Tendon anti-adhesion membrane for strengthening tendon anastomotic stoma

Abstract

The invention provides an anti-adhesion composite membrane for tendon repair. The anti-adhesion composite membrane comprises a polycaprolactone / nano-hydroxyapatite fiber reinforced layer, a PLGA (poly (lactic-co-glycolic acid)) double-drug-loaded microsphere sustained-release layer and a modified hyaluronic acid barrier layer from inside to outside. According to the structure, the defects in the prior art are overcome in the following mode that the inner-layer nano-composite fiber provides mechanical support matched with the tendon; the middle-layer microspheres realize gradient release of the anti-inflammatory drug; the outer biological barrier inhibits fibroblast migration. The three-layer functional design synchronously meets the requirements of mechanical protection, drug controlled release and physical isolation; a double-drug synergistic system covers tendon healing complete cycle inflammation control; and the material degradation rate is accurately matched with the tissue regeneration process.

Description

Technical Field

[0001] The invention relates to the technical field of medical implant materials, in particular to a tendon anti-adhesion membrane for strengthening a tendon anastomosis. Background Art

[0002] Existing tendon anti-adhesion materials face two major technical bottlenecks: First, a single material cannot simultaneously provide both mechanical support and biological barrier functions. While common polymer membranes can provide short-term protection, they lack degradation properties that match the tendon healing cycle. While gel-based materials offer anti-adhesion effects, they cannot withstand the mechanical stress generated by tendon movement. Second, there are flaws in the design of the drug delivery system. Most drug-loaded materials release the drug explosively during the initial implantation phase, failing to cover the peak inflammation period. Insufficient drug concentration in the later stages leads to a decrease in anti-adhesion effectiveness.

[0003] These issues lead to two major clinical complications: premature material degradation, which leaves the anastomotic stoma unprotected and increases the risk of secondary tendon rupture; and unbalanced drug release, which leads to insufficient inflammation control and excessive fibroblast proliferation, resulting in dense adhesions. Therefore, there is an urgent need to develop a three-dimensional composite structure that combines mechanical adaptability, controllable degradation, and sustained drug release. Summary of the Invention

[0004] The purpose of this section is to summarize some aspects of the embodiments of the present invention and briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section and the abstract and title of this application to avoid obscuring the purpose of this section, the abstract and the title of the invention, and such simplifications or omissions should not be used to limit the scope of the present invention.

[0005] In view of the above problems in the prior art, the inventors proposed the present invention.

[0006] Therefore, the object of the present invention is to overcome the deficiencies in the prior art and provide a tendon anti-adhesion membrane for strengthening a tendon anastomosis.

[0007] To solve the above technical problems, the present invention provides the following technical solution: a tendon anti-adhesion membrane for strengthening a tendon anastomosis, comprising a three-layer structure: The inner layer is a reinforced fiber layer containing polycaprolactone and nano-hydroxyapatite; The middle layer is the PLGA drug-loaded microsphere layer; The outer layer is a cross-linked modified hyaluronic acid barrier layer.

[0008] As a preferred embodiment of the tendon anti-adhesion membrane for strengthening tendon anastomosis of the present invention, the nano-hydroxyapatite content in the inner layer is 10-20wt%, the thickness is 50-100μm, and the tensile strength is ≥10MPa.

[0009] As a preferred embodiment of the tendon anti-adhesion membrane for strengthening tendon anastomosis according to the present invention, the middle layer PLGA microspheres are simultaneously loaded with dexamethasone and diclofenac sodium, wherein the dexamethasone loading amount is 5-15wt%, and the diclofenac sodium loading amount is 2-8wt%.

[0010] As a preferred embodiment of the tendon anti-adhesion membrane for strengthening tendon anastomosis of the present invention, the PLGA microspheres have a lactic acid / glycolic acid molar ratio of 70:30 to 85:15 and an average particle size of 5-25 μm.

[0011] As a preferred embodiment of the tendon anti-adhesion membrane for strengthening tendon anastomosis described in the present invention, the outer layer is a film formed by thiolated hyaluronic acid cross-linked by ultraviolet light, with a degree of substitution of 20-40% and a thickness of 80-150 μm.

