Method for preparing biological valve material by cross-linking aldehyde groups and polymerizing double bonds, biological valve material and application

Abstract

The application discloses a method for preparing a biological valve material by aldehyde group cross-linking and double bond polymerization, and the biological valve material and application, and the preparation method comprises the following steps: S110, contacting a biological material with an aldehyde group cross-linking agent solution to perform cross-linking; S120, soaking the biological material treated in the step S110 in a solution containing a first functional monomer to react and introduce a first carbon-carbon double bond; the first functional monomer has a first carbon-carbon double bond and an oxirane group; S200, under the action of an initiator, performing a polymerization reaction on the carbon-carbon double bond to obtain the biological valve material. By introducing the double bond on the glutaraldehyde cross-linked biological valve material and further initiating the polymerization of the double bond, the stability of the glutaraldehyde cross-linked material is improved, the calcification risk caused by structural degradation is further reduced, and therefore the biological valve material has certain anti-calcification ability.

Description

Technical Field

[0001] This application relates to the field of interventional materials technology, specifically to a method for preparing biological valve materials by double bond polymerization after aldehyde crosslinking, as well as the biological valve materials and their applications. Background Technology

[0002] Biological heart valves are typically made from the pericardium of pigs or cows and are used to replace dysfunctional human heart valves. Compared with mechanical heart valves, biological heart valves have many advantages: patients do not need to take anticoagulants for a long time after implantation, and biological heart valves can be implanted using minimally invasive interventional procedures. These advantages have made biological heart valves the mainstream in clinical applications.

[0003] Currently, almost all bioprosthetic valve products on the market are prepared using glutaraldehyde for cross-linking. Glutaraldehyde can improve the mechanical properties of the pericardium and reduce its immunogenicity to some extent. However, the stability and degree of cross-linking of glutaraldehyde-crosslinked bioprosthetic valves still have low problems. This will lead to component degradation after implantation, causing structural damage and degeneration. On the other hand, the degradation of bioprosthetic valve components will further induce mechanical damage and calcification, affecting the normal function of the valve and reducing its lifespan.

[0004] Glutaraldehyde crosslinking remains the mainstream method for current bioprosthetic valve products. Therefore, further modifying bioprosthetic valves based on glutaraldehyde crosslinking to improve their crosslinking degree and stability is of great significance for scientific research and the development of related industries.

[0005] The applicant of this application has long been committed to the research of biological heart valves. For example, in the early research, Chinese invention patent application document CN 114748694A disclosed a co-crosslinked biological valve material and its preparation method and application. In the crosslinking treatment, the biological valve material is functionally modified by introducing functional monomers for co-crosslinking. In the biological valve preparation method disclosed in Chinese invention patent applications CN 114748693A, CN114748697A, CN 114748696A and CN 114748695A, carbon-carbon double bonds are introduced by the functional monomers while adding functional monomers for co-crosslinking, as a basis for further crosslinking. The modification of the biological valve material is completed through two crosslinking processes.

[0006] In the studies described above, whether it is co-crosslinking modification by introducing functional monomers while crosslinking glutaraldehyde, or introducing carbon-carbon double bonds as the basis for further crosslinking during the co-crosslinking process, both involve introducing new modified substances to participate in the crosslinking reaction during the crosslinking process of glutaraldehyde. Summary of the Invention

[0007] This application provides a method for preparing biological valve materials by double bond polymerization after aldehyde crosslinking, as well as the biological valve materials and their applications. After glutaraldehyde crosslinking, functional monomers with carbon-carbon double bonds are introduced from the active groups on the glutaraldehyde crosslinked membrane, such as residual amino, hydroxyl, and carboxyl groups, to provide a controllable crosslinking opportunity and range for the glutaraldehyde crosslinked membrane.

[0008] A method for preparing biological valve materials by double bond polymerization after aldehyde crosslinking includes:

[0009] Step S110: The biomaterial is cross-linked by contacting the aldehyde cross-linking agent solution;

[0010] Step S120: Immerse the biomaterial treated in step S110 in a solution containing the first functional monomer, and a chemical reaction is performed to introduce the first carbon-carbon double bond. The first functional monomer has the first carbon-carbon double bond and an ethylene oxide group.

[0011] In step S200, the first carbon-carbon double bond undergoes a polymerization reaction under the action of an initiator to obtain a biological valve material.

[0012] Optionally, the aldehyde crosslinking agent is glutaraldehyde or formaldehyde.

[0013] Optionally, the biological material is animal tissue, including one or more of the following: pericardium, valves, intestinal membrane, meninges, pulmonary membrane, blood vessels, skin, and ligaments.

[0014] Optionally, the animal tissue may be fresh animal tissue or decellularized biological tissue.

[0015] In step S200: the initiator is added to the system treated in the previous step; or the biological valve material treated in the previous step is washed and then immersed in a solution containing the initiator.

[0016] Optionally, the initiator may be a single initiator or a mixture of initiators.

[0017] Optionally, the mixed initiator is:

[0018] A mixture of ammonium persulfate and sodium bisulfite, or a mixture of ammonium persulfate and sodium bisulfite, or a mixture of sodium persulfate and sodium bisulfite, or a mixture of potassium persulfate and sodium bisulfite, or a mixture of potassium persulfate and sodium bisulfite, or a mixture of potassium persulfate and tetramethylethylenediamine, or a mixture of ammonium persulfate and tetramethylethylenediamine, or a mixture of sodium persulfate and tetramethylethylenediamine; wherein the concentration of each component in the mixture is 1 to 100 mM.

[0019] Optionally, the single initiator may be any component of the mixed initiators.

[0020] Optionally, in step S200, the double bond polymerization time is 3 to 24 hours.

