Biological adhesive tape for nerve stump after amputation and preparation method of biological adhesive tape

Abstract

The invention discloses a biological adhesive tape for nerve stumps after amputation and a preparation method thereof.The biological adhesive tape comprises an outer layer and an inner layer, the outer layer and the inner layer are connected through a layer of PEG-based adhesive, and the outer surface of the outer layer is coated with a PDMS hydrophobic coating; the inner surface of the inner layer is also coated with a PEG-based adhesive layer; wherein the outer layer is prepared from recombinant human-derived I-type collagen and contains dexamethasone drug-loaded microspheres; and the inner layer is prepared from recombinant human I-type collagen and contains gabapentin drug-loaded microspheres. According to the biological adhesive tape, the outer layer inhibits inflammatory reaction and reduces foreign body reaction by slowly releasing glucocorticoid, and the inner layer prevents and relieves neuralgia by slowly releasing gabapentin; the physical fitting effect of the adhesive tape can prevent nerve fibers from growing outwards, so that the risk of neuroma formation is reduced. The biological adhesive tape is high in application flexibility, suitable for nerve stumps with different diameters and shapes and suitable for complex trauma conditions.

Description

Technical Field

[0001] The invention relates to the technical field of biomedicine, and in particular to a biological adhesive tape used for nerve stumps after amputation and a preparation method thereof. Background Art

[0002] In recent years, the number of amputees has shown a significant upward trend worldwide. In the United States alone, there are currently about 1.7 million amputees, and more than 230,000 new amputees are discharged from hospitals each year. However, about 25% of amputees are unable to start rehabilitation or resume daily activities due to persistent pain in their residual limbs. This pain mainly comes from neuromas and phantom limb pain in nerve stumps. Current clinical treatment methods include traction neurectomy, or burying the nerve stump in muscle or bone drill holes and suturing and fixing it, but these surgical methods have many defects such as high difficulty in operation.

[0003] Existing bioimplants include degradable polymer nerve tubes (such as Polyganics NEUROCAP) or nerve sealing tubes with stents (such as AXOGEN NerveCap). However, these nerve sheaths require suturing of the epineurium with 8-0 sutures under a microscope during surgery, which can easily leave residual thread ends and continue to stimulate the axons, and the operation is difficult. In addition, nerves of different diameters require sheaths of different specifications, which makes clinical application cumbersome. Summary of the invention

[0004] The purpose of the present invention is to provide a biological adhesive tape for nerve stumps after amputation and a preparation method thereof in view of the deficiencies in the prior art.

[0005] To achieve the above object, the technical solution adopted by the present invention is:

[0006] The first aspect is to provide a biological adhesive tape for nerve stumps after amputation, comprising an outer layer and an inner layer, wherein the outer layer and the inner layer are connected by a layer of PEG-based adhesive, the outer surface of the outer layer is coated with a layer of PDMS hydrophobic coating; the inner surface of the inner layer is also coated with a PEG-based adhesive layer;

[0007] Wherein, the outer layer is made of recombinant human type I collagen and contains dexamethasone-loaded microspheres, and the dexamethasone-loaded microspheres are made of PEG-PLGA copolymer; dexamethasone is used to inhibit inflammatory response and reduce foreign body reaction;

[0008] The inner layer is made of recombinant human type I collagen and contains gabapentin-loaded microspheres, which are made of PEG-PLA copolymers; gabapentin is used to prevent and relieve neuralgia;

[0009] The PEG-based adhesive is formed by cross-linking four-arm PEG-acrylate and dithiothreitol.

[0010] Among them, the matrix material uses recombinant human type I collagen, which has good biocompatibility; the drug-loaded microspheres use PEG-PLGA and PEG-PLA copolymers to achieve slow release of drugs.

[0011] Furthermore, the average particle size of the dexamethasone-loaded microspheres is 4-5 μm.

[0012] Furthermore, the average particle size of the gabapentin-loaded microspheres is 2-3 μm.

[0013] Furthermore, the thickness of the outer layer is 0.4-0.5 mm, and the thickness of the inner layer is 0.8-1 mm.

