A self-adhesive artificial dura mater and its preparation method

Abstract

This invention relates to the field of medical repair materials technology, and discloses a self-adhesive artificial dura mater and its preparation method. The dura mater comprises a repair layer, an adhesive layer, and a protective layer sequentially composited from the inside out. The repair layer is made by mixing collagen, hyaluronic acid, and polycaprolactone in a specific mass ratio. The adhesive layer of this self-adhesive artificial dura mater is made by mixing a cell-free matrix, chitosan, and medical-grade polyacrylate in a specific ratio. The surface is plasma-treated to form a micro-roughened structure, exhibiting good adhesion at room temperature. It can tightly adhere to the edge tissue of dura mater defects. The self-adhesive design eliminates the need for additional sutures, staples, or other fixation operations, simplifying the surgical procedure, shortening the operation time, and reducing the difficulty of the surgeon's operation. This effectively shortens the operation time. Simultaneously, the adhesive layer forms a tight interface with the tissue, effectively sealing the defect edge, reducing postoperative cerebrospinal fluid leakage, material displacement, and the resulting infection risk, thus improving the safety and success rate of the surgery.

Description

Technical Field

[0001] This invention relates to the field of medical repair materials technology, and in particular to a self-adhesive artificial dura mater and its preparation method. Background Technology

[0002] The dura mater is an important protective barrier surrounding the brain tissue. It plays a crucial role in preventing direct contact between the brain tissue and the skull, maintaining stable cerebrospinal fluid pressure, and protecting the brain tissue from mechanical damage. In neurosurgery, dura mater defects often occur due to tumor resection, trauma, congenital defects, etc., requiring repair. Currently, the commonly used dura mater repair materials in clinical practice are mainly divided into two categories: bio-derived artificial dura mater and synthetic polymer-derived artificial dura mater.

[0003] Bio-derived artificial dura mater mainly includes allogeneic or xenogeneic dura mater, collagen membranes, etc. These materials have good biocompatibility and high compatibility with human tissues, but they also have significant drawbacks: First, the source of bio-derived materials is limited, making it difficult to meet clinical needs; second, there is a potential risk of immune rejection, which may trigger postoperative inflammatory reactions; more importantly, bio-derived materials may carry pathogens, posing a risk of disease transmission, such as viruses and bacteria, and thus threatening patient safety.

[0004] Synthetic polymer-derived artificial dura mater mainly includes polylactic acid and polyglycolic acid. These materials are stable in origin and can be mass-produced, but they suffer from poor adhesion to autologous tissue. During surgery, they need to be fixed to the defect site using sutures, staples, and other fixation methods. This not only increases the complexity and prolongs the operation time, but also easily leads to problems such as marginal leakage and tissue displacement, increasing the risk of postoperative complications such as cerebrospinal fluid leakage and infection. To address the issue of adhesion and fixation, some studies have attempted to add bio-adhesive to the surface of the artificial dura mater to aid bonding. However, this approach has significant drawbacks: the bio-adhesive and the artificial dura mater are not compatible enough, and interface separation is likely to occur during use; the additional use of bio-adhesive will prolong the operation time and increase medical costs; moreover, the bio-adhesive itself may trigger an immune response, increasing the risk of postoperative complications. Summary of the Invention

[0005] In view of the fact that although some studies have attempted to improve the adhesion performance of artificial dura mater in the above-mentioned prior art, the problems of poor adhesion between artificial dura mater and autologous tissue, complicated operation and many postoperative complications have not been fundamentally solved, this invention is proposed.

[0006] Therefore, the purpose of this invention is to provide a self-adhesive artificial dura mater, the purpose of which is to develop an artificial dura mater that is self-adhesive, requires no additional fixation, has excellent biocompatibility and good repair effect.

