Asymmetric bioadhesive patch with controllable modulus adhesion as well as preparation method and application of asymmetric bioadhesive patch

Abstract

The invention relates to an asymmetric bioadhesive patch with controllable modulus adhesion as well as a preparation method and application of the asymmetric bioadhesive patch. The asymmetric bioadhesive patch is of a double-layer composite gel structure and comprises an elastomer layer used for being adhered to a medical instrument and a hydrogel layer used for being adhered to soft tissue. The elastomer layer is prepared from the following raw material components: hexadecyl acrylate, a long-chain cross-linking agent and a photoinitiator; the raw materials of the hydrogel layer comprise any one of the following two groups of raw material components: acrylic acid, gelatin, acrylic acid N-hydroxysuccinimide ester, methacrylated gelatin, alpha-ketoglutaric acid and the balance of water; or acrylic acid, acrylic acid N-hydroxysuccinimide ester, N, N '-methylene bisacrylamide, alpha-ketoglutaric acid and the balance of water. Compared with the prior art, the two sides of the asymmetric bioadhesive patch can be adhered to medical equipment and soft tissue respectively, so that the medical equipment can be effectively fixed in the soft tissue.

Description

Technical Field

[0001] The invention belongs to the technical field of biomedical materials, and in particular relates to an asymmetric bioadhesive patch with controllable modulus adhesion and a preparation method and application thereof. Background Art

[0002] Achieving effective integration of medical devices with soft tissue is a critical and common problem in clinical practice. Poor soft tissue-device interface integration leads to insufficient device retention and suboptimal interface sealing, with a high risk of infection, especially for percutaneous / transmucosal devices. The infection rate around percutaneous / transmucosal implants is significantly higher than that of other types of permanent implants. For example, the infection rate of prosthetic joints is less than 2%, while the infection rate of bone-anchored implants is between 5% and 30%, the infection rate of external fixators is more than 50%, and the infection rate of oral implants is approximately 47.1%.

[0003] Traditional bioengineering methods combine soft tissue with permanent implants, which cannot be sealed immediately after implantation. Achieving good integration between medical devices and soft tissues requires overcoming various challenges. First, there are significant differences between soft tissue and device interfaces, especially in mechanical properties and surface energy, which makes it difficult for existing homogeneous adhesives to fully wet both sides, thus hindering effective bonding and sealing. Secondly, there are many types of medical device materials and they need to be applied to different parts of the human body, so they need to have a wide range of adhesion compatibility on both sides of the interface. Furthermore, since most temporary devices involve implantation and removal processes, the adhesive needs to remain non-stick before implantation to facilitate handling and placement, while also allowing for on-demand peeling after implantation. Finally, in order to ensure the stability of the bond, the expansion of the adhesive must also be controlled.

[0004] Therefore, in order to solve the problem that the above-mentioned medical devices cannot be effectively fixed in soft tissues, it is urgent to develop a bioadhesive patch that can achieve instant and reversible sealing between the medical device and the soft tissue. Summary of the invention

[0005] The purpose of the present invention is to provide an asymmetric bioadhesive patch with controllable modulus adhesion and a preparation method and application thereof in order to overcome the defect that existing medical devices cannot be effectively fixed in soft tissues.

[0006] The purpose of the present invention can be achieved by the following technical solutions:

[0007] The present invention first provides an asymmetric bioadhesive patch with controllable modulus adhesion, wherein the asymmetric bioadhesive patch is a double-layer composite gel structure, which includes an elastomer layer for adhering to a medical device and a hydrogel layer for adhering to soft tissue;

[0008] The raw materials of the elastomer layer include the following components by weight: 60-80 parts of acrylate monomer, 20-40 parts of long-chain crosslinking agent, and 1 part of photoinitiator;

[0009] The raw materials of the hydrogel layer include any one of the following two groups of raw material components, based on a total of 100 parts by weight:

[0010] 25-35 parts of acrylic acid, 8-12 parts of gelatin, 0.8-1.2 parts of acrylic acid N-hydroxysuccinimide ester, 0.1 parts of methacrylic acid acylated gelatin, 0.2 parts of α-ketoglutaric acid, and the balance is water;

[0011] Or 25-35 parts of acrylic acid, 0.8-1.2 parts of N-hydroxysuccinimide acrylic acid ester, 0.1 parts of N,N'-methylenebisacrylamide, 0.2 parts of α-ketoglutaric acid, and the balance is water.

