymer in the drug-loaded micelle solution is 7-11% w/v.
  • an alkaline solution is added to the phenylboronic acid polymer aqueous solution containing drug-loaded micelles and/or hydrophilic drugs, and the pH value is adjusted to 8.5 to prepare the injectable hydrogel.
  • step (4) the concentration of the phenylboronic acid polymer in the drug-loaded micelle solution is 9% w/v.
  • the functional polymer containing ortho hydroxyl groups is a biological macromolecule containing amino groups and ortho hydroxyl groups or a biological macromolecule containing carboxyl groups and ortho hydroxyl groups.
  • the biological macromolecules containing carboxyl groups and ortho-hydroxyl groups are sodium alginate, hyaluronic acid or modified products thereof, and phenylboronic acid containing amino and hydroxyl groups is grafted to the side chain by amidation reaction or esterification reaction and contains carboxyl group.
  • the side chain of the biological macromolecule containing the ortho hydroxyl group; the biological macromolecule containing the amino group and the ortho hydroxyl group is chitosan or its modified product, and the phenylboronic acid with carboxyl group is grafted to The side chain contains the amino group and contains the ortho hydroxyl group on the side chain of the biological macromolecule.
  • the phenylboronic acid containing an amino group, a hydroxyl group or a carboxyl group is ortho-aminophenylboronic acid, meta-aminophenylboronic acid, para-aminophenylboronic acid, ortho-hydroxyphenylboronic acid, meta-hydroxyphenylboronic acid, and para-hydroxyphenylboronic acid , Ortho-carboxyphenylboronic acid, meta-carboxyphenylboronic acid, or para-carboxyphenylboronic acid.
  • hydrophilic drugs include one of growth factors, genes, and water-soluble protein drugs.
  • hydrophobic drugs include one of anti-inflammatory drugs, pro-angiogenesis drugs, pro-cell proliferation drugs, and pro-cell migration drugs.
  • anti-inflammatory drugs include one of aspirin, paracetamol, amoxicillin, and phenylbutazone.
  • the application also provides a hydrogel for repairing heart damage, and the hydrogel is the above-mentioned injectable hydrogel that acts on the damaged part of the heart.
  • the application also provides a hydrogel for treating heart failure, the hydrogel being the above-mentioned injectable hydrogel acting on the heart disease site.
  • the application also provides a hydrogel for treating myocardial infarction, and the hydrogel is the injectable hydrogel that acts on the site of myocardial infarction.
  • the application also provides the application of the injectable hydrogel with anti-inflammatory and repair-promoting functions in the repair of heart damage.
  • the application also provides the application of the injectable hydrogel with anti-inflammatory and repair promoting functions in the treatment of heart failure.
  • the application also provides the application of the injectable hydrogel with anti-inflammatory and promoting repair functions in the treatment of myocardial infarction.
  • the application also provides a method for repairing heart damage, which applies the injectable hydrogel to the damaged part of the heart.
  • the application also provides a method for treating heart failure, which applies the injectable hydrogel to the heart disease site.
  • This application also provides a method for repairing heart damage, in which the injectable hydrogel is injected into the heart disease site.
  • This application also provides a method for treating heart failure, in which the injectable hydrogel is injected into the site of myocardial infarction.
  • This application also provides a method for treating myocardial infarction, in which the injectable hydrogel is injected into the site of myocardial infarction.
  • the hydrogel provided in this application can be used for injection into the heart. Based on different usage scenarios, the selection of hydrophilic drugs, hydrophobic drugs, and extracellular matrix is not completely the same, and appropriate selections can be made according to actual needs.
  • the hydrogel is prepared from a single and definite polymer composition.
  • the synthesis steps of the hydrogel are simple, easy to operate, and the reaction conditions are mild. It still has good rheology after loading two different drugs. Performance and complete structure, and the hydrogel has a variety of dynamic functions such as self-healing, remodeling, injection, etc., has good cell compatibility, and has no adverse reactions in the body.
  • the phenylborate bond in the injectable hydrogel breaks quickly under the conditions of high active oxygen and low pH, and the structure of the hydrogel is destroyed, thereby releasing hydrophilic and hydrophobic drugs in a rapid response.
  • the injectable hydrogel is loaded with extracellular matrix and hydrophilic drugs and/or hydrophobic drugs at the same time. Normally, the molecules of hydrophilic drugs and hydrophobic drugs are smaller, and the molecules of extracellular matrix are larger. The magnitude of steric hindrance is different. Firstly, hydrophilic drugs and hydrophobic drugs with smaller molecules are released to reduce inflammation of the injured tissue, and then the extracellular matrix is released to promote cell regeneration, which is more conducive to tissue repair.
  • the hydrophobic drug uses the amphiphilic polymer as the carrier, by adjusting the structure and dosage of the amphiphilic polymer, the overall micelle size after the hydrophobic drug is loaded on the amphiphilic polymer can be adjusted to adjust its size. Relative to the order in which other substances are released from the hydrogel.
  • Figure 1 is the hydrogen nuclear magnetic spectrum of CMC and CMC-BA in Example 1 of the present application.
  • Example 2 is a diagram of the particle size of the drug-loaded nanoparticles in Example 1 of the present application.
  • Figure 3 is a gel forming diagram of the hydrogel in Example 1 of the present application.
  • Figure 4 is a graph showing the results of the injectability of the hydrogel in Example 1 of the present application.
  • Figure 5 is a graph showing the cell survival rate of endothelial cells treated with different hydrogels in Example 1 of the present application at 24, 48 and 72 hours;
  • Fig. 6 is a graph showing the cell viability results of cardiomyocytes treated with different hydrogels in Example 1 of the present application at 24, 48 and 72 hours;
  • Figure 7 shows the expression results of IL-6 and TNF- ⁇ in macrophages treated with different hydrogels in Example 1 of the present application at 24 and 48 hours;
  • FIG. 8 is a diagram of H&E staining and Masson staining of the rat heart in Example 1 of the present application;
  • Fig. 9 is a hydrogen NMR spectrum of ALG, BA and ALG-BA described in Example 6 of the present application.
  • Fig. 10 is a hydrogen NMR spectrum of CHOL, HA and HA-CHOL described in Example 6 of the present application;
  • Figure 11 is a schematic diagram of the reaction process of phenylboronic acid grafting carboxymethyl cellulose functional polymer.
  • the chemical reagents other than the matrix are all chemically pure unless otherwise stated.
  • CMC carboxymethyl cellulose
  • BA 3-aminophenylboronic acid
  • EDC ⁇ HCl 1-ethyl -(3-Dimethylaminopropyl)carbodiimide hydrochloride
  • NHS N-hydroxysuccinimide
  • Polylactic acid-glycolic acid copolymer (PLGA, 60mg) and curcumin (Cur, 12mg) were completely dissolved in DMSO (5mL) at 37°C, and then added dropwise to 15mL of deionized water under stirring. Stir continuously at 37°C for 4 hours; then dialyze it in water for 3 days to obtain PLGA@Cur solution, and store it at 4°C in the dark after lyophilization;
  • the hydrogel can be prepared immediately.
  • a preparation method of an injectable hydrogel with anti-inflammatory and repair promoting functions the preparation steps are as follows:
  • HA hyaluronic acid
  • BA 4-aminophenylboronic acid
  • EDC ⁇ HCl 1-ethyl-( 3-Dimethylaminopropyl)carbodiimide hydrochloride
  • NHS N-hydroxysuccinimide
  • Polylactic acid-glycolic acid copolymer (PLGA, 60mg) and naproxen (Nap, 12mg) were completely dissolved in DMSO (5mL) at 37°C, and then added dropwise to 15mL of deionized water under stirring. Stir continuously at 37°C for 4 hours; then dialyze it in water for 3 days to obtain PLGA@Nap solution, and store it at 4°C in the dark after lyophilization;
  • HA-BA 1% w/v water
  • human recombinant type I collagen 2mg/mL
  • PLGA@Nap 100 ⁇ g/mL
  • the gel can be prepared immediately.
  • a preparation method of an injectable hydrogel with anti-inflammatory and repair promoting functions the preparation steps are as follows:
  • Polyethylene glycol phospholipid (DSPE-PEG, 60mg) and surivastatin (12mg) were completely dissolved in DMSO (5mL) at 37°C, and then added dropwise to 15mL of deionized water under stirring. Stir continuously at 37°C for 4 hours; then dialyze it in water for 3 days to obtain the drug-loaded nanoparticle solution, and store it at 4°C in the dark after lyophilization;
  • the injectable hydrogel can be prepared immediately.
  • a preparation method of an injectable hydrogel with anti-inflammatory and repair promoting functions the preparation steps are as follows:
  • phospholipid polyethylene glycol polylactic acid-glycolic acid copolymer 60mg
  • aspirin 12mg
  • the functional polymer (1% w/v) aqueous solution containing the vascular endothelial growth factor (1mg/mL) and the drug-loaded nanoparticles (100 ⁇ g/mL) prepared above and the 1% polyvinyl alcohol solution are mixed in equal volume, and water can be injected
  • the gel can be prepared immediately.
  • a preparation method of an injectable hydrogel with anti-inflammatory and repair promoting functions the preparation steps are as follows:
  • PEG-PLA Polyethylene glycol polylactic acid copolymer
  • verapamil (12mg) were completely dissolved in DMSO (5mL) at 37°C, and then added dropwise to 15mL deionized under stirring conditions Stir continuously in water at 37°C for 4 hours; then dialyze it in water for 3 days to obtain the drug-loaded nanoparticle solution, and store it at 4°C in the dark after lyophilization;
  • the functional polymer (1%w/v) aqueous solution containing mangiferin (1mg/mL) and the drug-loaded nanoparticles (100 ⁇ g/mL) prepared above and the 1% polyvinyl alcohol solution are mixed in equal volume, and the hydrogel can be injected Can be prepared immediately.
  • Example 1 Taking the substance prepared in Example 1 as an example, the detection is carried out.
  • the specific operation process and results are as follows:
  • the particle size of the drug-loaded nanoparticles prepared in step (2) is measured. As shown in Figure 2, the particle size distribution results show that the particle size of the PLGA nanoparticles before drug loading is 126.4nm, and the particle size after drug loading It is 133.8nm, and the PDI of the nanoparticles before and after loading is less than 0.2, which proves its good uniform dispersion and the successful preparation of drug-loaded nanoparticles.
  • hydrogel groups 1-4 respectively represent the following combinations: hydrogel group 1 (Hydrogel 1): blank hydrogel; hydrogel group 2 (Hydrogel 2): loaded with PLGA@ Cur's hydrogel; Hydrogel group 3 (Hydrogel 3): hydrogel loaded with recombinant human type III collagen; Hydrogel group 4 (Hydrogel 4): loaded with PLGA@Cur and recombinant human type III collagen Protein hydrogel.
  • Figure 3 is a gel formation diagram of the hydrogel, which proves that the preparation of the hydrogel is successful;
  • Figure 4 is a diagram of the injectability of the hydrogel.
  • the hydrogel can be injected from a 1mL syringe and can be injected into the heart.
  • the letter “HEART” proves the good injectability of the hydrogel.
  • HUVECs Human umbilical vein endothelial cells
  • the hydrogel prepared under aseptic conditions was soaked in a cell culture medium (0.2 g/mL) containing 1 mM H 2 O 2 at pH 5.0 for 24 h.
  • HUVECs cells were seeded in 96-well plates at a seeding density of 8000 cells per well. After 12h, remove the cell culture solution and add different hydrogel extracts to continue incubating the cells.
  • the proliferation rate of HUVECs at 24h, 48h and 72h was detected by CCK-8. After incubating for 24h, 48h, 72h, add 10% CCK-8 fresh medium solution to each well. After 2h, the cell proliferation rate was calculated by measuring the absorbance at 450nm with a microplate reader.
  • the results of the survival rate of the hydrogel on endothelial cells are shown in Figure 5.
  • the results show that all hydrogel groups show no toxicity to endothelial cells at 24h, 48h, and 72h, indicating that the hydrogel has good cytocompatibility .
  • the cell survival rate was higher than that of the control group and the blank hydrogel group, indicating that the recombinant human type III collagen effectively promoted the proliferation of endothelial cells.
  • the cardiomyocytes H9C2 were seeded in a 96-well plate with a seeding density of 8000 cells per well. After 12h, remove the cell culture solution and add different hydrogel extracts to continue incubating the cells. The proliferation rate of H9C2 cells at 24h, 48h and 72h was detected by CCK-8. The results of the survival rate of the hydrogel on cardiomyocytes are shown in Figure 6. The results show that the hydrogel after loading recombinant human type III collagen, compared with the control group and the blank hydrogel group, the cell proliferation is the most, indicating that the recombinant Human-derived type III collagen effectively promotes the proliferation of cardiomyocytes.
  • Hydrogel inhibits the expression of inflammation-related proteins
  • a density of 10 106 cells per well macrophages were seeded in a 6-well plate, and lipopolysaccharide was added to macrophages preincubated 2h. Then add 2mL hydrogel extract to incubate the cells. At 24h and 48h, aspirate the cell culture supernatant and use the tumor necrosis factor- ⁇ (TNF- ⁇ ) and interleukin-6 (IL-6) ELISA kit to determine the tumor necrosis factor- ⁇ and interleukin-6 (IL-6) in the supernatant. -6) The concentration.
  • TNF- ⁇ tumor necrosis factor- ⁇
  • IL-6 interleukin-6
  • curcumin is effectively loaded into PLGA nanoparticles through hydrophilic-hydrophobic interactions.
  • the functional polymer is obtained by grafting 3-aminophenylboronic acid to the side chain of carboxymethyl cellulose by amide reaction, and finally prepared by using the boronic acid group of the functional polymer and the hydroxyl group of polyvinyl alcohol to easily form a boronic ester bond.