[0007] To solve the above-mentioned technical problems, the present invention provides the following technical solution: a self-adhesive artificial dura mater, comprising a repair layer, an adhesive layer and a protective layer sequentially laminated from the inside out; The repair layer is made of collagen, hyaluronic acid and polycaprolactone in a mass ratio of 2~4:2~3:4~6, and has a porous structure with a pore size range of 50-200μm. The adhesive layer is made of decellularized matrix, chitosan and medical polyacrylate mixed in a mass ratio of 3~5:2~3:3~4, and its surface is plasma treated to form a micro-rough structure. The protective layer is a biodegradable medical polymer film.

[0008] In a preferred embodiment of the self-adhesive artificial dura mater of the present invention, the mass ratio of collagen, hyaluronic acid and polycaprolactone in the repair layer is 3:2:5.

[0009] In a preferred embodiment of the self-adhesive artificial dura mater of the present invention, the mass ratio of decellularized matrix, chitosan and medical polyacrylate in the adhesive layer is 4:3:3.

[0010] As a preferred embodiment of the self-adhesive artificial dura mater of the present invention, the adhesive strength of the adhesive layer is 0.5-1.5 N / cm².

[0011] As a preferred embodiment of the self-adhesive artificial dura mater of the present invention, the protective layer is a polyvinyl alcohol film with a thickness of 0.02-0.1 mm, preferably 0.05 mm.

[0012] In a preferred embodiment of the self-adhesive artificial dura mater of the present invention, the decellularized matrix is ​​a decellularized dermal matrix.

[0013] To achieve the above objectives, the present invention provides the following technical solution: a method for preparing a self-adhesive artificial dura mater, comprising the following steps: S1. Preparation of repair layer: Collagen and hyaluronic acid are dissolved in buffer solution in proportion, polycaprolactone is added, and the mixture is stirred to form a uniform slurry. The slurry is then freeze-dried to form a porous scaffold, which is then sterilized for later use. S2. Preparation of adhesive layer: The decellularized matrix, chitosan and medical polyacrylate are mixed in proportion to prepare adhesive slurry, which is then coated on the surface of the repair layer. After drying, the surface is subjected to plasma treatment. S3, Protective layer composite: A biodegradable polymer material solution is coated onto the surface of the adhesive layer after step S2, and after curing, a protective layer is formed to obtain the self-adhesive artificial dura mater. S4. Finished product preparation: Cut, sterilize and package the obtained composite film.

[0014] In a preferred embodiment of the method for preparing the self-adhesive artificial dura mater of the present invention, in step S1, the freeze-drying time is 20-28 hours; in step S2, the plasma treatment time is 20-40 seconds.

[0015] In a preferred embodiment of the self-adhesive artificial dura mater preparation method of the present invention, in step S2, the coating thickness of the adhesive slurry is 0.03-0.1 mm.

[0016] In a preferred embodiment of the self-adhesive artificial dura mater preparation method of the present invention, in step S3, the biodegradable polymer material is polyvinyl alcohol, the solution concentration is 8%-12%, and the thickness of the protective layer formed after coating and curing is 0.05 mm.

[0017] Compared with the prior art, the present invention has at least the following beneficial effects: 1. The adhesive layer of this invention is made by mixing decellularized matrix, chitosan and medical polyacrylate in a specific ratio. The surface is plasma-treated to form a micro-rough structure, which has good adhesion at room temperature and can be closely adhered to the edge tissue of dural defect. The self-adhesive design eliminates the need for additional suturing, staples and other fixation operations, simplifying the surgical procedure, shortening the operation time, and reducing the difficulty of operation for doctors. This can effectively shorten the operation time. At the same time, the adhesive layer forms a close interface with the tissue, effectively sealing the edge of the defect, significantly reducing the risk of postoperative cerebrospinal fluid leakage, material displacement and the resulting infection, and improving the safety and success rate of the operation.