[0012] Further, in the elastomer layer, the acrylate monomer includes one or both of hexadecyl acrylate (HA) and octadecyl acrylate (SA).

[0013] Furthermore, in the elastomer layer, the long-chain cross-linking agent is polyurethane diacrylate.

[0014] Furthermore, in the elastomer layer, the photoinitiator is benzil dimethyl ether.

[0015] Furthermore, both the elastic layer and the hydrogel layer can be peeled off from the medical device or soft tissue on the corresponding side by a sodium bicarbonate solution.

[0016] Furthermore, the mass concentration of the sodium bicarbonate solution is 0.08-0.12%, preferably a sodium bicarbonate solution with a mass concentration of 0.1% refrigerated to 4-10°C.

[0017] Furthermore, the interface toughness between the elastomer layer and the hydrogel layer is greater than 500 J / m 2 .

[0018] Furthermore, the elastomer layer has temperature and modulus response characteristics, and changes from a non-adhesive state to an adhesive state at physiological temperature. Since the elastomer layer is a semi-crystalline elastomer layer, before implantation, the elastomer layer maintains high modulus and non-adhesive properties, which is convenient for application; once implanted, the crystal region is induced to melt at body temperature, triggering a decrease in modulus to enhance conformal adhesion to various device materials.

[0019] Furthermore, the hydrogel layer adheres to the moist soft tissue through water absorption and chemical bonding, effectively sealing both sides of the interface.

[0020] The present invention also provides a method for preparing an asymmetric bioadhesive patch with controllable modulus adhesion, comprising the following steps:

[0021] S1. Preparation of elastomer layer:

[0022] The acrylate monomer and the long-chain crosslinking agent are mixed, a photoinitiator is added, and after ultrasonic treatment, ultraviolet light curing is performed in a mold, and the elastomer layer is obtained after cooling;

[0023] S2. Preparing a hydrogel layer on the elastomer layer:

[0024] The elastomer layer is placed in a mold, a pre-crosslinked aqueous solution containing raw material components of the hydrogel layer is added, and then ultraviolet light curing is performed to finally obtain an asymmetric bioadhesive patch in which the elastomer layer and the hydrogel layer are tightly combined.

[0025] Furthermore, in step S1, the UV curing time is 8-12s.

[0026] Furthermore, in step S1, the wavelength of the ultraviolet light is 365 nm.

[0027] Furthermore, in step S1, the ultrasonic treatment time is 20-40 minutes.

[0028] Furthermore, the cooling temperature is less than 0°C and the cooling time is 8-12 minutes.

[0029] Furthermore, in step S2, the UV curing time is 1.5-3 hours.

[0030] Furthermore, in step S2, the wavelength of the ultraviolet light is 365 nm.

[0031] The present invention also provides an application of an asymmetric bioadhesive patch with controllable modulus adhesion, wherein the asymmetric bioadhesive patch is used to achieve connection between medical devices and soft tissues, and is specifically used for drainage tube fixation, denture retention, and prevention of peri-implantitis.

[0032] Furthermore, the medical devices correspondingly include a medical catheter, a denture base and an implant base.

[0033] Compared with the prior art, the present invention has the following beneficial effects:

[0034] (1) The present invention creates an asymmetric double-layer bioadhesive patch that can effectively adhere to the soft tissue-medical device interface with opposite properties, ensuring that the elastomer layer can adhere to various medical device materials and the hydrogel layer can adhere to different types of soft tissues to achieve effective fixation of medical devices in soft tissues.

