Degradable in-vivo pressure-sensitive adhesive taking decellularized matrix material as base material and preparation method therefor

Abstract

The present application provides a degradable in-vivo pressure-sensitive adhesive taking a decellularized matrix material as a base material and a preparation method therefor. The degradable in-vivo pressure-sensitive adhesive comprises a biological base material layer and pressure-sensitive adhesive layers arranged on both sides of the biological base material layer. On the basis of the total mass of raw materials of the pressure-sensitive adhesive layer as 100%, the raw materials of the pressure-sensitive adhesive layer comprise, by mass percentage, 5%-18% of a tissue-active material, 5%-25% of a base material, 10%-35% of a thickener, 10%-50% of a plasticizer, and 10%-60% of deionized water. The degradable in-vivo pressure-sensitive adhesive provided by the present application not only has good compatibility with human tissues, but also has adjustable viscosity. Moreover, the degradable in-vivo pressure-sensitive adhesive can be absorbed or completely discharged out of the body after degradation in vivo. Therefore, it is suitable for in-vivo wound closure, prevention of fluid (gas) leakage at suture sites, tissue repair, drug delivery, wound healing, and other applications.

Description

A degradable pressure-sensitive adhesive for in vivo use based on acellular matrix material and its preparation method Technical Field

[0001] The present application belongs to the technical field of pressure-sensitive adhesive materials, and specifically relates to a degradable in vivo pressure-sensitive adhesive based on an acellular matrix material and a preparation method thereof. Background Art

[0002] Pressure-sensitive adhesive (PSA) is a pressure-sensitive adhesive that adheres when pressure is applied and does not adhere when pressure is absent. It can be used as an alternative to existing bio-glue. It has attracted attention for its ease of use and ability to quickly secure and adhere items. In the medical field, medical PSA is often used in exposed areas such as suturing superficial wounds and securing bandages, reducing the risk of infection caused by non-degradable residues of traditional adhesive tape left on wounds.

[0003] However, the medical pressure-sensitive adhesives disclosed in the prior art cannot be used inside the body, and the internal adhesives used are limited to sealants, such as Progel™, Sealant sealants like Tisseel and Adherus meet the needs of specific surgical situations by sealing gaps between tissue surfaces such as the lungs or dura mater. Clinically, these sealants have different application scenarios depending on the needs of the internal adhesion site, such as wound closure, preventing liquid (gas) leakage at suture sites, tissue repair, drug delivery, and wound healing. Currently used sealants cannot achieve these multiple uses.

[0004] To address the above problems, researchers have developed a degradable pressure-sensitive adhesive that can connect similar or dissimilar surfaces to each other, thereby providing new ideas for the development of internal adhesive materials suitable for different scenarios. For example, CN113908327A discloses that by adjusting the molecular weight of the block polyester and the ratio of the multi-component block polyester, it is melted into a film after a series of complex and tedious processes, and then coated with glue and covered with polytetrafluoroethylene to form a bioadhesive double-sided tape. The raw materials used in this adhesive are mostly degradable materials synthesized after chemical modification and other production processes, but their degradation products are easily released in the body, causing inflammatory reactions and other problems.

[0005] Furthermore, CN115895593A discloses a biodegradable pressure-sensitive adhesive whose overall glass transition temperature can be adjusted by adjusting the ratio of hard monomers to soft monomers. The biodegradable pressure-sensitive adhesive tape prepared with this pressure-sensitive adhesive exhibits advantages such as high initial tack, high peel strength, good holding power, and excellent biodegradability. However, the disclosure does not mention its application in the human body.

[0006] Therefore, in this field, there is an urgent need to develop a degradable pressure-sensitive adhesive that is not only suitable for various application scenarios, but also does not produce any rejection reaction and has a simple and easy preparation method. Summary of the Invention

[0007] This application provides a degradable pressure-sensitive adhesive for in vivo use based on an acellular matrix material and a method for preparing the same. The degradable pressure-sensitive adhesive for in vivo use provided in this application not only exhibits good compatibility with human tissue and has adjustable viscosity, but also can be absorbed or completely excreted from the body after degradation in the body. This makes it suitable for applications such as wound closure, preventing liquid (gas) leakage from sutures, tissue repair, and wound healing.

[0008] In a first aspect, the present application provides a degradable pressure-sensitive adhesive for in vivo use using an acellular matrix material as a base material, wherein the degradable pressure-sensitive adhesive for in vivo use comprises a biological base material layer and pressure-sensitive adhesive layers disposed on both sides of the biological base material layer;

[0009] Taking the total mass of the raw materials of the pressure-sensitive adhesive layer as 100%, the raw materials of the pressure-sensitive adhesive layer include 5%-18% of tissue active material, 5%-25% of base material, 10%-35% of thickener, 10%-50% of plasticizer and 10%-60% of deionized water in mass percentage respectively.

[0010] The present application provides a biodegradable pressure-sensitive adhesive for in vivo use. On the one hand, a biomaterial is used as a base material layer. The above-mentioned biomaterial has good biocompatibility and will not cause body reactions such as rejection and inflammation after application. However, some biodegradable materials synthesized after physical or chemical modification of production processes disclosed in the prior art, such as bioadhesives with caprolactone, glycolide or lactide as the base material, are prone to inflammatory reactions and other problems after concentrated release of their degradation products; on the other hand, the adhesive of the degradable pressure-sensitive adhesive for in vivo use does not need to undergo complex chemical modification and process synthesis, and partially adds biologically derived tissue active ingredients, which not only gives the pressure-sensitive adhesive good fluidity and water retention, but also promotes wound healing and repair of defective tissue. At the same time, the other components of the pressure-sensitive adhesive are also raw materials that are degradable in vivo and have good biocompatibility. They are safe for use in vivo and avoid the problems of inflammatory reactions caused by adhesives prepared by means of chemical synthesis and modification.

[0011] The viscosity of the degradable pressure-sensitive adhesive for in vivo use provided by the present application can be adjusted to meet the pasting requirements of different scenarios. For example, for scenarios such as hemostasis, closure, reducing the exchange of body fluids between regions and infectious contamination, a degradable medical pressure-sensitive adhesive with a higher viscosity can be used. For some scenarios that only require temporary bonding, such as transferring patch materials from the outside of the body to tissues and organs, a degradable medical pressure-sensitive adhesive with a lower viscosity can be used. In addition, the above-mentioned pressure-sensitive adhesive can be completely degraded after being implanted in the body, without any foreign matter remaining, and will not form cystic tissue or hard lump tissue. In particular, when imaging is performed again after the cancerous tissue is removed, no shadow structure will be generated. Optionally, the pressure-sensitive adhesive component can also be added with a drug component, and when applied, it is affixed to the skin or tissue. As the degradation reaction occurs, the drug is gradually released, thereby realizing the function of drug delivery.

[0012] In the present application, the mass percentage of the tissue active material is 5%-18%, for example, it can be 5%, 8%, 10%, 12%, 15% or 18%.

[0013] In the present application, by regulating the mass percentage of tissue active materials, the degradable pressure-sensitive adhesive for in vivo use can have the function of tissue or wound repair; if the content is too low, a good repair effect cannot be achieved; if the content is too high, the viscosity of the degradable pressure-sensitive adhesive for in vivo use will decrease after irradiation sterilization.

[0014] In the present application, the mass percentage of the base material is 5%-25%, for example, it can be 5%, 8%, 10%, 12%, 15%, 18%, 20%, 22% or 25%.

[0015] In this application, by regulating the base material's mass percentage, the degradable pressure-sensitive adhesive for in vivo use can exhibit excellent bonding properties. Because the base material plays a primary role in bonding two adherends, it determines the adhesive's fundamental properties. If its content is too low, the adhesive's viscosity will be low, making it unsuitable for applications requiring higher strength. However, if its content is too high, the adhesive's viscosity may be too high, making it difficult to effectively apply to the surface to be bonded, affecting its fluidity and coating properties.

[0016] In this application, the addition of the binder imparts good bonding properties to the pressure-sensitive adhesive.

[0017] In the present application, the mass percentage of the thickener is 10%-35%, for example, it can be 10%, 15%, 20%, 22%, 25%, 30% or 35%.

[0018] In the present application, by regulating the mass percentage of the thickener, the viscosity and fluidity meet the application requirements. If the content is too low, the adhesive may be too fluid, making it difficult to control and apply, which may cause the adhesive to be too thin during application, affecting its adhesion performance; otherwise, the viscosity of the adhesive will be greatly increased, making it too viscous, which may make it difficult to effectively apply and adhere to the adhesive during application.

