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CN-122005431-A - Injectable piezoelectric hydrogel for treating osteoarthritis and preparation method and application thereof

CN122005431ACN 122005431 ACN122005431 ACN 122005431ACN-122005431-A

Abstract

The invention discloses an injectable piezoelectric hydrogel for treating osteoarthritis and a preparation method and application thereof. The injectable piezoelectric hydrogel comprises an oxidized chondroitin sulfate-3-aminophenylboric acid polymer hydrogel matrix and piezoelectric nanoparticles dispersed in the polymer hydrogel matrix, wherein the piezoelectric nanoparticles comprise a core layer formed by biocompatible piezoelectric nanoparticles and a cartilage cell membrane layer coating the core layer, and the surface of the cartilage cell membrane layer is conjugated with cartilage targeting peptide. The injectable piezoelectric hydrogel material provided by the invention has strong antioxidation capability, and simultaneously, the piezoelectrically induced mitochondrial autophagy can reduce the generation of active oxygen substances from the source, and cooperatively protect chondrocytes.

Inventors

  • ZHENG HUI
  • YAN PENGFEI
  • WANG ZUYONG
  • ZHANG RUIXING

Assignees

  • 湖南大学

Dates

Publication Date
20260512
Application Date
20251230

Claims (10)

  1. 1. The injectable piezoelectric hydrogel for treating osteoarthritis is characterized by comprising an oxidized chondroitin sulfate-3-aminophenylboric acid polymer hydrogel matrix and piezoelectric nanoparticles dispersed in the polymer hydrogel matrix, wherein the piezoelectric nanoparticles comprise a core layer formed by biocompatible piezoelectric nanoparticles and a cartilage cell membrane layer coating the core layer, and the surface of the cartilage cell membrane layer is conjugated with cartilage targeting peptide.
  2. 2. The injectable piezoelectric hydrogel of claim 1, wherein the hydrogel matrix further comprises collagen, and the piezoelectric nanoparticles comprise 0.05% to 2.00% by mass of the injectable piezoelectric hydrogel.
  3. 3. A method of preparing an injectable piezoelectric hydrogel according to claim 1 or 2, comprising the steps of: S1, preparing piezoelectric nanoparticles, namely mixing a suspension of the biocompatible piezoelectric nanoparticles with a cartilage cell membrane protein solution, coating a cartilage cell membrane on the biocompatible piezoelectric nanoparticles by an extrusion method to obtain cartilage cell membrane coated biocompatible piezoelectric nanoparticles; S2, preparing a hydrogel matrix, namely dissolving periodate oxidized chondroitin sulfate OCS in water, adding 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide EDC and N-hydroxysuccinimide NHS, adjusting pH, adding a dimethyl sulfoxide solution of 3-aminophenylboric acid APBA, reacting overnight under a weak acid condition, dialyzing the obtained reaction solution, and freeze-drying to obtain oxidized chondroitin sulfate-3-aminophenylboric acid APBA-OCS polymer; S3, compounding the hydrogel, namely preparing the APBA-OCS polymer obtained in the step S2 into an APBA-OCS polymer solution, adding the piezoelectric nanoparticle suspension into the APBA-OCS polymer solution, and fully stirring and uniformly mixing to obtain the injectable piezoelectric hydrogel.
  4. 4. The preparation method of the cartilage cell membrane coated biocompatible piezoelectric nanoparticle according to claim 3, wherein the specific step of modifying the cartilage targeting peptide to coat the surface of the cartilage cell membrane coated biocompatible piezoelectric nanoparticle in the step S1 is to mix cholesterol-polyethylene glycol-maleimide CLS-PEG-MAL with thiolated CAP peptide in PBS at a molar ratio of 2:1-1:2, perform an oscillation reaction at room temperature for 8-12 hours, obtain powdery CLS-PEG-CAP after dialysis and freeze-drying, mix the cartilage cell membrane coated biocompatible piezoelectric nanoparticle with CLS-PEG-CAP at a mass ratio of membrane protein to polymer of 10-20:1, incubate at 4 ℃ overnight, and finish surface modification through hydrophobic interaction, thereby obtaining the piezoelectric nanoparticle CAP-CM@BTO.
  5. 5. The preparation method according to claim 3 or 4, wherein the specific step of step S3 is to dissolve collagen in dilute acetic acid to prepare an acidic collagen solution, mix the acidic collagen solution with PBS, adjust pH to neutral to form a neutral collagen Col solution, mix the Col solution with APBA-OCS solution to obtain a mixed solution, add the piezoelectric nanoparticles obtained in step S1 into the mixed solution, and mix the mixed solution with sufficient stirring to obtain the injectable piezoelectric hydrogel.
  6. 6. Use of an injectable piezoelectric hydrogel according to claim 1 or 2 or an injectable piezoelectric hydrogel obtained by the method of preparation according to any one of claims 3 to 5 for the preparation of a pharmaceutical formulation for the treatment of osteoarthritis.
  7. 7. A pharmaceutical preparation for treating osteoarthritis, characterized in that the injectable piezoelectric hydrogel according to claim 1 or 2 or the injectable piezoelectric hydrogel obtained by the preparation method according to any one of claims 3 to 5 is used as an active ingredient.
  8. 8. A method of using a pharmaceutical formulation for treating osteoarthritis as claimed in claim 7, wherein the pharmaceutical formulation is administered to a bone joint.
  9. 9. A method of enhancing mitochondrial autophagy in chondrocytes, comprising contacting chondrocytes with the injectable piezoelectric hydrogel of claim 1 or 2 or the injectable piezoelectric hydrogel obtained by the method of any one of claims 3 to 5.
  10. 10. A kit for treating osteoarthritis, characterized by comprising the following steps: (1) An injector preloaded with the injectable piezoelectric hydrogel according to claim 1 or 2 or the injectable piezoelectric hydrogel obtained by the production method according to any one of claims 3 to 5; (2) Description of intra-articular injection.