[0012] As a preferred embodiment of the tendon anti-adhesion membrane for strengthening tendon anastomosis according to the present invention, the inner layer further comprises 1-8 wt % of titanate nanowires, and the nanowires are surface-modified with polydopamine.

[0013] A method for preparing a tendon anti-adhesion membrane for strengthening a tendon anastomosis, comprising the following steps: (a) Preparation of the inner fiber membrane by electrospinning; (b) Spraying the PLGA drug-loaded microsphere dispersion onto the surface of the inner layer to form a middle layer; (c) Coating the outer layer with hyaluronic acid solution and cross-linking and curing.

[0014] As a preferred embodiment of the method for preparing a tendon anti-adhesion membrane for strengthening a tendon anastomosis according to the present invention, the electrospinning voltage in step (a) is 15-22 kV, and the spinning solution concentration is 10-15 wt%; and the crosslinking in step (c) adopts ultraviolet light with a wavelength of 365 nm and an irradiation intensity of 40-100 mW / cm².

[0015] The tendon anti-adhesion membrane for strengthening the tendon anastomosis of the present invention is used in tendon anastomosis surgery, wherein: the membrane is wrapped around the anastomotic area, with the two ends overlapping by 5-10mm.

[0016] The tendon anti-adhesion membrane for strengthening the tendon anastomosis of the present invention is used in tendon anastomosis surgery, wherein: the amount of drug released within 2 weeks after surgery is not less than 50% of the total drug loading amount, and the complete degradation period of the material is 12-18 weeks.

[0017] Beneficial effects of the present invention: The core advantage of the present invention lies in the synergistic protection achieved through a three-layer functional design: the inner layer of nano-composite fibers provides continuous mechanical support, and its elastic modulus is highly matched with that of natural tendons, effectively dispersing anastomotic stress; the middle layer of dual-drug-loaded microsphere system establishes a gradient release mechanism, with the rapid-release component rapidly suppressing acute inflammation and the sustained-release component continuously blocking adhesion pathways; the outer layer of the biological barrier inhibits fibroblast migration through the dual effects of physical isolation and charge repulsion.

[0018] This structure solves the following problems: 1) The material degradation cycle is precisely controlled by the polymer molecular weight, completely covering the golden window period for tendon healing; 2) The drug release curve is dynamically matched with the stage of inflammation progression to avoid fluctuations in blood drug concentration; 3) The hydrophilic modified surface of the outer layer significantly reduces nonspecific adhesion to surrounding tissues, preventing secondary damage during removal. DETAILED DESCRIPTION

[0019] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are described in detail below in conjunction with the embodiments of the specification.

[0020] In the following description, many specific details are set forth to facilitate a full understanding of the present invention. However, the present invention may also be implemented in other ways different from those described herein. Those skilled in the art may make similar generalizations without violating the connotation of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0021] Secondly, the term "one embodiment" or "embodiment" herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The phrase "in one embodiment" appearing in various places throughout this specification does not necessarily refer to the same embodiment, nor does it constitute a separate or selective embodiment that is mutually exclusive with other embodiments.

[0022] Example 1 This embodiment provides a tendon anti-adhesion membrane for strengthening a tendon anastomosis, specifically, the preparation and performance verification of a basic anti-adhesion membrane.

[0023] Raw materials and processes As a preferred embodiment, the preparation is carried out according to the following steps: (1) Preparation of inner fiber membrane Specifically: 85 parts by weight of polycaprolactone (Mn=80kDa) and 15 parts by weight of nanohydroxyapatite (particle size 50nm, 15 parts by weight) were placed in a chloroform / acetone (7:3 v / v) mixed solvent to prepare a 12wt% spinning solution; Furthermore: an electrospinning device (spinning voltage 18 kV, receiving distance 15 cm, ambient humidity ≤ 40%) was used to collect fiber membranes with a thickness of 80 ± 5 μm; (2) Construction of the middle drug-carrying layer As an embodiment: PLGA (75:25) microspheres (average particle size 12 μm) loaded with 10 wt% dexamethasone were dispersed in a 5 wt% polyvinyl alcohol aqueous solution; Preferably, a continuous coating is formed on the surface of the fiber membrane by ultrasonic spraying equipment (nozzle diameter 0.3 mm, carrier gas pressure 0.2 MPa), and a 50±3 μm drug-loaded layer is obtained after vacuum drying at 50°C; (3) Cross-linking of the outer barrier layer Specifically: coating an aqueous solution containing 2.5wt% thiolated hyaluronic acid (degree of substitution 28%), crosslinking for 120 seconds using a 365nm UV light source (irradiation intensity 80mW / cm²) under nitrogen protection to form a 120±10μm barrier layer; Performance Verification Key performance test results of basic anti-adhesion film It can be seen that through the sequential assembly of the three-layer structure, an anti-adhesion membrane that meets the design indicators can be obtained, among which the charge repulsion effect of the outer barrier is the key mechanism for inhibiting cell migration.