[0019] In the present application, the addition of a thickener can impart good viscosity to the pressure-sensitive adhesive, thereby meeting the needs of specific surgical situations such as wound closure, tissue repair, drug delivery, tissue reinforcement or wound healing.

[0020] In the present application, the mass percentage of the plasticizer is 10%-50%, for example, it can be 10%, 17%, 20%, 22%, 27%, 30%, 32%, 37%, 40%, 42%, 45%, 48% or 50%, etc.

[0021] In this application, the plasticizer content is adjusted to adjust the adhesive's flexibility, making it more adaptable and resistant to surface deformation, vibration, or temperature changes. Too little plasticizer content may result in insufficient adhesive adhesion, making it difficult to adapt to objects of varying shapes, structures, or surface characteristics. Conversely, too much plasticizer content may make the adhesive too viscous, resulting in poor flowability, which may affect coating and application uniformity.

[0022] In this application, the addition of plasticizers can impart flexibility, ductility, and plasticity to pressure-sensitive adhesives. These effects make it easier for the adhesive to form elastic, soft connections on different surfaces and improve its applicability.

[0023] In the present application, the mass percentage of the deionized water is 10%-60%, for example, it can be 10%, 20%, 30%, 40%, 50% or 60%.

[0024] Further preferably, based on the total mass of the pressure-sensitive adhesive layer as 100%, the raw materials of the pressure-sensitive adhesive layer include 8%-15% of a base material, 10%-16% of a tissue active material, 20%-30% of a thickener, 15%-20% of a plasticizer and 19%-45% of deionized water in percentage by mass.

[0025] Preferably, the tissue active material comprises any one of mammalian skin, pericardium, amniotic membrane, small intestinal submucosa or bladder basement membrane, or a combination of at least two acellular matrix gels.

[0026] The acellular matrix gel is prepared by decellularizing the above-mentioned biomaterials and then digesting them. Existing methods can be used for the preparation. For specific decellularization methods, reference can be made to the extracellular matrix preparation method described in paragraphs [0076-0082] of CN115006597B. For specific digestion methods for preparing acellular matrix gel, reference can be made to the collagen gel preparation method described in paragraphs [0091-0093] of the patent.

[0027] Preferably, the base material comprises a degradable natural polymer compound and / or a degradable modified natural polymer compound.

[0028] Preferably, the degradable natural polymer compound includes any one or a combination of at least two of starch, dextrin, peach gum, gum arabic, bone glue, hide glue, gelatin, fish glue, shellac, plant protein or casein.

[0029] Preferably, the degradable modified natural polymer compound includes any one of carboxymethyl cellulose, modified starch, and polyvinyl alcohol, or a combination of at least two thereof.

[0030] Preferably, the thickener comprises any one of starch, modified starch, xanthan gum, maltitol, oligofructose, sorbitol, xylitol, lactitol, mannitol, erythritol, hydrogenated starch hydrolysate, gelatin, cellulose, methylcellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, gum arabic, tamarind polysaccharide gum, sesbania gum, agar, sodium alginate, carrageenan, pectin or β-cyclodextrin, or a combination of at least two thereof.

[0031] Preferably, the plasticizer comprises a polyol compound.

[0032] Preferably, the polyol compound includes any one of glycerol, sorbitol or ethylene glycol, or a combination of at least two of them.

[0033] Preferably, the base material, thickener and plasticizer are of different types.

[0034] Further preferably, the base material includes carboxymethyl cellulose, the degree of substitution of which is in the range of 0.59-1.0, for example, it can be 0.59, 0.6, 0.7, 0.8, 0.9 or 1.0, etc.; the viscosity range is 600-1000mPa.s, for example, it can be 600mPa.s, 650mPa.s, 700mPa.s, 750mPa.s, 800mPa.s, 850mPa.s, 900mPa.s, 950mPa.s or 1000mPa.s, etc.

[0035] Further preferably, the thickener comprises gum arabic.

[0036] Further preferably, the plasticizer comprises glycerol.

[0037] Preferably, based on 100% of the total mass of the raw materials of the pressure-sensitive adhesive layer, the raw materials of the pressure-sensitive adhesive layer further include 0.1%-21.6% of a moisturizer and 2.5%-5.2% of an antioxidant.

[0038] In the present application, the mass percentage of the moisturizing agent is 0.1%-21.6%, for example, it can be 0.1%, 0.5%, 1%, 2.5%, 5%, 8%, 10%, 12%, 15%, 18%, 20%, 21%, 21.6%, etc.

[0039] In this application, regulating the percentage by mass of the humectant can prevent the pressure-sensitive adhesive from drying and solidifying in the container, ensuring that it maintains good fluidity and application performance during storage and use. If the content is too low, it will not prevent the pressure-sensitive adhesive from drying and solidifying. If the content is too high, it will change the viscosity of the pressure-sensitive adhesive and may significantly affect the weather resistance of the pressure-sensitive adhesive, such as affecting the product in high-humidity environments.

[0040] In the present application, the mass percentage of the antioxidant is 2.5%-5.2%, for example, it can be 2.5%, 2.8%, 3%, 3.5%, 4%, 4.5%, 5% or 5.2%.

[0041] In this application, by regulating the percentage by weight of the antioxidant, color change of the pressure-sensitive adhesive due to oxidation can be reduced or prevented, which is very important for applications that require consistent appearance. Too low a content will not prevent the pressure-sensitive adhesive from discoloring due to oxidation, while too high a content may cause product instability, affect its performance during storage, and increase product production costs.

[0042] Preferably, the moisturizing agent comprises a polyol moisturizing agent and / or a sugar moisturizing agent.

[0043] In the present application, the moisturizing agent may further include a pseudo-natural moisturizing factor, for example, any one of sodium lactate and trehalose, or a combination of at least two thereof.

[0044] Preferably, the antioxidant comprises any one or a combination of at least two of vitamin E, vitamin C, flavonoids, tea polyphenols, phytic acid, glucosamine, lactic acid or sodium hyaluronate.

[0045] In the present application, the thickness of the pressure-sensitive adhesive layer is 0.2-2 mm, for example, it can be 0.2 mm, 0.5 mm, 0.8 mm, 1 mm, 1.2 mm, 1.5 mm, 1.8 mm or 2 mm.

[0046] In this application, the viscosity of the pressure-sensitive adhesive can be selectively adjusted by regulating the thickness of the pressure-sensitive adhesive layer. A thinner coating may result in insufficient adhesion and fail to meet usage requirements. A thicker coating may increase internal stress, thereby affecting its stability and durability, while also increasing production costs.

[0047] Preferably, the material of the biological substrate layer comprises an acellular matrix material.

[0048] Preferably, the acellular matrix material comprises any one or a combination of at least two of mammalian skin, pericardium, amniotic membrane, small intestinal submucosa or bladder basement membrane.

[0049] The specific decellularization treatment method can be prepared using existing methods, for example, reference can be made to the preparation method of the extracellular matrix mentioned in paragraphs [0076-0082] of CN115006597B.

[0050] In a second aspect, the present application provides a method for preparing a degradable in vivo pressure-sensitive adhesive based on the acellular matrix material according to the first aspect, the method comprising the following steps:

[0051] The tissue active material, base material, thickener, plasticizer and deionized water are mixed according to the formula to obtain a pressure-sensitive adhesive slurry, and then the pressure-sensitive adhesive slurry is coated on both sides of the biological substrate layer. After drying, the degradable in vivo pressure-sensitive adhesive with the decellularized matrix material as the base material is obtained.

[0052] In the present application, moisturizers and antioxidants may also be added before mixing.

[0053] In the present application, the specific mixing process is: the thickener and the moisturizer are mixed once according to the formula amount, and then deionized water is added and stirred at room temperature for 1 hour, and then the tissue active material is slowly added and stirred for 1 hour, and then the plasticizer and the base material heated to 65-75°C are added and stirred for 1 hour, and finally the antioxidant is added and stirred at room temperature for 1 hour.

[0054] Preferably, the drying temperature is 20-50°C, for example, 20°C, 30°C, 40°C or 50°C, etc.; the drying time is 4-24h, for example, 4h, 8h, 12h, 14h, 18h, 20h or 24h, etc.

[0055] In the present application, the pressure-sensitive adhesive is coated on both sides of the biological substrate layer and dried to obtain the degradable pressure-sensitive adhesive. The specific process is as follows: the pressure-sensitive adhesive is coated on both sides of the biological substrate layer, dried at 20-50°C for 4-24 hours, and covered with release paper for use.