[0018] 2. The repair layer of this invention adopts a porous structure with a specific pore size range and is composed of bioactive ingredients such as collagen and hyaluronic acid. It can provide a three-dimensional scaffold for cell migration, colonization and proliferation, actively guide the regeneration of autologous dura mater tissue, and achieve functional repair, rather than a simple physical barrier. Moreover, the main components of each layer, such as collagen, chitosan, polycaprolactone, and polyvinyl alcohol, are all medical-grade biodegradable or biocompatible materials with no risk of immune rejection in vivo. After completing their repair mission, the materials can be gradually degraded and absorbed over a predetermined time without the need for secondary surgery to remove them. The degradation products are safe for the human body.

[0019] 3. Through systematic optimization experiments on the material ratio of the repair layer and adhesive layer, as well as the thickness of the protective layer, this invention has determined the optimal combination of parameters for overall performance, such as a repair layer ratio of 3:2:5, an adhesive layer ratio of 4:3:3, and a protective layer thickness of 0.05mm. This results in an optimal balance between the product's cell guidance properties, adhesive strength, adhesive retention time, and ease of use, ensuring the product's effectiveness and reliability.

[0020] 4. By setting a peelable protective layer, the present invention effectively protects the adhesiveness of the adhesive layer and the microstructure of the repair layer during storage and transportation. In clinical use, it can be easily peeled off, making the operation convenient and the performance stable. Attached Figure Description

[0021] Figure 1 This is a flowchart illustrating the preparation process of the self-adhesive artificial dura mater of the present invention. Detailed Implementation

[0022] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below with reference to the accompanying drawings.

[0023] Example 1: Preparation of self-adhesive artificial dura mater (optimal formulation) 1. Materials and Equipment Repair layer materials: Type I collagen (purity ≥95%) derived from bovine Achilles tendon, sodium hyaluronate (molecular weight 150kDa), and polycaprolactone (PCL, molecular weight 80 kDa).

[0024] Adhesive layer materials: porcine decellularized dermal matrix (treated with virus inactivation), chitosan (degree of deacetylation ≥92%), and medical-grade polyacrylate pressure-sensitive adhesive (medical grade, purity ≥99%).

[0025] Protective layer material: medical grade polyvinyl alcohol (PVA, degree of alcoholysis 98.5%).

[0026] Reagents and equipment: Phosphate buffer (PBS, pH 7.4), anhydrous ethanol (medical grade), plasma surface treatment instrument, freeze dryer, constant temperature stirrer, coating machine, universal testing machine, ethylene oxide sterilizer.

[0027] 2. Preparation steps Step 1: Preparation of the repair layer Weigh the raw materials according to the mass ratio of collagen:sodium hyaluronate:polycaprolactone = 3:2:5.

[0028] First, completely dissolve 3 parts collagen and 2 parts sodium hyaluronate in an appropriate amount of PBS to obtain a homogeneous proteoglycan solution.

[0029] Under a constant temperature water bath of 60℃, slowly add 5 parts of polycaprolactone powder to the above solution and continue mechanical stirring for 2 hours until a uniform and viscous composite slurry is formed.

[0030] The slurry is injected into a flat mold and pre-frozen at -80°C for 4 hours. Then it is transferred to a freeze dryer and freeze-dried at -50°C and 10 Pa for 24 hours to form a support with an interconnected porous structure.

[0031] The porous scaffold was cut to the required size (e.g., 3cm × 5cm), sterilized with ethylene oxide, and set aside for later use. The scaffold thickness was measured to be approximately 0.15mm, and the average pore size was 160μm.

[0032] Step 2: Preparation and lamination of the adhesive layer Weigh the raw materials according to the mass ratio of decellularized matrix: chitosan: polyacrylate = 4:3:3.

[0033] The decellularized matrix was pulverized and dissolved in anhydrous ethanol, then stirred until swollen. Chitosan and polyacrylate were added sequentially, and the mixture was stirred continuously at 50°C for 1.5 hours to form a homogeneous viscous slurry.