[0024] Example 2 This embodiment provides the implementation of a dual-drug synergistic system for strengthening a tendon anti-adhesion membrane of a tendon anastomosis.

[0025] Formula and process improvements: Preferably, the middle layer drug loading system is improved as follows: (1) Design of dual-phase microsphere structure Specific: W / O / W double emulsion method was used to prepare core-shell structure microspheres Internal oil phase: PLGA / dichloromethane solution containing 8wt% diclofenac sodium External aqueous phase: 1% polyvinyl alcohol solution containing 12wt% dexamethasone Further: high-speed shear emulsification (10000 rpm, 5 min) and then solidification into microspheres with a particle size of 15±2 μm; (II) Regulation of release kinetics As an implementation method: adjusting the molecular weight of PLGA (50 kDa for the inner layer / 20 kDa for the outer layer) to construct a degradation gradient; Preferred: Layered deposition technology is used in the spraying process, with the bottom layer of microspheres loaded with diclofenac sodium and the surface layer of microspheres loaded with dexamethasone The synergistic advantages of the two drugs were confirmed by the following experiments: Anti-inflammatory synergy: In the LPS-induced macrophage model, the TNF-α inhibition rate was 52.7% in the single-drug group → 79.3% in the dual-drug group (p<0.01). IL-6 secretion decreased to 28.4% of the control group; The results of the release curve matching show that: Dexamethasone: 24h release peak reaches 12.4μg / mL (covering the acute inflammatory period) Diclofenac sodium: Maintains 5.2±0.3μg / mL for 14 days (effective concentration >4μg / mL) Furthermore, through the design of drug release timing, the rapid-release component (dexamethasone) and the sustained-release component (diclofenac sodium) form a drug efficacy relay mechanism, covering the entire inflammatory cycle of tendon healing.

[0026] Example 3 This embodiment provides a tendon anti-adhesion membrane for strengthening a tendon anastomosis, and further provides the preparation and mechanical strengthening of a nano-enhanced structure.

[0027] As an enhanced implementation method, the following techniques are used: (1) Nano-enhanced phase treatment: Specifically, titanate nanowires (diameter 50 nm, aspect ratio > 100) were immersed in dopamine hydrochloride solution (2 mg / mL, pH = 8.5) for 24 h to obtain polydopamine-modified nanowires; Preferably, the amount of nanowires added is 5 wt % of the PCL matrix and mixed with the spinning solution after ultrasonic dispersion (40 kHz, 30 min); (2) Interface strengthening process Furthermore, an electrostatic adsorption system (field strength 0.8 kV / cm) is set in the electrospinning receiving device to induce axial alignment of the nanowires; preferably, a hot pressing step (70°C, 0.5 MPa, 10 seconds) is added after the middle drug-loaded layer is sprayed to enhance the interlayer bonding strength; Enhancement effect comparison: Performance comparison between nano-enhanced and basic types Fatigue life: simulated tendon flexion and extension motion (frequency 1Hz, load 0-5N) This embodiment can significantly improve the mechanical durability of the composite membrane through nano-enhanced phase orientation arrangement and interface modification technology, meeting the repair needs of high-intensity tendons.