[0056] Preferably, the thickness of the pressure-sensitive adhesive layer formed after drying is 0.2-2 mm, for example, 0.2 mm, 0.5 mm, 0.8 mm, 1 mm, 1.2 mm, 1.5 mm, 1.8 mm or 2 mm.

[0057] In this application, the degradable in vivo pressure-sensitive adhesive provided herein can be used for applications such as wound closure, tissue repair, tissue reinforcement, and wound healing in vivo. It has good biocompatibility and does not cause body reactions such as rejection and inflammation after application. In addition, the pressure-sensitive adhesive provided herein for in vivo application can restore tissue integrity in a rapid, targeted, and non-invasive manner, and can provide support for tissue remodeling and healing, significantly improving surgical wound healing.

[0058] Compared with the prior art, this application has the following beneficial effects:

[0059] Existing degradable pressure-sensitive adhesives often use paper, cellulose film, or polylactic acid-based materials as their base materials. However, these pressure-sensitive adhesives can usually only degrade in vitro and cannot complete the degradation process in the complex human body. In contrast, the degradable pressure-sensitive adhesive for in vivo use proposed in this application, which uses a decellularized matrix material as a base material, can be completely degraded under the action of in vivo enzymes. The decellularized matrix material and the decellularized matrix gel components can both be degraded in vivo, and all other components of the degradable pressure-sensitive adhesive for in vivo use provided in this application can also be degraded in vivo.

[0060] In addition, the present application proposes a degradable in vivo pressure-sensitive adhesive with acellular matrix material as the base material, in which a tissue active material, acellular matrix gel, is added. Acellular matrix gel is obtained by digesting the acellular matrix and is rich in collagen and active factors, such as fibroblast growth factor (FGF), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), etc. These growth factors can regulate cell proliferation, differentiation and migration, and promote tissue regeneration and repair. Compared with the acellular matrix, the matrix gel obtained after digestion has a smaller molecular weight and is easier to be absorbed by the body. Therefore, it can more effectively promote wound healing at the wound site.

[0061] The present application provides a degradable pressure-sensitive adhesive for in vivo use. On the one hand, a biomaterial is used as a substrate layer, which plays a structural support role. The above-mentioned biomaterial has good biocompatibility and itself has a certain tensile strength and tear resistance. Therefore, it can ensure that the pressure-sensitive adhesive is not easy to break or damage during use, and no body reactions such as rejection and inflammation will occur after application. Some degradable materials synthesized after physical or chemical modification of the production process disclosed in the prior art, such as bioadhesives with materials such as caprolactone, glycolide or lactide as the substrate, have concentrated release of degradation products and are prone to inflammatory reactions and other problems; on the other hand, the adhesive of the degradable pressure-sensitive adhesive for in vivo use does not need to be obtained through complex chemical modification and process synthesis, and partially adds biologically derived tissue active ingredients, which not only gives the pressure-sensitive adhesive good fluidity and water retention, but also promotes wound healing and repair of defective tissue. At the same time, the other components of the pressure-sensitive adhesive are also raw materials that are degradable and biocompatible in vivo, and are safe for use in vivo, avoiding the problems of inflammatory reactions caused by adhesives prepared by means of chemical synthesis and modification.

[0062] The viscosity of the degradable pressure-sensitive adhesive for in vivo use provided by the present application can be adjusted to meet the pasting requirements of different scenarios. For example, for scenarios such as hemostasis, closure, reducing the exchange of body fluids between regions and infectious contamination, a degradable medical pressure-sensitive adhesive with a higher viscosity can be used. For some scenarios that only require temporary bonding, such as the application scenario of transferring patch materials from the outside of the body to tissues and organs, a degradable medical pressure-sensitive adhesive with a lower viscosity can be used. In addition, the above-mentioned pressure-sensitive adhesive can be completely degraded after being implanted in the body, without any foreign matter remaining, and will not form cystic tissue or hard lump tissue. In particular, when imaging is performed again after the cancerous tissue is removed, no shadow structure will be generated. The optional pressure-sensitive adhesive component can also be added with a drug component. When applied, it is affixed to the skin or tissue. As the degradation reaction occurs, the drug is gradually released, thereby realizing the function of drug delivery. BRIEF DESCRIPTION OF THE DRAWINGS

[0063] FIG1 is a schematic diagram of the structure of the degradable pressure-sensitive adhesive for in vivo use provided in Example 1 of the present application. DETAILED DESCRIPTION

[0064] The technical solution of the present application is further described below with reference to the accompanying drawings and specific embodiments. Those skilled in the art should understand that the embodiments are only for facilitating understanding of the present application and should not be regarded as specific limitations of the present application.

[0065] The raw material composition of the pressure-sensitive adhesive layer of the degradable pressure-sensitive adhesive for in vivo use provided in the examples and comparative examples of this application is shown in Table 1:

[0066] Table 1

[0067] Example 1

[0068] This embodiment provides a degradable pressure-sensitive adhesive for in vivo use with a decellularized matrix material as a base material. As shown in FIG1 , the degradable pressure-sensitive adhesive for in vivo use comprises a decellularized porcine small intestinal submucosa base material layer and pressure-sensitive adhesive layers disposed on both sides of the decellularized porcine small intestinal submucosa base material layer.

[0069] The substrate layer is obtained from the submucosa of the porcine small intestine through virus inactivation, decellularization, freeze-drying, defatting, and secondary freeze-drying. The submucosa comes from boars weighing 150 kg, house-fed on a plant-based diet. The small intestine is harvested within half an hour of death, and the mucosa, muscle layer, and serosal layer are removed within 12 hours, leaving only the submucosa.

[0070] Taking the total mass of the raw materials of the pressure-sensitive adhesive layer as 100%, the raw materials of the pressure-sensitive adhesive layer include 14% by mass of decellularized porcine small intestinal submucosa matrix gel, 12% by mass of polyvinyl alcohol base material, 24% by mass of maltitol thickener, 5% by mass of trehalose moisturizer, 3.5% by mass of vitamin E antioxidant, 18% by mass of sorbitol plasticizer, and the balance being deionized water.

[0071] The present application provides a method for preparing the above-mentioned decellularized porcine small intestinal submucosa substrate, which comprises the following steps:

[0072] (1) Virus inactivation: Soak the treated porcine small intestinal submucosa material in 0.5% PAA solution for 30 min, and wash away the residual PAA solution with purified water.

[0073] (2) Decellularization: The cells were washed with a mixed solution of 0.1% trypsin and 0.1% SDS for 2 h, and the residual solvent was washed with purified water.

[0074] (3) Freeze-drying: freeze-dry the decellularized matrix material.

[0075] (4) Degreasing: Place the freeze-dried material in a degreasing reactor containing ether solution and operate the equipment for 16 hours. Remove the sample and decompose it in a fume hood for 2 hours, then wash away the residual ether solution with purified water.

[0076] (5) Secondary freeze-drying: The defatted matrix material is placed in a freeze dryer again for freeze-drying until it is dry to obtain a single-layer decellularized porcine small intestinal submucosa matrix.

[0077] This embodiment also provides a method for preparing the above-mentioned degradable pressure-sensitive adhesive, which comprises the following steps:

[0078] (1) Prepare the required raw materials and reagents:

[0079] ① 40 mg / mL decellularized porcine small intestinal submucosa matrix gel: Grind the decellularized porcine small intestinal submucosa matrix into a powder with a particle size of 250 μm. Dissolve 2 g of the decellularized porcine small intestinal submucosa matrix powder with 200 mg of pepsin (activity 3450 U / mg, Sigma P6887-5G, derived from porcine gastric mucosa) in 25 mL of 0.01 mol / L HCl and digest for 40 hours. Then, add 2.8 mL of 10x PBS solution, 2.5 mL of 0.01 mol / L NaOH solution, and 19.7 mL of 1x PBS solution to the digestion solution, stir well, and set aside. ② Polyvinyl alcohol: Dissolve it in deionized water to a concentration of 0.5 g / mL and heat to 90°C until completely dissolved.

[0080] (2) Mix in proportion

[0081] Take 40g of maltitol, weigh out trehalose, sorbitol, and vitamin E according to the proportion of the components, and then take out the decellularized porcine small intestinal submucosa matrix gel, polyvinyl alcohol solution, and deionized water according to the proportion of the components. Mix the maltitol, trehalose, and deionized water, stir at room temperature for 1 hour, then slowly add the decellularized porcine small intestinal submucosa matrix gel and continue stirring for 1 hour. Then, add sorbitol and polyvinyl alcohol solution and continue stirring for 1 hour. Finally, add vitamin E and stir at room temperature for 1 hour to obtain a pressure-sensitive adhesive.