[0034] The adhesive slurry was evenly coated onto one side of the sterilized repair layer using a coating machine, with the wet film thickness controlled to be approximately 0.1 mm.

[0035] Dry in a clean environment at room temperature (25°C) for 12 hours to form a solid adhesive layer.

[0036] The composite membrane with the adhesive layer was placed in the reaction chamber of a plasma processor. Using oxygen as the treatment gas, the surface of the adhesive layer was treated for 30 seconds at a power of 100W and a pressure of 30Pa to form a micro-rough structure, thereby activating and enhancing its surface adhesion. The dry thickness of the adhesive layer after treatment was measured to be approximately 0.05mm.

[0037] Step 3: Lamination of protective layer and finished product processing Prepare a 10% (w / v) aqueous solution of polyvinyl alcohol and stir it in an 80°C water bath until completely dissolved.

[0038] The PVA solution was uniformly coated onto the surface of the plasma-treated adhesive layer, and the coating thickness was controlled so that the film thickness after drying was precisely 0.05 mm.

[0039] After cooling and solidification at room temperature, a complete three-layer composite film of "repair layer - adhesive layer - protective layer" is formed, which is the initial product of self-adhesive artificial dura mater.

[0040] Cut according to commonly used clinical specifications (such as 2cm×3cm, 3cm×5cm).

[0041] The cut product is sealed in a medical aluminum foil bag and sterilized again with ethylene oxide to obtain a final sterile product. The total thickness of the product is approximately 0.25 mm.

[0042] How to use self-adhesive artificial dura mater: In neurosurgery, when there is a defect in the dura mater, take out the finished product of this invention, peel off the protective layer, and attach the autologous dura mater tissue with the adhesive layer facing the edge of the defect directly to the defect site. Apply gentle pressure with sterile gauze for 30 seconds to achieve fixation. No additional sutures are required after attachment, and subsequent surgical operations can be performed directly. One to three months after the surgery, the adhesive layer and the repair layer gradually degrade, and autologous cells complete the regeneration of the dura mater under the guidance of the repair layer, thus achieving defect repair.

[0043] Example 2: Product Performance Testing and Verification 1. Adhesion strength test: Using a universal testing machine, the adhesive layer of the product of this invention was bonded to porcine dura mater tissue, and the peel strength was tested according to GB / T 14074-2017 standard. The results showed that the peel strength was 0.8-1.2 N / cm², which meets the requirements for surgical fixation.

[0044] 2. Biocompatibility test: In accordance with GB / T 16886 "Biological Evaluation of Medical Devices" standard, cytotoxicity, sensitization and irritation tests were performed in sequence. The results showed no cytotoxicity (cell survival rate ≥90%), and no sensitization or irritation reactions.

[0045] 3. Degradation performance test: The product was immersed in a simulated body fluid (PBS with pH 7.4) at a constant temperature of 37°C, and the mass loss rate was tested regularly. The results showed that the degradation rate of the product reached more than 80% within 3 months and was completely degraded within 6 months. The degradation products were tested and found to be non-cytotoxic.

[0046] 4. Clinical trial: Ten patients with dural defects (defect area 1-4cm²) were selected and repaired using the product of this invention. After 3 months of follow-up, no complications such as cerebrospinal fluid leakage or infection were observed. Imaging examination (MRI) showed good regeneration at the dural defect site and the repair effect met the target.

[0047] Example 3: Comparative Experiment on Optimized Proportions ; Conclusion: In the repair layer, the ratio of collagen:hyaluronic acid:polycaprolactone (polycaprolactone) is 3:2:5, resulting in the optimal synergistic effect between pore structure and degradation rate. In the adhesive layer, the ratio of decellularized matrix:chitosan:polyacrylate (polyacrylate) is 4:3:3, achieving the best balance between adhesion performance and biosafety. Deviations from these ratios will lead to decreased cell migration ability, degradation imbalance, or insufficient adhesive strength.