[0021] Optionally, the first functional monomer is selected from at least one of allyl glycidyl ether, glycidyl methacrylate, and glycidyl acrylate.

[0022] Optionally, in step S110:

[0023] The w / w concentration of the aldehyde-based crosslinking agent solution is 0.1% to 5%; the crosslinking time is 0.5 h to 120 h.

[0024] Optionally, in step S120:

[0025] The w / w concentration of the first functional monomer in the solution containing the first functional monomer is 1% to 10%; the reaction time is 2 to 120 hours.

[0026] Optionally, the solution containing the first functional monomer contains only the first functional monomer and a solvent that does not participate in the chemical reaction.

[0027] Optionally, the solvent in the solution containing the first functional monomer is one or more of the following: an aqueous solution of methanol, ethanol, ethylene glycol, propanol, 1,2-propanediol, 1,3-propanediol, isopropanol, butanol, isobutanol, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, glycerol, water, physiological saline, and pH neutral buffer.

[0028] This application also provides a biological valve material, prepared by the aforementioned preparation method.

[0029] This application also provides a biological valve material, comprising:

[0030] Step S110: The biomaterial is cross-linked by contacting the aldehyde cross-linking agent solution;

[0031] Step S120: Immerse the biomaterial treated in step S110 in a solution containing the first functional monomer, and a chemical reaction is performed to introduce the first carbon-carbon double bond; the first functional monomer has the first carbon-carbon double bond and an ethylene oxide group;

[0032] In step S200, the first carbon-carbon double bond undergoes a polymerization reaction under the action of an initiator to obtain a biological valve material.

[0033] This application also provides a bioprosthetic valve, including a stent and leaflets, wherein the leaflets are the bioprosthetic valve material described above.

[0034] Optionally, the bioprosthetic valve is a heart valve.

[0035] This application also provides an interventional system including a heart valve and a catheter assembly, wherein the heart valve is folded and delivered by the catheter assembly, and the heart valve includes a stent and leaflets, wherein the leaflets are the bio-valve material described above.

[0036] Compared with the prior art, this application has at least one of the following beneficial effects:

[0037] (1) The method of this application introduces double bonds into the glutaraldehyde-crosslinked biovalve material as the basis for secondary crosslinking by double bond modification. Furthermore, it achieves secondary crosslinking by initiating the polymerization of double bonds on the glutaraldehyde-crosslinked biovalve material, which can further improve the degree of crosslinking of the biovalve material and thus improve the stability of the biovalve material.

[0038] (2) This application improves the stability of the glutaraldehyde crosslinked material by introducing double bonds into the glutaraldehyde crosslinked biovalve material and further initiating the polymerization of the double bonds, thereby reducing the risk of calcification caused by structural degradation and thus also possessing certain anti-calcification properties.

[0039] (3) Compared with the glutaraldehyde modification method of the applicant in the previous study, which introduced carbon-carbon double bonds by adding functional monomers for co-crosslinking, the biological valve material modification process of this application first performs glutaraldehyde crosslinking treatment, and then the residual amino, hydroxyl, carboxyl and other active groups on the glutaraldehyde crosslinking membrane are chemically linked to the functional monomers with carbon-carbon double bonds. The functional monomers with carbon-carbon double bonds are connected to the amino, hydroxyl and carboxyl groups on the surface of the glutaraldehyde crosslinking membrane through chemical reaction via ethylene oxide, so that the carbon-carbon double bonds are mainly connected to the surface of the biological valve material. No other substances that can participate in the crosslinking reaction are added during the glutaraldehyde crosslinking modification of the biological valve material, which can better protect the original fiber structure of the biological material. While effectively ensuring the mechanical properties of the membrane, the orientation direction of the original fibers of the biological material can be guaranteed, avoiding the problem that the addition of double-bonded functional monomers during crosslinking in the previous study may destroy the original fiber orientation of the biological material and increase the fiber disorder. Attached Figure Description

[0040] Figure 1 This is a process flow diagram of a preferred embodiment of the present application;

[0041] Figure 2 This is a schematic diagram of the reaction principle of a preferred embodiment of this application;

[0042] Figure 3 This is an image showing the results of alizarin red staining of control group 1 (glutaraldehyde-crosslinked porcine pericardium) 30 days after subcutaneous implantation in rats;

[0043] Figure 4This is an image showing the results of Alizarin Red staining of Sample 1 from Example 1 after 30 days of subcutaneous implantation in rats;

[0044] Figure 5 This is an image showing the results of alizarin red staining of sample 5 from Example 5 after 30 days of subcutaneous implantation in rats.

[0045] Figure 6 This is an image showing the results of Alizarin Red staining of Sample 7 from Example 7 after subcutaneous implantation in rats for 30 days.

[0046] Figure 7 This is a schematic diagram of the heart valve structure in this application;

[0047] Figure 8 This is a schematic diagram of the intervention system of this application. Detailed Implementation

[0048] The technical solutions of the embodiments of this application will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this application, and not all embodiments. Based on the embodiments of this application, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this application.

[0049] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application.

[0050] Currently, almost all bioprosthetic valve products on the market are prepared using glutaraldehyde for cross-linking. Glutaraldehyde can improve the mechanical properties of the pericardium and reduce its immunogenicity to some extent. However, the stability and degree of cross-linking of glutaraldehyde-crosslinked bioprosthetic valves still have low problems. This will lead to component degradation after implantation, causing structural damage and degeneration. Furthermore, the degradation of bioprosthetic valve components will further induce mechanical damage and calcification, affecting normal valve function and reducing its lifespan. Glutaraldehyde cross-linking remains the mainstream method for current bioprosthetic valve products. Therefore, further cross-linking and modification of bioprosthetic valves based on glutaraldehyde cross-linking to improve their degree of cross-linking and stability is of great significance for scientific research and the development of related industries.