[0082] (3) Coating the pressure-sensitive adhesive on the biomaterial substrate

[0083] The pressure-sensitive adhesive was coated on one side of the decellularized porcine small intestinal submucosa substrate, the substrate thickness was 50 μm, the coating thickness was 500 μm, and the substrate was dried at 26°C for 5 hours. After covering with release paper, the pressure-sensitive adhesive was continued to be coated on the other side of the decellularized porcine small intestinal submucosa substrate, dried at 26°C for 5 hours, and covered with release paper to obtain the degradable pressure-sensitive adhesive.

[0084] (4) Packaging and sterilization

[0085] The prepared degradable pressure-sensitive adhesive is placed in an aluminum foil bag for packaging and sterilized at 25 kGy.

[0086] Example 2

[0087] This embodiment provides a degradable pressure-sensitive adhesive for in vivo use with a decellularized matrix material as a base material, the degradable pressure-sensitive adhesive for in vivo use comprising a decellularized porcine small intestinal submucosa base material layer and pressure-sensitive adhesive layers arranged on both sides of the decellularized porcine small intestinal submucosa base material layer;

[0088] The substrate layer is made from porcine small intestinal submucosa, which has been subjected to virus inactivation, decellularization, freeze-drying, defatting, and secondary freeze-drying. The porcine small intestinal submucosa is sourced from boars weighing 150 kg, house-fed on a plant-based diet. The small intestine is harvested within half an hour of death, and the mucosa, muscle layer, and serosal layer are removed within 12 hours, leaving only the submucosa.

[0089] Taking the total mass of the raw materials of the pressure-sensitive adhesive layer as 100%, the raw materials of the pressure-sensitive adhesive layer include 14% by mass of decellularized porcine small intestinal submucosa matrix gel, 12% by mass of polyvinyl alcohol base material, 24% by mass of gum arabic thickener, 5% by mass of trehalose moisturizer, 3.5% by mass of vitamin E antioxidant, 18% by mass of sorbitol plasticizer, and the balance being deionized water.

[0090] The present application provides a method for preparing the above-mentioned decellularized porcine small intestinal submucosa substrate, which comprises the following steps:

[0091] (1) Virus inactivation: The treated porcine small intestinal submucosa material was immersed in 0.5% polyacrylic acid (PAA) solution for 30 min, and the residual PAA solution was washed with purified water.

[0092] (2) Decellularization: The cells were washed with a mixed solution of 0.1% trypsin and 0.1% sodium dodecyl sulfate (SDS) for 2 h, and the residual solvent was washed with purified water.

[0093] (3) Freeze-drying: freeze-dry the decellularized matrix material.

[0094] (4) Degreasing: Place the freeze-dried material in a degreasing reactor containing ether solution and operate the equipment for 16 hours. Remove the sample and decompose it in a fume hood for 2 hours, then wash away the residual ether solution with purified water.

[0095] (5) Secondary freeze-drying: The defatted matrix material is placed in a freeze dryer again for freeze-drying until it is dry to obtain a single-layer decellularized porcine small intestinal submucosa matrix.

[0096] This embodiment also provides a method for preparing the above-mentioned degradable pressure-sensitive adhesive for in vivo use, which comprises the following steps:

[0097] (1) Prepare the required raw materials and reagents:

[0098] ① 40 mg / mL decellularized porcine small intestinal submucosa matrix gel: Grind the decellularized porcine small intestinal submucosa matrix into a powder with a particle size of 250 μm. Dissolve 2 g of the decellularized porcine small intestinal submucosa matrix powder with 200 mg of pepsin (activity 3450 U / mg, Sigma P6887-5G, derived from porcine gastric mucosa) in 25 mL of 0.01 mol / L HCl and digest for 40 hours. Then, add 2.8 mL of 10x PBS solution, 2.5 mL of 0.01 mol / L NaOH solution, and 19.7 mL of 1x PBS solution to the digestion solution, stir well, and set aside. ② Polyvinyl alcohol: Dissolve it in deionized water to a concentration of 0.5 g / mL and heat to 90°C until completely dissolved.

[0099] (2) Mix in proportion

[0100] Take 40g of gum arabic, weigh out trehalose, sorbitol, and vitamin E according to the proportion of the components, and then take out the decellularized porcine small intestinal submucosa matrix gel, polyvinyl alcohol solution, and deionized water according to the proportion of the components. Mix the gum arabic, trehalose, and deionized water, stir at room temperature for 1 hour, then slowly add the decellularized porcine small intestinal submucosa matrix gel and continue stirring for 1 hour. Then, add sorbitol and polyvinyl alcohol solution and continue stirring for 1 hour. Finally, add vitamin E and stir at room temperature for 1 hour to obtain a pressure-sensitive adhesive.

[0101] (3) Coating the pressure-sensitive adhesive on the biomaterial substrate

[0102] The pressure-sensitive adhesive was coated on one side of the decellularized porcine small intestinal submucosa substrate, the substrate thickness was 50 μm, the coating thickness was 500 μm, and the substrate was dried at 26°C for 5 hours. After covering with release paper, the pressure-sensitive adhesive was continued to be coated on the other side of the decellularized porcine small intestinal submucosa substrate, dried at 26°C for 5 hours, covered with release paper, and cut to obtain the degradable pressure-sensitive adhesive.

[0103] (4) Packaging and sterilization

[0104] The prepared degradable pressure-sensitive adhesive is placed in an aluminum foil bag for packaging and sterilized at 25 kGy.

[0105] Example 3

[0106] This embodiment provides a degradable pressure-sensitive adhesive for in vivo use with a decellularized matrix material as a base material, the degradable pressure-sensitive adhesive for in vivo use comprising a decellularized porcine small intestinal submucosa base material layer and pressure-sensitive adhesive layers arranged on both sides of the decellularized porcine small intestinal submucosa base material layer;

[0107] The substrate layer is made from porcine small intestinal submucosa, which has been subjected to virus inactivation, decellularization, freeze-drying, defatting, and secondary freeze-drying. The porcine small intestinal submucosa is sourced from boars weighing 150 kg, house-fed on a plant-based diet. The small intestine is harvested within half an hour of death, and the mucosa, muscle layer, and serosal layer are removed within 12 hours, leaving only the submucosa.

[0108] Taking the total mass of the raw materials of the pressure-sensitive adhesive layer as 100%, the raw materials of the pressure-sensitive adhesive layer include 14% by mass of decellularized porcine small intestinal submucosal matrix gel, 12% by mass of sodium carboxymethyl cellulose base material (degree of substitution 0.86, viscosity 800 mPa.s), 24% by mass of maltitol thickener, 5% by mass of trehalose moisturizer, 3.5% by mass of vitamin E antioxidant and 18% by mass of sorbitol plasticizer, and the balance being deionized water.

[0109] The present application provides a method for preparing the above-mentioned decellularized porcine small intestinal submucosa substrate, which comprises the following steps:

[0110] (1) Virus inactivation: Soak the treated porcine small intestinal submucosa material in 0.5% PAA solution for 30 min, and wash away the residual PAA solution with purified water.

[0111] (2) Decellularization: The cells were washed with a mixed solution of 0.1% trypsin and 0.1% SDS for 2 h, and the residual solvent was washed with purified water.

[0112] (3) Freeze-drying: freeze-dry the decellularized matrix material.

[0113] (4) Degreasing: The freeze-dried material was placed in a degreasing reactor containing ether solution. The equipment was operated for 16 h. The sample was taken out and analyzed in a fume hood for 2 h. The residual ether solution was then washed with purified water.

[0114] (5) Secondary freeze-drying: The defatted matrix material is placed in a freeze dryer again for freeze-drying until it is dry to obtain a single-layer decellularized porcine small intestinal submucosa matrix.

[0115] This embodiment also provides a method for preparing the above-mentioned degradable pressure-sensitive adhesive, which comprises the following steps:

[0116] (1) Prepare the required raw materials and reagents:

[0117] ① 40mg / mL decellularized porcine small intestinal submucosa matrix gel: Grind the decellularized porcine small intestinal submucosa matrix into a powder with a particle size of 250μm. Dissolve 2g of the decellularized porcine small intestinal submucosa matrix powder and 200mg of pepsin (activity 3450U / mg, Sigma P6887-5G, derived from porcine gastric mucosa) in 25mL of 0.01mol / L HCl and digest for 40h. Then, add 2.8mL of 10x concentration PBS solution, 2.5mL of 0.01mol / L NaOH solution, and 19.7mL of 1x concentration PBS solution to the digestion solution, stir well, and set aside.