Description

Injectable piezoelectric hydrogel for treating osteoarthritis and preparation method and application thereof Technical Field The invention relates to the technical field of biological materials and degenerative joint diseases, in particular to an injectable piezoelectric hydrogel for treating osteoarthritis, and a preparation method and application thereof. Background Osteoarthritis (OA) is a very common degenerative joint disease, affected by which about 5 hundred million people worldwide, and is characterized by progressive degeneration of articular cartilage, chondrocyte aging, mitochondrial dysfunction, and chronic inflammation. Currently, there is no drug that can alter the condition of osteoarthritis (DMOADs). The treatment regimen is primarily directed to alleviating symptoms but is unable to arrest or reverse the progression of the condition. A great difficulty in the treatment of osteoarthritis drugs is how to effectively deliver therapeutic agents to chondrocytes, i.e. those cells that are present in a avascular cartilage matrix. The dense and negatively charged extracellular matrix (ECM) of cartilage acts as a substantial barrier to the passage of drugs administered systemically or intra-articular into the body. Furthermore, the drug can rapidly drain from the joint cavity (within 1-4 hours) through synovial drainage, which requires frequent injections, thereby increasing the risk of infection. Mitochondrial dysfunction in chondrocytes is a key pathological feature of osteoarthritis, which leads to excessive production of Reactive Oxygen Species (ROS) and promotes cellular senescence. While antioxidants are capable of scavenging existing reactive oxygen species, they do not address the underlying problem-accumulation of damaged mitochondria. Mitochondrial autophagy, i.e., selective autophagy of damaged mitochondria, is a critical cellular process that maintains mitochondrial quality. Enhancing mitochondrial autophagy provides a promising strategy for the treatment of osteoarthritis, but there is currently no effective method for safely and effectively inducing its occurrence in cartilage. Piezoelectric materials, which generate electrical charges when subjected to mechanical stress, have potential in biomedical applications because they can affect cellular behavior through electrical signals. Ultrasound can act as a non-invasive, deep penetrating external stimulus to activate such materials. However, their use in the treatment of osteoarthritis is limited due to the difficulty in achieving targeted delivery of chondrocytes and lack of knowledge of the underlying molecular mechanisms. There is therefore still an urgent and unmet need in the art for a targeted, sustained release and non-invasive therapeutic platform that can effectively penetrate cartilage, survive long-term in the joint, and act against the underlying pathological processes of osteoarthritis (such as mitochondrial dysfunction and chondrocyte aging). Disclosure of Invention The invention solves the problems existing in the prior art, provides an injectable piezoelectric hydrogel for treating osteoarthritis, a preparation method and application thereof, the injectable piezoelectric hydrogel material provided by the invention has strong antioxidation capability, and meanwhile, the piezoelectrically induced mitochondrial autophagy can reduce the generation of active oxygen substances from the source, and cooperatively protect chondrocytes. The first object of the invention is to provide an injectable piezoelectric hydrogel for treating osteoarthritis, which comprises an oxidized chondroitin sulfate-3-aminophenylboric acid polymer hydrogel matrix and piezoelectric nanoparticles dispersed in the hydrogel matrix, wherein the piezoelectric nanoparticles comprise a core layer formed by biocompatible piezoelectric nanoparticles and a cartilage cell membrane layer coating the core layer, and the surface of the cartilage cell membrane layer is conjugated with cartilage targeting peptide. The hydrogel matrix provides an injectable scaffold and biocompatible environment, and is formed from periodate-Oxidized Chondroitin Sulfate (OCS) and 3-aminophenylboronic acid (APBA) crosslinked by dynamic boronic acid ester linkages. This dynamic bond imparts excellent shear thinning (thinning upon injection) and self-healing (recovery after injection) properties to the hydrogel. Piezoelectric nanoparticles are functional cores for generating therapeutic signals and are finely designed to achieve targeting and biomimetic. Piezoelectric core is composed of biocompatible piezoelectric material, the invention is preferably barium titanate nano-particles (BTO-NPs), and the core size of the nano-particles is preferably between 40 and 60 nm. The bionic coating layer (the material of the piezoelectric core takes BTO-NPs as an example) is formed by coating a layer of cartilage Cell Membrane (CM) on the periphery of the BTO-NPs core to form CM@BTO. This coating was