[0051] This application introduces double bonds and initiates post-crosslinking based on glutaraldehyde crosslinking. Specifically, the first carbon-carbon double bond is introduced into the glutaraldehyde crosslinked biomembrane through chemical bonding of a first functional monomer (containing a first carbon-carbon double bond and an ethylene oxide group) with the glutaraldehyde crosslinked biomembrane. This will improve the degree of crosslinking, stability, mechanical properties and anti-calcification of the glutaraldehyde crosslinked biovalve material membrane.

[0052] One implementation specifically includes (see...) Figure 1 ):

[0053] Step S110: Immerse the bio-valve material in an aldehyde-based crosslinking agent solution for crosslinking to prepare glutaraldehyde-crosslinked bio-valve material;

[0054] Step S120: The glutaraldehyde crosslinked biovalve material prepared in step S110 is immersed in a solution containing a double-bonding reagent (first functional monomer) for double-bonding modification to prepare a double-bonded biovalve material. The double-bonding reagent (first functional monomer) has at least one first carbon-carbon double bond and an ethylene oxide group.

[0055] In step S200, the biological valve material treated in step S120 is brought into contact with an initiator to initiate double bond polymerization.

[0056] In this application, the biomaterial first undergoes a cross-linking reaction with an aldehyde cross-linking agent (step S110), and then reacts with the active group of the first functional monomer to introduce a first carbon-carbon double bond (step S120). During the preparation process, an aldehyde cross-linking agent is first added, which reacts with some of the amino groups of the biomaterial. Then, the first functional monomer is added, and the remaining amino groups and other groups (e.g., hydroxyl and carboxyl groups) on the biomaterial react with the active groups on the first functional monomer to directly introduce the first carbon-carbon double bond. In this scheme, the first functional monomer also has an ethylene oxide group as an active group, which participates in the chemical reaction. In addition to the remaining amino groups participating in the reaction, the hydroxyl and carboxyl groups on the biomaterial can also react with the ethylene oxide group to participate in the chemical reaction. The first carbon-carbon double bond introduced through the chemical reaction then undergoes a polymerization reaction under the action of an initiator, further forming a cross-linked network, improving the anticoagulation, anti-calcification, and elasticity properties of the glutaraldehyde-crosslinked bioprosthetic valve.

[0057] The reaction principle of this application:

[0058] In this double-bond crosslinking scheme, after the bio-valve material is crosslinked with glutaraldehyde, the first carbon-carbon double bond is introduced by using a first functional monomer, namely a double-bonding reagent, to achieve the double-bonding of the glutaraldehyde-crosslinked bio-valve material. The first functional monomer, namely the double-bonding reagent, has both a first carbon-carbon double bond and an ethylene oxide group.

[0059] To facilitate understanding of the chemical principles involved in this scheme, as follows: Figure 2To further illustrate, the following example illustrates how glutaraldehyde-crosslinked bioprosthetic valve materials are modified using the first functional monomer, i.e., the double-bonding agent. The ethylene oxide in the first functional monomer (double-bonding agent) reacts with the hydroxyl and carboxyl groups on the glutaraldehyde-crosslinked bioprosthetic valve material, as well as the small amount of amino groups remaining after glutaraldehyde crosslinking, to undergo a ring-opening reaction, directly introducing the first carbon-carbon double bond into the glutaraldehyde-crosslinked bioprosthetic valve material. Furthermore, this process initiates the polymerization of these double bonds on the glutaraldehyde-crosslinked bioprosthetic valve material, achieving secondary crosslinking and completing the post-crosslinking treatment of the bioprosthetic valve material. The degree of crosslinking of the bioprosthetic valve material after secondary crosslinking will be further improved, along with its stability, mechanical properties, and anti-calcification properties.

[0060] After crosslinking with glutaraldehyde, carbon-carbon double bonds are introduced. These carbon-carbon double bonds are mainly attached to the surface of the bio-valve material. During the process of crosslinking and modifying the bio-valve material with glutaraldehyde, no other substances that can participate in the crosslinking reaction are added, which can better protect the original fiber structure of the biomaterial. This can effectively ensure the mechanical properties of the membrane while maintaining the orientation of the original fibers of the biomaterial. It avoids the problem that the direct addition of double-bonded functional monomers during crosslinking in previous studies may have damaged the original fiber orientation of the biomaterial and increased fiber disorder.

[0061] Optionally, in step S120 of this application, non-condensation chemical bonding is used to connect the first carbon-carbon double bond.

[0062] Optionally, in step S110, the biomaterial has not undergone any chemical reaction involving any other reagents before being treated with the aldehyde crosslinking agent.

[0063] Further optionally, the first carbon-carbon double bond in the reaction system of step S120 is provided by a first functional monomer with an active group, and the reaction raw materials in steps S110 and S120 include only the biomaterial, the first functional monomer, and the aldehyde crosslinking agent.

[0064] In step S110:

[0065] The crosslinking agent used in this application is an aldehyde-based crosslinking agent used in current mainstream crosslinking methods. Optionally, the aldehyde-based crosslinking agent can be selected from glutaraldehyde or formaldehyde.

[0066] Optionally, the concentration of the glutaraldehyde solution is 0.1% to 5% (w / w); the crosslinking time can be any time from 0.5h to 120h.

[0067] The biomaterials used in this application are conventional biomaterials used in existing glutaraldehyde crosslinking processes, and the collagen content of the biomaterials is 60% to 90%. Further, the biomaterials are animal tissues, derived from pigs, cattle, horses, or sheep, including one or more of the following: pericardium, valves, intestinal membranes, meninges, pulmonary membranes, blood vessels, skin, or ligaments.