[0118] (2) Mix in proportion

[0119] Take 40g of maltitol, weigh out trehalose, sodium carboxymethyl cellulose, sorbitol, and vitamin E according to the component content ratio, and take out decellularized porcine small intestinal submucosa matrix gel and deionized water according to the component content ratio. After mixing the maltitol, trehalose, and deionized water at room temperature for 1 hour, slowly add the decellularized porcine small intestinal submucosa matrix gel and continue stirring for 1 hour. Then, add sorbitol and sodium carboxymethyl cellulose and continue stirring for 1 hour. Finally, add vitamin E and stir at room temperature for 1 hour to obtain a pressure-sensitive adhesive.

[0120] (3) Coating the pressure-sensitive adhesive on the biomaterial substrate

[0121] The pressure-sensitive adhesive was coated on one side of the decellularized porcine small intestinal submucosa substrate, the substrate thickness was 50 μm, the coating thickness was 500 μm, and the substrate was dried at 26°C for 5 hours. After covering with release paper, the pressure-sensitive adhesive was continued to be coated on the other side of the decellularized porcine small intestinal submucosa substrate, dried at 26°C for 5 hours, and covered with release paper to obtain the degradable pressure-sensitive adhesive.

[0122] (4) Packaging and sterilization

[0123] The prepared degradable pressure-sensitive adhesive is placed in an aluminum foil bag for packaging and sterilized at 25 kGy.

[0124] Example 4

[0125] This embodiment provides a degradable pressure-sensitive adhesive for in vivo use with a decellularized matrix material as a base material, the degradable pressure-sensitive adhesive for in vivo use comprising a decellularized porcine small intestinal submucosa base material layer and pressure-sensitive adhesive layers arranged on both sides of the decellularized porcine small intestinal submucosa base material layer;

[0126] The substrate layer is made from porcine small intestinal submucosa, which has been subjected to virus inactivation, decellularization, freeze-drying, defatting, and secondary freeze-drying. The porcine small intestinal submucosa is sourced from boars weighing 150 kg, house-fed on a plant-based diet. The small intestine is harvested within half an hour of death, and the mucosa, muscle layer, and serosal layer are removed within 12 hours, leaving only the submucosa.

[0127] Taking the total mass of the raw materials of the pressure-sensitive adhesive layer as 100%, the raw materials of the pressure-sensitive adhesive layer include 14% by mass of decellularized porcine small intestinal submucosal matrix gel, 12% by mass of sodium carboxymethyl cellulose base material (degree of substitution of 0.86, viscosity of 800 mPa.s), 24% by mass of gum arabic thickener, 5% by mass of trehalose moisturizer, 3.5% by mass of vitamin E antioxidant, 18% by mass of sorbitol plasticizer, and the balance being deionized water.

[0128] The present application provides a method for preparing the above-mentioned decellularized porcine small intestinal submucosa substrate, which comprises the following steps:

[0129] (1) Virus inactivation: Soak the treated porcine small intestinal submucosa material in 0.5% PAA solution for 30 min, and wash away the residual PAA solution with purified water.

[0130] (2) Decellularization: The cells were washed with a mixed solution of 0.1% trypsin and 0.1% SDS for 2 h, and the residual solvent was washed with purified water.

[0131] (3) Freeze-drying: freeze-dry the decellularized matrix material.

[0132] (4) Degreasing: Place the freeze-dried material in a degreasing reactor containing ether solution and operate the equipment for 16 hours. Remove the sample and decompose it in a fume hood for 2 hours, then wash away the residual ether solution with purified water.

[0133] (5) Secondary freeze-drying: The defatted matrix material is placed in a freeze dryer again for freeze-drying until it is dry to obtain a single-layer decellularized porcine small intestinal submucosa matrix.

[0134] This embodiment also provides a method for preparing the above-mentioned degradable pressure-sensitive adhesive, which comprises the following steps:

[0135] (1) Prepare the required raw materials and reagents:

[0136] ① 40mg / mL decellularized porcine small intestinal submucosa matrix gel: Grind the decellularized porcine small intestinal submucosa matrix into a powder with a particle size of 250μm. Dissolve 2g of the decellularized porcine small intestinal submucosa matrix powder and 200mg of pepsin (activity 3450U / mg, Sigma P6887-5G, derived from porcine gastric mucosa) in 25mL of 0.01mol / L HCl and digest for 40h. Then, add 2.8mL of 10x concentration PBS solution, 2.5mL of 0.01mol / L NaOH solution, and 19.7mL of 1x concentration PBS solution to the digestion solution, stir well, and set aside.

[0137] (2) Mix in proportion

[0138] Take 40g of gum arabic, weigh out trehalose, sodium carboxymethyl cellulose, sorbitol, and vitamin E according to the component content ratio, and then take out the decellularized porcine small intestinal submucosa matrix gel and deionized water according to the component content ratio. Mix the gum arabic, trehalose, and deionized water, stir at room temperature for 1 hour, then slowly add the decellularized porcine small intestinal submucosa matrix gel and continue stirring for 1 hour. Then, add sorbitol and sodium carboxymethyl cellulose and continue stirring for 1 hour. Finally, add vitamin E and stir at room temperature for 1 hour to obtain a pressure-sensitive adhesive.

[0139] (3) Coating the pressure-sensitive adhesive on the biomaterial substrate

[0140] The pressure-sensitive adhesive was coated on one side of the decellularized porcine small intestinal submucosa substrate, the substrate thickness was 50 μm, the coating thickness was 500 μm, and the substrate was dried at 26°C for 5 hours. After covering with release paper, the pressure-sensitive adhesive was continued to be coated on the other side of the decellularized porcine small intestinal submucosa substrate, dried at 26°C for 5 hours, and covered with release paper to obtain the degradable pressure-sensitive adhesive.

[0141] (4) Packaging and sterilization

[0142] The prepared degradable pressure-sensitive adhesive is packaged in an aluminum foil bag and sterilized at 25 kGy.

[0143] Example 5

[0144] This embodiment provides a degradable pressure-sensitive adhesive for in vivo use with a decellularized matrix material as a base material, the degradable pressure-sensitive adhesive for in vivo use comprising a decellularized porcine small intestinal submucosa base material layer and pressure-sensitive adhesive layers arranged on both sides of the decellularized porcine small intestinal submucosa base material layer;

[0145] The substrate layer is made from porcine small intestinal submucosa, which has been subjected to virus inactivation, decellularization, freeze-drying, defatting, and secondary freeze-drying. The porcine small intestinal submucosa is sourced from boars weighing 150 kg, house-fed on a plant-based diet. The small intestine is harvested within half an hour of death, and the mucosa, muscle layer, and serosal layer are removed within 12 hours, leaving only the submucosa.

[0146] Taking the total mass of the raw materials of the pressure-sensitive adhesive layer as 100%, the raw materials of the pressure-sensitive adhesive layer include 14% by mass of decellularized porcine small intestinal submucosa matrix gel, 12% by mass of sodium carboxymethyl cellulose base material (degree of substitution 0.86, viscosity 800 mPa.s), 24% by mass of gum arabic thickener, 5% by mass of trehalose moisturizer, 3.5% by mass of vitamin E antioxidant, 18% by mass of glycerin plasticizer, and the balance being deionized water.

[0147] The present application provides a method for preparing the above-mentioned decellularized porcine small intestinal submucosa substrate, which comprises the following steps:

[0148] (1) Virus inactivation: Soak the treated porcine small intestine material in 0.5% PAA solution for 30 min, and wash away the residual PAA solution with purified water.

[0149] (2) Decellularization: The cells were washed with a mixed solution of 0.1% trypsin and 0.1% SDS for 2 h, and the residual solvent was washed with purified water.

[0150] (3) Freeze-drying: freeze-dry the decellularized matrix material.

[0151] (4) Degreasing: Place the freeze-dried material in a degreasing reactor containing ether solution and operate the equipment for 16 hours. Remove the sample and decompose it in a fume hood for 2 hours, then wash away the residual ether solution with purified water.

[0152] (5) Secondary freeze-drying: The defatted matrix material is placed in a freeze dryer again for freeze-drying until it is dry to obtain a single-layer decellularized porcine small intestinal submucosa matrix.

