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CN-121987853-A - Hydrogel capable of releasing growth factors after heat absorption and shrinkage and preparation method thereof

CN121987853ACN 121987853 ACN121987853 ACN 121987853ACN-121987853-A

Abstract

The invention discloses hydrogel capable of releasing growth factors after heat absorption and shrinkage and a preparation method thereof, and belongs to the field of biomedical materials. The hydrogel has a three-layer composite structure, wherein the first layer is a sodium alginate-chitosan polyelectrolyte semi-interpenetrating network layer serving as a compact protective layer, the second layer is a bacterial cellulose-sodium alginate high-strength and toughness layer serving as a bearing layer and a shrinkage driving layer, and the third layer is a basic fibroblast growth factor (bFGF) -loaded poly (adipic acid)/butylene terephthalate (PBAT) electrostatic spinning film serving as a drug reservoir. The invention uses the characteristic that the bacterial cellulose/sodium alginate layer can reversibly absorb heat and shrink in volume at a specific temperature, takes the reversible heat absorption volume shrinkage as a physical driving force, and extrudes and promotes bFGF in the third layer PBAT fiber membrane to be released outwards in a directional manner.

Inventors

  • Hu zhengrui
  • WANG CHANGJIN
  • ZHENG KEXIN
  • Ran Qiuhua
  • Cai Guanqiao

Assignees

  • 胡正蕊

Dates

Publication Date
20260508
Application Date
20260313

Claims (9)

  1. 1. A hydrogel capable of releasing growth factors after heat absorption and shrinkage is characterized by comprising a composite bracket with a three-layer structure, wherein a first layer is a first hydrogel layer formed by compounding sodium alginate and chitosan, a second layer is a second hydrogel layer formed by compounding bacterial cellulose and sodium alginate, the second hydrogel layer has a temperature-responsive reversible shrinkage characteristic, a third layer is a supporting layer formed by a polybutylene adipate/terephthalate (PBAT) material, and basic fibroblast growth factors (bFGF) are loaded in the third layer, wherein the second layer is compounded on the lower surface of the first layer, and the third layer is compounded on the lower surface of the second layer.
  2. 2. The hydrogel for release of growth factors after endothermic shrinkage according to claim 1, wherein the mass ratio of sodium alginate to chitosan in the first layer is 1:0.2 to 1:1.5, the thickness of the first layer is 50 μm to 300 μm, and the first layer forms a polyelectrolyte complex by electrostatic interaction between carboxyl groups of sodium alginate and amino groups of chitosan.
  3. 3. The hydrogel for release of growth factors after endothermic shrinkage according to claim 1, wherein the bacterial cellulose is present in the form of a three-dimensional nanofiber network skeleton, sodium alginate is filled in and crosslinked in the skeleton gaps, the dry weight ratio of the bacterial cellulose to sodium alginate is 1:0.5 to 1:3, and the thickness of the second layer is 200 μm to 800 μm.
  4. 4. The hydrogel of claim 1, wherein the second layer undergoes isotropic shrinkage at an ambient temperature rise from 25 ℃ to 37 ℃ with a volume shrinkage of 5% to 20% and a volume recovery of not less than 90% at a temperature recovery to 25 ℃.
  5. 5. The hydrogel for releasing growth factors after endothermic shrinkage according to claim 1, wherein the third layer is a PBAT electrospun fiber membrane, the bFGF is loaded in or on the PBAT fiber by physical adsorption or embedding, and the thickness of the third layer is 50 μm to 150 μm.
  6. 6. The hydrogel for release of growth factors after endothermic shrinkage according to claim 1, wherein the third layer further comprises heparin sodium, the mass ratio of heparin sodium to bFGF is 100:1 to 10:1, for stabilizing the biological activity of bFGF and controlling the release rate thereof.
  7. 7. A method for preparing the hydrogel capable of releasing growth factors after endothermic shrinkage according to any one of claims 1 to 6 is characterized by comprising the following steps of S1, preparing a first layer of hydrogel, mixing a sodium alginate solution and a chitosan solution, introducing a cross-linking agent, casting and curing to obtain a first hydrogel layer, S2, preparing a second layer of hydrogel, mixing bacterial cellulose dispersion liquid and the sodium alginate solution, pouring the bacterial cellulose dispersion liquid and the sodium alginate solution on the surface of the first hydrogel layer obtained in the step S1, introducing the cross-linking agent for cross-linking to form a double-layer composite hydrogel, S3, preparing a PBAT fiber layer loaded with bFGF, dissolving PBAT in an organic solvent, adding bFGF solution or heparin sodium-bFGF compound, preparing a drug-loaded fiber membrane through an electrostatic spinning technology, S4, compounding the drug-loaded PBAT fiber membrane obtained in the step S3 onto the surface of the double-layer composite hydrogel obtained in the step S2 through a physical bonding or interfacial chemical cross-linking method, and drying to obtain the three-layer hydrogel.
  8. 8. The preparation method of the electrostatic spinning machine according to claim 7, wherein the cross-linking agent introduced in the S1 and the S2 is a calcium chloride solution, gluconolactone or calcium sulfate, the cross-linking time is 1-12 hours, the parameters of the electrostatic spinning of the S3 are that the voltage is 15-25kV, the receiving distance is 10-20cm, and the propelling speed is 0.5-2.0mL/h.
  9. 9. The preparation method of the composite material according to claim 7, wherein the interfacial chemical crosslinking method in S4 is specifically that EDC/NHS crosslinking agent is coated on the surface of the second layer of hydrogel, meanwhile, the PBAT fiber membrane is subjected to hydrophilization plasma treatment, and after bonding, the bonding is performed, the bonding force between the layers is enhanced by pressurizing and curing for 0.5-2 hours, so that amide bonds are formed.