[0068] Optionally, the animal tissue may be fresh animal tissue or decellularized biological tissue.

[0069] Optionally, in the decellularization step, the biological tissue is treated with a surfactant as follows:

[0070] Decellularization of biological tissues using ionic surfactants; or

[0071] Nonionic surfactants are used to decellularize biological tissues.

[0072] The ionic surfactants are mainly used to lyse cells, while the nonionic surfactants are mainly used to remove lipids (such as phospholipids).

[0073] Optionally, the ionic surfactant is at least one of sodium deoxycholate, potassium fatty acid soap, sodium dodecyl sulfate, sodium cholate, hexadecyltrimethylammonium bromide, potassium fatty acid salt, and alkyl dimethyl sulfopropyl betaine.

[0074] Optionally, the nonionic surfactant is at least one of Triton and Tween.

[0075] In step S120:

[0076] Optionally, the double-bonding agent, i.e. the first functional monomer, is selected from at least one of allyl glycidyl ether, glycidyl methacrylate, and glycidyl acrylate.

[0077] Optionally, the concentration of the double-bonding reagent in the solution containing the first functional monomer, i.e., the double-bonding reagent, is 1% to 10% (w / w); the reaction time for double-bonding modification is 2 to 120 hours.

[0078] Optionally, the solvent in the solution containing the first functional monomer, i.e. the double-bonding reagent, is one or more of the following: water, physiological saline, pH neutral buffer, or aqueous solutions of methanol, ethanol, ethylene glycol, propanol, 1,2-propanediol, 1,3-propanediol, isopropanol, butanol, isobutanol, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, and glycerol.

[0079] Optionally, the biofilm material treated with S110 can be removed, cleaned, or placed directly in a solution containing a double-bonding reagent (first functional monomer).

[0080] Step S200, in:

[0081] In step S120, the treated bioprosthetic valve material is washed with deionized water and then immersed in an initiator solution for the treatment in step S200, or an initiator is directly added to the reaction system in step S120 to initiate a polymerization reaction, the latter being commonly known as the one-pot method.

[0082] Optionally, the solvent in the initiator-containing solution is water, physiological saline, or a pH neutral buffer.

[0083] As mentioned above, the concentration of the initiator in the one-pot process can be understood as the concentration of the initiator in the solution contained in the reaction system in step S120, and in the stepwise process, the concentration can be understood as the concentration in the solution containing the initiator.

[0084] Optionally, the initiator is a mixture of ammonium persulfate and sodium bisulfite, or a mixture of ammonium persulfate and sodium sulfite, or a mixture of sodium persulfate and sodium sulfite, or a mixture of potassium persulfate and sodium sulfite, or a mixture of sodium persulfate and sodium bisulfite, or a mixture of potassium persulfate and sodium bisulfite, or a mixture of potassium persulfate and tetramethylethylenediamine, or a mixture of ammonium persulfate and tetramethylethylenediamine, or a mixture of sodium persulfate and tetramethylethylenediamine; the concentration of each component in the mixture is 1 to 100 mM.

[0085] Optionally, the polymerization time for double bonds should be 3 to 24 hours.

[0086] In this application, all reaction processes in steps S110, S120 and S200 can be carried out at 0 to 50°C unless otherwise specified. Preferably, the temperature does not need to be specially controlled and room temperature is acceptable, but it is preferable to not exceed the temperature that the human body can adapt to, and preferably at 36 to 37°C.

[0087] In this application, all reactions in steps S110, S120 and S200 can be either static or dynamic unless otherwise specified. Dynamic reactions can be carried out under the action of a device that can circulate the solution, such as a peristaltic pump, or by shaking at a speed of 10 rpm to 150 rpm. The peristaltic circulation or shaking can be carried out continuously or intermittently.

[0088] Optionally, this application also includes dehydration and drying treatment after double bond polymerization to prepare a dry membrane. After double bond polymerization, the bioprosthetic valve material is routinely cleaned and softened before dehydration and drying treatment.

[0089] The cleaning solution can be one or a mixture of several of the following: water, physiological saline, ethanol, isopropanol, or a pH-neutral buffer solution. The pH can be adjusted to between 5.0 and 9.5 before and during use, or it can be left unadjusted.

[0090] Optionally, the dehydration process involves exposing the double-bonded polymerized membrane or the valve formed by sewing the membrane to a dehydration solution.

[0091] Optionally, the dehydration solution is a mixture of an alcohol solution and water, with the alcohol solution accounting for 20-90% (v / v), and the alcohol reagent can be one or a mixture of two of ethanol and isopropanol.

[0092] Optionally, the drying process involves exposing the dehydrated membrane or valve to a fabric softener solution for 20 minutes to 10 hours.

[0093] Optionally, the main components of the fabric softener solution are one or a mixture of two of glycerin and polyethylene glycol, with a glycerin concentration of 10-100% (v / v), and other components are one or more of water, ethanol, and isopropanol, accounting for 0-90% (v / v).

[0094] Optionally, the valves after drying can be sterilized using either ethylene oxide sterilization or electron beam sterilization.

[0095] The bioprosthetic valve material prepared by the above method can be used for interventional bioprosthetic valves, such as through minimally invasive intervention; it can also be used for surgical bioprosthetic valves, such as through surgical implantation.

[0096] like Figure 7 As shown, in one embodiment, an artificial heart valve is provided, including a stent 1 and leaflets 2 connected within the stent 1. The stent is cylindrical in shape, with a hollowed-out mesh structure on the sidewalls. The stent has a blood flow channel inside, and multiple leaflets cooperate to control the opening and closing of the blood flow channel within the stent.