[0153] This embodiment also provides a method for preparing the above-mentioned degradable pressure-sensitive adhesive, which comprises the following steps:

[0154] (1) Prepare the required raw materials and reagents:

[0155] ① 40mg / mL decellularized porcine small intestinal submucosa matrix gel: Grind the decellularized porcine small intestinal submucosa matrix into a powder with a particle size of 250μm. Dissolve 2g of the decellularized porcine small intestinal submucosa matrix powder and 200mg of pepsin (activity 3450U / mg, Sigma P6887-5G, derived from porcine gastric mucosa) in 25mL of 0.01mol / L HCl and digest for 40h. Then, add 2.8mL of 10x concentration PBS solution, 2.5mL of 0.01mol / L NaOH solution, and 19.7mL of 1x concentration PBS solution to the digestion solution, stir well, and set aside.

[0156] (2) Mix in proportion

[0157] Take 40g of gum arabic, weigh out trehalose, sodium carboxymethyl cellulose, and vitamin E according to the component content ratio, and then take out decellularized porcine small intestinal submucosa matrix gel, glycerol, and deionized water according to the component content ratio. After mixing the gum arabic, trehalose, and deionized water and stirring at room temperature for 1 hour, slowly add the decellularized porcine small intestinal submucosa matrix gel and continue stirring for 1 hour. Then, add glycerol and sodium carboxymethyl cellulose and continue stirring for 1 hour. Finally, add vitamin E and stir at room temperature for 1 hour to obtain a pressure-sensitive adhesive.

[0158] (3) Coating the pressure-sensitive adhesive on the biomaterial substrate

[0159] The pressure-sensitive adhesive was coated on one side of the decellularized porcine small intestinal submucosa substrate, the substrate thickness was 50 μm, the coating thickness was 500 μm, and the substrate was dried at 26°C for 5 hours. After covering with release paper, the pressure-sensitive adhesive was continued to be coated on the other side of the decellularized porcine small intestinal submucosa substrate, dried at 26°C for 5 hours, and covered with release paper to obtain the degradable pressure-sensitive adhesive.

[0160] (4) Packaging and sterilization

[0161] The prepared degradable pressure-sensitive adhesive is packaged in an aluminum foil bag and sterilized at 25 kGy.

[0162] Example 6

[0163] This example differs from Example 5 in that, based on the total weight of the pressure-sensitive adhesive layer's raw materials as 100%, the pressure-sensitive adhesive layer comprises, by weight, 14% decellularized porcine small intestinal submucosa matrix gel, 36% sodium carboxymethyl cellulose, 5% trehalose moisturizer, 3.5% vitamin E antioxidant, and 18% glycerol plasticizer, with the balance being deionized water. In other words, gum arabic is not added to the adhesive system as a thickener; instead, sodium carboxymethyl cellulose serves as both the base and thickener. All other aspects are the same as in Example 5.

[0164] Example 7

[0165] This embodiment differs from Example 1 in that, based on the total mass of the raw materials for the pressure-sensitive adhesive layer being 100%, the raw materials for the pressure-sensitive adhesive layer comprise, by weight, 14% decellularized porcine small intestinal submucosa matrix gel, 12% polyvinyl alcohol base, 5% trehalose moisturizer, 3.5% vitamin E antioxidant, and 42% sorbitol, with the balance being deionized water. In other respects, maltitol thickener is not added to the adhesive system, but sorbitol is used as both a plasticizer and a thickener. All other aspects are the same as in Example 1.

[0166] Example 8

[0167] This embodiment differs from Example 5 in that, based on the total mass of the raw materials for the pressure-sensitive adhesive layer being 100%, the raw materials for the pressure-sensitive adhesive layer comprise, by weight, 14% decellularized porcine small intestinal submucosa matrix gel, 12% sodium carboxymethyl cellulose base, 24% gum arabic thickener, 5% trehalose humectant, 2.5% vitamin E antioxidant, and 18% glycerin plasticizer, with the balance being deionized water. All other components are the same as those in Example 5.

[0168] Example 9

[0169] This embodiment differs from Example 5 in that, based on the total mass of the raw materials for the pressure-sensitive adhesive layer being 100%, the raw materials for the pressure-sensitive adhesive layer comprise, by weight, 14% decellularized porcine small intestinal submucosa matrix gel, 12% sodium carboxymethyl cellulose base, 24% gum arabic thickener, 5% trehalose humectant, 5.2% vitamin E antioxidant, and 18% glycerin plasticizer, with the balance being deionized water. All other components are the same as those in Example 5.

[0170] Example 10

[0171] This embodiment differs from Example 5 in that, based on the total mass of the raw materials for the pressure-sensitive adhesive layer being 100%, the raw materials for the pressure-sensitive adhesive layer comprise, by weight, 10% decellularized porcine small intestinal submucosa matrix gel, 12% sodium carboxymethyl cellulose base, 24% gum arabic thickener, 5% trehalose humectant, 3.5% vitamin E antioxidant, and 18% glycerin plasticizer, with the balance being deionized water. All other components are the same as those in Example 5.

[0172] Example 11

[0173] This embodiment differs from Example 5 in that, based on the total mass of the raw materials for the pressure-sensitive adhesive layer being 100%, the raw materials for the pressure-sensitive adhesive layer comprise, by weight, 16% decellularized porcine small intestinal submucosa matrix gel, 12% sodium carboxymethyl cellulose base, 24% gum arabic thickener, 5% trehalose humectant, 3.5% vitamin E antioxidant, and 18% glycerin plasticizer, with the balance being deionized water. All other components are the same as those for Example 5.

[0174] Example 12

[0175] The difference between this embodiment and Example 5 is that, based on the total mass of the raw materials of the pressure-sensitive adhesive layer as 100%, the raw materials of the pressure-sensitive adhesive layer include 14% by mass of decellularized porcine small intestinal submucosa matrix gel, 12% by mass of sodium carboxymethyl cellulose base material, 20% by mass of gum arabic thickener, 5% by mass of trehalose moisturizer, 3.5% by mass of vitamin E antioxidant and 18% by mass of glycerin plasticizer, and the balance is deionized water. The rest is the same as in Example 5.

[0176] Example 13

[0177] The difference between this embodiment and Example 5 is that, based on the total mass of the raw materials of the pressure-sensitive adhesive layer as 100%, the raw materials of the pressure-sensitive adhesive layer include 14% by mass of decellularized porcine small intestinal submucosa matrix gel, 12% by mass of sodium carboxymethyl cellulose base material, 30% by mass of gum arabic thickener, 5% by mass of trehalose moisturizer, 3.5% by mass of vitamin E antioxidant and 18% by mass of glycerin plasticizer, and the balance is deionized water. The rest is the same as in Example 5.

[0178] Example 14

[0179] The difference between this embodiment and Example 5 is that, based on the total mass of the raw materials of the pressure-sensitive adhesive layer as 100%, the raw materials of the pressure-sensitive adhesive layer include 14% by mass of decellularized porcine small intestinal submucosa matrix gel, 8% by mass of sodium carboxymethyl cellulose base material, 24% by mass of gum arabic thickener, 5% by mass of trehalose moisturizer, 3.5% by mass of vitamin E antioxidant and 18% by mass of glycerin plasticizer, and the balance is deionized water. The rest is the same as in Example 5.

[0180] Example 15

[0181] The difference between this embodiment and Example 5 is that, based on the total mass of the raw materials of the pressure-sensitive adhesive layer as 100%, the raw materials of the pressure-sensitive adhesive layer include 14% by mass of decellularized porcine small intestinal submucosa matrix gel, 15% by mass of sodium carboxymethyl cellulose base material, 24% by mass of gum arabic thickener, 5% by mass of trehalose moisturizer, 3.5% by mass of vitamin E antioxidant and 18% by mass of glycerin plasticizer, and the balance is deionized water. The rest is the same as in Example 5.

[0182] Comparative Example 1

[0183] The difference between this comparative example and Example 5 is that, based on the total mass of the raw materials of the pressure-sensitive adhesive layer as 100%, the raw materials of the pressure-sensitive adhesive layer include 14% by mass of decellularized porcine small intestinal submucosa matrix gel, 12% by mass of sodium carboxymethyl cellulose base material, 5% by mass of gum arabic thickener, 5% by mass of trehalose moisturizer, 3.5% by mass of vitamin E antioxidant and 18% by mass of glycerin plasticizer, and the balance is deionized water. The rest are the same as in Example 5.