[0014] The second aspect is to provide a method for preparing the above-mentioned biological tape for nerve stumps after amputation, comprising the following steps:

[0015] Step 1, preparing an outer layer solution and an inner layer solution respectively;

[0016] Step 2, pouring the inner layer solution into a mold and cross-linking at 35-37° C. for 0.5-1 hour;

[0017] Step 3, uniformly coating the inner and outer surfaces of the cross-linked inner layer with a PEG-based adhesive;

[0018] Step 4, pour the outer layer solution onto the inner layer and cross-link at 35-37° C. for 0.5-1 hour;

[0019] Step 5, coating a PDMS hydrophobic layer on the outer surface after cross-linking molding;

[0020] Step six, vacuum drying for 10-12 hours and sterilization to obtain the biological tape for the nerve stump after amputation.

[0021] Furthermore, the specific preparation method of the inner layer solution is as follows:

[0022] Gabapentin-loaded microspheres were prepared by spray drying: gabapentin and PEG-PLA copolymer were dissolved in dichloromethane, and microspheres were prepared by spray drying at an inlet temperature of 70°C, an outlet temperature of 40°C, and a pump speed of 5 mL / min. Gabapentin-loaded microspheres were collected and freeze-dried.

[0023] The gabapentin-loaded microspheres were dispersed in a recombinant human type I collagen solution with a concentration of 12 mg / mL, and stirred at 37° C. for 1 hour to uniformly disperse the microspheres.

[0024] Furthermore, the specific preparation method of the outer layer solution is as follows:

[0025] Dexamethasone drug-loaded microspheres were prepared by double emulsion method: dexamethasone and PEG-PLGA copolymer were dissolved in dichloromethane as the oil phase; the oil phase was slowly added dropwise to a 2% w / w PVA aqueous solution, and ultrasonic emulsification was performed using an ultrasonic probe to form colostrum; the colostrum was slowly poured into a 0.5% w / w PVA aqueous solution, stirred to evaporate the solvent, and the dexamethasone drug-loaded microspheres were collected by centrifugation and freeze-dried;

[0026] The dexamethasone-loaded microspheres were dispersed in a recombinant human type I collagen solution at a concentration of 8 mg / mL, and stirred at 37° C. for 1 hour to uniformly disperse the microspheres.

[0027] Furthermore, the specific preparation method of the PEG-based adhesive is as follows: four-arm PEG-acrylate is dissolved in a PBS solution, dithiothreitol is added, and the mixture is reacted at 37° C. for 30 minutes to form a hydrogel. The PEG-based hydrogel is used to ensure good adhesion between the adhesive tape and the nerve stump.

[0028] Furthermore, the specific operation of coating the PDMS hydrophobic layer on the surface of the outer layer is as follows: dissolving the PDMS prepolymer in n-hexane, coating the outer layer surface by spin coating (to ensure uniformity), and curing at 80° C. for 2 hours to form a PDMS hydrophobic layer to prevent scar tissue deposition.

[0029] The present invention adopts the above technical solution, and has the following technical effects compared with the prior art:

[0030] The biological tape of the present invention has an outer layer (non-stick layer) that suppresses inflammatory response and reduces foreign body reaction by slowly releasing glucocorticoids, and an inner layer (adhesive layer) that prevents and relieves neuralgia by slowly releasing gabapentin. At the same time, the physical adhesion of the tape can prevent nerve fibers from growing outward, thereby reducing the risk of neuroma formation.

[0031] In addition, the biological tape of the present invention has low difficulty in application, simple clinical application, high application flexibility, is suitable for nerve stumps of different diameters and shapes, is suitable for complex trauma situations, and can cover multiple nerve stumps and surrounding damaged tissues. DETAILED DESCRIPTION

[0032] The present invention is further described below in conjunction with specific embodiments, but is not intended to be limiting of the present invention. It should be noted that the embodiments and features in the embodiments of the present invention may be combined with each other without conflict.

[0033] Experimental reagents and instruments:

[0034] Recombinant human type I collagen, Shanxi Jinbo Biopharmaceutical Co., Ltd., China;

[0035] Acetic acid solution, Sigma-Aldrich, USA;

[0036] Dexamethasone, Sigma-Aldrich, USA;

[0037] Dichloromethane, Merck, Germany;

[0038] PEG-PLGA copolymer, LA:GA=75:25, Mw=20 kDa, Evonik, Germany;

[0039] PVA, Sigma-Aldrich, USA;

[0040] Gabapentin, Sigma-Aldrich, USA;

[0041] PEG-PLA copolymer, Mw = 15 kDa, Polysciences, USA;

[0042] Four-arm PEG-acrylate, molecular weight 10 kDa, Laysan Bio, USA;

[0043] PBS solution, pH = 7.4, Gibco, USA;

[0044] Dithiothreitol, DTT, Sigma-Aldrich, USA;

[0045] PDMS prepolymer, Dow Corning, USA;

[0046] n-Hexane, Sigma-Aldrich, USA;

[0047] Ultrasound probe, Sonics & Materials, USA;

[0048] Freeze drying equipment, FreeZone series, Labconco, USA;

[0049] Spray dryer, B-290, BUCHI, Switzerland;

[0050] PTFE mold, custom made, Shanghai Jinpan Medical Instrument Co., Ltd., China;

[0051] Spin coater, WS-650, Laurell Technologies, USA;

[0052] Vacuum drying oven, DZF-6050, Shanghai Yiheng Scientific Instrument Co., Ltd., China.