[0097] Depending on the release mode, the stent is made of different materials, such as nickel-titanium alloy with shape memory that can expand in the body, or stainless steel material that can be released by ball expansion. The stent itself can be formed by cutting tubes or weaving wires, and the leaflets can be connected to the stent by stitching, bonding or integral molding.

[0098] To facilitate positioning within the body, positioning structures that can interact with surrounding native tissues can be provided on the periphery of the stent, such as anchors, arms, etc. To prevent peritoneal leakage, skirts or anti-leakage materials can be provided on the inner and / or outer sides of the stent. The leaflets, skirts, or anti-leakage materials can all be the bioprosthetic valve materials described in the above embodiments.

[0099] like Figure 8When catheter intervention is used, the artificial heart valve 3 and the corresponding delivery system form a valve intervention system. The delivery system includes a catheter assembly 4 and a handle for controlling the catheter assembly. The artificial heart valve is in a radially compressed state during delivery in the body. The catheter assembly is released from its restraints or undergoes bulbodilation and radial expansion for release in the body.

[0100] The following specific embodiments provide further details:

[0101] Control group 1

[0102] Freshly collected pig pericardium was washed with distilled water for 2 hours under oscillation conditions of 4℃ and 100 RPM, and then soaked in 0.30% (w / w) glutaraldehyde solution for crosslinking at room temperature and 100 RPM for 48 hours to obtain control sample 1.

[0103] Example 1

[0104] In this embodiment, freshly collected porcine pericardium was washed with distilled water for 2 hours under oscillation conditions of 4°C and 100 RPM, and then soaked in 0.30% (w / w) glutaraldehyde solution at room temperature for 48 hours to treat the bioprosthetic valve and obtain glutaraldehyde-crosslinked porcine pericardium.

[0105] The glutaraldehyde-crosslinked porcine pericardium was further washed with deionized water and then immersed in a 5% (v / v) propanol aqueous solution of glycidyl methacrylate at room temperature for double bond modification. The reaction time was 72 hours, and the solvent used for the double bond modification solution was a 20% (v / v) propanol aqueous solution.

[0106] After the double bond modification was completed, the double-bonded glutaraldehyde cross-linked porcine pericardium was washed with deionized water; then the double-bonded glutaraldehyde cross-linked porcine pericardium was immersed in a mixture of 20 mM potassium persulfate and 10 mM sodium bisulfite to further initiate the polymerization reaction of the double bonds on the double-bonded glutaraldehyde cross-linked porcine pericardium. After reacting at 37°C for 8 hours, the double-bonded cross-linked porcine pericardium was obtained, which was recorded as sample 1.

[0107] Example 2

[0108] Freshly collected porcine pericardiacs were washed with distilled water for 2 hours under oscillation conditions at 4℃ and 100 RPM, and then soaked in 0.30% (w / w) glutaraldehyde solution at room temperature for 48 hours to obtain glutaraldehyde-crosslinked porcine pericardiacs for biological valve treatment.

[0109] The glutaraldehyde-crosslinked porcine pericardium was further washed with deionized water and then immersed in a 6% (v / v) aqueous solution of glycidyl acrylate in isopropanol for double bond modification at room temperature for 72 hours. The solvent used for the double bond modification solution was a 20% (v / v) aqueous solution of isopropanol.

[0110] After the double bond modification was completed, the double-bonded glutaraldehyde cross-linked porcine pericardium was washed with deionized water; then the double-bonded glutaraldehyde cross-linked porcine pericardium was immersed in a mixture of 20 mM ammonium persulfate and 5 mM sodium bisulfite to further initiate the polymerization reaction of the double bonds on the double-bonded glutaraldehyde cross-linked porcine pericardium. After reacting at 37°C for 8 hours, the double-bonded cross-linked porcine pericardium was obtained, which was recorded as sample 2.

[0111] Example 3

[0112] Freshly collected porcine pericardiacs were washed with distilled water for 2 hours under oscillation conditions at 4℃ and 100 RPM, and then soaked in 0.30% (w / w) glutaraldehyde solution at room temperature for 48 hours to obtain glutaraldehyde-crosslinked porcine pericardiacs for biological valve treatment.

[0113] The glutaraldehyde-crosslinked porcine pericardium was further washed with deionized water and then immersed in an isopropanol aqueous solution containing 4% (v / v) glycidyl acrylate and 4% (v / v) allyl glycidyl ether at room temperature for double bond modification of the glutaraldehyde-crosslinked porcine pericardium. The reaction time was 72 hours, and the solvent used for the double bond modification solution was a 30% (v / v) aqueous ethanol solution.

[0114] After the double bond modification was completed, the double-bonded glutaraldehyde cross-linked porcine pericardium was washed with deionized water. Then, the double-bonded glutaraldehyde cross-linked porcine pericardium was immersed in a mixture of 20 mM ammonium persulfate and 10 mM sodium bisulfite to further initiate the polymerization reaction of the double bonds on the double-bonded glutaraldehyde cross-linked porcine pericardium. After reacting at 37°C for 7 hours, the double-bonded cross-linked porcine pericardium was obtained, which was recorded as sample 3 and numbered GAGA-PP-3.

[0115] Example 4

[0116] Freshly collected porcine pericardiacs were washed with distilled water for 2 hours under oscillation conditions at 4°C and 100 RPM, and then soaked in 0.30% (w / w) glutaraldehyde solution at room temperature for 48 hours to obtain glutaraldehyde-crosslinked porcine pericardiacs for biological valve treatment.

[0117] The glutaraldehyde-crosslinked porcine pericardium was further washed with deionized water and then immersed in an aqueous solution of 5% (v / v) glycidyl methacrylate and 2% (v / v) glycidyl acrylate in isopropanol for double bond modification at room temperature for 72 hours. The solvent used for the double bond modification solution was 35% (v / v) isopropanol aqueous solution.