  • the released curcumin inhibits the expression of inflammation-related factors and can effectively reduce the inflammatory response at the site of myocardial infarction; recombinant human type III collagen can promote the proliferation of endothelial cells and cardiomyocytes, and promote the expression of angiogenesis-related factors, thereby promoting The formation of new blood vessels at the infarct site; combined anti-inflammatory and pro-vascular treatment strategies to accelerate the repair of the damaged heart in an inflammatory environment, and effectively improve the cardiac function after myocardial infarction.
  • the drug-loaded nanomicelles can be made into micelles as long as they are covalently combined with hydrophilic and hydrophobic high-molecular polymers. If hyaluronic acid is used as the hydrophilic end, cholesterol, etc. can be used as the hydrophobic end to synthesize drug-loaded micelles.
  • Biomacromolecules with amino groups and ortho-hydroxyl groups are chitosan and one of its natural macromolecules.
  • the biological macromolecule with carboxyl group and ortho-hydroxyl group is one of sodium alginate, hyaluronic acid and their modified products.
  • phenylboronic acid groups such as ortho-aminophenylboronic acid, meta-aminophenylboronic acid, para-aminophenylboronic acid, ortho-carboxyphenylboronic acid, meta-carboxyphenylboronic acid, and para-carboxyphenylboronic acid, ortho-hydroxyphenylboronic acid , One of meta-hydroxyphenylboronic acid and para-carboxyphenylboronic acid.
  • Hydrophobic drugs can be divided into anti-inflammatory drugs, pro-angiogenesis drugs and pro-cell proliferation and migration drugs according to their pharmacological activities.
  • the hydrophilic drugs can be divided into growth factors and DNA, RNA and protein drugs according to their pharmacological activities.
  • the structural unit of the injectable hydrogel is phenylboronic acid with amino group which is grafted to the side chain of polymer with carboxyl group and ortho hydroxyl through amidation reaction.
  • Such polymer can be sodium alginate, One of hyaluronic acid and its modified products.
  • the structural unit of the injectable hydrogel can also be phenylboronic acid with carboxyl group, which is grafted to the side chain of polymer with amino group and ortho hydroxyl through amidation reaction.
  • Such polymer is chitosan.
  • the chemical reagents other than the matrix are all chemically pure unless otherwise stated.
  • a preparation method of an injectable hydrogel with anti-inflammatory and repair-promoting functions includes the following steps to obtain:
  • ALG sodium alginate
  • MES buffer 0.1mol, pH5.0
  • 1-ethyl-(3-dimethylaminopropyl) carbodioxide Amine hydrochloride (EDC ⁇ HCl, 4.80 g, 25.0 mmol) and 3-aminophenylboronic acid (BA, 1.95 g, 12.5 mmol). Then, it was stirred at 37°C for 24 hours, and finally dialyzed in deionized water (pH 7.4) for 3 days. After 3 days, it was freeze-dried with a lyophilizer to obtain purified ALG-BA.
  • HA (2.00g) and cholesterol (CHOL, 1.50g) were completely dissolved in dimethyl sulfoxide (DMSO, 30mL) at 80°C, and N,N'-dicyclohexylcarbodiimide (DCC, 1.00 g) and 4-dimethylaminopyridine (DMAP, 0.50g), stirring continuously at 80°C for 48h. Then the mixture was dialyzed in water for 2 days, the excess cholesterol was removed by centrifugal separation, and finally the finished product was lyophilized for use.
  • DMSO dimethyl sulfoxide
  • DCC N,N'-dicyclohexylcarbodiimide
  • DMAP 4-dimethylaminopyridine
  • HA-CHOL (40.0 mg) and naproxen (Nap, 8.00 mg) were dissolved in DMSO (10 mL) and heated to 80°C. Then, while stirring slowly, 10 mL of H 2 O was added dropwise to the mixed solution. Finally, the mixture was dialyzed in water for 2 days to prepare a drug-loaded micelle solution.
  • the ALG-BA (1.00g) and amikacin (AM, 100mg) prepared in step (1) were respectively dissolved in the drug-loaded micelle solution (1mg/mL) prepared in step (3), so that The final concentration of ALG-BA in the drug micelle solution was 9% w/v.
  • the pH of the drug micelle solution was adjusted to 8.5 with an alkaline solution, the drug micelle solution quickly gelled to form a hydrogel.
  • a preparation method of an injectable hydrogel with anti-inflammatory and repair promoting functions the preparation steps are as follows:
  • step (2) Dissolve 10 mg of the amphiphilic drug carrier in step (2) and 1 mg of anti-inflammatory drug (piroxicam) in DMSO (1 mL), and then add it dropwise to 10 ml of water with slow stirring. Finally, the mixture Dialysis in water for 2 days;
  • a preparation method of an injectable hydrogel with anti-inflammatory and repair promoting functions the preparation steps are as follows:
  • the amphiphilic drug carrier directly selects the polylactic acid-glycolic acid copolymer (PLGA) purchased by the company, which is made by polymerizing lactic acid and glycolic acid in a ratio of 50:50.
  • PLGA polylactic acid-glycolic acid copolymer
  • step (1) Dissolve the phenylboronic acid-modified chitosan polymer (1g) and 100mg of deferoxamine in step (1) respectively in the drug-loaded micelle solution (1mg/mL), and then add an appropriate amount of sodium hydroxide solution to adjust the pH of the solution At 8.5, the solution can quickly gel.
  • a preparation method of an injectable hydrogel with anti-inflammatory and repair promoting functions the preparation steps are as follows:
  • step (2) Dissolve 10 mg of the amphipathic drug carrier in step (2) and 1 mg of anti-inflammatory drug (Surevastatin) in DMSO (1 mL), and then add them dropwise to 10 ml of water while stirring slowly, and finally , The mixture was dialyzed in water for 2 days;