[0028] Furthermore, the inner fiber network, through nanophase composites and oriented arrangement, forms a biomimetic mechanical framework, essentially mimicking the collagen fiber bundle structure of tendon tissue. The ductility of polycaprolactone and the rigidity of nanohydroxyapatite complement each other, forming energy dissipation nodes at the molecular level. This allows for efficient stress transfer along the fiber axis during cyclic tensile loads (such as finger flexion and extension), rather than concentrating stress at the anastomotic site. The middle drug delivery system dynamically couples drug release with the inflammatory process: the degradation rate of the PLGA microspheres is precisely controlled by the copolymer ratio, while the core-shell design imparts a timed release capability. This release kinetics is due to the fact that the hydrophobic drug (diclofenac sodium) is encapsulated in the highly crystalline PLGA core, requiring slow hydrolysis of ester bonds before diffusion can occur. The hydrophilic drug (dexamethasone) is rapidly released through the hydrophilic channels in the outer layer, creating a dual-phase protection mechanism that suppresses the inflammatory storm early and blocks fibrosis later. The anti-adhesion mechanism of the outer hyaluronic acid barrier goes beyond simple physical isolation. Its thiol cross-linked network forms a hydrated molecular layer in body fluids, which repels positively charged fibroblast surface receptors through its high negative charge density. Simultaneously, the "slip layer" formed by water molecules at the material interface significantly reduces the adhesion and anchoring force of cell pseudopodia. This three-layer synergy enables the material to form a closed-loop protective system in the three dimensions of mechanical support, drug delivery, and biological barrier.

[0029] Furthermore, the hydrolysis rate of polycaprolactone chains is dominated by their crystallinity, and the introduction of nanohydroxyapatite modulates this process in two ways: on the one hand, the nanoparticles act as nucleation sites for hydrolysis, accelerating ester bond cleavage; on the other hand, their strong interfacial interaction with the polymer chains restricts segmental motion, delaying overall disintegration. This seemingly contradictory effect is dynamically balanced by adjusting the nanoparticle content (10-20wt%). When the content is below 15wt%, the acceleration effect dominates, suitable for younger patients with faster healing; above 15wt%, the delaying effect is enhanced, suitable for the slower healing of degenerative tendons. A deeper logic lies in the coordinated degradation and drug release of the middle PLGA microspheres: the microsphere shell degrades first, opening the drug channel, while the core hydrolysis continues to maintain drug concentrations later. This synergistic "degradation-release" mechanism ensures that more than 35% of dexamethasone is released during the peak inflammation period (1-3 days after surgery), maintains effective diclofenac concentrations during the fibrosis initiation period (2-4 weeks), and retains only the necessary mechanical support during the remodeling period (8-12 weeks). The entire degradation process avoids foreign body reactions by controlling the size of residual fragments (<50μm), and the final metabolites participate in the tricarboxylic acid cycle in the body, achieving the unity of biocompatibility and functional durability.

[0030] Chemically, thiolated hyaluronic acid undergoes UV crosslinking to form a disulfide bond network. Its bond energy (~240 kJ / mol) is significantly higher than that of hydrogen bonds (5-30 kJ / mol), ensuring structural stability under fluid flushing. The retained carboxyl groups (-COOH) simultaneously enhance the surface zeta potential to over -35 mV, interfering with the binding of integrin α5β1 to fibronectin through electrostatic repulsion—the molecular basis of fibroblast adhesion. Physically, the crosslinking density is controlled to create a micro-nanostructured surface (protrusions 1-3 μm in height, 5-8 μm in spacing). This scale specifically inhibits the migration of fibroblasts larger than 10 μm in diameter while allowing nutrients smaller than 5 μm to pass freely. Even more ingenious is the material's balanced surface energy strategy: by regulating the thiol substitution degree (20-40%), the water contact angle is stabilized at 105°±3°. This hydrophobic range both reduces nonspecific protein adsorption (adsorption on hydrophilic surfaces is reduced by 62%) and prevents excessive hydrophobicity from causing lipid reorganization in the cell membrane. This multiple protection mechanism is converted into functional isolation in the body: when the membrane wraps the anastomosis, its outer layer blocks cell invasion through charge repulsion and topological screening, while the inner fiber network allows tendon synovial fluid to penetrate and maintain nutrient supply, establishing a dynamic balance between "isolation" and "communication".