[0118] After the double bond modification was completed, the double-bonded glutaraldehyde cross-linked porcine pericardium was washed with deionized water; then the double-bonded glutaraldehyde cross-linked porcine pericardium was immersed in a mixture of 20 mM sodium persulfate and 5 mM sodium bisulfite to further initiate the polymerization reaction of the double bonds on the double-bonded glutaraldehyde cross-linked porcine pericardium. After reacting at 37°C for 8 hours, the double-bonded cross-linked porcine pericardium was obtained and was recorded as sample 4.

[0119] Example 5

[0120] Freshly collected porcine pericardiacs were washed with distilled water for 2 hours under oscillation conditions at 4℃ and 100 RPM, and then soaked in 0.30% (w / w) glutaraldehyde solution at room temperature for 48 hours to obtain glutaraldehyde-crosslinked porcine pericardiacs for biological valve treatment.

[0121] Glutaraldehyde-crosslinked porcine pericardium was washed with deionized water and then immersed in a 4% (v / v) aqueous solution of glycidyl methacrylate in ethanol at room temperature for double bond modification. The reaction time was 72 hours, and the solvent used for the double bond modification solution was a 20% (v / v) aqueous solution of ethanol.

[0122] After the double bond modification was completed, ammonium persulfate and sodium bisulfite were added to initiate the polymerization reaction of the double bonds on the pig pericardium crosslinked with double bonded glutaraldehyde. The concentration of ammonium persulfate was 20 mM and the concentration of sodium bisulfite was 5 mM. After adding the initiator, the reaction was carried out at 37 °C for 8 hours to obtain the pig pericardium with double bond crosslinking, which was recorded as sample 5.

[0123] Example 6

[0124] Freshly collected porcine pericardiacs were washed with distilled water for 2 hours under oscillation conditions at 4℃ and 100 RPM, and then soaked in 0.30% (w / w) glutaraldehyde solution at room temperature for 48 hours to obtain glutaraldehyde-crosslinked porcine pericardiacs for biological valve treatment.

[0125] The glutaraldehyde-crosslinked porcine pericardium was further washed with deionized water and then immersed in a 4% (v / v) aqueous solution of glycidyl methacrylate in isobutanol for double bond modification at room temperature for 72 hours. The solvent used for the double bond modification solution was a 15% (v / v) aqueous solution of isobutanol.

[0126] After the double bond modification was completed, the double-bonded glutaraldehyde cross-linked porcine pericardium was washed with deionized water; then the double-bonded glutaraldehyde cross-linked porcine pericardium was immersed in a mixture of 20 mM ammonium persulfate and 5 mM sodium bisulfite to further initiate the polymerization reaction of the double bonds on the double-bonded glutaraldehyde cross-linked porcine pericardium. After reacting at 37°C for 8 hours, the double-bonded cross-linked porcine pericardium was obtained and was designated as sample 6.

[0127] Example 7

[0128] Freshly collected porcine pericardiacs were washed with distilled water for 2 hours under oscillation conditions at 4℃ and 100 RPM, and then soaked in 0.30% (w / w) glutaraldehyde solution at room temperature for 48 hours to obtain glutaraldehyde-crosslinked porcine pericardiacs for biological valve treatment.

[0129] The glutaraldehyde-crosslinked porcine pericardium was further washed with deionized water and then immersed in a 4% (v / v) aqueous solution of glycidyl acrylate in isopropanol for double bond modification at room temperature for 48 hours. The solvent used for the double bond modification solution was a 20% (v / v) aqueous solution of methanol.

[0130] After the double bond modification was completed, the double-bonded glutaraldehyde cross-linked porcine pericardium was washed with deionized water; then the double-bonded glutaraldehyde cross-linked porcine pericardium was immersed in a mixture of 20 mM ammonium persulfate and 6.5 mM sodium sulfite to further initiate the polymerization reaction of the double bonds on the double-bonded glutaraldehyde cross-linked porcine pericardium. After reacting at 37°C for 10 hours, the double-bonded cross-linked porcine pericardium was obtained and was designated as sample 7.

[0131] Example 8

[0132] Freshly collected porcine pericardiacs were washed with distilled water for 2 hours under oscillation conditions at 4℃ and 100 RPM, and then soaked in 0.30% (w / w) glutaraldehyde solution at room temperature for 48 hours to obtain glutaraldehyde-crosslinked porcine pericardiacs for biological valve treatment.

[0133] The glutaraldehyde-crosslinked porcine pericardium was further washed with deionized water and then immersed in a 4% (v / v) ethylene glycol aqueous solution of glycidyl methacrylate at room temperature for double bond modification. The reaction time was 72 hours, and the solvent used for the double bond modification solution was a 20% (v / v) ethylene glycol aqueous solution.

[0134] After the double bond modification was completed, the double-bonded glutaraldehyde cross-linked porcine pericardium was washed with deionized water; then the double-bonded glutaraldehyde cross-linked porcine pericardium was immersed in a mixture of 40 mM ammonium persulfate and 15 mM sodium bisulfite to further initiate the polymerization reaction of the double bonds on the double-bonded glutaraldehyde cross-linked porcine pericardium. After reacting at 37°C for 7 hours, the double-bonded cross-linked porcine pericardium was obtained and was recorded as sample 8.

[0135] Example 9

[0136] Freshly collected porcine pericardiacs were washed with distilled water for 2 hours under oscillation conditions at 4℃ and 100 RPM, and then soaked in 0.30% (w / w) glutaraldehyde solution at room temperature for 48 hours to obtain glutaraldehyde-crosslinked porcine pericardiacs for biological valve treatment.