[0184] Comparative Example 2

[0185] This comparative example differs from Example 5 in that, based on the total mass of the raw materials for the pressure-sensitive adhesive layer being 100%, the raw materials for the pressure-sensitive adhesive layer comprise, by weight, 14% decellularized porcine small intestinal submucosa matrix gel, 12% sodium carboxymethylcellulose base, 40% gum arabic thickener, 5% trehalose humectant, 3.5% vitamin E antioxidant, and 18% glycerin plasticizer, with the balance being deionized water. All other components are the same as those in Example 5.

[0186] Comparative Example 3

[0187] This comparative example differs from Example 5 in that, based on the total mass of the raw materials for the pressure-sensitive adhesive layer being 100%, the raw materials for the pressure-sensitive adhesive layer comprise, by weight, 14% decellularized porcine small intestinal submucosa matrix gel, 2% sodium carboxymethylcellulose base, 24% gum arabic thickener, 5% trehalose humectant, 3.5% vitamin E antioxidant, and 18% glycerin plasticizer, with the balance being deionized water. All other components are the same as those in Example 5.

[0188] Comparative Example 4

[0189] This comparative example differs from Example 5 in that, based on the total mass of the raw materials for the pressure-sensitive adhesive layer being 100%, the raw materials for the pressure-sensitive adhesive layer comprise, by weight, 14% decellularized porcine small intestinal submucosa matrix gel, 30% sodium carboxymethylcellulose base, 24% gum arabic thickener, 5% trehalose humectant, 3.5% vitamin E antioxidant, and 18% glycerin plasticizer, with the balance being deionized water. All other components are the same as those in Example 5.

[0190] Comparative Example 5

[0191] The difference between this comparative example and Example 5 is that, based on the total mass of the raw materials of the pressure-sensitive adhesive layer as 100%, the raw materials of the pressure-sensitive adhesive layer include 14% by mass of decellularized porcine small intestinal submucosa matrix gel, 24% by mass of gum arabic thickener, 5% by mass of trehalose moisturizer, 3.5% by mass of vitamin E antioxidant and 18% by mass of glycerin plasticizer, and the balance is deionized water. Other contents are the same as in Example 5.

[0192] Comparative Example 6

[0193] This comparative example differs from Example 5 in that, based on the total mass of the raw materials for the pressure-sensitive adhesive layer being 100%, the raw materials for the pressure-sensitive adhesive layer comprise, by weight, 3% decellularized porcine small intestinal submucosa matrix gel, 12% sodium carboxymethylcellulose base, 24% gum arabic thickener, 5% trehalose humectant, 3.5% vitamin E antioxidant, and 18% glycerin plasticizer, with the balance being deionized water. All other components are the same as those in Example 5.

[0194] Comparative Example 7

[0195] This comparative example differs from Example 5 in that, based on the total mass of the raw materials for the pressure-sensitive adhesive layer being 100%, the raw materials for the pressure-sensitive adhesive layer comprise, by weight, 30% decellularized porcine small intestinal submucosa matrix gel, 12% sodium carboxymethyl cellulose base, 24% gum arabic thickener, 5% trehalose humectant, 3.5% vitamin E antioxidant, and 18% glycerin plasticizer, with the balance being deionized water. All other components are the same as those in Example 5.

[0196] Comparative Example 8

[0197] This comparative example differs from Example 5 in that, based on the total mass of the raw materials for the pressure-sensitive adhesive layer being 100%, the raw materials for the pressure-sensitive adhesive layer comprise, by weight, 12% sodium carboxymethylcellulose as a base material, 24% gum arabic as a thickener, 5% trehalose as a humectant, 3.5% vitamin E as an antioxidant, and 18% glycerin as a plasticizer, with the balance being deionized water. All other conditions are the same as those for Example 5.

[0198] Comparative Example 9

[0199] This comparative example differs from Example 5 in that, based on the total mass of the raw materials for the pressure-sensitive adhesive layer being 100%, the raw materials for the pressure-sensitive adhesive layer comprise, by weight, 14% decellularized porcine small intestinal submucosa matrix gel, 12% sodium carboxymethylcellulose base, 24% gum arabic thickener, 5% trehalose humectant, 1% vitamin E antioxidant, and 18% glycerin plasticizer, with the balance being deionized water. All other components are the same as in Example 5.

[0200] Comparative Example 10

[0201] This comparative example differs from Example 5 in that, based on the total mass of the raw materials for the pressure-sensitive adhesive layer being 100%, the raw materials for the pressure-sensitive adhesive layer comprise, by weight, 14% decellularized porcine small intestinal submucosa matrix gel, 12% sodium carboxymethylcellulose base, 24% gum arabic thickener, 5% trehalose humectant, 10% vitamin E antioxidant, and 18% glycerin plasticizer, with the balance being deionized water. All other aspects are the same as in Example 5.

[0202] Comparative Example 11

[0203] This comparative example differs from Example 5 in that, based on the total mass of the raw materials for the pressure-sensitive adhesive layer being 100%, the raw materials for the pressure-sensitive adhesive layer comprise, by weight, 14% decellularized porcine small intestinal submucosa matrix gel, 12% sodium carboxymethylcellulose base, 24% gum arabic thickener, 5% trehalose humectant, and 18% glycerin plasticizer, with the balance being deionized water. All other conditions are the same as those for Example 5.

[0204] Test conditions

[0205] The degradable in vivo pressure-sensitive adhesives provided in Examples 1 to 15 and Comparative Examples 1 to 11 were packaged and sterilized for testing. The testing method was as follows:

[0206] (1) Initial adhesion: The test was conducted in accordance with GB / T 4852-2002. The test results were expressed as the maximum steel ball that the pressure-sensitive tape could adhere to within the specified range. Three parallel tests were conducted for each group of samples, and the average value was taken.

[0207] (2) Adhesion: The test was conducted according to GB 4851-1984. Three parallel samples were run for each group, and the average value was taken.

[0208] (3) 180° peel strength: The test was conducted according to GB / T 2792-1998. Three parallel samples were tested in each group, and the average value was taken.

[0209] (4) Discoloration: Place the sterilized pressure-sensitive adhesive in a test chamber at 50±2°C for 5 days, observe the degree of yellowing of the pressure-sensitive adhesive, and evaluate the degree of color change within 24 hours according to the ASTM D1925 standard as shown in Table 2:

[0210] Table 2: Discoloration classification levels

[0211] (5) Elongation at break: The test was conducted in accordance with GB 6329-1986. Three parallel samples were measured for each group, and the average value was taken.

[0212] (6) Wound healing rate in mice: A mouse wound model was established, and mice aged 6-8 weeks were prepared (the mice were purchased from a commercial laboratory animal company with relevant qualifications). The back of the mice was shaved, and the skin and subcutaneous membrane were removed from the dorsal area between the base of the neck and the shoulder to form a wound with a diameter of 1 cm. A layer of 0.5 mm thick circular silicone splint membrane was sutured with 6-0 nylon suture to prevent wound contraction. To observe the differences in wound healing in mice, the wound was covered with transparent sulfuric acid paper on the 3rd, 7th, 10th, 12th, and 15th day after the injury, and a line was drawn along the wound. The wound area was measured and the wound healing rate was calculated as (1-incision area / initial incision area) × 100%.

[0213] (7) pH value test: The test was conducted according to GB / T 14518-1993. Three parallel samples were tested for each group, and the average value was taken.

[0214] (8) Cytotoxicity test: The MTT method was used for determination according to GB / T 16886.5-2017 Biological Evaluation of Medical Devices Part 5: In Vitro Cytotoxicity Test Results.

[0215] (9) Pyrogen test: According to the pyrogen test method in Part IV of the Chinese Pharmacopoeia 2020 Edition, rabbit pyrogen test is used to evaluate the potential pyrogenic reaction of the sample.

[0216] The test results are shown in Table 3:

[0217] Table 3

[0218] As can be seen from Table 3:

[0219] In Example 1 and Example 2, maltitol and gum arabic were used as thickeners, respectively. The initial tack, sustained tack, and peel strength of the biodegradable pressure-sensitive adhesives prepared with these ingredients were not significantly different. However, the addition of sodium carboxymethylcellulose as a base material significantly improved the final viscosity characteristics of the product.

[0220] The formulation of Example 5 includes 14% decellularized porcine small intestinal submucosa matrix gel, 12% sodium carboxymethylcellulose base, 24% gum arabic thickener, 5% trehalose humectant, 3.5% vitamin E antioxidant, and 18% glycerin plasticizer, with the balance being deionized water. The resulting degradable in vivo pressure-sensitive adhesive exhibits optimal initial tack, sustained tack, and peel strength, and the lowest discoloration level. This indicates that the degradable in vivo pressure-sensitive adhesive prepared in Example 5 exhibits the strongest adhesion when connecting contact surfaces and exhibits superior stability during storage.