[0035] (2) The elastomeric layer of the present invention has a temperature-responsive modulus variability to achieve a hard, non-adhesive state before implantation for ease of handling, and a soft, adhesive state after implantation for ease of immediate sealing; in addition, low-temperature sodium bicarbonate can be used to eliminate adhesion, allowing for peeling on demand.

[0036] (3) The present invention utilizes the cross-linking of the double-layer acrylic monomers to eventually integrate the two layers into a whole, thereby ensuring that the elastomer layer and the hydrogel layer are not separated during use, and can effectively control the expansion of the hydrogel layer, thereby enhancing the stability of adhesion.

[0037] (4) The asymmetric bioadhesive patch of the present invention can achieve good integration between medical devices and soft tissues, and has good sealing and adhesion effects in clinical situations such as drainage tube fixation, denture retention and peri-implantitis prevention. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 The figure is a schematic diagram of the process for preparing the asymmetric bioadhesive patch of the present invention.

[0039] Figure 2 This is a Fourier transform infrared spectrum of the asymmetric bioadhesive patch prepared in Example 1 of the present invention.

[0040] Figure 3 This is a graph showing the double-layer bonding strength test results of Example 1 and Comparative Example 3 of the present invention.

[0041] Figure 4 The storage modulus test results of Example 1 and Comparative Example 4 of the present invention are shown.

[0042] Figure 5 This is a diagram showing the adhesion of the asymmetric bioadhesive patch prepared in Example 1 of the present invention to soft tissue.

[0043] Figure 6 This is a diagram showing the adhesion results of the asymmetric bioadhesive patch prepared in Example 1 of the present invention to a medical device.

[0044] Figure 7 Schematic diagram of the state of the patches prepared in Example 1 and Comparative Examples 1-2 of the present invention after being immersed in PBS solution for 24 hours.

[0045] Figure 8 This is a diagram showing the animal experiment effect of Application Example 1 of the present invention.

[0046] Fig. 9 This is an animal experiment effect diagram of Application Example 2 of the present invention.

[0047] Fig.10 This is an animal experiment effect diagram of Application Example 3 of the present invention. DETAILED DESCRIPTION

[0048] The present invention is described in detail below in conjunction with the accompanying drawings and specific embodiments. This embodiment is implemented based on the technical solution of the present invention, and provides a detailed implementation method and specific operation process, but the protection scope of the present invention is not limited to the following embodiments.

[0049] Unless otherwise specified, the reagents, methods, instruments and equipment used in the present invention are conventional reagents, methods, instruments and equipment in the art. Unless otherwise specified, the reagents and materials used in the following examples are commercially available. Among them, the long-chain crosslinking agent is polyurethane diacrylate (UDA, CN9021), the photoinitiator is benzil dimethyl ether (DMPA, CAS: 24650-42-8); methacrylated gelatin (GelMA, MA degree 60%).

[0050] Embodiment 1:

[0051] This embodiment provides an asymmetric bioadhesive patch with controllable modulus adhesion, such as Figure 1 As shown, the preparation method is as follows:

[0052] S1. Preparation of elastomer layer (HA patch):

[0053] Hexadecyl acrylate (HA) and crosslinker polyurethane diacrylate were mixed in a weight ratio of 80%:20%. After adding 1% of the total mass of DMPA as a photoinitiator, the entire HA-UDA mixture was ultrasonically treated for 30 minutes (ultrasonic frequency 40-70Hz), and then injected into a glass mold; after 365nm UV curing for 10s, it was placed in a -4℃ refrigerator for 10min to obtain a HA patch.