[0053] Example 1

[0054] This embodiment provides a biological tape for nerve stumps after amputation, and the specific preparation method thereof is as follows:

[0055] 1. Preparation of required solutions

[0056] 1.1 Preparation of inner layer solution

[0057] Gabapentin-loaded microspheres were prepared by spray drying: 500 mg of gabapentin and 1 g of PEG-PLA copolymer were dissolved in 100 mL of dichloromethane. Microspheres were prepared using a spray dryer (inlet temperature 70°C, outlet temperature 40°C, pump speed 5 mL / min), and the microspheres were collected and freeze-dried for 24 hours.

[0058] 1 g of gabapentin-loaded microspheres were dispersed in 100 mL of recombinant human type I collagen solution (12 mg / mL) and stirred at 37° C. for 1 hour to uniformly disperse the microspheres.

[0059] The solvent of the recombinant human type I collagen solution is 0.1 M acetic acid solution.

[0060] 1.2 Preparation of outer layer solution

[0061] Dexamethasone-loaded microspheres were prepared by double emulsion method (W / O / W): 200 mg of dexamethasone and 100 mg of PEG-PLGA copolymer were dissolved in 10 mL of dichloromethane as the oil phase. The oil phase was slowly added dropwise to 10 mL of 2 w / w% PVA aqueous solution, and ultrasonic emulsification was performed using an ultrasonic probe for 5 minutes (power 300 W, working for 2 seconds, interval 1 second) to form colostrum. The colostrum was slowly poured into 100 mL of 0.5% PVA aqueous solution and stirred for 4 hours (400 rpm) to evaporate the solvent. The microspheres were collected by centrifugation (10000 g, 10 minutes) and freeze-dried for 24 hours.

[0062] 1 g of dexamethasone-loaded microspheres were dispersed in 100 mL of recombinant human type I collagen solution (8 mg / mL) and stirred at 37° C. for 1 hour to uniformly disperse the microspheres.

[0063] The solvent of the recombinant human type I collagen solution is 0.1 M acetic acid solution.

[0064] 1.3 Preparation of PEG-based adhesive

[0065] 2 g of four-arm PEG-acrylate was dissolved in 10 mL of PBS solution, 15.4 mg of dithiothreitol was added, and the mixture was reacted at 37° C. for 30 minutes to form a hydrogel.

[0066] 2. Preparation of Biotape

[0067] 1) Pour the inner layer solution into a polytetrafluoroethylene mold with a thickness of 1 mm and crosslink at 37°C for 1 hour;

[0068] 2) evenly coating 0.5 mL of PEG-based adhesive on the inner layer surface;

[0069] 3) Pour the outer layer solution onto the inner layer with a thickness of 0.5 mm and crosslink at 37°C for 1 hour;

[0070] 4) Coating a PDMS hydrophobic layer on the outer surface: dissolving a PDMS prepolymer (components A and B of the curing agent Sylgard 184 in a mass ratio of 10:1) in n-hexane to obtain a 5% (w / v) PDMS solution, coating a layer of PDMS on the outer surface by spin coating (3000 rpm, 30 seconds), and curing at 80° C. for 2 hours;

[0071] 5) Place in a vacuum drying oven and dry at 50°C for 12 hours;

[0072] 6) Sterilize with ethylene oxide gas at a temperature of 54° C., a relative humidity of 60%, an ethylene oxide concentration of 600 mg / L, and a sterilization time of 4 hours to obtain a biological tape for nerve stumps after amputation.

[0073] Application Example 1

[0074] After amputation, the biological tape prepared in Example 1 can be used in the following manner according to the specific conditions of the nerve stump:

[0075] 1. Fitting: For nerve stumps with smaller diameters (e.g., less than 5 mm in diameter), cut the biotape into appropriate sizes, place the nerve stump in the center of the tape, and then fold the tape in half so that the inner layer (adhesive layer) completely wraps the nerve stump. Press gently to ensure that the tape is in full contact with the nerve stump.