[0221] In Example 6, carboxymethyl cellulose was used as both a base and a thickener, and its initial tack, sustained tack, and peel strength were significantly lower than those of Examples 1-5. In Example 7, sorbitol was used as both a thickener and a plasticizer, and its initial tack, sustained tack, and peel strength were also significantly lower than those of Examples 1-5.

[0222] Comparative Example 1, which contains less thickener, exhibits reduced initial tack and sustained tack, demonstrating that thickeners play an important role in regulating the viscosity of biodegradable pressure-sensitive adhesives for in vivo use. However, when the thickener content is increased to 40%, the surface fluidity of the biodegradable pressure-sensitive adhesive increases after irradiation sterilization, while the sustained tack and peel strength drop dramatically. This is because irradiation breaks the glycosidic bonds in the thickener, creating new groups that alter the chemical bonds, reactive groups, and crystal structure of the thickener polysaccharide, thereby changing the overall viscosity of the biodegradable pressure-sensitive adhesive. The formulation of Comparative Example 3 contains less base material, resulting in reduced initial tack and sustained tack. The formulation of Comparative Example 4, which contains more base material, exhibits higher initial tack, sustained tack, and peel strength. However, during actual coating, the poor fluidity of the adhesive system can easily cause the substrate to curl during operation, leading to an uneven surface of the pressure-sensitive adhesive product. Comparative Example 5, in which no binder component was added, exhibited significantly reduced initial tack, sustained tack, and peel strength of the pressure-sensitive adhesive. This demonstrates the importance of the binder in the product formulation. Furthermore, a comparison of Examples 5 and 6 with Comparative Example 5 demonstrates the synergistic effect between the thickener provided herein and the binder; neither is indispensable, as otherwise the overall performance of the degradable pressure-sensitive adhesive for in vivo use would be compromised.

[0223] Comparative Example 6 contains less decellularized matrix gel, Comparative Example 7 contains more decellularized matrix gel, and Comparative Example 8 does not contain decellularized matrix gel. The results show that when the decellularized matrix gel is added in excessive amounts, the adhesiveness of the pressure-sensitive adhesive decreases significantly. The reason is that the irradiation energy causes the water in the gel system to ionize, generating a large number of free radicals that react with proteins, thereby causing irreversible cross-linking reactions between amino and hydroxyl groups in the molecules. During the wound repair process, the addition of decellularized matrix gel significantly promoted the wound healing rate (Table 4), indicating that decellularized matrix gel plays an important role in pressure-sensitive adhesives.

[0224] Table 4: Wound healing rate of mice (%)

[0225] Comparative Example 9 added a small amount of vitamin E, Comparative Example 10 added a large amount of vitamin E, and Comparative Example 11 did not add vitamin E. Although the viscosity results showed that the amount of vitamin E added had little effect on the viscosity, the yellowing test showed that Comparative Examples 9 and 11 had a high degree of discoloration, indicating that the antioxidant vitamin E plays an important role in the pressure-sensitive adhesive.

[0226] Table 5

[0227] Table 5 shows the elongation at break, pH, cytotoxicity and pyrogen reaction results of a degradable pressure-sensitive adhesive for in vivo use, which is made of decellularized porcine small intestinal submucosa as the base material, coated on both sides with decellularized porcine small intestinal submucosa gel as the active substance, sodium carboxymethyl cellulose as the base material, gum arabic as the thickener, trehalose as the humectant, vitamin E as the antioxidant, and glycerin as the plasticizer. All of the results meet the requirements of national standards for use.

[0228] The applicant declares that while the above-mentioned embodiments are used to illustrate the process of the present application, the present application is not limited to the above-mentioned process steps, which does not mean that the present application must rely on the above-mentioned process steps in order to be implemented. Those skilled in the art should understand that any improvements to the present application, equivalent replacements for the raw materials used in the present application, addition of auxiliary components, and selection of specific methods, etc., fall within the scope of protection and disclosure of the present application.

Claims

1. A degradable pressure-sensitive adhesive for in vivo use based on an acellular matrix material, comprising a biological substrate layer and pressure-sensitive adhesive layers disposed on both sides of the biological substrate layer; Taking the total mass of the raw materials of the pressure-sensitive adhesive layer as 100%, the raw materials of the pressure-sensitive adhesive layer include 5%-25% of base material, 5%-18% of tissue active material, 10%-35% of thickener, 10%-50% of plasticizer and 10%-60% of deionized water in mass percentages.

2. The degradable pressure-sensitive adhesive for in vivo use according to claim 1, wherein: Taking the total mass of the pressure-sensitive adhesive layer as 100%, the raw materials of the pressure-sensitive adhesive layer include 8%-15% of base material, 10%-16% of tissue active material, 20%-30% of thickener, 15%-20% of plasticizer and 19%-45% of deionized water in mass percentages.

3. The degradable pressure-sensitive adhesive for in vivo use according to claim 1 or 2, wherein: The tissue active material comprises any one of mammalian skin, pericardium, amniotic membrane, small intestinal submucosa or bladder basement membrane, or a combination of at least two decellularized matrix gels.

4. The degradable pressure-sensitive adhesive for in vivo use according to claim 1, wherein: The base material includes a degradable natural polymer compound and / or a degradable modified natural polymer compound; The degradable natural polymer compound includes any one or a combination of at least two of starch, dextrin, peach gum, gum arabic, bone glue, hide glue, gelatin, fish glue, shellac, plant protein or casein; The degradable modified natural polymer compound includes any one of sodium carboxymethyl cellulose, modified starch, and polyvinyl alcohol, or a combination of at least two of them.

5. The degradable pressure-sensitive adhesive for in vivo use according to claim 1, wherein: The thickener includes any one of starch, modified starch, xanthan gum, maltitol, oligofructose, sorbitol, xylitol, lactitol, mannitol, erythritol, hydrogenated starch hydrolysate, gelatin, cellulose, methylcellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, gum arabic, tamarind polysaccharide gum, sesbania gum, agar, sodium alginate, carrageenan, pectin or β-cyclodextrin, or a combination of at least two thereof.

6. The degradable pressure-sensitive adhesive for in vivo use according to claim 1, wherein: The plasticizer includes a polyol compound; The polyol compound includes any one of glycerol, sorbitol or ethylene glycol, or a combination of at least two of them.

7. The degradable pressure-sensitive adhesive for in vivo use according to any one of claims 4 to 6, wherein: The base material, thickener and plasticizer are of different types.

8. The degradable pressure-sensitive adhesive for in vivo use according to any one of claims 4 to 6, wherein: The base material includes sodium carboxymethyl cellulose; The thickening agent includes gum arabic; The plasticizer includes glycerin.

9. The degradable pressure-sensitive adhesive for in vivo use according to claim 1, wherein: Based on the total mass of the raw materials of the pressure-sensitive adhesive layer being 100%, the raw materials of the pressure-sensitive adhesive layer further comprise 0.1%-21.6% of a moisturizer and 2.5%-5.2% of an antioxidant; The moisturizing agent includes a polyol moisturizing agent and / or a sugar moisturizing agent; The antioxidant includes any one of vitamin E, vitamin C, flavonoids, tea polyphenols, phytic acid, glucosamine, lactic acid or sodium hyaluronate, or a combination of at least two of them.

10. The degradable pressure-sensitive adhesive for in vivo use according to claim 1, wherein: The material of the biological substrate layer includes acellular matrix material; The acellular matrix material includes any one of mammalian skin, pericardium, amniotic membrane, small intestinal submucosa or bladder basement membrane, or a combination of at least two thereof.

11. A method for preparing a degradable pressure-sensitive adhesive for in vivo use based on an acellular matrix material according to any one of claims 1 to 10, comprising the following steps: The tissue active material, base material, thickener, plasticizer and deionized water are mixed according to the formula to obtain a pressure-sensitive adhesive slurry, and then the pressure-sensitive adhesive slurry is coated on both sides of the biological substrate layer. After drying, the degradable in vivo pressure-sensitive adhesive with the decellularized matrix material as the base material is obtained.

12. The method according to claim 11, wherein The drying temperature is 20-50° C. and the drying time is 4-24 hours.

13. The method according to claim 11, wherein The thickness of the pressure-sensitive adhesive layer formed after drying is 0.2-2 mm.

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