[0054] S2. Preparing a hydrogel layer (PA patch) on the elastomer layer:

[0055] The cured HA patch was taken out and placed on a glass plate. A silicone rubber mold was added above the HA patch, and an acrylic hydrogel (PA) pre-crosslinking liquid was added to the mold. The components of the pre-crosslinking liquid are: 30% (w / w) acrylic acid, 10% (w / w) gelatin (300Bloom), 1% (w / w) acrylic acid N-hydroxysuccinimide ester (CAS: 38862-24-7), 0.1% (w / w) methacryloyl gelatin (GelMA, grafting rate 60%) and 0.2% (w / w) α-ketoglutaric acid dissolved in deionized water. Subsequently, the curing was continued under 365nm ultraviolet light for 2h, and finally an asymmetric bioadhesive patch (HAPA patch) with a double-layer structure was obtained.

[0056] The Fourier transform infrared spectrum of the HAPA patch of this embodiment is as follows Figure 2As shown. After 10 seconds of ultraviolet irradiation (i.e., during the preparation of the HA patch), the C=C peak of HA is still at 1630cm-1 (curve HA-1 in the figure), indicating that HA is not completely cured. However, after 2 hours of ultraviolet irradiation (i.e., the preparation of the HAPA patch is completed), the peak disappears, indicating that HA has been completely polymerized (curve HA-2 in the figure). After co-curing of PA and HA, the C=C peak disappears (HA-interface), while the peaks corresponding to polyacrylic acid (1696cm-1, carboxylic acid C=O) and NHS ester (1158cm-1 and 1209cm-1, CNC) still exist. This shows that the C=C bonds of the two layers react and cross-link under ultraviolet irradiation, thereby forming covalent bonds at the interface. It can be seen that the present invention successfully integrates the HA layer and the PA layer using a co-curing strategy. The polymerization level of HA can be adjusted by adjusting the UV irradiation time, so the HA layer is first semi-cured, then applied and cured together with the PA monomer, and finally subjected to additional UV irradiation, and the asymmetric bioadhesive patch with a double-layer gel composite structure of the present invention can be successfully prepared.

[0057] Embodiment 2:

[0058] This embodiment provides an asymmetric bioadhesive patch with controllable modulus adhesion. The difference from Embodiment 1 is that this embodiment is prepared by mixing hexadecyl acrylate and cross-linking agent polyurethane diacrylate in a weight ratio of 60%:40%.

[0059] Embodiment 3:

[0060] This embodiment provides an asymmetric bioadhesive patch with controllable modulus adhesion. The difference from Embodiment 1 is that the acrylate monomer of this embodiment is octadecyl acrylate, and the elastomer layer is prepared by mixing octadecyl acrylate and cross-linking agent polyurethane diacrylate in a weight ratio of 80%:20%.

[0061] Embodiment 4:

[0062] This embodiment provides an asymmetric bioadhesive patch with controllable modulus adhesion. The difference from Embodiment 1 is that the acrylate monomer of this embodiment is octadecyl acrylate, and the elastomer layer is prepared by mixing octadecyl acrylate and cross-linking agent polyurethane diacrylate in a weight ratio of 60%:40%.

[0063] Embodiment 5:

[0064] This embodiment provides an asymmetric bioadhesive patch with controllable modulus adhesion. The difference from Example 1 is that the hydrogel layer of this embodiment is 30% (w / w) acrylic acid, 1% (w / w) acrylic acid N-hydroxysuccinimide ester (CAS: 38862-24-7), 0.1% (w / w) N,N'-methylenebisacrylamide (CAS: 110-26-9) and 0.2% (w / w) α-ketoglutaric acid dissolved in deionized water, and then further cured under 365nm ultraviolet light.

[0065] Comparative Example 1:

[0066] Compared with Example 1, this comparative example is a single-layer elastomer layer (i.e., HA patch), and the preparation method is: hexadecyl acrylate (HA) and cross-linking agent polyurethane diacrylate are mixed in a weight ratio of 80%:20%. After adding 1% of the total mass of DMPA as a photoinitiator, the entire HA-UDA mixture is ultrasonically treated for 30 minutes and then injected into a glass mold; after 365nm ultraviolet light curing for 10s, it is placed in a -4°C refrigerator and cooled for 10min to obtain a HA patch.