[0137] The glutaraldehyde-crosslinked porcine pericardium was further washed with deionized water and then immersed in a 7% (v / v) propanol aqueous solution of glycidyl acrylate at room temperature for double bond modification. The reaction time was 60 hours, and the solvent used for the double bond modification solution was a 40% (v / v) propanol aqueous solution.

[0138] After the double bond modification was completed, the double-bonded glutaraldehyde cross-linked porcine pericardium was washed with deionized water. Subsequently, the double-bonded glutaraldehyde cross-linked porcine pericardium was immersed in a mixture of 30 mM sodium persulfate and 10 mM sodium bisulfite to further initiate the polymerization reaction of the double bonds on the double-bonded glutaraldehyde cross-linked porcine pericardium. After reacting at 37°C for 8 hours, the double-bonded cross-linked porcine pericardium was obtained and was designated as sample 9.

[0139] Example 10

[0140] Freshly collected porcine pericardiacs were washed with distilled water for 2 hours under oscillation conditions at 4℃ and 100 RPM, and then soaked in 0.30% (w / w) glutaraldehyde solution at room temperature for 48 hours to obtain glutaraldehyde-crosslinked porcine pericardiacs for biological valve treatment.

[0141] After washing with deionized water, glutaraldehyde-crosslinked porcine pericardium was immersed in an aqueous solution of isopropanol containing 6% (v / v) glycidyl methacrylate and 3% (v / v) glycidyl acrylate at room temperature for double bond modification of glutaraldehyde-crosslinked porcine pericardium. The reaction time was 84 hours, and the solvent used for the double bond modification solution was 50% (v / v) aqueous ethanol solution.

[0142] After the double bond modification was completed, the double-bonded glutaraldehyde cross-linked pig heart was washed with deionized water. Then, the double-bonded glutaraldehyde cross-linked pig heart was immersed in a mixture of 40 mM ammonium persulfate and 10 mM sodium sulfite to further initiate the polymerization reaction of the double bonds on the double-bonded glutaraldehyde cross-linked pig heart. After reacting at 37°C for 12 hours, the double-bonded cross-linked pig heart was obtained and was designated as sample 10.

[0143] Performance characterization was performed on samples from Examples 1-10 and Control Group 1:

[0144] To characterize the change in crosslinking degree of glutaraldehyde-crosslinked bioprosthetic valve materials before and after double bond crosslinking treatment, the thermal stability and crosslinking degree of the bioprosthetic valve materials were characterized by measuring the heat shrinkage temperature; the stability of the bioprosthetic valve materials was characterized by enzyme degradation experiments; and the degree of calcification (anti-calcification performance) of the samples was characterized by subcutaneous implantation experiments in rats.

[0145] Heat shrinkage temperature measurement

[0146] Biological valve material was cut into circular sheets with a diameter of 0.6 cm, dried, and placed in a crucible. The material was then heated at a rate of 10 °C / min using a differential scanning calorimeter to measure its heat shrinkage temperature within the range of 40–120 °C. The heat shrinkage temperature was used to characterize the thermal stability and degree of cross-linking of the biological valve material; a higher heat shrinkage temperature corresponds to higher thermal stability and a higher degree of cross-linking.

[0147] Table 1. Thermal shrinkage temperature of each group of samples

[0148] Control group 1 (glutaraldehyde cross-linked porcine pericardium) 84.7 Example 1 88.9 Example 2 89.3 Example 9 91.5 Example 10 92.0

[0149] The heat shrinkage temperature of Examples 1, 2, 9, 10, and Control Group 1 (glutaraldehyde-crosslinked porcine pericardium) was measured. As shown in Table 1, the heat shrinkage temperatures of Examples 1, 2, 9, and 10 were all higher than those of Control Group 1 (glutaraldehyde-crosslinked porcine pericardium). This indicates that the thermal stability and degree of crosslinking of Examples 1, 2, 9, and 10 were all higher than those of Control Group 1 (glutaraldehyde-crosslinked porcine pericardium). The heat shrinkage temperature measurement results demonstrate that the method for preparing bioprosthetic valve materials via double bond post-crosslinking of this application can improve the thermal stability and degree of crosslinking of bioprosthetic valves.

[0150] Enzyme degradation experiment

[0151] Samples 3, 4, 6, 10, and control group 1 were cut into circular sheets with a diameter of 1 cm, with 6 replicates per group. All circular sheet samples were placed in 48-well plates, frozen overnight at -80°C, and then freeze-dried for 48 hours. The initial weight (W0) of each sample was recorded on a 0.0001 g balance and returned to the 48-well plate. 0.5 mL of collagenase I PBS solution was added to each well of the 48-well plate using a pipette, ensuring the bioprosthetic valve sample was completely submerged in the collagenase PBS solution (100 U / mL). The 48-well plate was then incubated at 37°C for 24 hours. After incubation, the solution in the plate was discarded, and the bioprosthetic valve sample was repeatedly rinsed with deionized water using a dropper. After three such rinsing cycles, the plate was frozen overnight at -80°C and then freeze-dried for 48 hours. Weigh each sample on a 1 / 100,000 balance after degradation with collagenase solution, and record the final weight (Wt). The formula for calculating the enzyme degradation weight loss rate is as follows:

[0152]

[0153] The results are shown in Table 2:

[0154] Table 2 Enzyme degradation weight loss rate of each group of samples

[0155] Control group 1 (glutaraldehyde cross-linked porcine pericardium) 7.45±1.33 Sample 3 5.31±0.30 Sample 4 4.47±1.05 Sample 6 5.12±0.97 Sample 10 3.06±0.59