  • a preparation method of an injectable hydrogel with anti-inflammatory and repair promoting functions the preparation steps are as follows:
  • the amphiphilic carrier is directly selected from the polylactic acid-glycolic acid copolymer (PLGA) purchased by the company.
  • PLGA polylactic acid-glycolic acid copolymer
  • step (1) Dissolve the phenylboronic acid-modified chitosan polymer (1g) and 100mg of the pro-angiogenic drug (deferoxamine mesylate) in step (1) in the drug-loaded micelle solution (1mg/mL), and then add When the pH of the solution is adjusted to 8.5 with a proper amount of sodium hydroxide solution, the solution can quickly gel.
  • a preparation method of an injectable hydrogel with anti-inflammatory and repair promoting functions the preparation steps are as follows:
  • step (2) Dissolve 10 mg of the amphiphilic drug carrier in step (2) and 1 mg of anti-inflammatory drug (piroxicam) in DMSO (1 mL), and then add it dropwise to 10 ml of water with slow stirring. Finally, the mixture Dialysis in water for 2 days;
  • a preparation method of an injectable hydrogel with anti-inflammatory and repair promoting functions the preparation steps are as follows:
  • the amphiphilic carrier is directly selected from the polylactic acid-glycolic acid copolymer (PLGA) purchased by the company.
  • PLGA polylactic acid-glycolic acid copolymer
  • step (1) Dissolve the phenylboronic acid-modified chitosan polymer (1g) and 100mg of the pro-angiogenic drug (deferoxamine mesylate) in step (1) in the drug-loaded micelle solution (1mg/mL), and then add When the pH of the solution is adjusted to 8.5 with a proper amount of sodium hydroxide solution, the solution can quickly gel.
  • Example 1 Taking the substance prepared in Example 1 as an example, the detection is carried out.
  • the specific operation process and results are as follows:
  • HA-CHOL prepared in step (2) see Fig. 10 for details, as shown in Fig. 10, which proves that HA-CHOL was successfully prepared; quantification by nuclear magnetic field showed that the grafting degree of CHOL was 13.5%.
  • the hydrogel prepared in Example 9 was used to test the effect of in vivo heart repair
  • hydrogel groups 1-4 respectively represent the following combinations: hydrogel group 1 (Hydrogel 1): blank hydrogel; hydrogel group 2 (Hydrogel 2): loaded with anti-inflammatory drugs (piroxicam) drug-loaded micelles Hydrogel; Hydrogel group 3 (Hydrogel 3): hydrogel loaded with epidermal growth factor (EGF); Hydrogel group 4 (Hydrogel 4): loaded with anti-inflammatory drug (Surevastatin) drug carrier Bundles and epidermal growth factor (EGF) hydrogels.

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Abstract

本申请公开了一种具有抗炎及促修复功能的水凝胶及其制备方法和应用，可注射水凝胶通过聚合物的功能基团与聚合物的邻羟基相互作用形成凝胶，且响应于酸性条件和/或活性氧条件，聚合物的功能基团与聚合物的邻羟基解除相互作用后，水凝胶发生崩解。制备方法包括：制备含有功能基团的第一聚合物；将细胞外基质或者亲水性药物或者疏水性药物中的一种或一种以上、第一聚合物、含邻羟基的聚合物混合，制备得到所述可注射水凝胶。

Description

具有抗炎及促修复功能的可注射水凝胶及其制备方法和在心脏修复中的应用 技术领域
本申请涉及生物医用材料技术领域，具体涉及一种具有抗炎及促修复功能的可注射水凝胶及其制备方法和在心脏修复中的应用。
背景技术
心肌梗死(MI)是冠状动脉闭塞，血流中断，致使部分心肌因严重的持久性缺血而发生的局部坏死，而大面积的心肌梗死将发生心力衰竭(HF)并而危及患者生命，心力衰竭是全世界发病率和死亡率的主要原因之一。心力衰竭影响着全球约4000万人，在发达国家整体患病率为1-2％，在65岁以上的人群中上升到10％以上。即使依靠目前最好的治疗手段，心衰再住院率也高达24.5％，约20％的心衰患者在确诊后1年内死亡，约50％的心衰患者确诊后5年内死亡。2019年的调查结果显示，在我国≥35岁的居民中，心衰患病率为1.3％，即大约1370万人患有心衰疾病。随着年龄的增长，心衰患病率将逐年升高，导致社会医疗负担持续上升。截止目前，只有心衰的治疗仍然是心血管领域尚未被征服的巨大挑战。高发病率、高住院率和再住院率、高死亡率、患者生活质量差和经济负担重等诸多问题依然严峻。
急性心肌梗死是心内科常见的危急重症之一，严重威胁着患者的生命。心肌梗死治疗的主要困难在于心脏组织自身再生能力有限，即心脏损伤的不可逆性以及缺血后心脏组织存活时间极短等。由于血流不足导致梗塞组织供氧减少而发生的心肌细胞死亡或心肌组织坏死，将破坏心肌细胞间连接的胶原纤维，削弱细胞外基质，导致心室壁变薄和扩张。梗塞组织的成纤维细胞、内皮细胞和干细胞/祖细胞形成的肉芽组织被细胞外基质逐渐取代，最后形成疤痕组织。新产生的疤痕组织由于缺乏心脏泵血所需的收缩特性，从而导致心脏衰竭。心力衰竭可能由很多因素引起，但最常见的风险因素是高血压、冠状动脉疾病(心脏动脉堵塞)、糖尿病、肥胖、吸烟和遗传等。目前，临床上治疗心力衰竭的三种方法包括心脏移植、医疗设备(包括心室辅助装置)的介入治疗和药物治疗。心脏移植仍然是用健康供体心脏取代梗死心脏的唯一有效治疗方法。然而，需要心脏移植的人数众多，但是可用的供体数却很少，且随着患者数量的增加、供体数量的减少以及心脏移植后出现的免疫并发症等问题，导致心脏移植仍然是一项低效的技术。而医疗设备的介入治疗和药物治疗虽然能在一定程度上改善心脏收缩力、缓解心脏负荷以及减轻疼痛等，然而患者长期服用药物会引起药物副作用加剧等问题，同时心脏辅助装置也无法从根本上治愈心力衰竭并缓解心力衰竭疾病的发展，从而导致有限的治疗效率。因此，迫切需要新的治疗方法来更有效地解决心脏损伤问题。
用组织工程和再生医学技术进行心脏修复是一种很有前途的治疗方案。其中，可注射水凝胶因其可以注射到梗死心脏组织附近，为受损的心脏组织提供机械支持而受到关注。同时，可注射水凝胶自身也能作为药物载体，将药物或活性治疗物质原位递送到梗死部位，从而实现心脏梗死部位的有效再生修复。目前，已有几种可注射水凝胶在心脏组织修复方面表现出了巨大的潜力，如海藻酸钙水凝胶通过为心室壁提供机械支持用于MI治疗，并已取得一定的治疗效果。同时，其他的可降解水凝胶也已被用来装载不同的药物用于MI的治疗，如细胞生长因子、蛋白质、化学和基因药物等。然而，这类负载药物或活性因子的水凝胶无法针对心肌梗死疾病的不同特点和不同阶段响应释放所需药物，导致被动的药物释放行为，因此其治疗效果有限，并限制了临床的进一步转化。近年来，针对疾病部位微环境特点构建的智能响应水凝胶已被广泛用于癌症，类风湿关节炎，胃肠疾病及慢性伤口等疾病的治疗，并已 取得优越的治疗效果。相比于传统的载药水凝胶，智能响应水凝胶在疾病部位通过实现药物的精准按需响应释放显著提高了患者的治疗效果，还能减少给药频率和降低药物的副作用。可以预见，随着精准给药技术的成熟，将极大地促进智能响应水凝胶的临床转化。
近年来研究发现，心梗后心力衰竭的发生与炎症因子、信号传导、基因等多个因素有关。心肌梗死后坏死的心肌细胞可刺激机体发生局部炎症反应，产生大量炎性因子，包括白介素-6(interleukin-6，IL-6)和肿瘤坏死因子-α(tumor necrosis factor-α，TNF-α)等，使炎症因子水平升高，并持续对心肌产生损伤，最后导致心肌细胞凋亡。大量实验已经证明，心肌梗死后强烈的炎症反应是造成心肌组织继发性损伤的因素之一。在严重缺血引起的心肌梗死病理过程中，特别是在心肌梗死的初期炎症阶段，氧化应激和弱酸性环境是心肌病变组织炎症微环境的两个主要特征。然而目前，针对心肌梗死部位炎性微环境特点设计的智能响应水凝胶还非常少。更重要的是，如何抑制心肌梗死后的炎症反应以及挽救心梗早期损伤的心肌细胞，减少心肌细胞凋亡，促进缺血区域的血管再生是心梗后心肌修复的关键。因此构建多功能微环境响应水凝胶不仅对改善心肌梗死治疗具有重要的意义，而且也为智能响应水凝胶在心肌梗死治疗领域的应用拓宽了道路。
发明内容
针对心力衰竭发病率持续上升、临床现有方法治疗效果不佳，迫切需要改善的临床事实，以及针对现有技术中存在的上述问题，本申请的目的是提供一种具有抗炎及促修复功能的可注射水凝胶的制备方法及其在心脏损伤修复中的应用，可有效解决现有心力衰竭治疗方法效果不佳等问题，同时本申请提供的水凝胶具有制备方法简单以及成本低的优点。
一种具有抗炎及促修复功能的可注射水凝胶，所述可注射水凝胶通过聚合物的功能基团与聚合物的邻羟基相互作用形成凝胶，且响应于酸性条件和/或活性氧条件，聚合物的功能基团与聚合物的邻羟基解除相互作用后，水凝胶发生崩解。
可选的，所述可注射水凝胶负载有亲水性药物、疏水性药物、细胞外基质中的至少一种。
可选的，含功能基团的聚合物为含苯硼酸基团的海藻酸钠、壳聚糖、壳聚糖季铵盐、聚赖氨酸、聚乙烯亚胺、明胶、海藻酸钠、透明质酸、肝素、羧甲基纤维素、葡聚糖、甲基纤维素、淀粉、环糊精中的至少一种。
在弱碱性条件下，苯硼酸基团与邻羟基通过硼酯键相互作用形成凝胶，在酸性条件和/或活性氧条件，硼酯键断裂，凝胶发生解离。
所述可注射水凝胶在弱碱性条件下，呈凝胶状态，在酸性条件和/或活性氧条件下，凝胶解离，凝胶中的亲水性药物、疏水性药物、细胞外基质等释放。
苯硼酸基团与邻羟基可以存在于同一聚合物中，即同一聚合物中同时含有多个苯硼酸基团和邻羟基，苯硼酸基团与邻羟基也可以分别存在于不同的聚合物中，即其中一聚合物中含有多个苯硼酸基团，另一聚合物中含有多个邻羟基。
酸性条件和弱碱性条件为一相对概念，苯硼酸基团和邻羟基的数量较多时，在中性条件即可形成凝胶，苯硼酸基团和邻羟基的数量较少时，需要在弱碱性条件下形成凝胶。
本申请中，天然高分子应理解为包括其改性产物，即壳聚糖包括未经修饰的壳聚糖，也包括壳聚糖的改性产物，同理，壳聚糖季铵盐、聚赖氨酸、聚乙烯亚胺、明胶、海藻酸钠、透明质酸、肝素、羧甲基纤维素、葡聚糖、甲基纤维素、淀粉、环糊精也都包括其相应的改性产物，改性产物本身不对凝胶的形成和解离产生不良影响。