[0067] Comparative Example 2:

[0068] Compared with Example 1, this comparative example is a single-layer hydrogel layer (i.e., PA patch), and the preparation method is: adding a silicone rubber mold to a glass plate, and adding an acrylic hydrogel (PA) pre-crosslinking liquid into the mold. The components of the pre-crosslinking liquid are: 30% (w / w) acrylic acid, 10% (w / w) gelatin, 1% (w / w) acrylic acid N-hydroxysuccinimide ester, 0.1% (w / w) methacryloyl gelatin and 0.2% (w / w) α-ketoglutaric acid dissolved in deionized water. Subsequently, the curing is continued for 2 hours under 365nm ultraviolet light to obtain a single-layer PA patch.

[0069] Comparative Example 3:

[0070] Compared with Example 1, in this comparative example, a single-layer elastomer layer and a single-layer hydrogel layer are prepared separately, and then directly adhered at room temperature, that is, the HA layer and the PA layer are attached together, and left to stand in a humid environment for 24 hours under a pressure of about 50 N. The preparation method of the single-layer elastomer layer and the single-layer hydrogel layer refers to Comparative Examples 1 and 2, which will not be repeated here.

[0071] Comparative Example 4:

[0072] The difference between this comparative example and Example 1 is that the acrylic acid ester monomer in this comparative example is octadecyl acrylate, and the elastomer layer is prepared by mixing octadecyl acrylate and a cross-linking agent, polyurethane diacrylate, in a weight ratio of 40%:60%.

[0073] The present invention carries out the following tests on the above-mentioned embodiments and comparative examples:

[0074] (1) Double-layer bonding strength test: The double-layer bonding strength test adopts a 180° peel test (modified according to ASTM D3330), and a backing is added to both layers. The specific steps are as follows: Cut the sample into an appropriate size of 20mm×80mm. Fix one end of the sample on the testing machine and pull up the other end at an angle of 180°. Pull up the sample at a constant speed of 50mm / min and record the peel force. Calculate the peel strength (usually expressed in N / mm) and interface toughness (J / m based on the test results. 2 ).

[0075] (2) Modulus change test: A dynamic temperature scanning test was performed on a dynamic mechanical analyzer (TA Instruments RSAIII) to obtain the storage modulus. The test conditions were: a heating rate of 1°C / min, a frequency of 1 Hz, and a temperature test range of 15-50°C.

[0076] (3) Soft tissue adhesion test: In order to verify the adhesion of the patch prepared in Example 1 to soft tissue and the peeling effect under sodium bicarbonate solution, the 180° peeling strength between the patch and skin, muscle and collagen casing, as well as the peeling strength of the patch after the patch adhered to the skin and dripped with a refrigerated 0.1wt% sodium bicarbonate solution (4-10°C) at the bonding interface were tested. The specific adhesion process is that a PA sample with a width of 15mm and a length of 60mm is adhered to a flat tissue surface, a pressure of 50N is applied in a humid environment, and the adhesion interface strength between PA and tissue is tested by 180° peeling after standing for 24 hours.

[0077] (4) Swelling performance test: The patches were cut into circular samples with a diameter of 4 mm, and then immersed in a PBS solution at 37°C for 24 h to observe the swelling effect.

[0078] The test results of the double-layer bonding strength of Example 1 (referred to as Combined group) and Comparative Example 3 (referred to as Adhered group) are as follows: Figure 3 The results show that the failure occurred inside the PA layer during 180° peeling, rather than at the interface between the HA layer and the PA layer. The interface toughness of the co-cured patch is 816.97 J / m 2 , while the interface toughness of the simple adhesion group was only 176.72 J / m 2 The cross-linking method of the present invention ensures the integrity of the bioadhesive patch during subsequent use.