[0076] 2. Wrapping and fitting: For nerve stumps with larger diameters (such as diameters greater than 5mm) or irregular shapes, the biological tape can be cut into strips and wrapped from one end of the nerve stump, ensuring that each circle has a 50% overlap until the nerve stump is completely covered. When wrapping, pay attention to maintaining appropriate tension to ensure that the tape fits tightly to the nerve stump but does not cause compression.

[0077] 3. Complex trauma situations: For complex trauma situations with multiple nerve stumps or surrounding tissue damage, the above two methods can be combined according to actual needs. First, each nerve stump is treated individually, and then a larger area of ​​tape can be used to cover the entire trauma area to provide additional protection and drug release.

[0078] Through these application methods, the biological tape of the present invention can be applied to nerves of different diameters and complex trauma situations. The outer layer (non-stick layer) suppresses inflammatory reactions and reduces foreign body reactions by slowly releasing glucocorticoids, and the inner layer (adhesive layer) prevents and relieves neuralgia by slowly releasing gabapentin. At the same time, the physical bonding effect of the tape can prevent nerve fibers from growing outward, thereby reducing the risk of neuroma formation. During the application process, care should be taken to maintain the sterility of the surgical area.

[0079] Verification Example 1

[0080] In order to simulate the sustained release of two drugs (dexamethasone and gabapentin) in the biotape prepared in Example 1 in vitro, the present invention placed the biotape film sample in PBS buffer for sustained release experiment, and measured the released drug concentration by high performance liquid chromatography at fixed time points, and finally obtained the sustained release data at different time points.

[0081] 1. Experimental conditions

[0082] Buffer: PBS (phosphate buffered saline), pH = 7.4

[0083] Temperature: 37℃±0.5℃

[0084] Stirring speed: 100 rpm

[0085] Sampling time points: 0h, 2h, 4h, 8h, 12h, 24h, 48h, 72h, 96h, 120h, 168h; sampling was performed 3 times at each time point, and the experiment was repeated 3 times

[0086] Experimental film size: 1cm×1cm; thickness: 1.5mm

[0087] PBS buffer volume: Use 50 mL PBS buffer in a 100 mL beaker

[0088] 2. Drug concentration determination method: High performance liquid chromatography (HPLC)

[0089] The chromatographic conditions are:

[0090] Chromatographic column: C18 reverse phase column (150mm×4.6mm, 5μm)

[0091] Mobile Phase:

[0092] Dexamethasone: acetonitrile: water = 60:40 (v / v)

[0093] Gabapentin: methanol: 0.05M potassium dihydrogen phosphate buffer (pH 6.5) = 20:80 (v / v)

[0094] Flow rate: 1.0mL / min

[0095] Detection wavelength: dexamethasone 240nm; gabapentin 210nm

[0096] Injection volume: 20 μL

[0097] Sampling method: 1 mL of sample was taken at each time point, and 1 mL of fresh PBS was immediately added after sampling to keep the volume constant.

[0098] 3. Dexamethasone sustained-release data (unit: cumulative release percentage)

[0099] Time point | Release percentage (mean ± SD)

[0100] 0h|0%±0%

[0101] 2h|5.2%±0.8%

[0102] 4h|9.7%±1.2%

[0103] 8h|18.3%±1.5%

[0104] 12h|25.6%±1.9%

[0105] 24h|38.4%±2.3%

[0106] 48h | 52.7% ± 2.8%

[0107] 72h | 63.5% ± 3.1%

[0108] 96h|72.1%±3.4%

[0109] 120h|78.9%±3.6%

[0110] 168h|85.3%±3.8%

[0111] visible:

[0112] 1) The release rate was relatively fast in the first 24 hours, with a cumulative release of 38.4%;

[0113] 2) The release rate tended to be flat during 24-72 hours, and the cumulative release increased from 38.4% to 63.5%;

[0114] 3) The release rate slowed down further from 72 to 168 hours, and the final cumulative release reached 85.3%;

[0115] 4) After 168 hours (7 days), the cumulative release reached 85.3%, indicating that most of the drug had been released, but about 15% of the drug was still retained in the carrier.