可选的，含邻羟基的聚合物为海藻酸钠、聚乙烯醇、海藻酸钠、透明质酸、葡聚糖、淀 粉中的至少一种。
可选的，所述可注射水凝胶负载有细胞外基质；
以及亲水性药物和/或疏水性药物。
可注射水凝胶中至少负载有细胞外基质，同时负载有亲水性药物、疏水性药物中的至少一种。
可注射水凝胶中负载的物质根据实际治疗的需要，选择性的负载在水凝胶中。
可选的，所述细胞外基质为胶原蛋白、非胶原蛋白、弹性蛋白、蛋白聚糖、氨基聚糖中的至少一种。
可选的，所述细胞外基质为重组人源化胶原蛋白。
可选的，所述细胞外基质为重组I型人源化胶原蛋白、重组III型人源化胶原蛋白中的至少一种。
可选的，所述重组I型人源化胶原蛋白和重组III型人源化胶原蛋白中包含可以与细胞整合素结合的氨基酸序列片段。
所述重组I型人源化胶原蛋白和重组III型人源化胶原蛋白是由DNA重组技术制备的人胶原蛋白特定型别基因编码的可以与细胞整合素结合的氨基酸序列片段。
可选的，所述细胞外基质为重组III型人源化胶原蛋白。
可选的，所述疏水性药物萘普生、舒瑞伐他汀、姜黄素、阿司匹林中的至少一种。
可选的，所述疏水性药物以两亲性聚合物为载体，负载在所述可注射水凝胶中。
可选的，所述可注射水凝胶负载有：姜黄素和重组人源化胶原蛋白。
可选的，所述可注射水凝胶负载有：姜黄素和重组III型人源化胶原蛋白。
本申请还提供了一种用于修复心脏损伤的水凝胶，所述水凝胶为作用于心脏损伤部位的上述的可注射水凝胶。
所述姜黄素用于损伤部位消炎，所述重组人源III型胶原蛋白促进心肌细胞再生，二者相互作用，可以有效促进心肌细胞增值，生长，修复心脏损伤。
本申请还提供了一种用于治疗心衰的水凝胶，所述水凝胶为作用于心脏病变部位的上述的可注射水凝胶。
本申请还提供了一种用于治疗心肌梗死的水凝胶，所述水凝胶为作用于心肌梗死部位的所述的可注射水凝胶。
本申请还提供了所述的具有抗炎及促修复功能的可注射水凝胶在心脏损伤修复中的应用。
本申请还提供了所述的具有抗炎及促修复功能的可注射水凝胶在治疗心衰中的应用。
本申请还提供了所述的具有抗炎及促修复功能的可注射水凝胶在治疗心肌梗死中的应用。
本申请还提供了一种心脏损伤修复方法，将所述的可注射水凝胶作用于心脏损伤部位。
本申请还提供了一种治疗心衰的方法，将所述的可注射水凝胶作用于心脏病变部位。
本申请还提供了一种心脏损伤修复方法，在心脏病变部位注射所述的可注射水凝胶。
本申请还提供了一种治疗心衰的方法，在心肌梗死部位注射所述的可注射水凝胶。
本申请还提供了一种治疗心肌梗死的方法，在心肌梗死部位注射所述的可注射水凝胶。
本申请还提供了一种所述的可注射水凝胶的制备方法，包括：
制备含有苯硼酸基团的第一聚合物；
将亲水性药物、细胞外基质、疏水性药物中的至少一种、第一聚合物、含邻羟基的聚合物混合，制备得到所述可注射水凝胶。
含邻羟基的聚合物中含有多个邻羟基基团，第一聚合物与含邻羟基的聚合物混合后，即可形成凝胶，不需要额外调节pH值。
可选的，所述第一聚合物采用以下任意一种原料组合方式在缩合剂及催化剂存在的条件下反应制得：
a)含氨基或羟基的聚合物与含羧基的苯硼酸；
b)含羧基的聚合物与含氨基或羟基的苯硼酸。
在聚合物中引入苯硼酸基团，可以通过氨基和羧基的酰胺化反应，也可以通过羟基和羧基的酯化反应进行，因此，聚合物和苯硼酸，其中一者含有氨基或羟基，另一者含有羧基，都可以在聚合物中引入苯硼酸基团。
缩合剂为1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐、O-苯并三氮唑-四甲基脲六氟磷酸酯、六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷、二环己基碳二亚胺中的至少一种，催化剂为4-二甲氨基吡啶、N-羟基琥珀酰亚胺、1-羟基苯并三氮唑中的至少一种。
可选的，所述第一聚合物的制备方法如下：
原料溶解后，在30～40℃条件下反应30-60h，制备得到所述含苯硼酸基团的第一聚合物。
原料反应完毕后，需要进行适当的后处理，包括在去离子水中透析、冷冻干燥等，第一聚合物中侧链含有苯硼酸基团。
聚合物中苯硼酸基团的数量会影响凝胶的形成和解离，苯硼酸基团的引入数量需适当。
可选的，含氨基或羟基的聚合物、含羧基的苯硼酸、缩合剂、催化剂的质量比为7:(4-5):(2-3):1；或含羧基的聚合物、含氨基或羟基的苯硼酸、缩合剂、催化剂的质量比为7:(4-5):(2-3):1。
可选的，所述第一聚合物的制备方法如下：
原料溶解后，在37℃条件下反应48小时后在去离子水中透析3天，然后再进行冷冻干燥制备具有侧链接枝苯硼酸基团的聚合物；其中，含氨基或羟基的聚合物、含羧基的苯硼酸、1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐、N-N-羟基琥珀酰亚胺的质量比为7:4.5:2.5:1；或含羧基的聚合物、含氨基或羟基的苯硼酸、1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐、N-N-羟基琥珀酰亚胺的质量比为7:4.5:2.5:1。
亲水性药物、细胞外基质等水溶性较好的物质可以与第一聚合物、含邻羟基的聚合物直接混合，得到可注射水凝胶，对于疏水性药物需要进行特殊处理后，与第一聚合物、含邻羟基的聚合物进行混合。
可选的，所述疏水性药物以两亲性聚合物作为载体，制作为载药纳米胶束，载药纳米胶束与第一聚合物、含邻羟基的聚合物混合，制备得到含疏水性药物的所述可注射水凝胶。
两亲性聚合物与疏水性药物之间通过自组装形式制备载药纳米胶束，两亲性聚合物为药物载体，疏水性药物为所包裹的药物。
所述两亲性聚合物由亲水链段和疏水链段组成，亲水链段为聚乙二醇、聚乙烯醚、聚乙烯醇、聚乙烯亚胺、聚乙烯吡咯烷酮、聚丙烯酞胺中的至少一种，疏水链段为聚环氧丙烷、聚苯乙烯、聚硅氧烷、聚丁二烯、聚甲基丙烯酸甲酯、聚丙烯酸甲酯、聚丙烯酸丁酯中的至少一种。
可选的，所述载药纳米胶束的制备包括：
将两亲性聚合物和疏水性药物溶于良性溶剂中，在持续搅拌状态下缓慢滴加入水中，透析后得到浓度为1-2mg/mL的载药纳米胶束溶液。
所述良性溶剂为DMSO、DMF、甲醇、丙酮中的至少一种。进一步优选，所述良性溶剂为DMSO和/或丙酮。
具体地，将两亲性聚合物和疏水性药物溶解于良性溶剂中，在持续搅拌条件下缓慢滴加到去离子水中，搅拌3-6小时，在去离子水中透析后，制得载药纳米胶束。
可选的，两亲性聚合物与疏水性药物的质量比为4-8:1。
具体地，将两亲性聚合物和疏水性药物溶解于良性溶剂中，在持续搅拌条件下缓慢滴加到去离子水中，搅拌4小时，在去离子水中透析后，制得载药纳米胶束，两亲性聚合物和疏水性药物的质量比为5:1。
可选的，将第一聚合物的水溶液与含邻羟基的聚合物的水溶液混合，得到所述可注射水凝胶，第一聚合物的水溶液中含有亲水性药物、细胞外基质、载药纳米胶束中的至少一种，第一聚合物水溶液中，第一聚合物的质量浓度为0.5～10％w/v。
可选的，将第一聚合物的水溶液与含邻羟基的聚合物的水溶液混合，得到所述可注射水凝胶，第一聚合物的水溶液中含有亲水性药物、细胞外基质、载药纳米胶束中的至少一种，第一聚合物水溶液中，第一聚合物的质量浓度为0.5～5％w/v。
可选的，将第一聚合物的水溶液与含邻羟基的聚合物的水溶液混合，得到所述可注射水凝胶，第一聚合物的水溶液中含有亲水性药物、细胞外基质、载药纳米胶束中的至少一种，第一聚合物水溶液中，第一聚合物的质量浓度为0.5～3％w/v。
可选的，第一聚合物水溶液中，亲水性药物的质量浓度为1～1000μg mg/mL。
可选的，第一聚合物水溶液中，亲水性药物的质量浓度为1～500μg mg/mL。
可选的，第一聚合物水溶液中，细胞外基质的质量浓度为1～6mg/mL。
可选的，第一聚合物水溶液中，细胞外基质的质量浓度为1～3mg/mL。
可选的，第一聚合物水溶液中，载药纳米胶束的质量浓度为30～200μg/mL。
可选的，第一聚合物水溶液中，载药纳米胶束的质量浓度为50～150μg/mL。
可选的，含邻羟基的聚合物的水溶液中，含邻羟基的聚合物的质量浓度为0.5～10％w/v。
可选的，含邻羟基的聚合物的水溶液中，含邻羟基的聚合物的质量浓度为0.5～5％w/v。
可选的，含邻羟基的聚合物的水溶液中，含邻羟基的聚合物的质量浓度为0.5～3％w/v。
可选的，第一聚合物水溶液与含邻羟基的聚合物的水溶液的体积比为1:0.5～1.5。
可选的，第一聚合物水溶液与含邻羟基的聚合物的水溶液的体积比为1:0.8～1.2。
可选的，第一聚合物水溶液与含邻羟基的聚合物的水溶液的体积比为1:1。
可选的，将第一聚合物的水溶液与含邻羟基的聚合物的水溶液混合，得到所述可注射水凝胶，第一聚合物的水溶液中含有亲水性药物、细胞外基质、载药纳米胶束中的至少一种，第一聚合物水溶液中，第一聚合物的质量浓度为1％w/v，聚乙烯醇水溶液中，聚乙烯醇的质量浓度为1％w/v，第一聚合物水溶液与聚乙烯醇水溶液等体积混合，得到水凝胶。
可选的，含氨基的聚合物为壳聚糖、壳聚糖季铵盐、聚赖氨酸、聚乙烯亚胺、明胶中的至少一种。
可选的，含羧基的聚合物为海藻酸钠、透明质酸、肝素、羧甲基纤维素中的至少一种。
可选的，含羟基的聚合物为淀粉、纤维素(甲基纤维素)、龙胶、魔芋胶、阿拉伯树胶、木质素、葡聚糖、环糊精中的至少一种。
可选的，含邻羟基的聚合物为聚乙烯醇、海藻酸钠、透明质酸、葡聚糖、淀粉中的至少一种。
可选的，含邻羟基的聚合物为聚乙烯醇。
可选的，含羧基的苯硼酸为4-羧基苯硼酸、2-羧基苯硼酸、3-羧基苯硼酸、4-羧基-3-氟苯硼酸、3-羧基-4-氟苯硼酸、5-羧基-2-氯苯硼酸及4-羧基-2-氯苯硼酸中的至少一种；
含氨基的苯硼酸为4-氨基苯硼酸、2-氨基苯硼酸、3-氨基苯硼酸、3-氨基甲酰基苯硼酸、3-氨基-4-氟苯硼酸、3-氨基-4-甲基苯硼酸中的至少一种；
含羟基的苯硼酸为4-羟基苯硼酸、3-氟-4-羟基苯硼酸、2-氟-3-羟基苯硼酸、2-氟-5-羟基苯硼酸、3-羟基-4-氯苯硼酸、3-氟-4-羟基苯硼酸中的至少一种。
可选的，所述细胞外基质为胶原蛋白、非胶原蛋白、弹性蛋白、蛋白聚糖、氨基聚糖中的至少一种。
细胞外基质区别于药物，只要作用在于促进细胞增值、生长，加快修复进程。
可选的，所述细胞外基质为碱性成纤维细胞生长因子(bFGF)、血管内皮生长因子(VEGF)、重组人源化胶原蛋白、去铁胺(DFO)中的至少一种。
可选的，所述细胞外基质为重组人源化胶原蛋白。
可选的，所述疏水性药物为抗炎药、镇痛药、促血管生成药、利尿剂、血管紧张素转换酶抑制剂、β受体阻滞剂、洋地黄类药物、醛固酮拮抗剂、血管紧张素二受体拮抗剂、抗凝药、抗血小板药中的至少一种。
可选的，所述疏水性药物为萘普生、舒瑞伐他汀、姜黄素、阿司匹林中的至少一种。
本申请还提供所述制备方法制备得到具有抗炎及促修复功能的可注射水凝胶。
本申请还提供了一种用于修复心脏损伤的水凝胶，所述水凝胶为作用于心脏损伤部位的上述的可注射水凝胶。
本申请还提供了一种用于治疗心衰的水凝胶，所述水凝胶为作用于心脏病变部位的上述的可注射水凝胶。
本申请还提供了一种用于治疗心肌梗死的水凝胶，所述水凝胶为作用于心肌梗死部位的所述的可注射水凝胶。
本申请还提供了所述的具有抗炎及促修复功能的可注射水凝胶在心脏损伤修复中的应用。
本申请还提供了所述的具有抗炎及促修复功能的可注射水凝胶在治疗心衰中的应用。
本申请还提供了所述的具有抗炎及促修复功能的可注射水凝胶在治疗心肌梗死中的应用。
本申请还提供了一种心脏损伤修复方法，将所述的可注射水凝胶作用于心脏损伤部位。
本申请还提供了一种治疗心衰的方法，将所述的可注射水凝胶作用于心脏病变部位。
本申请还提供了一种心脏损伤修复方法，在心脏病变部位注射所述的可注射水凝胶。
本申请还提供了一种治疗心衰的方法，在心肌梗死部位注射所述的可注射水凝胶。
本申请还提供了一种治疗心肌梗死的方法，在心肌梗死部位注射所述的可注射水凝胶。
上述制备方法以及制备得到的可注射水凝胶至少产生如下有益效果之一：
1、从材料上说，用于制备具有抗炎及促修复功能水凝胶载体的材料为天然高分子材料，来源广泛且成本较低，同时具备良好的生物相容性；
2、使用的亲水性细胞外基质其免疫和排斥反应均较小，且溶解度良好，是一种非常安全 的生物细胞外基质；
3.双响应水凝胶制备过程简单且理化性质优越，如成胶时间短以及可注射性能良好等；
4.双响应水凝胶同时具备pH和ROS响应性能，可实现疏水性药物和亲水性细胞外基质的响应按需释放；
5.双响应水凝胶通过抗氧化、抗炎和促血管再生机制促进受损心脏的快速修复。
综上所述，双响应水凝胶的微环境响应按需刺激药物释放的策略和自身良好的生物相容性将实现心肌梗死部位的快速修复。
本申请还提供一种具有抗炎及促修复功能的可注射水凝胶，包括以下原料成分：含氨基和邻羟基的生物大分子、含羧基和邻羟基的生物大分子和含有氨基、羟基或羧基的苯硼酸。
可选的，还包括以下成分：亲水性药物和/或疏水性药物。
本申请还提供了一种具有抗炎及促修复功能的可注射水凝胶，包括以下原料成分：亲水性药物、疏水性药物、含氨基和邻羟基的生物大分子、含羧基和邻羟基的生物大分子和含有氨基、羟基或羧基的苯硼酸。
进一步地，亲水性药物包括生长因子、多肽类药、基因药和水溶性蛋白药。
进一步地，疏水性药物包括抗炎药、促血管生成药、促细胞增殖药和促细胞迁移药。
进一步地，抗炎药包括阿司匹林、扑热息痛、阿莫西林和保泰松等脂溶性药物。
进一步地，含氨基和邻羟基的生物大分子包括壳聚糖、海藻酸钠改性产物、透明质酸改性产物中的至少一种。
海藻酸钠改性产物和透明质酸改性产物是在海藻酸钠和透明质酸主要是在海藻酸钠和透明质酸中引入氨基，同理，天然高分子中如果能通过化学反应引入供反应的氨基、羧基或邻羟基，理论上都可以作为可注射水凝胶的原料。