[0079] In order to verify that the modulus of the elastomer layer at physiological temperature is controllable, the storage modulus change results of Example 1 and Comparative Example 4 are as follows: Figure 4As shown. Among them, the modulus G' of the HAPA patch of Example 1 is less than 0.1MPa after 37°C, which meets the Dalhquist criterion and has the characteristics of a pressure-sensitive adhesive. In addition, the modulus of the bioadhesive patches prepared in Examples 2-4 is less than or equal to 0.1MPa after heating, and they also have the characteristics of a pressure-sensitive adhesive. However, the bioadhesive patch prepared in Comparative Example 4 cannot achieve a significant decrease in modulus and loses the characteristics of a pressure-sensitive adhesive. It can be seen that the ratio of the acrylate monomer and the long-chain cross-linking agent of the present invention is controlled within a certain range to achieve good controllability of the modulus adhesion of the elastomer layer.

[0080] In order to verify that the adhesion of the hydrogel layer to the soft tissue is controllable, the adhesion and peeling results of the HAPA patch prepared in Example 1 to various soft tissues are shown in the following table. Figure 5 As shown in the figure, the HAPA patch prepared in Example 1 has good adhesion to skin, muscle and collagen. In addition, after adding sodium bicarbonate, the adhesion of the HAPA patch to the skin can be reduced to a peel strength of less than 5N / m, indicating that the sodium bicarbonate solution can effectively eliminate the adhesion of the HAPA patch to soft tissue and can be peeled off as needed.

[0081] In order to verify the adhesion between the elastomer layer and the medical device, the adhesion between the HAPA patch prepared in Example 1 and various medical device materials is as follows: Figure 6 As shown in the figure, the HAPA patch prepared in Example 1 has good adhesion to titanium (alloy), methyl methacrylate (PMMA) and polyethylene (PVC) commonly used in medical applications at 37°C, and the adhesion strength is not significantly different from that of commonly used medical tapes; and it is very easy to peel off at 25°C, indicating that the bioadhesive patch of the present invention can achieve effective adhesion to medical devices at physiological temperature.

[0082] In addition, in order to ensure the stability of adhesion, the expansion of the bioadhesive patch must be controlled. The state of the patch finally prepared in Example 1 and Comparative Examples 1-2 after being immersed in PBS solution for 24 hours is as follows: Figure 7 As shown in the figure, the elastomer layer (HA) of Comparative Example 1 does not swell in water, while the single-layer hydrogel layer (PA) of Comparative Example 2 has a higher expansion capacity, which will lead to a decrease in its mechanical properties, thereby limiting its practical application. The HAPA patch of Example 1 can effectively regulate the expansion of the PA layer through the combination of the elastomer layer and the hydrogel layer. It can be seen that the combination of the hydrophilic PA layer and the hydrophobic HA layer can greatly limit the expansion of the hydrogel layer. This control of the swelling of the HAPA patch ensures its stability during clinical use.

[0083] The present invention utilizes the Janus structure to prepare a universal double-layer asymmetric bioadhesive patch that can instantly bridge the contrasting interfaces between soft tissue and medical device devices. The structure includes a semi-crystalline elastomer layer with adjustable stiffness and adhesion, and a hydrogel layer that ensures strong tissue adhesion. Before implantation, the semi-crystalline elastomer maintains high modulus and non-adhesive properties for ease of application. Once implanted, body temperature induces melting of the crystalline region, triggering modulus reduction and enhanced conformal adhesion to various device materials. The hydrogel layer further promotes adhesion to moist soft tissue by absorbing water and chemical bonding, effectively sealing both sides of the interface. The interpenetration and cross-linking between the two layers prevents delamination and excessive expansion in a humid environment, improving the overall performance and reliability of the adhesive patch.

[0084] Hereby, the present invention provides the universal sealing adhesion effect of asymmetric bioadhesive patch in different simulated clinical situations such as drainage tube fixation, denture retention and peri-implantitis prevention, as shown in Application Examples 1 to 3. All animal experiments in the following application examples were approved by the Animal Care and Experiment Committee of the Ninth People's Hospital.