Description

Hydrogel capable of releasing growth factors after heat absorption and shrinkage and preparation method thereof Technical Field The invention belongs to the field of biomedical high molecular materials and tissue engineering, and in particular relates to a composite hydrogel dressing/bracket material which has a triple network structure and can release basic fibroblast growth factor (bFGF) as required after heat absorption and shrinkage, and a preparation method and application thereof. Background With the development of regenerative medicine, growth factors are increasingly gaining importance in promoting tissue repair and revascularization. Basic fibroblast growth factor (bFGF) is a multifunctional cell growth factor, can strongly promote proliferation of fibroblasts and vascular endothelial cells, and has key effects in wound healing, fracture repair and nerve regeneration. However, bFGF is extremely susceptible to degradation by proteases in physiological environments, has a very short half-life (usually less than 10 minutes), and is susceptible to toxic side effects such as hypotension, proteinuria, etc. by direct systemic or local administration at large doses. Therefore, how to realize stable loading, targeted delivery and controllable release of bFGF at a focal site is a core problem to be solved in the field. Hydrogels are considered ideal growth factor carriers because of their high water content, good biocompatibility, and structural characteristics that mimic the extracellular matrix (ECM). The conventional hydrogel is controlled to release by passive diffusion or biodegradation of materials, and the release mode is often accompanied by serious sudden release phenomenon, so that growth factors are rapidly exhausted in the early treatment stage, and the treatment requirement of chronic wound surfaces for a plurality of weeks cannot be met. In recent years, stimulus-responsive hydrogels (e.g., pH response, enzyme response, temperature response) have become a research hotspot. Although the temperature-responsive hydrogel (such as Pluronic, PNIPAM) can realize phase-change controlled release, the synthesized polymer is often poor in biodegradability, and degradation products are acidic and have potential cytotoxicity. In the prior art, sodium alginate and chitosan are widely used for tissue engineering due to their excellent biocompatibility and gel properties as natural polysaccharide. However, single alginate hydrogel has poor mechanical strength and too fast degradation rate, and chitosan has antibacterial property but poor solubility at neutral pH. Bacterial cellulose has extremely high purity and nanofiber network structure and excellent tensile strength, but lacks swelling property and does not have intelligent response characteristics. As a biodegradable aliphatic-aromatic copolyester, PBAT has good flexibility and film forming property, and is often used for tissue engineering scaffolds, but PBAT is hydrophobic and lacks cell recognition sites, and is not beneficial to cell adhesion when used alone. More importantly, how to complement the advantages of the materials and endow the composite material with an intelligent release function is not researched systematically at present. Particularly, the natural polymer composite system is used as a trigger switch to realize the on-demand release of the growth factors by taking the tiny physical change (such as volume phase change) of the natural polymer composite system in the physiological temperature range, and no disclosure report is found yet. The invention is aimed at the technical blank, skillfully designs the three-layer structured composite hydrogel, and firstly utilizes the reversible shrinkage characteristic of the bacterial cellulose/sodium alginate composite layer under the heat absorption condition as a physical extrusion driving force to act on the bottom PBAT fiber reservoir, thereby realizing the efficient, stable and on-demand release of bFGF. Disclosure of Invention The invention aims to solve the technical problems of serious burst effect, short biological activity maintenance time, poor biocompatibility of a carrier material or toxic degradation products and lack of an active controlled release mechanism of the existing growth factor carrier, and provides a three-layer structure composite hydrogel with excellent mechanical property, good biocompatibility and intelligent temperature-sensitive shrinkage controlled release characteristic and a preparation method thereof. The hydrogel can stably seal the growth factors when not in use, after being implanted or applied to a wound surface, the hydrogel triggers the second layer of hydrogel to slightly but effectively shrink by using the body temperature (37 ℃), so that the growth factors adsorbed in the pores of the third layer of fibrous membrane are stably extruded to the wound surface like 'extrusion sponge', and bionic on-demand administration is realized. Technical proposal In or