进一步地，含羧基和邻羟基的生物大分子包括海藻酸钠、透明质酸和其改性产物、羧甲基纤维素、或羧甲基纤维素改性产物。
进一步地，所述含氨基、羟基或羧基的苯硼酸为邻位氨基苯硼酸、间位氨基苯硼酸、对位氨基苯硼酸、邻位羟基苯硼酸、间位羟基苯硼酸、对位羟基苯硼酸、邻位羧基苯硼酸、间位羧基苯硼酸、或对位羧基苯硼酸。
本申请还提供了一种用于修复心脏损伤的水凝胶，所述水凝胶为作用于心脏损伤部位的上述的可注射水凝胶。
本申请还提供了一种用于治疗心衰的水凝胶，所述水凝胶为作用于心脏病变部位的上述的可注射水凝胶。
本申请还提供了一种用于治疗心肌梗死的水凝胶，所述水凝胶为作用于心肌梗死部位的所述的可注射水凝胶。
本申请还提供了所述的具有抗炎及促修复功能的可注射水凝胶在心脏损伤修复中的应用。
本申请还提供了所述的具有抗炎及促修复功能的可注射水凝胶在治疗心衰中的应用。
本申请还提供了所述的具有抗炎及促修复功能的可注射水凝胶在治疗心肌梗死中的应用。
本申请还提供了一种心脏损伤修复方法，将所述的可注射水凝胶作用于心脏损伤部位。
本申请还提供了一种治疗心衰的方法，将所述的可注射水凝胶作用于心脏病变部位。
本申请还提供了一种心脏损伤修复方法，在心脏病变部位注射所述的可注射水凝胶。
本申请还提供了一种治疗心衰的方法，在心肌梗死部位注射所述的可注射水凝胶。
本申请还提供了一种治疗心肌梗死的方法，在心肌梗死部位注射所述的可注射水凝胶。
上述的具有抗炎及促修复功能的可注射水凝胶的制备方法，包括以下步骤：
(1)合成两亲性聚合物，作为包载疏水性药物的载体；
(2)通过将两亲性聚合物和疏水性药物共同溶解在良性溶剂中，然后在不断搅拌的过程中缓慢滴入到不良溶剂(例如去离子水)中制备载药纳米胶束；
(3)通过羧基和氨基的酰胺化反应制备接枝苯硼酸基团的聚合物；
(4)将接枝苯硼酸基团的聚合物和亲水性药物溶解在载药胶束溶液中，通过加入适量碱性溶液调整混合溶液pH值到8.5，制得。
进一步地，步骤(2)中载药纳米胶束呈球形，粒径均一，具有较高的药物装载率和包封率。
进一步地，步骤(2)中载药纳米胶束的载体为两亲性聚合物。
进一步地，步骤(2)中载药纳米胶束用于包载疏水性药物。
进一步地，步骤(2)中载药纳米胶束在炎症部位结构会崩解，加速释放药物。
进一步地，上述具有抗炎及促修复功能的可注射水凝胶仅仅通过改变溶液pH值就可制得。
进一步地，上述具有抗炎及促修复功能的可注射水凝胶具有自愈合、重塑、可注射等多种动态功能。
进一步地，上述具有抗炎及促修复功能的可注射水凝胶可通过pH和活性氧(ROS)响应介导的可控药物释放系统工作。
进一步地，上述具有抗炎及促修复功能的可注射水凝胶具有良好的细胞相容性，在体内无不良反应。
上述的具有抗炎及促修复功能的可注射水凝胶在制备或用作心脏修复中的应用。
上述水凝胶至少产生如下有益效果之一：
1、多响应性水凝胶是由一种单一和确定的聚合物成分制备。
2、多响应性水凝胶是通过最少的合成步骤和操作过程来制备成功的；
3、可注射水凝胶配方在装载两种不同药物之后仍然具有良好的流变学性能和保持结构
完整性；
4、可注射水凝胶配方具有自愈合、重塑、注射等多种动态功能；
5、可注射水凝胶配方在炎症区域具有超强的响应性释药特性；
7、可注射水凝胶配方具有良好的细胞相容性，在体内无不良反应。
9、具有操作简单、反应条件温和易行等优点，通过此方法制作的具有抗炎及促修复功能的可注射水凝胶，可增大在水凝胶敷料中的药物装载量、药物装载种类等。不仅可以更换不同的聚合物形成多种类水凝胶，还可更换不同的药物包括亲水性药物或疏水性药物赋予水凝胶不同的活性功能。
10、本申请提供的水凝胶可注射性良好，注射在心脏受损部位，免疫和排斥反应较小，通过其负载的亲水性药物和/或疏水性药物在心脏受损部位处通过抗氧化、抗炎和促血管再生等多种作用促进受损心脏快速修复。
本申请还提供一种具有抗炎及促修复功能的可注射水凝胶的制备方法，包括以下步骤：
步骤1，用含邻位羟基的功能聚合物和含氨基、羟基或羧基的苯硼酸反应制得侧链接枝苯硼酸的聚合物；所述含邻位羟基的功能聚合物为含氨基和邻羟基的生物大分子或含羧基和邻羟基的生物大分子；
步骤2，将苯硼酸聚合物溶解于水中，调整混合溶液pH值至8-9，制得水凝胶。
可选的，将亲水性药物和/或包载有疏水性药物的胶束与苯硼酸聚合物水溶液混合，调整混合溶液pH值至8-9，制得。
可选的，用良性溶剂溶解两亲性药物载体和疏水性药物，在搅拌状态下向其中缓慢加入水，制得载药胶束溶液，将亲水性药物和/或载药胶束溶液与苯硼酸聚合物水溶液混合，调整混合溶液pH值至8-9，制得。本申请还提供了一种具有抗炎及促修复功能的可注射水凝胶的制备方法，包括以下步骤：
(1)用含邻位羟基的功能聚合物和含氨基、羟基或羧基的苯硼酸反应制得苯硼酸聚合物；
(2)制备两亲性药物载体；
(3)用良性溶剂将步骤(2)中制得的两亲性药物载体和疏水性药物溶解，然后在搅拌状态下向其中加入水，制得载药胶束溶液；
(4)将亲水性药物和步骤(1)中制得的苯硼酸聚合物溶解于步骤(3)制得的载药胶束溶液中，然后调整混合溶液pH值至8-9，制得。
苯硼酸聚合物中同时含有苯硼酸基团和邻羟基，由于邻羟基和苯硼酸基团的数量以及位阻所限，需要调整pH值，以形成凝胶。
进一步地，步骤(1)中的具体反应过程为：将含邻位羟基的功能聚合物溶解得含邻位羟基的功能聚合物溶液，向该溶液中加入缩合剂和含氨基、羟基或羧基的苯硼酸，于30-40℃条件下搅拌20-30h后在去离子水中透析，然后再进行冷冻干燥得纯化的苯硼酸聚合物。
进一步地，邻位羟基的功能聚合物、缩合剂和氨基、羟基或羧基的苯硼酸的质量比为4-6:4-6:1-2。
进一步地，步骤(1)中的具体反应过程为：将含邻位羟基的功能聚合物溶解得含邻位羟基的功能聚合物溶液，向该溶液中加入缩合剂和含氨基、羟基或羧基的苯硼酸，于37℃条件下搅拌24h后在去离子水中透析3天，然后再进行冷冻干燥得纯化的苯硼酸聚合物，其中，邻位羟基的功能聚合物、缩合剂和氨基、羟基或羧基的苯硼酸的质量比为5:4.8:1.95。
进一步地，缩合剂包括1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐和N-羟基琥珀酰亚胺。
进一步地，步骤(2)中的具体反应过程为：将亲水高分子聚合物和疏水性分子在80℃条件下完全溶解于二甲基亚砜中，并向其中加入N,N'-二环己基碳二亚胺和4-二甲氨基吡啶，在80℃条件下连续搅拌48h，将反应物在水中透析2天后去除未反应的疏水性分子，最后进行冻干备用，其中，亲水高分子、疏水分子、N,N'-二环己基碳二亚胺和4-二甲氨基吡啶的质量比为2:1.5:1:0.5。
进一步地，亲水高分子聚合物包括透明质酸、淀粉、纤维素、聚丙烯酸、聚丙烯酞胺、聚乙烯醇、羟基乙酸和聚赖氨酸。
进一步地，疏水性分子包括胆固醇、聚烯烃、聚碳酸酯、聚酰胺、聚丙烯腈、聚酯、聚乳酸和丙烯酸酯。
进一步地，步骤(3)中的具体反应过程为：将步骤(2)中制得的两亲性药物载体和疏水性药物溶解于良性溶剂中，然后加热70-90℃，在搅拌条件下向其中逐滴滴加水，透析后制得浓度为0.5-1.5mg/mL的载药胶束溶液。
进一步地，步骤(3)中的具体反应过程为：将0.04份步骤(2)中制得的两亲性药物载体和0.008份疏水性药物溶解于良性溶剂中，然后加热80℃，在搅拌条件下向其中逐滴滴加水，透析后制得浓度为1mg/mL的载药胶束溶液。
进一步地，步骤(3)中的良性溶剂包括DMSO、DMF、甲醇和丙酮。
进一步地，步骤(4)中的具体反应过程为：将亲水性药物和步骤(1)中制得的苯硼酸聚合物溶解于步骤(3)中制得的载药胶束溶液中，使得载药胶束溶液中苯硼酸聚合物的浓度为7-11％w/v。
进一步地，在含有载药胶束和/或亲水性药物的苯硼酸聚合物水溶液中加入碱性溶液，调整pH值为8.5，制得所述可注射水凝胶。
进一步地，步骤(4)中载药胶束溶液中苯硼酸聚合物的浓度为9％w/v。
进一步地，含邻位羟基的功能聚合物为含氨基和邻羟基的生物大分子或含羧基和邻羟基的生物大分子。
进一步地，含羧基和邻羟基的生物大分子为海藻酸钠、透明质酸或其改性产物，含氨基、羟基基团的苯硼酸通过酰胺化反应或酯化反应接枝到侧链含有羧基基团并含有邻位羟基的生物大分子侧链上；所述含氨基和邻羟基的生物大分子为壳聚糖或其改性产物，带羧基基团的苯硼酸通过酰胺化反应接枝到侧链含有氨基基团并含有邻位羟基的生物大分子侧链上。
进一步地，所述含氨基、羟基或羧基的苯硼酸为邻位氨基苯硼酸、间位氨基苯硼酸、对位氨基苯硼酸、邻位羟基苯硼酸、间位羟基苯硼酸、对位羟基苯硼酸、邻位羧基苯硼酸、间位羧基苯硼酸、或对位羧基苯硼酸。
进一步地，亲水性药物包括生长因子、基因和水溶性蛋白药中的一种。
进一步地，疏水性药物包括抗炎药、促血管生成药、促细胞增殖药和促细胞迁移药中的一种。
进一步地，抗炎药包括阿司匹林、扑热息痛、阿莫西林和保泰松中的一种。
本申请还提供了一种用于修复心脏损伤的水凝胶，所述水凝胶为作用于心脏损伤部位的上述的可注射水凝胶。
本申请还提供了一种用于治疗心衰的水凝胶，所述水凝胶为作用于心脏病变部位的上述的可注射水凝胶。
本申请还提供了一种用于治疗心肌梗死的水凝胶，所述水凝胶为作用于心肌梗死部位的所述的可注射水凝胶。
本申请还提供了所述的具有抗炎及促修复功能的可注射水凝胶在心脏损伤修复中的应用。
本申请还提供了所述的具有抗炎及促修复功能的可注射水凝胶在治疗心衰中的应用。
本申请还提供了所述的具有抗炎及促修复功能的可注射水凝胶在治疗心肌梗死中的应用。
本申请还提供了一种心脏损伤修复方法，将所述的可注射水凝胶作用于心脏损伤部位。
本申请还提供了一种治疗心衰的方法，将所述的可注射水凝胶作用于心脏病变部位。
本申请还提供了一种心脏损伤修复方法，在心脏病变部位注射所述的可注射水凝胶。
本申请还提供了一种治疗心衰的方法，在心肌梗死部位注射所述的可注射水凝胶。
本申请还提供了一种治疗心肌梗死的方法，在心肌梗死部位注射所述的可注射水凝胶。
本申请提供的水凝胶可用于注射入心脏，基于使用场景的不同，对于亲水性药物、疏水 性药物以及细胞外基质的选择也不完全相同，根据实际需要进行适当选择。
上述方法制备的水凝胶至少产生如下有益效果之一：
1、水凝胶是由一种单一和确定的聚合物成分制备获得，该水凝胶的合成步骤简单，便于操作，反应条件温和，在装载两种不同的药物后仍然具有良好的流变学性能和完整的结构，且该水凝胶具有自愈合、重塑、注射等多种动态功能，具有良好的细胞相容性，在体内无不良反应。
3、可注射水凝胶中的苯硼酸酯键在高活性氧和低pH值的情况下快速断裂，水凝胶结构被破坏，从而快速响应释放出亲水性药物和疏水性药物。
4、可注射水凝胶中同时负载细胞外基质、以及亲水性药物和/或疏水性药物，通常情况下，亲水性药物和疏水性药物分子较小，细胞外基质分子较大，由于位阻大小不同，首先释放分子较小的亲水性药物和疏水性药物，对受伤组织进行消炎，然后释放细胞外基质促进细胞再生，更有利于组织修复。
由于疏水性药物以两亲性聚合物作为载体，因此通过调整两亲性聚合物的结构、用量等参数，可以调整疏水性药物负载在两亲性聚合物后的整体胶束大小，进而调整其相对于其他物质从水凝胶中释放的次序。
附图说明
图1是本申请实施例1中CMC和CMC-BA的核磁氢谱图；
图2是本申请实施例1中载药纳米颗粒的粒径大小图；
图3是本申请实施例1中水凝胶的成胶图；
图4是本申请实施例1中水凝胶的可注射性结果图；
图5是本申请实施例1中不同水凝胶处理后的内皮细胞在24，48和72小时的细胞存活率结果图；
图6是本申请实施例1中不同水凝胶处理后的心肌细胞在24，48和72小时的细胞存活率结果图；
图7本申请实施例1中不同水凝胶处理后的巨噬细胞在24和48小时的IL-6和TNF-α的表达结果图；
图8是本申请实施例1中大鼠心脏的H&E染色和Masson染色图；
图9是本申请实施例6中所述ALG、BA和ALG-BA的核磁氢谱图；
图10是本申请实施例6中所述CHOL、HA和HA-CHOL核磁氢谱图；
图11是苯硼酸接枝羧甲基纤维素功能聚合物的反应过程示意图。
具体实施方式
下面结合附图对本申请的具体实施方式做详细的说明。
在以下实施例中，基体以外的化学试剂除特别声明的外均为化学纯。
实施例1
一种具有抗炎及促修复功能的可注射水凝胶的制备方法，其反应方程式及制备步骤参见图11所示。
(1)苯硼酸接枝羧甲基纤维素功能聚合物(CMC-BA)的制备
精密称取羧甲基纤维素(CMC，10.00g)和3-氨基苯硼酸(BA，6.50g)溶于500mL的MES缓冲液(0.1mol，pH5.0)中，向其中加入1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDC·HCl，4.00g)和N-羟基琥珀酰亚胺(NHS，1.5g)。然后，在37℃条件下搅拌48h，最后在去离子水中(pH7.4)透析3天，3天后用冻干机对其进行冷冻干燥，得到纯化的CMC-BA；
(2)载药纳米颗粒(PLGA@Cur)的制备
将聚乳酸-羟基乙酸共聚物(PLGA，60mg)和姜黄素(Cur，12mg)在37℃条件下完全溶解于DMSO(5mL)中，然后在搅拌条件下逐滴加入到15mL去离子水中，在37℃条件下连续搅拌4h；然后将其在水中透析3天，得到PLGA@Cur溶液，冻干后避光在4℃储存；
(3)水凝胶的制备
将包含人源重组III型胶原蛋白(2mg/mL)和PLGA@Cur(100μg/mL)的CMC-BA(1％w/v)水溶液与质量分数1％聚乙烯醇溶液等体积混合，可注射水凝胶可立即制备。
实施例2
一种具有抗炎及促修复功能的可注射水凝胶的制备方法，制备步骤如下：