[0085] Application Example 1:

[0086] This application example is the application of the asymmetric bioadhesive patch of Example 1 in the fixation of drainage tubes. The specific operation is as follows: establish a rat peritoneal drainage model. 12-week-old male Sprague Dawley rats were anesthetized and the abdominal hair was removed. Use scissors to cut two circular wounds with a diameter of 4 mm at a position symmetrical to the midline of the abdomen. Two silicone catheters were implanted, with a length of 15 mm, a diameter of 4 mm, and an implantation depth of 10 mm. In the HAPA group, a 10 mm wide HAPA patch was pasted to the part where the catheter extended out of the abdominal cavity outlet to seal the abdominal mucosa and the catheter outlet. The control group was fixed by suture. Three days later, HE-stained sections showed that the inflammatory cells in the HAPA group were significantly less than those in the suture group, and the HAPA patch was in place, with good retention and no gaps between the mucosa.

[0087] In order to evaluate the retention and sealing effect of HAPA patch in vivo, the present invention established a rat peritoneal drainage model. In this model, the control group used conventional suture technology to fix the drainage tube. Figure 8 It can be seen that after implantation, exudate was observed around the drainage tube in the control group, while the HAPA patch effectively absorbed these exudates and maintained a relatively clean external environment to resist bacterial growth. The catheter was pulled out with forceps to evaluate the stability of catheter fixation. The sutured catheter was easily displaced, creating a gap at the soft tissue-device interface. In contrast, the HAPA patch provided immediate adhesion at the interface; when the tube was lifted, the attached tissue in the HAPA group moved seamlessly around the tube without any gap at the interface. At the same time, tissue sections showed that the HAPA group had less inflammation, and the patch, as shown by the yellow arrow, was closely adhered to the underlying tissue.

[0088] Application Example 2:

[0089] This application example is the application of the asymmetric bioadhesive patch of Example 1 in denture retention. The specific operation is as follows: 16-week-old male Sprague Dawley rats (400±10g) (n=3) were imprinted with alginate on a 1.5cm×2.5cm wax disk, and then a rat maxillary plaster model was perfused. A polymethyl methacrylate base was prepared on the customized plaster mold. The dentures lined with HAPA patches were divided into HAPA group and denture paste lined with commercially available denture paste. The dentures of 3 rats were used as the control group. The 3 rats were anesthetized with 1% sodium pentobarbital (40 mg / kg), and the dentures were placed into the maxillary mucosa to observe the retention.

[0090] Depend on Fig. 9 It can be seen that HAPA patch can help the base to be well retained in the rat's palate and no residue is left in the palate after removal, while commercial denture adhesives will have a large amount of residue in the palate tissue.

[0091] Application Example 3:

[0092] This application example is the application of the asymmetric bioadhesive patch of Example 1 in the prevention of peri-implantitis. The specific operation is as follows: a one-piece titanium implant (300±10g) (n=5) with a diameter of 1.4mm and a length of 4mm without an independent base was implanted into the edentulous area on both sides of 12-week-old male Sprague Dawley rats. The rats were fasted overnight, had free access to water, and were anesthetized with 1% sodium pentobarbital (40mg / kg). The HAPA patch was applied between the implant base and the mucosa in the HAPA group.

[0093] Depend on Fig.10 It can be seen that the HAPA patch makes the titanium alloy base of the implant and the mucosa well sealed, food residues are not easy to enter, and there are fewer bleeding sites around the implant. Hard tissue sections showed that the epithelium of the HAPA group was smooth on the third day, while the epithelial spikes of the control group increased under inflammatory stimulation. Immunofluorescence showed that the inflammation of the control group was more obvious; on the seventh day, the bone tissue around the implant was tightly combined with the implant in the HAPA group, while the control group had obvious bone resorption.

[0094] The above description of the embodiments is to facilitate the understanding and use of the invention by those skilled in the art. It is obvious that those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative work. Therefore, the present invention is not limited to the above embodiments, and improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the present invention should be within the scope of protection of the present invention.