[0031] In summary, traditional materials often act unidirectionally on a specific healing step (such as a simple barrier or drug release). However, the three-layer structure of this invention leverages its inherent properties to dynamically intervene in the entire "inflammation-proliferation-remodeling" cycle. The mechanical adaptability of the inner fiber layer not only protects the anastomosis, but also, through moderate stress stimulation (in the range of 1-2 MPa), activates the integrin-FAK signaling pathway in tendon cells through mechanotransduction, promoting orderly collagen deposition rather than chaotic regeneration. The dual-drug system in the middle layer disrupts the pharmacokinetic model of local drug delivery. Dexamethasone's glucocorticoid receptor acts on the NF-κB transcription factor, directly inhibiting gene expression of proinflammatory cytokines such as TNF-α and IL-1β. Diclofenac reduces prostaglandin E2 levels by blocking COX-2, creating a steric blockade of the upstream and downstream signaling pathways. Crucially, the bioactivity of the degradation products is modulated: ε-hydroxycaproic acid, produced by the hydrolysis of polycaprolactone, activates the PPARγ receptor at local concentrations <0.5 mM, inhibiting the TGF-β1 / Smad3 pathway and thus alleviating fibrosis.

[0032] Overall, multi-level functional integration has solved the three major clinical pain points in the field of tendon repair, namely "insufficient mechanical protection", "drug release mismatch" and "secondary surgical trauma", providing a new paradigm for the development of functional regenerative medicine materials.

[0033] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the spirit and scope of the technical solutions of the present invention, which should all be included in the scope of the claims of the present invention.

Claims

1. A tendon anti-adhesion membrane for strengthening a tendon anastomosis, characterized by: It includes three-layer structure: The inner layer is a reinforced fiber layer containing polycaprolactone and nano-hydroxyapatite; The middle layer is the PLGA drug-loaded microsphere layer; The outer layer is a cross-linked modified hyaluronic acid barrier layer.

2. The tendon anti-adhesion membrane for strengthening a tendon anastomosis according to claim 1, characterized in that: The inner layer has a nano-hydroxyapatite content of 10-20 wt%, a thickness of 50-100 μm, and a tensile strength of ≥10 MPa.

3. The tendon anti-adhesion membrane for strengthening a tendon anastomosis according to claim 1, characterized in that: The middle layer PLGA microspheres are loaded with dexamethasone and diclofenac sodium at the same time, wherein the dexamethasone loading amount is 5-15wt%, and the diclofenac sodium loading amount is 2-8wt%.

4. The tendon anti-adhesion membrane for strengthening a tendon anastomosis according to claim 1, characterized in that: The PLGA microspheres have a lactic acid / glycolic acid molar ratio of 70:30 to 85:15, and an average particle size of 5-25 μm.

5. The tendon anti-adhesion membrane for strengthening a tendon anastomosis according to claim 1, characterized in that: The outer layer is a film formed by cross-linking thiolated hyaluronic acid through ultraviolet light, with a substitution degree of 20-40% and a thickness of 80-150 μm.

6. The tendon anti-adhesion membrane for strengthening a tendon anastomosis according to claim 1, characterized in that: The inner layer further comprises 1-8 wt % of titanate nanowires, and the nanowires are surface-modified with polydopamine.

7. The method for preparing a tendon anti-adhesion membrane for strengthening a tendon anastomosis according to any one of claims 1 to 6, characterized in that: The following steps are involved: (a) Preparation of the inner fiber membrane by electrospinning; (b) Spraying the PLGA drug-loaded microsphere dispersion onto the surface of the inner layer to form a middle layer; (c) Coating the outer layer with hyaluronic acid solution and cross-linking and curing.

8. The tendon anti-adhesion membrane for strengthening a tendon anastomosis according to claim 7, characterized in that: In step (a), the electrospinning voltage is 15-22 kV, and the spinning solution concentration is 10-15 wt %. In step (c), crosslinking is performed using ultraviolet light with a wavelength of 365 nm and an irradiation intensity of 40-100 mW / cm².

9. Use of the tendon anti-adhesion membrane for strengthening a tendon anastomosis according to any one of claims 1 to 6 in tendon anastomosis surgery, characterized in that: The membrane was wrapped around the anastomotic area, with both ends overlapping by 5-10 mm.

10. Use of the tendon anti-adhesion membrane for strengthening a tendon anastomosis according to claim 9 in tendon anastomosis surgery, characterized in that: The amount of drug released within 2 weeks after surgery is no less than 50% of the total drug loading, and the complete degradation period of the material is 12-18 weeks.

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