(1)苯硼酸接枝透明质酸功能聚合物(HA-BA)的制备
精密称取透明质酸(HA，10.00g)和4-氨基苯硼酸(BA，6.50g)溶于500mL的MES缓冲液(0.1mol，pH5.0)中，向其中加入1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDC·HCl，4.00g)和N-羟基琥珀酰亚胺(NHS，1.5g)。然后，在37℃条件下搅拌48h，最后在去离子水中(pH7.4)透析3天，3天后用冻干机对其进行冷冻干燥，得到纯化的HA-BA；
(2)载药纳米颗粒(PLGA@Nap)的制备
将聚乳酸-羟基乙酸共聚物(PLGA，60mg)和萘普生(Nap，12mg)在37℃条件下完全溶解于DMSO(5mL)中，然后在搅拌条件下逐滴加入到15mL去离子水中，在37℃条件下连续搅拌4h；然后将其在水中透析3天，得到PLGA@Nap溶液，冻干后避光在4℃储存；
(3)水凝胶的制备
将包含人源重组I型胶原蛋白(2mg/mL)和PLGA@Nap(100μg/mL)的HA-BA(1％w/v水)溶液与1％聚乙烯醇溶液等体积混合，可注射水凝胶可立即制备。
实施例3
一种具有抗炎及促修复功能的可注射水凝胶的制备方法，制备步骤如下：
(1)苯硼酸接枝淀粉功能聚合物的制备
精密称取淀粉(10.00g)和4-羧基苯硼酸(6.50g)溶于500mL的去离子水(pH7.4)中，向其中加入二环己基碳二亚胺(DCC，1.00g)和4-二甲氨基吡啶(DMAP，0.50g)。然后，在37℃条件下搅拌48h，最后在去离子水中(pH7.4)透析3天，3天后用冻干机对其进行冷冻干燥，得到纯化的功能聚合物；
(2)载药纳米颗粒的制备
将聚乙二醇磷脂(DSPE-PEG，60mg)和舒瑞伐他汀(12mg)在37℃条件下完全溶解于DMSO(5mL)中，然后在搅拌条件下逐滴加入到15mL去离子水中，在37℃条件下连续搅拌4h；然后将其在水中透析3天，得到载药纳米颗粒溶液，冻干后避光在4℃储存；
(3)水凝胶的制备
将包含碱性成纤维细胞生长因子(1mg/mL)和上述制备的载药纳米颗粒(100μg/mL)的功能聚合物(1％w/v)水溶液与1％聚乙烯醇溶液等体积混合，可注射水凝胶可立即制备。
实施例4
一种具有抗炎及促修复功能的可注射水凝胶的制备方法，制备步骤如下：
(1)苯硼酸接枝聚赖氨酸功能聚合物的制备
精密称取聚赖氨酸(10.00g)和3-羧基苯硼酸(6.50g)溶于500mL的MES缓冲液(0.1mol，pH5.0)中，向其中加入1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDC·HCl，4.00g)和N-羟基琥珀酰亚胺(NHS，1.5g)。然后，在37℃条件下搅拌48h，最后在去离子水中(pH7.4)透析3天，3天后用冻干机对其进行冷冻干燥，得到纯化的功能聚合物；
(2)载药纳米颗粒的制备
将磷脂聚乙二醇聚乳酸-羟基乙酸共聚物(DSPE-PEG-PLGA,60mg)和阿司匹林(12mg)在37℃条件下完全溶解于DMSO(5mL)中，然后在搅拌条件下逐滴加入到15mL去离子水中，在37℃条件下连续搅拌4h；然后将其在水中透析3天，得到载药纳米颗粒溶液，冻干后避光在4℃储存；
(3)水凝胶的制备
将包含血管内皮生长因子(1mg/mL)和上述制备的载药纳米颗粒(100μg/mL)的功能聚合物(1％w/v)水溶液与1％聚乙烯醇溶液等体积混合，可注射水凝胶可立即制备。
实施例5
一种具有抗炎及促修复功能的可注射水凝胶的制备方法，制备步骤如下：
(1)苯硼酸接枝海藻酸钠功能聚合物的制备
精密称取海藻酸钠10.00g)和3-羟基苯硼酸(6.50g)溶于500mL的去离子水(pH 7.4)中，向其中加入二环己基碳二亚胺(DCC，1.00g)和4-二甲氨基吡啶(DMAP，0.50g)。然后，在37℃条件下搅拌48h，最后在去离子水中(pH 7.4)透析3天，3天后用冻干机对其进行冷冻干燥，得到纯化的功能聚合物；
(2)载药纳米颗粒的制备
将聚乙二醇聚乳酸共聚物(PEG-PLA，60mg)和维拉帕米(12mg)在37℃条件下完全溶解于DMSO(5mL)中，然后在搅拌条件下逐滴加入到15mL去离子水中，在37℃条件下连续搅拌4h；然后将其在水中透析3天，得到载药纳米颗粒溶液，冻干后避光在4℃储存；
(3)水凝胶的制备
将包含芒果苷(1mg/mL)和上述制备的载药纳米颗粒(100μg/mL)的功能聚合物(1％w/v)水溶液与1％聚乙烯醇溶液等体积混合，可注射水凝胶可立即制备。
试验例1
以实施例1中制得的物质为例，进行检测，具体操作过程及结果如下：
一、对步骤(1)中制得的CMC-BA进行检测，具体结果见图1，如图1所示，CMC-BA聚合物的 1H NMR谱上存在苯硼酸基团的芳香质子峰(δ～7.5ppm)，证明CMC-BA聚合物的成功制备。
二、对步骤(2)中制得的载药纳米粒子进行粒径检测，如图2所示，粒径分布结果表明载药前PLGA纳米粒子的粒径为126.4nm，载药后的粒径为133.8nm，且载药前和载药后的纳米粒子的PDI均小于0.2，证明其良好的均一分散性，证明载药纳米颗粒的成功制备。
以下实验图例，如无特殊说明，水凝胶组1-4组分别代表以下组合：水凝胶组1(Hydrogel 1)：空白水凝胶；水凝胶组2(Hydrogel 2)：装载PLGA@Cur的水凝胶；水凝胶组3(Hydrogel 3)：装载重组人源III型胶原蛋白的水凝胶；水凝胶组4(Hydrogel 4)：装载PLGA@Cur和重组人源III型胶原蛋白的水凝胶。
三、对步骤(3)制得的水凝胶的成胶性能和注射性能进行检测。
图3为水凝胶的成胶图，证明水凝胶的制备成功；图4为水凝胶的可注射性图，水凝胶能从1mL注射器里被注射出来，并能注射成心脏的英文字母“HEART”，证明了水凝胶良好的可注射性。
四、水凝胶的生物相容性检测
采用人脐静脉内皮细胞(HUVECs)对水凝胶的生物相容性进行评价。将在无菌条件下制备的水凝胶在pH 5.0和包含1mM H 2O 2的细胞培养基(0.2g/mL)中浸泡24h。在96孔板接种HUVECs细胞，接种密度为每孔8000个。12h后，移出细胞培养液，加入不同的水凝胶浸出液继续孵育细胞。24h、48h和72h的HUVECs细胞的增殖率用CCK-8进行检测。孵育24h、48h、72h后，每孔加入10％CCK-8的新鲜培养基溶液。2h后，通过用酶标仪测定450nm处的吸收值来计算细胞增殖率。
水凝胶对内皮细胞的存活率结果如图5所示，结果表明，所有水凝胶组对内皮细胞在24h，48h，和72h均显示无毒性，表明水凝胶具有良好的细胞相容性。此外，水凝胶在负载重组人源III型胶原蛋白后，细胞存活率高于对照组和空白水凝胶组，表明重组人源III型胶原蛋白有效地促进了内皮细胞的增殖。
五、水凝胶的促心肌细胞增殖能力
将心肌细胞H9C2接种在96孔板，接种密度为每孔8000个。12h后，移出细胞培养液，加入不同的水凝胶浸出液继续孵育细胞。24h、48h和72h的H9C2细胞的增殖率用CCK-8进行检测。水凝胶对心肌细胞的存活率结果如图6所示，结果表明，水凝胶在负载重组人源III型胶原蛋白后，相比对照组和空白水凝胶组，细胞增殖最多，表明重组人源III型胶原蛋白有效地促进了心肌细胞的增殖。
六、水凝胶抑制炎症相关蛋白的表达
ELISA实验
按10 6个细胞每孔的密度巨噬细胞分别接种于6孔板，加入脂多糖与巨噬细胞预孵育2h。然后加入2mL水凝胶提取液孵育细胞。在24h，48h，吸取细胞培养上清液用肿瘤坏死因子-α(TNF-α)和白介素-6(IL-6)ELISA试剂盒测定上清液中肿瘤坏死因子-α和白介素-6(IL-6)的浓度。结果如图7所示，水凝胶4组处理后的巨噬细胞的TNF-α和IL-6的表达量低于脂多糖处理组和水凝胶1组。以上结果表明水凝胶4组能够有效抑制巨噬细胞的炎症反应。
七、水凝胶的体内心脏修复效果检测
为了研究水凝胶对体内心脏修复效果的影响，建立了大鼠心肌梗死疾病模型。在第28天的苏木精伊红(H&E)染色结果、Masson染色结果如图8所示，水凝胶4组的心脏组织的心室壁厚度最高，且疤痕区域面积最小，表明水凝胶治疗组4有效地降低了心肌梗死部位的疤痕 区域，证明其心脏修复功能良好。
实施例1水凝胶的制备过程及促进心肌修复的机制具体如下：
首先，通过亲疏水相互作用将姜黄素有效装载到PLGA纳米颗粒中。利用酰胺反应将3-氨基苯硼酸接枝到羧甲基纤维素侧链上得到功能聚合物，最后利用功能聚合物的硼酸基团与聚乙烯醇的羟基基团易形成硼酯键的特性制备水凝胶，同时，在凝胶化过程中，加入包载姜黄素的PLGA纳米颗粒和重组人源III型胶原蛋白成功得到多功能水凝胶，该水凝胶将在酸性环境和高ROS下降解，以“按需”响应可控的方式释放抗炎药姜黄素和重组人源III型胶原蛋白。释放的姜黄素抑制炎症相关因子的表达，能够有效地降低心肌梗死部位的炎症反应；重组人源III型胶原蛋白能够促进内皮细胞和心肌细胞的增殖，并促进血管生成相关因子的表达，从而促进梗死部位新生血管的生成；通过抗炎和促血管联合治疗策略加速炎症环境下受损心脏的修复，并且有效改善了心梗发生后的心脏功能。
以下实施例中：
所用的载药纳米胶束只要用亲水和疏水的高分子聚合物通过共价结合后即可制成胶束。如使用透明质酸等为亲水端，可以选用胆固醇等为疏水端合成载药胶束。
具有氨基和邻羟基的生物大分子为壳聚糖及它天然大分子中的一种。
具有羧基和邻羟基的生物大分子为海藻酸钠和透明质酸及其改性产物中的一种。
提供苯硼酸基团的化合物如邻位氨基苯硼酸、间位氨基苯硼酸、对位氨基苯硼酸、邻位羧基苯硼酸、间位羧基苯硼酸、和对位羧基苯硼酸，邻位羟基苯硼酸、间位羟基苯硼酸以及对位羧基苯硼酸中的一种。
疏水性药物按药理活性可分为抗炎药物，促血管生成药物以及促细胞增殖、迁移药物等的一种。
所述亲水性药物按药理活性可分为生长因子以及DNA、RNA以及蛋白药物等的一种。
可注射水凝胶结构单元是带氨基基团的苯硼酸通过酰胺化反应接枝到侧链含有羧基基团并含有邻位羟基的聚合物侧链上，此类聚合物可以是海藻酸钠，透明质酸及其改性产物中的一种。
可注射水凝胶结构单元也可以是带羧基基团的苯硼酸通过酰胺化反应接枝到侧链含有氨基基团并含有邻位羟基的聚合物侧链上，此类聚合物是壳聚糖及其它天然大分子的一种。
在以下实施例中，基体以外的化学试剂除特别声明的外均为化学纯。
实施例6
一种具有抗炎及促修复功能的可注射水凝胶的制备方法，包括如下步骤获得：
1)苯硼酸改性海藻酸盐(ALG-BA)的合成
精密称取海藻酸钠(ALG，5.00g)溶于500mL的MES缓冲液(0.1mol，pH5.0)中，向其中加入1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDC·HCl，4.80g，25.0mmol)和3-氨基苯硼酸(BA，1.95g，12.5mmol)。然后，在37℃条件下搅拌24h，最后在去离子水中(pH7.4)透析3天。3天后用冻干机进行冷冻干燥，得到纯化的ALG-BA。
2)胆固醇修饰透明质酸(HA-CHOL)的合成
HA(2.00g)和胆固醇(CHOL，1.50g)在80℃条件下完全溶解于二甲基亚砜(DMSO，30mL)中，加入N,N'-二环己基碳二亚胺(DCC，1.00g)和4-二甲氨基吡啶(DMAP，0.50g)，在 80℃条件下连续搅拌48h。然后将混合物在水中透析2天，用离心分离法去除多余的胆固醇，最后将成品进行冻干备用。
3)载药胶束(MIC)的制备
将HA-CHOL(40.0mg)和萘普生(Nap，8.00mg)溶于DMSO(10mL)中，加热至80℃。然后在缓慢搅拌的情况下，将10mL H 2O逐滴加入混合溶液中。最终，混合物在水中透析2天，制备得到载药胶束溶液。
4)水凝胶的制备
分别将步骤(1)中制得的ALG-BA(1.00g)和阿米卡星(AM，100mg)溶于步骤(3)制得的载药胶束溶液(1mg/mL)中，使得载药胶束溶液中ALG-BA的最终浓度为9％w/v，使用碱性溶液调整载药胶束溶液的pH到8.5时，载药胶束溶液迅速的成胶，形成水凝胶。
实施例7
一种具有抗炎及促修复功能的可注射水凝胶的制备方法，制备步骤如下：
(1)苯硼酸改性透明质酸(HA-BA)的合成
精密称取5g透明质酸溶于500mL的MES缓冲液(0.1mol，pH 5.0)中，加入1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDC·HCl，4.80g，25.0mmol)和3-氨基苯硼酸(BA，1.95g，12.5mmol)，然后，在37℃搅拌24h，最后在去离子水中(pH 7.4)透析3天，用冻干机进行冷冻干燥，得到纯化的HA-BA；
(2)两亲性药物载体
将海藻酸钠(2.00g)和胆固醇(CHOL，1.50g)完全溶解于二甲基亚砜和水的混合溶液中(DMSO，30mL)中，并向其中加入N,N'-二环己基碳二亚胺(DCC，1.00g)和4-二甲氨基吡啶(DMAP，0.50g)，连续搅拌48h；然后将混合物在水中透析2天，用离心分离法去除多余的胆固醇；最后将成品进行冻干备用；
(3)载药胶束的制备
将10mg步骤(2)中的两亲性药物载体和1mg抗炎药物(吡罗昔康)溶于DMSO(1mL)中，然后在缓慢搅拌的情况下，将其逐滴加入到10ml水中，最终，混合物在水中透析2天；
(4)水凝胶的制备
在制备可注射水凝胶时，分别将1g HA-BA聚合物和100mg细胞生长因子溶于载药胶束溶液(1mg/mL)中，添加适量氢氧化钠溶液调整溶液的pH到8.5时，溶液能迅速成胶。