[0116] 4. Gabapentin sustained-release data (unit: cumulative release percentage)

[0117] Time point | Release percentage (mean ± SD)

[0118] 0h|0%±0%

[0119] 2h|7.8%±1.1%

[0120] 4h|14.5%±1.6%

[0121] 8h|25.9%±2.0%

[0122] 12h|35.2%±2.4%

[0123] 24h|49.7%±2.9%

[0124] 48h | 65.3% ± 3.3%

[0125] 72h | 76.8% ± 3.6%

[0126] 96h|84.5%±3.8%

[0127] 120h|90.2%±4.0%

[0128] 168h|94.7%±4.1%

[0129] visible:

[0130] 1) The release rate was relatively fast in the first 24 hours, with the cumulative release reaching 49.7%;

[0131] 2) The release rate slowed down slightly during the 24-72 hour period, and the cumulative release increased from 49.7% to 76.8%;

[0132] 3) The release rate slowed down further from 72 to 168 hours, and the final cumulative release reached 94.7%;

[0133] 4) After 168 hours (7 days), the cumulative release reached 94.7%, indicating that almost all the drugs were released and only about 5% of the drugs remained in the carrier.

[0134] Verification Example 2

[0135] In order to test the effectiveness of the bio-tape of the present invention, we conducted a series of in vivo experiments:

[0136] 2.1 Experimental Animal Selection:

[0137] Adult male Sprague-Dawley rats weighing 250-300 g were selected.

[0138] 2.2 Group design:

[0139] The rats were randomly divided into 2 groups, 6 in each group, and samples were collected at 4 time points;

[0140] Control group: only sciatic nerve transection

[0141] Experimental group: Sciatic nerve was cut and then wrapped with the biological tape of the present invention

[0142] 2.3 Evaluation Metrics

[0143] Neuroma formation assessment: Assess the incidence of neuromas.

[0144] The positive criteria for neuroma formation are:

[0145] (1) Gross observation: Obvious spherical or spindle-shaped swelling appears at the stump of the nerve, and the diameter of the swelling exceeds 1.5 times the diameter of the normal nerve. Histological observation: HE staining shows disordered arrangement of nerve fibers, obvious proliferation of collagen fibers, disordered axon regeneration, and a "whirlpool" or "maze" arrangement. Immunohistochemistry: Positive staining of nerve fiber markers (such as NF200) is disorderly distributed, and the expression of collagen fiber markers (such as type I collagen) increases.

[0146] (2) Scar formation assessment: Masson trichrome staining was used to observe the thickness and density of collagen fibers.

[0147] (3) Evaluation of anti-inflammatory effect: Western blot was used to detect the expression of inflammatory factors (IL-1β, TNF-α).

[0148] 2.4 Experimental Results

[0149] 1) Incidence of neuroma

[0150] Time point | Neuroma incidence in the control group | Neuroma incidence in the experimental group

[0151] 2 weeks | 33.3% (2 / 6) | 0% (0 / 6)

[0152] 4 weeks | 66.7% (4 / 6) | 0% ( / 6)

[0153] 8 weeks | 100% (6 / 6) | 0% (0 / 6)

[0154] 12 weeks | 100% (6 / 6) | 0% (0 / 6)

[0155] 2) Collagen fiber thickness and density

[0156] Time point|Control group collagen fiber thickness (μm)|Experimental group collagen fiber thickness (μm)|Control group collagen fiber density (%)|Experimental group collagen fiber density (%) (mean ± SD)

[0157] 2 weeks|52.3±5.1|38.6±4.2|35.7±3.8|27.9±3.1

[0158] 4 weeks|78.5±7.3|54.2±5.7|48.3±4.5|36.2±3.7

[0159] 8 weeks|95.7±8.9|67.3±6.5|57.6±5.2|42.8±4.3

[0160] 12 weeks|108.2±10.1|75.9±7.2|63.4±5.8|47.5±4.6

[0161] 3) Expression levels of inflammatory factors in Western blot experiments

[0162] Time point|IL-1β in control group (relative expression)|IL-1β in experimental group (relative expression)|

[0163] TNF-α(relative expression) in control group | TNF-α(relative expression) in experimental group (mean ±

[0164] Standard Deviation

[0165] 2 weeks|2.87±0.31|1.95±0.22|2.53±0.28|1.76±0.19

[0166] 4 weeks|2.41±0.26|1.52±0.17|2.12±0.23|1.38±0.15

[0167] 8 weeks|1.93±0.21|1.14±0.13|1.75±0.19|1.05±0.11

[0168] 12 weeks|1.56±0.17|0.89±0.10|1.43±0.16|0.82±0.09

[0169] The above data show that the biological tape prepared by the present invention can effectively inhibit the formation of neuroma after nerve transection, reduce the generation of scar tissue, and reduce local inflammatory response.