Claims

1. An asymmetric bioadhesive patch with controllable modulus adhesion, characterized in that: The asymmetric bioadhesive patch is a double-layer composite gel structure, which includes an elastomer layer for adhering to medical devices and a hydrogel layer for adhering to soft tissues; The raw materials of the elastomer layer include the following components by weight: 60-80 parts of acrylate monomer, 20-40 parts of long-chain crosslinking agent, and 1 part of photoinitiator; The raw materials of the hydrogel layer include any one of the following two groups of raw material components, based on a total of 100 parts by weight: 25-35 parts of acrylic acid, 8-12 parts of gelatin, 0.8-1.2 parts of acrylic acid N-hydroxysuccinimide ester, 0.1 parts of methacrylic acid acylated gelatin, 0.2 parts of α-ketoglutaric acid, and the balance is water; Or 25-35 parts of acrylic acid, 0.8-1.2 parts of N-hydroxysuccinimide acrylic acid ester, 0.1 parts of N,N'-methylenebisacrylamide, 0.2 parts of α-ketoglutaric acid, and the balance is water.

2. The asymmetric bioadhesive patch with controllable modulus adhesion according to claim 1, characterized in that: In the elastomer layer, the acrylate monomer includes one or both of hexadecyl acrylate and octadecyl acrylate.

3. The asymmetric bioadhesive patch with controllable modulus adhesion according to claim 1, characterized in that: In the elastomer layer, the long-chain crosslinking agent is polyurethane diacrylate, and the photoinitiator is benzil dimethyl ether.

4. The asymmetric bioadhesive patch with controllable modulus adhesion according to claim 1, characterized in that: The elastic body layer and the hydrogel layer can be peeled off from the medical device or soft tissue on the corresponding side by a sodium bicarbonate solution; the mass concentration of the sodium bicarbonate solution is 0.08-0.12%.

5. The asymmetric bioadhesive patch with controllable modulus adhesion according to claim 1, characterized in that: The interface toughness between the elastomer layer and the hydrogel layer is greater than 500 J / m 2 ; The elastomer layer has temperature and modulus response characteristics, and changes from a non-adhesive state to an adhesive state at physiological temperature; the hydrogel layer adheres to the moist soft tissue by absorbing water and combining chemical bonds.

6. A method for preparing an asymmetric bioadhesive patch with controllable modulus adhesion according to any one of claims 1 to 5, characterized in that: The following steps are involved: S1. Preparation of elastomer layer: The acrylate monomer and the long-chain crosslinking agent are mixed, a photoinitiator is added, and after ultrasonic treatment, ultraviolet light curing is performed in a mold, and the elastomer layer is obtained after cooling; S2. Preparing a hydrogel layer on the elastomer layer: The elastomer layer is placed in a mold, a pre-crosslinked aqueous solution containing raw material components of the hydrogel layer is added, and then ultraviolet light curing is performed to finally obtain an asymmetric bioadhesive patch in which the elastomer layer and the hydrogel layer are tightly combined.

7. The method for preparing an asymmetric bioadhesive patch with controllable modulus adhesion according to claim 6, characterized in that: In step S1, the UV curing time is 8-12 seconds.

8. The method for preparing an asymmetric bioadhesive patch with controllable modulus adhesion according to claim 6, characterized in that: In step S1, the ultrasonic treatment time is 20-40 minutes, the cooling temperature is less than 0°C, and the cooling time is 8-12 minutes.

9. The method for preparing an asymmetric bioadhesive patch with controllable modulus adhesion according to claim 6, characterized in that: In step S2, the UV curing time is 1.5-3 hours.

10. Use of the asymmetric bioadhesive patch with controllable modulus adhesion according to any one of claims 1 to 5, characterized in that: The asymmetric bioadhesive patch is used to achieve connection between medical devices and soft tissues, and is specifically used for drainage tube fixation, denture retention, and peri-implantitis prevention; The medical devices include medical catheters, denture bases and implant bases.

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