实施例8
一种具有抗炎及促修复功能的可注射水凝胶的制备方法，制备步骤如下：
(1)苯硼酸改性壳聚糖的合成
精密称取5g壳聚糖溶于500mL MES缓冲液(0.1mol,pH 5.0)中，加入EDC·HCl(4.80g，25.0mmol)和2-羧基苯硼酸(BA，1.95g，12.5mmol)。然后，在37℃搅拌24h，最后在去离子水中(pH 7.4)透析3天。用冻干机进行冷冻干燥。
(2)两亲性药物载体
两亲性药物载体直接选用由公司购买的聚乳酸-羟基乙酸共聚物(PLGA)，其由乳酸和羟基乙酸按照50:50的比例聚合而成。
(3)载药胶束的制备
将10mg PLGA和抗炎药物(布洛芬，1mg)溶于DMSO(10mL)中，然后在缓慢搅拌的 情况下，将其逐滴加入到10mL水中，最终，混合物在水中透析2天，制得；
(4)水凝胶的制备
分别将步骤(1)中的苯硼酸改性壳聚糖聚合物(1g)和100mg去铁胺溶于载药胶束溶液(1mg/mL)中，然后添加适量氢氧化钠溶液调整溶液的pH到8.5时，溶液能迅速成胶。
实施例9
一种具有抗炎及促修复功能的可注射水凝胶的制备方法，制备步骤如下：
(1)苯硼酸改性透明质酸(HA-BA)的合成
精密称取5g透明质酸溶于500mL的MES缓冲液(0.1mol，pH 5.0)中，加入1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDC·HCl，4.80g，25.0mmol)和3-氨基苯硼酸(BA，1.95g，12.5mmol)，然后，在37℃搅拌24h，最后在去离子水中(pH 7.4)透析3天，用冻干机进行冷冻干燥，得到纯化的HA-BA；
(2)两亲性药物载体
将海藻酸钠(2.00g)和胆固醇(CHOL，1.50g)完全溶解于二甲基亚砜和水的混合溶液中(DMSO，30mL)中，并向其中加入N,N'-二环己基碳二亚胺(DCC，1.00g)和4-二甲氨基吡啶(DMAP，0.50g)，连续搅拌48h；然后将混合物在水中透析2天，用离心分离法去除多余的胆固醇；最后将成品进行冻干备用；
(3)载药胶束的制备
将10mg步骤(2)中的两亲性药物载体和1mg抗炎药物(舒瑞伐他汀)溶于DMSO(1mL)中，然后在缓慢搅拌的情况下，将其逐滴加入到10ml水中，最终，混合物在水中透析2天；
(4)水凝胶的制备
在制备可注射水凝胶时，分别将1g HA-BA聚合物和100mg表皮生长因子(EGF)溶于载药胶束溶液(1mg/mL)中，添加适量氢氧化钠溶液调整溶液的pH到8.5时，溶液能迅速成胶。
实施例10
一种具有抗炎及促修复功能的可注射水凝胶的制备方法，制备步骤如下：
(1)苯硼酸改性壳聚糖的合成
精密称取5g壳聚糖溶于500mL MES缓冲液(0.1mol,pH 5.0)中，加入EDC·HCl(4.80g，25.0mmol)和3-羧基苯硼酸(BA，1.95g，12.5mmol)。然后，在37℃搅拌24h，最后在去离子水中(pH 7.4)透析3天。用冻干机进行冷冻干燥。
(2)两亲性药物载体
两亲性载体直接选用由公司购买的聚乳酸-羟基乙酸共聚物(PLGA)。
(3)载药胶束的制备
将10mg PLGA和抗炎药物(布洛芬，1mg)溶于DMSO(10mL)中，然后在缓慢搅拌的情况下，将其逐滴加入到10mL水中，最终，混合物在水中透析2天，制得；
(4)水凝胶的制备
分别将步骤(1)中的苯硼酸改性壳聚糖聚合物(1g)和100mg促血管生成药物(甲磺酸去铁胺)溶于载药胶束溶液(1mg/mL)中，然后添加适量氢氧化钠溶液调整溶液的pH到8.5时，溶液能迅速成胶。
实施例11
一种具有抗炎及促修复功能的可注射水凝胶的制备方法，制备步骤如下：
(1)苯硼酸改性透明质酸(HA-BA)的合成
精密称取5g透明质酸溶于500mL去离子水中，向其中加入N,N'-二环己基碳二亚胺(DCC，3.00g)和4-二甲氨基吡啶(DMAP，1.50g)和2-羟基苯硼酸(BA，1.95g，12.5mmol)中的一种，然后，在37℃搅拌24h，最后在去离子水中(pH 7.4)透析3天，用冻干机进行冷冻干燥，得到纯化的HA-BA；
(2)两亲性药物载体
将海藻酸钠(2.00g)和胆固醇(CHOL，1.50g)完全溶解于二甲基亚砜和水的混合溶液中(DMSO，30mL)中，并向其中加入N,N'-二环己基碳二亚胺(DCC，1.00g)和4-二甲氨基吡啶(DMAP，0.50g)，连续搅拌48h；然后将混合物在水中透析2天，用离心分离法去除多余的胆固醇；最后将成品进行冻干备用；
(3)载药胶束的制备
将10mg步骤(2)中的两亲性药物载体和1mg抗炎药物(吡罗昔康)溶于DMSO(1mL)中，然后在缓慢搅拌的情况下，将其逐滴加入到10ml水中，最终，混合物在水中透析2天；
(4)水凝胶的制备
在制备可注射水凝胶时，分别将1g HA-BA聚合物和100mg表皮生长因子(EGF)溶于载药胶束溶液(1mg/mL)中，添加适量氢氧化钠溶液调整溶液的pH到8.5时，溶液能迅速成胶。
实施例12
一种具有抗炎及促修复功能的可注射水凝胶的制备方法，制备步骤如下：
(1)苯硼酸改性壳聚糖的合成
精密称取5g壳聚糖溶于500mL去离子水中，向其中加入N,N'-二环己基碳二亚胺(DCC，3.00g)和4-二甲氨基吡啶(DMAP，1.50g)和和4-羟基苯硼酸(BA，1.95g，12.5mmol)中的一种。然后，在37℃搅拌24h，最后在去离子水中(pH 7.4)透析3天。用冻干机进行冷冻干燥。
(2)两亲性药物载体
两亲性载体直接选用由公司购买的聚乳酸-羟基乙酸共聚物(PLGA)。
(3)载药胶束的制备
将10mg PLGA和抗炎药物(布洛芬，1mg)溶于DMSO(10mL)中，然后在缓慢搅拌的情况下，将其逐滴加入到10mL水中，最终，混合物在水中透析2天，制得；
(4)水凝胶的制备
分别将步骤(1)中的苯硼酸改性壳聚糖聚合物(1g)和100mg促血管生成药物(甲磺酸去铁胺)溶于载药胶束溶液(1mg/mL)中，然后添加适量氢氧化钠溶液调整溶液的pH到8.5时，溶液能迅速成胶。
试验例2
以实施例1中制得的物质为例，进行检测，具体操作过程及结果如下：
一、对步骤(1)中制得的ALG-BA进行检测，具体结果见图9，如图9核磁结果所示，证明ALG-BA聚合物的成功制备。
二、对步骤(2)中制得的HA-CHOL进行检测，具体见图10，如图10所示，证明HA-CHOL成功制备；通过核磁定量，得到CHOL的接枝度为13.5％。
试验例3
以实施例9制备的水凝胶进行体内心脏修复效果检测
水凝胶组1-4组分别代表以下组合：水凝胶组1(Hydrogel 1)：空白水凝胶；水凝胶组2(Hydrogel 2)：装载抗炎药物(吡罗昔康)载药胶束的水凝胶；水凝胶组3(Hydrogel 3)：装载表皮生长因子(EGF)的水凝胶；水凝胶组4(Hydrogel 4)：装载抗炎药物(舒瑞伐他汀)载药胶束和表皮生长因子(EGF)的水凝胶。
为了研究水凝胶对体内心脏修复效果的影响，建立了大鼠心肌梗死疾病模型。大鼠在14天和28天的心脏超声结果显示水凝胶组4的大鼠心脏功能恢复结果明显快于其余组，在28天，水凝胶组4的大鼠其射血分数和左心室缩短分数相比MI组分别有了明显的提高，且收缩末心室容积和舒张末心室容积相比MI组明显降低，表明水凝胶组4能有效地修复心肌并恢复心肌功能，在第28天的苏木精伊红(H&E)染色结果、Masson染色结果及梗死区域定量结果所示，水凝胶组4的心脏组织的心室壁厚度最高，且疤痕区域面积最小，表明水凝胶组4有效地降低了心肌梗死部位的疤痕区域，证明其心脏修复功能良好。
以上内容仅仅是对本申请结构所作的举例和说明，所属本领域的技术人员不经创造性劳动即对所描述的具体实施例做的修改或补充或采用类似的方式替代仍属本专利的保护范围。

Claims (104)

  1. 一种具有抗炎及促修复功能的可注射水凝胶，其特征在于，所述可注射水凝胶通过聚合物的功能基团与聚合物的邻羟基相互作用形成凝胶，且响应于酸性条件和/或活性氧条件，聚合物的功能基团与聚合物的邻羟基解除相互作用后，水凝胶发生崩解。
  2. 如权利要求1所述的具有抗炎及促修复功能的可注射水凝胶，其特征在于，所述可注射水凝胶负载有细胞外基质、亲水性药物、疏水性药物中的一种或一种以上。
  3. 如权利要求1所述的具有抗炎及促修复功能的可注射水凝胶，其特征在于，含功能基团的聚合物为含苯硼酸基团的海藻酸钠、壳聚糖、壳聚糖季铵盐、聚赖氨酸、聚乙烯亚胺、明胶、透明质酸、肝素、羧甲基纤维素、葡聚糖、甲基纤维素、淀粉、环糊精中的至少一种。
  4. 如权利要求1所述的具有抗炎及促修复功能的可注射水凝胶，其特征在于，含邻羟基的聚合物为海藻酸钠、聚乙烯醇、透明质酸、葡聚糖、淀粉中的至少一种。
  5. 如权利要求1所述的具有抗炎及促修复功能的可注射水凝胶，其特征在于，所述可注射水凝胶负载有：细胞外基质；
    以及亲水性药物和/或疏水性药物。
  6. 如权利要求1所述的具有抗炎及促修复功能的可注射水凝胶，其特征在于，所述细胞外基质为胶原蛋白、非胶原蛋白、弹性蛋白、蛋白聚糖、氨基聚糖中的至少一种。
  7. 如权利要求1所述的具有抗炎及促修复功能的可注射水凝胶，其特征在于，所述细胞外基质为重组人源化胶原蛋白。
  8. 如权利要求1所述的具有抗炎及促修复功能的可注射水凝胶，其特征在于，所述细胞外基质为重组I型人源化胶原蛋白、重组III型人源化胶原蛋白中的至少一种。
  9. 如权利要求1所述的具有抗炎及促修复功能的可注射水凝胶，其特征在于，所述重组I型人源化胶原蛋白和重组III型人源化胶原蛋白中包含可以与细胞整合素结合的氨基酸序列片段。
  10. 如权利要求1所述的具有抗炎及促修复功能的可注射水凝胶，其特征在于，所述细胞外基质为重组III型人源化胶原蛋白。
  11. 如权利要求1所述的具有抗炎及促修复功能的可注射水凝胶，其特征在于，所述疏水性药物萘普生、舒瑞伐他汀、姜黄素、阿司匹林中的至少一种。
  12. 如权利要求1所述的具有抗炎及促修复功能的可注射水凝胶，其特征在于，所述疏水性药物以两亲性聚合物为载体，负载在所述可注射水凝胶中。
  13. 如权利要求1所述的具有抗炎及促修复功能的可注射水凝胶，其特征在于，所述可注射水凝胶负载有：姜黄素和重组人源化胶原蛋白。
  14. 如权利要求1所述的具有抗炎及促修复功能的可注射水凝胶，其特征在于，所述可注射水凝胶负载有：姜黄素和重组III型人源化胶原蛋白。
  15. 一种用于修复心脏损伤的水凝胶，其特征在于，所述水凝胶为作用于心脏损伤部位的如权利要求1～14任一项所述的可注射水凝胶。
  16. 一种用于治疗心衰的水凝胶，其特征在于，所述水凝胶为作用于心脏病变部位的如权利要求1～14任一项所述的可注射水凝胶。
  17. 一种用于治疗心肌梗死的水凝胶，其特征在于，所述水凝胶为作用于心肌梗死部位的如权利要求1～14任一项所述的可注射水凝胶。
  18. 如权利要求1～14任一项所述的具有抗炎及促修复功能的可注射水凝胶在心脏损伤修复中的应用。
  19. 如权利要求1～14任一项所述的具有抗炎及促修复功能的可注射水凝胶在治疗心衰中的应用。
  20. 如权利要求1～14任一项所述的具有抗炎及促修复功能的可注射水凝胶在治疗心肌梗死中的应用。
  21. 一种心脏损伤修复方法，其特征在于，将如权利要求1～14任一项所述的可注射水凝胶作用于心脏损伤部位。
  22. 一种治疗心衰的方法，其特征在于，将如权利要求1～14任一项所述的可注射水凝胶作用于心脏病变部位。
  23. 一种心脏损伤修复方法，其特征在于，在心脏病变部位注射如权利要求1～14任一项所述的可注射水凝胶。
  24. 一种治疗心衰的方法，其特征在于，在心肌梗死部位注射如权利要求1～14任一项所述的可注射水凝胶。
  25. 一种治疗心肌梗死的方法，其特征在于，在心肌梗死部位注射如权利要求1～14任一项所述的可注射水凝胶。
  26. 一种如权利要求1～14任一项所述的可注射水凝胶的制备方法，其特征在于，包括：
    制备含有苯硼酸基团的第一聚合物；
    将细胞外基质、亲水性药物、疏水性药物中的至少一种、第一聚合物、含邻羟基的聚合物混合，制备得到所述可注射水凝胶。
  27. 如权利要求26所述的可注射水凝胶的制备方法，其特征在于，所述第一聚合物采用以下任意一种原料组合方式在缩合剂及催化剂存在的条件下反应制得：
    a)含氨基或羟基的聚合物与含羧基的苯硼酸；
    b)含羧基的聚合物与含氨基或羟基的苯硼酸。
  28. 如权利要求27所述的可注射水凝胶的制备方法，其特征在于，所述第一聚合物的制备方法如下：
    原料溶解后，在30～40℃条件下反应30-60h，制备得到含苯硼酸基团的第一聚合物。
  29. 如权利要求27所述的可注射水凝胶的制备方法，其特征在于，含氨基或羟基的聚合物、含羧基的苯硼酸、缩合剂、催化剂的质量比为7:(4-5):(2-3):1；或含羧基的聚合物、含氨基或羟基的苯硼酸、缩合剂、催化剂的质量比为7:(4-5):(2-3):1。
  30. 如权利要求26所述的可注射水凝胶的制备方法，其特征在于，所述疏水性药物以两亲性聚合物作为载体，制作为载药纳米胶束，载药纳米胶束与第一聚合物、含邻羟基的聚合物混合，制备得到含疏水性药物的所述可注射水凝胶。
  31. 如权利要求30所述的可注射水凝胶的制备方法，其特征在于，所述载药纳米胶束的制备包括：
    将两亲性聚合物和疏水性药物溶于良性溶剂中，在持续搅拌状态下缓慢滴加入水中，透析后得到浓度为1-2mg/mL的载药纳米胶束溶液。