[0170] The above description is only a preferred embodiment of the present invention, and does not limit the implementation mode and protection scope of the present invention. For those skilled in the art, it should be aware that all solutions obtained by equivalent substitutions and obvious changes made using the contents of the specification of the present invention should be included in the protection scope of the present invention.

Claims

1. A biological tape for nerve stumps after amputation, characterized in that: The invention comprises an outer layer and an inner layer, wherein the outer layer and the inner layer are connected by a layer of PEG-based adhesive, the outer surface of the outer layer is coated with a layer of PDMS hydrophobic coating; and the inner surface of the inner layer is also coated with a PEG-based adhesive layer; Wherein, the outer layer is made of recombinant human type I collagen and contains dexamethasone-loaded microspheres, and the dexamethasone-loaded microspheres are made of PEG-PLGA copolymer; The inner layer is made of recombinant human type I collagen and contains gabapentin-loaded microspheres, and the gabapentin-loaded microspheres are made of PEG-PLA copolymer; The PEG-based adhesive is formed by cross-linking four-arm PEG-acrylate and dithiothreitol.

2. The biological tape for post-amputation nerve stump according to claim 1, characterized in that: The average particle size of the dexamethasone-loaded microspheres is 4-5 μm.

3. The biological tape for post-amputation nerve stump according to claim 1, characterized in that: The average particle size of the gabapentin-loaded microspheres is 2-3 μm.

4. The biological tape for post-amputation nerve stump according to claim 1, characterized in that: The thickness of the outer layer is 0.4-0.5 mm, and the thickness of the inner layer is 0.8-1 mm.

5. A method for preparing a biological tape for nerve stumps after amputation as claimed in any one of claims 1 to 4, characterized in that: The steps include: Step 1, preparing an outer layer solution and an inner layer solution respectively; Step 2, pouring the inner layer solution into a mold and cross-linking at 35-37° C. for 0.5-1 hour; Step 3, uniformly coating the inner and outer surfaces of the cross-linked inner layer with a PEG-based adhesive; Step 4, pour the outer layer solution onto the inner layer and cross-link at 35-37° C. for 0.5-1 hour; Step 5, coating a PDMS hydrophobic layer on the outer surface after cross-linking molding; Step six, vacuum drying for 10-12 hours and sterilization to obtain the biological tape for the nerve stump after amputation.

6. The preparation method according to claim 5, characterized in that: The specific preparation method of the inner layer solution is as follows: Gabapentin-loaded microspheres were prepared by spray drying: gabapentin and PEG-PLA copolymer were dissolved in dichloromethane, and microspheres were prepared by spray drying at an inlet temperature of 70°C, an outlet temperature of 40°C, and a pump speed of 5 mL / min. Gabapentin-loaded microspheres were collected and freeze-dried. The gabapentin-loaded microspheres were dispersed in a recombinant human type I collagen solution with a concentration of 12 mg / mL, and stirred at 37° C. for 1 hour to uniformly disperse the microspheres.

7. The preparation method according to claim 5, characterized in that: The specific preparation method of the outer layer solution is as follows: Dexamethasone drug-loaded microspheres were prepared by double emulsion method: dexamethasone and PEG-PLGA copolymer were dissolved in dichloromethane as the oil phase; the oil phase was slowly added dropwise to a 2% w / w PVA aqueous solution, and ultrasonic emulsification was performed using an ultrasonic probe to form colostrum; the colostrum was slowly poured into a 0.5% w / w PVA aqueous solution, stirred to evaporate the solvent, and the dexamethasone drug-loaded microspheres were collected by centrifugation and freeze-dried; The dexamethasone-loaded microspheres were dispersed in a recombinant human type I collagen solution at a concentration of 8 mg / mL, and stirred at 37° C. for 1 hour to uniformly disperse the microspheres.

8. The preparation method according to claim 5, characterized in that: The specific preparation method of the PEG-based adhesive is as follows: four-arm PEG-acrylate is dissolved in a PBS solution, dithiothreitol is added, and the mixture is reacted at 37° C. for 30 minutes to form a hydrogel.

9. The preparation method according to claim 5, characterized in that: The specific operation of coating the PDMS hydrophobic layer on the surface of the outer layer is as follows: dissolving the PDMS prepolymer in n-hexane, coating it on the surface of the outer layer by spin coating, and curing at 80° C. for 2 hours to form the PDMS hydrophobic layer.