[0048] The self-adhesive artificial dura mater prepared in this embodiment comprises, from the inside out, a repair layer, an adhesive layer, and a protective layer: The repair layer uses a composite porous structure of collagen, hyaluronic acid, and polycaprolactone in a 3:2:5 ratio to guide dura mater regeneration; the adhesive layer is made of decellularized matrix, chitosan, and medical-grade polyacrylate in a 4:3:3 ratio, and after plasma treatment, it has good adhesion and can be directly applied to tissues without additional fixation; the protective layer is a 0.05mm thick biodegradable polyvinyl alcohol film to protect the material properties. This invention solves the problems of poor adhesion, complicated operation, and many postoperative complications of existing artificial dura mater through material ratio optimization and structural design. It has the advantages of good biocompatibility, excellent repair effect, and convenient use, and is suitable for neurosurgical dura mater defect repair surgery, with clinical application value.

[0049] 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 it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. A self-adhesive artificial dura mater, characterized in that... It includes a repair layer, an adhesive layer, and a protective layer that are sequentially combined from the inside out; The repair layer is made of collagen, hyaluronic acid and polycaprolactone in a mass ratio of 2~4:2~3:4~6, and has a porous structure with a pore size range of 50-200μm. The adhesive layer is made of decellularized matrix, chitosan and medical polyacrylate mixed in a mass ratio of 3~5:2~3:3~4, and its surface is plasma treated to form a micro-rough structure. The protective layer is a biodegradable medical polymer film.

2. The self-adhesive artificial dura mater according to claim 1, characterized in that: The mass ratio of collagen, hyaluronic acid and polycaprolactone in the repair layer is 3:2:

5.

3. The self-adhesive artificial dura mater according to claim 1, characterized in that: The mass ratio of decellularized matrix, chitosan, and medical polyacrylate in the adhesive layer is 4:3:

3.

4. The self-adhesive artificial dura mater according to claim 1, characterized in that: The adhesive strength of the adhesive layer is 0.5-1.5 N / cm².

5. The self-adhesive artificial dura mater according to claim 4, characterized in that: The protective layer is a polyvinyl alcohol film with a thickness of 0.02-0.1 mm, preferably 0.05 mm.

6. The self-adhesive artificial dura mater according to any one of claims 1 to 5, characterized in that, The decellularized matrix is ​​a decellularized dermal matrix.

7. A method for preparing a self-adhesive artificial dura mater as described in any one of claims 1 to 6, characterized in that, Includes the following steps: S1. Preparation of repair layer: Collagen and hyaluronic acid are dissolved in buffer solution in proportion, polycaprolactone is added, and the mixture is stirred to form a uniform slurry. The slurry is then freeze-dried to form a porous scaffold, which is then sterilized for later use. S2. Preparation of adhesive layer: The decellularized matrix, chitosan and medical polyacrylate are mixed in proportion to prepare adhesive slurry, which is then coated on the surface of the repair layer. After drying, the surface is subjected to plasma treatment. S3, Protective layer composite: A biodegradable polymer material solution is coated onto the surface of the adhesive layer after step S2, and after curing, a protective layer is formed to obtain the self-adhesive artificial dura mater. S4. Finished product preparation: Cut, sterilize and package the obtained composite film.

8. The method for preparing the self-adhesive artificial dura mater according to claim 7, characterized in that: In step S1, the freeze-drying time is 20-28 hours; in step S2, the plasma treatment time is 20-40 seconds.

9. The method for preparing the self-adhesive artificial dura mater according to claim 7, characterized in that: In step S2, the coating thickness of the adhesive slurry is 0.03-0.1 mm.

10. The method for preparing the self-adhesive artificial dura mater according to claim 7, characterized in that: In step S3, the biodegradable polymer material is polyvinyl alcohol, with a solution concentration of 8%-12%, and the protective layer formed after coating and curing has a thickness of 0.05 mm.

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