  32. 如权利要求31所述的可注射水凝胶的制备方法，其特征在于，两亲性聚合物与疏水性药物的质量比为4-8:1。
  33. 如权利要求26所述的可注射水凝胶的制备方法，其特征在于，将第一聚合物的水溶液与含邻羟基的聚合物的水溶液混合，得到所述可注射水凝胶，第一聚合物的水溶液中含有亲水性药物、细胞外基质、载药纳米胶束中的至少一种，第一聚合物水溶液中，第一聚合物 的质量浓度为0.5～10％w/v。
  34. 如权利要求33所述的可注射水凝胶的制备方法，其特征在于，第一聚合物水溶液中，亲水性药物的质量浓度为1～1000μg/mL。
  35. 如权利要求33所述的可注射水凝胶的制备方法，其特征在于，第一聚合物水溶液中，细胞外基质的质量浓度为1～6mg/mL。
  36. 如权利要求33所述的可注射水凝胶的制备方法，其特征在于，第一聚合物水溶液中，载药纳米胶束的质量浓度为30～200μg/mL。
  37. 如权利要求33所述的可注射水凝胶的制备方法，其特征在于，含邻羟基的聚合物的水溶液中，含邻羟基的聚合物的质量浓度为0.5～10％w/v。
  38. 如权利要求27所述的可注射水凝胶的制备方法，其特征在于，含氨基的聚合物为壳聚糖、壳聚糖季铵盐、聚赖氨酸、聚乙烯亚胺、明胶中的至少一种。
  39. 如权利要求27所述的可注射水凝胶的制备方法，其特征在于，含羧基的聚合物为海藻酸钠、透明质酸、肝素、羧甲基纤维素中的至少一种。
  40. 如权利要求27所述的可注射水凝胶的制备方法，其特征在于，含羟基的聚合物为淀粉、纤维素、龙胶、魔芋胶、阿拉伯树胶、木质素、葡聚糖、环糊精中的至少一种。
  41. 如权利要求26所述的可注射水凝胶的制备方法，其特征在于，含邻羟基的聚合物为聚乙烯醇、海藻酸钠、透明质酸、葡聚糖、淀粉中的至少一种。
  42. 如权利要求27所述的可注射水凝胶的制备方法，其特征在于，含羧基的苯硼酸为4-羧基苯硼酸、2-羧基苯硼酸、3-羧基苯硼酸、4-羧基-3-氟苯硼酸、3-羧基-4-氟苯硼酸、5-羧基-2-氯苯硼酸及4-羧基-2-氯苯硼酸中的至少一种；
    含氨基的苯硼酸为4-氨基苯硼酸、2-氨基苯硼酸、3-氨基苯硼酸、3-氨基甲酰基苯硼酸、3-氨基-4-氟苯硼酸、3-氨基-4-甲基苯硼酸中的至少一种；
    含羟基的苯硼酸为4-羟基苯硼酸、3-氟-4-羟基苯硼酸、2-氟-3-羟基苯硼酸、2-氟-5-羟基苯硼酸、3-羟基-4-氯苯硼酸、3-氟-4-羟基苯硼酸中的至少一种。
  43. 如权利要求26所述的可注射水凝胶的制备方法，其特征在于，所述细胞外基质为胶原蛋白、非胶原蛋白、弹性蛋白、蛋白聚糖、氨基聚糖中的至少一种。
  44. 如权利要求26所述的可注射水凝胶的制备方法，其特征在于，所述细胞外基质为重组人源化胶原蛋白。
  45. 如权利要求26所述的可注射水凝胶的制备方法，其特征在于，所述疏水性药物为抗炎药、镇痛药、促血管生成药、利尿剂、血管紧张素转换酶抑制剂、β受体阻滞剂、洋地黄类药物、醛固酮拮抗剂、血管紧张素二受体拮抗剂、抗凝药、抗血小板药中的至少一种。
  46. 如权利要求26-45中任一项所述制备方法制备得到具有抗炎及促修复功能的可注射水凝胶。
  47. 一种用于修复心脏损伤的水凝胶，其特征在于，所述水凝胶为作用于心脏损伤部位的如权利要求46所述的可注射水凝胶。
  48. 一种用于治疗心衰的水凝胶，其特征在于，所述水凝胶为作用于心脏病变部位的如权利要求46所述的可注射水凝胶。
  49. 一种用于治疗心肌梗死的水凝胶，其特征在于，所述水凝胶为作用于心肌梗死部位的如权利要求46所述的可注射水凝胶。
  50. 如权利要求46所述的具有抗炎及促修复功能的可注射水凝胶在心脏损伤修复中的应 用。
  51. 如权利要求46所述的具有抗炎及促修复功能的可注射水凝胶在治疗心衰中的应用。
  52. 如权利要求46所述的具有抗炎及促修复功能的可注射水凝胶在治疗心肌梗死中的应用。
  53. 一种心脏损伤修复方法，其特征在于，将如权利要求46所述的可注射水凝胶作用于心脏损伤部位。
  54. 一种治疗心衰的方法，其特征在于，将如权利要求46所述的可注射水凝胶作用于心脏病变部位。
  55. 一种心脏损伤修复方法，其特征在于，在心脏病变部位注射如权利要求46所述的可注射水凝胶。
  56. 一种治疗心衰的方法，其特征在于，在心肌梗死部位注射如权利要求46所述的可注射水凝胶。
  57. 一种治疗心肌梗死的方法，其特征在于，在心肌梗死部位注射如权利要求46所述的可注射水凝胶。
  58. 一种具有抗炎及促修复功能的可注射水凝胶，其特征在于，包括以下原料成分：含氨基和邻羟基的生物大分子、含羧基和邻羟基的生物大分子和含有氨基、羟基或羧基的苯硼酸。
  59. 如权利要求58所述的具有抗炎及促修复功能的可注射水凝胶，其特征在于，还包括以下成分：亲水性药物和/或疏水性药物。
  60. 如权利要求59所述的具有抗炎及促修复功能的可注射水凝胶，其特征在于，所述亲水性药物为生长因子、基因药、水溶性蛋白药中的至少一种。
  61. 如权利要求59所述的具有抗炎及促修复功能的可注射水凝胶，其特征在于，所述疏水性药物为抗炎药、促血管生成药、促细胞增殖药、促细胞迁移药中的至少一种。
  62. 如权利要求61所述的具有抗炎及促修复功能的可注射水凝胶，其特征在于，所述抗炎药为阿司匹林、扑热息痛、阿莫西林和保泰松中的至少一种。
  63. 如权利要求58所述的具有抗炎及促修复功能的可注射水凝胶，其特征在于，所述含氨基和邻羟基的生物大分子为壳聚糖、海藻酸钠改性产物、透明质酸改性产物中的至少一种。
  64. 如权利要求58所述的具有抗炎及促修复功能的可注射水凝胶，其特征在于，所述含羧基和邻羟基的生物大分子为海藻酸钠、海藻酸钠改性产物、透明质酸、透明质酸改性产物、羧甲基纤维素、或羧甲基纤维素改性产物。
  65. 如权利要求58所述的具有抗炎及促修复功能的可注射水凝胶，其特征在于，所述含氨基、羟基或羧基的苯硼酸为邻位氨基苯硼酸、间位氨基苯硼酸、对位氨基苯硼酸、邻位羟基苯硼酸、间位羟基苯硼酸、对位羟基苯硼酸、邻位羧基苯硼酸、间位羧基苯硼酸、或对位羧基苯硼酸。
  66. 一种用于修复心脏损伤的水凝胶，其特征在于，所述水凝胶为作用于心脏损伤部位的如权利要求58-65任一项所述的可注射水凝胶。
  67. 一种用于治疗心衰的水凝胶，其特征在于，所述水凝胶为作用于心脏病变部位的如权利要求58-65任一项所述的可注射水凝胶。
  68. 一种用于治疗心肌梗死的水凝胶，其特征在于，所述水凝胶为作用于心肌梗死部位的如权利要求58-65任一项所述的可注射水凝胶。
  69. 如权利要求58-65任一项所述的具有抗炎及促修复功能的可注射水凝胶在心脏损伤修 复中的应用。
  70. 如权利要求58-65任一项所述的具有抗炎及促修复功能的可注射水凝胶在治疗心衰中的应用。
  71. 如权利要求58-65任一项所述的具有抗炎及促修复功能的可注射水凝胶在治疗心肌梗死中的应用。
  72. 一种心脏损伤修复方法，其特征在于，将如权利要求58-65任一项所述的可注射水凝胶作用于心脏损伤部位。
  73. 一种治疗心衰的方法，其特征在于，将如权利要求58-65任一项所述的可注射水凝胶作用于心脏病变部位。
  74. 一种心脏损伤修复方法，其特征在于，在心脏病变部位注射如权利要求58-65任一项所述的可注射水凝胶。
  75. 一种治疗心衰的方法，其特征在于，在心肌梗死部位注射如权利要求58-65任一项所述的可注射水凝胶。
  76. 一种治疗心肌梗死的方法，其特征在于，在心肌梗死部位注射如权利要求58-65任一项所述的可注射水凝胶。
  77. 一种具有抗炎及促修复功能的可注射水凝胶的制备方法，其特征在于，包括以下步骤：
    步骤1，用含邻位羟基的功能聚合物和含氨基、羟基或羧基的苯硼酸反应制得侧链接枝苯硼酸的聚合物；所述含邻位羟基的功能聚合物为含氨基和邻羟基的生物大分子或含羧基和邻羟基的生物大分子；
    步骤2，将苯硼酸聚合物溶解于水中，调整混合溶液pH值至8-9，制得水凝胶。
  78. 如权利要求77所述的具有抗炎及促修复功能的可注射水凝胶的制备方法，其特征在于，将亲水性药物和/或包载有疏水性药物的胶束与苯硼酸聚合物水溶液混合，调整混合溶液pH值至8-9，制得。
  79. 如权利要求77所述的具有抗炎及促修复功能的可注射水凝胶的制备方法，其特征在于，用良性溶剂溶解两亲性药物载体和疏水性药物，在搅拌状态下向其中缓慢加入水，制得载药胶束溶液，将亲水性药物和/或载药胶束溶液与苯硼酸聚合物水溶液混合，调整混合溶液pH值至8-9，制得。
  80. 如权利要求77所述的具有抗炎及促修复功能的可注射水凝胶的制备方法，其特征在于，步骤1的具体反应过程为：将含邻位羟基的功能聚合物溶解得含邻位羟基的功能聚合物溶液，向该溶液中加入缩合剂和含氨基或羧基的苯硼酸，于30-40℃条件下搅拌20-30h后在去离子水中透析，然后再进行冷冻干燥得纯化的苯硼酸聚合物。
  81. 如权利要求80所述的具有抗炎及促修复功能的可注射水凝胶的制备方法，其特征在于，邻位羟基的功能聚合物、缩合剂和氨基、羟基或羧基的苯硼酸的质量比为4-6:4-6:1-2。
  82. 如权利要求80所述的具有抗炎及促修复功能的可注射水凝胶的制备方法，其特征在于，缩合剂包括1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐和N-羟基琥珀酰亚胺。
  83. 如权利要求79所述的具有抗炎及促修复功能的可注射水凝胶的制备方法，其特征在于，两亲性药物载体的制备过程为：将亲水高分子聚合物和疏水性分子在80℃条件下完全溶解于二甲基亚砜中，并向其中加入N,N'-二环己基碳二亚胺和4-二甲氨基吡啶，在80℃条件下连续搅拌48h，将反应物在水中透析2天后去除未反应的疏水性分子，最后进行冻干备用，其中，亲水高分子、疏水分子、N,N'-二环己基碳二亚胺和4-二甲氨基吡啶的质量比为 2:1.5:1:0.5。
  84. 如权利要求83所述的具有抗炎及促修复功能的可注射水凝胶的制备方法，其特征在于，亲水高分子聚合物包括透明质酸、淀粉、纤维素、聚丙烯酸、聚丙烯酞胺、聚乙烯醇、羟基乙酸和聚赖氨酸。
  85. 如权利要求83所述的具有抗炎及促修复功能的可注射水凝胶的制备方法，其特征在于，疏水性分子包括胆固醇、聚烯烃、聚碳酸酯、聚酰胺、聚丙烯腈、聚酯、聚乳酸和丙烯酸酯。
  86. 如权利要求83所述的具有抗炎及促修复功能的可注射水凝胶的制备方法，其特征在于，将两亲性药物载体和疏水性药物溶解于良性溶剂中，然后加热70-90℃，在搅拌条件下向其中逐滴滴加水，透析后制得浓度为0.5-1.5mg/mL的载药胶束溶液。
  87. 如权利要求86所述的具有抗炎及促修复功能的可注射水凝胶的制备方法，其特征在于，将亲水性药物、苯硼酸聚合物溶解于载药胶束溶液中，使得载药胶束溶液中苯硼酸聚合物的浓度为7-11％w/v。
  88. 如权利要求87所述的具有抗炎及促修复功能的可注射水凝胶的制备方法，其特征在于，在含有载药胶束和/或亲水性药物的苯硼酸聚合物水溶液中加入碱性溶液，调整pH值为8.5，制得所述可注射水凝胶。
  89. 如权利要求87所述的具有抗炎及促修复功能的可注射水凝胶的制备方法，其特征在于，亲水性药物和苯硼酸聚合物的质量比为1:10。
  90. 如权利要求77所述的具有抗炎及促修复功能的可注射水凝胶的制备方法，其特征在于，所述含氨基、羟基或羧基的苯硼酸为邻位氨基苯硼酸、间位氨基苯硼酸、对位氨基苯硼酸、邻位羟基苯硼酸、间位羟基苯硼酸、对位羟基苯硼酸、邻位羧基苯硼酸、间位羧基苯硼酸、或对位羧基苯硼酸。
  91. 如权利要求78所述的具有抗炎及促修复功能的可注射水凝胶的制备方法，其特征在于，所述亲水性药物为生长因子、基因、水溶性蛋白药中的至少一种。
  92. 如权利要求78所述的具有抗炎及促修复功能的可注射水凝胶的制备方法，其特征在于，所述疏水性药物为抗炎药、促血管生成药、促细胞增殖药、促细胞迁移药中的至少一种。
  93. 如权利要求77-92中任一项所述的制备方法制备得到具有抗炎及促修复功能的可注射水凝胶。
  94. 一种用于修复心脏损伤的水凝胶，其特征在于，所述水凝胶为作用于心脏损伤部位的如权利要求93所述的可注射水凝胶。
  95. 一种用于治疗心衰的水凝胶，其特征在于，所述水凝胶为作用于心脏病变部位的如权利要求93所述的可注射水凝胶。
  96. 一种用于治疗心肌梗死的水凝胶，其特征在于，所述水凝胶为作用于心肌梗死部位的如权利要求93所述的可注射水凝胶。
  97. 如权利要求93所述的具有抗炎及促修复功能的可注射水凝胶在心脏损伤修复中的应用。
  98. 如权利要求93所述的具有抗炎及促修复功能的可注射水凝胶在治疗心衰中的应用。
  99. 如权利要求93所述的具有抗炎及促修复功能的可注射水凝胶在治疗心肌梗死中的应用。
  100. 一种心脏损伤修复方法，其特征在于，将如权利要求93所述的可注射水凝胶作用于 心脏损伤部位。
  101. 一种治疗心衰的方法，其特征在于，将如权利要求93所述的可注射水凝胶作用于心脏病变部位。
  102. 一种心脏损伤修复方法，其特征在于，在心脏病变部位注射如权利要求93所述的可注射水凝胶。
  103. 一种治疗心衰的方法，其特征在于，在心肌梗死部位注射如权利要求93所述的可注射水凝胶。
  104. 一种治疗心肌梗死的方法，其特征在于，在心肌梗死部位注射如权利要求93所述的可注射水凝胶。
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