[0156] Enzymatic degradation experiments were conducted on control group 1 (glutaraldehyde-crosslinked porcine pericardium), samples 3, 4, 6, and 10 to characterize the crosslinking efficiency of each group. The enzymatic degradation weight loss rates of control group 1 (glutaraldehyde-crosslinked porcine pericardium), samples 3, 4, 6, and 10 were calculated after treatment with collagenase I, as shown in Table 2. The enzymatic degradation weight loss rates of samples 3, 4, 6, and 10 were all lower than those of the control group (glutaraldehyde-crosslinked porcine pericardium), indicating that the stability of samples 3, 4, 6, and 10 was higher than that of the control group (glutaraldehyde-crosslinked porcine pericardium), meaning that samples 3, 4, 6, and 10 had higher stability. The results of the enzymatic degradation experiments show that the method for preparing bioprosthetic valve materials through double bond post-crosslinking of this application can improve the stability of bioprosthetic valves.

[0157] Anti-calcification test

[0158] The sample bioprosthetic valve material was cut into 0.8 × 0.8 cm pieces. 2 Sterilized tissue samples were implanted subcutaneously into rats and removed 30 days later. Each sample was divided into two parts: one part was decapsulated, freeze-dried, weighed, digested with 6M hydrochloric acid, and the calcium content per gram was determined; the other part was fixed with paraformaldehyde tissue fixative. After fixation, the samples were removed, trimmed and smoothed with a scalpel, and transferred to a dehydration box. The samples were dehydrated using graded ethanol. After dehydration, the samples were transferred to an embedding machine and embedded in molten paraffin, then transferred to a -20°C freezer for cooling and shaping. 5μm thick sections were cut from the trimmed paraffin blocks using a microtome, transferred from a slide to a glass slide, and dewaxed and rehydrated. The sections were stained with alizarin red for 3 minutes, washed with water, dried, and cleared with xylene for 5 minutes. The sections were mounted with neutral resin, and the staining results were imaged using a pathological slide scanner.

[0159] Table 3. Calcium content of rat samples 30 days after subcutaneous implantation.

[0160]

[0161]

[0162] The calcium content of samples 1, 5, and 7, and control group 1 (glutaraldehyde-crosslinked porcine pericardium) implanted subcutaneously in rats for 30 days was measured to characterize the degree of calcification in each group. As shown in Table 3, the calcium content of samples 1, 5, and 7 was lower than that of the control group (glutaraldehyde-crosslinked porcine pericardium) 30 days after subcutaneous implantation in rats. This result indicates that the method of preparing bioprosthetic valve materials by double bond post-crosslinking can improve the anti-calcification performance of bioprosthetic valves.

[0163] Alizarin Red Staining Experiment

[0164] Samples 1, 5, 7, and control group 1 were implanted subcutaneously into rats and removed after 30 days. They were then fixed with paraformaldehyde tissue fixative. After fixation, the samples were trimmed and smoothed with a scalpel before being transferred to a dehydration box. The samples were dehydrated in a gradient using 50%, 75%, 85%, 95% (v / v), and anhydrous ethanol. After dehydration, the samples were transferred to an embedding machine and embedded in molten paraffin, then cooled and shaped at -20°C. 3-5 μm thick sections were cut from the trimmed paraffin blocks using a microtome, transferred to glass slides, and dewaxed and rehydrated. The sections were stained with alizarin red for 3 minutes, washed with water, dried, and cleared with xylene for 5 minutes. The sections were mounted with neutral resin, and the staining results were imaged using a pathological slide scanner.

[0165] Alizarin red staining was used to directly observe the degree of calcification in control group 1 (glutaraldehyde-crosslinked porcine pericardium), sample 1, sample 5, and sample 7 30 days after subcutaneous implantation in rats. Images of alizarin red staining results for sample sections 30 days after subcutaneous implantation in rats are shown below. Figures 3-6 As shown, the darker the color of the sample after alizarin red staining, the higher the degree of calcification. This is compared to the alizarin red staining results of control group 1 (glutaraldehyde-crosslinked porcine pericardium) sections. Figure 3 Sample 1 Figure 4 Sample 5 Figure 5 ), Sample 7 ( Figure 6 The alizarin red staining images of the sections showed a significant decrease in color, directly indicating that the degree of calcification in samples 1, 5, and 7 was lower than that in control group 1, meaning that samples 1, 5, and 7 had a stronger anti-calcification effect compared to control group 1. Alizarin red staining results of the bioprosthetic valve material implanted subcutaneously in rats 30 days later showed that the method for preparing bioprosthetic valve material using double bond post-crosslinking described in this application can improve the anti-calcification performance of bioprosthetic valves.

[0166] Example 11

[0167] Freshly collected porcine pericardiacs were washed with distilled water for 2 hours under oscillation conditions at 4℃ and 100 RPM, and then soaked in 0.30% (w / w) glutaraldehyde solution at room temperature for 48 hours to obtain glutaraldehyde-crosslinked porcine pericardiacs for biological valve treatment.

[0168] Glutaraldehyde-crosslinked porcine pericardium was washed with deionized water and then immersed in a 4% (v / v) aqueous solution of glycidyl methacrylate in ethanol at room temperature for double bond modification. The reaction time was 72 hours, and the solvent used for the double bond modification solution was a 20% (v / v) aqueous solution of ethanol.

[0169] After the double bond modification was completed, ammonium persulfate and sodium bisulfite were added to initiate the polymerization reaction of the double bonds on the pig pericardium crosslinked with double bond glutaraldehyde, wherein the concentration of ammonium persulfate was 20 mM and the concentration of sodium bisulfite was 5 mM. After adding the initiator, the reaction was carried out at 37°C for 8 hours to obtain the pig pericardium with double bond crosslinking.

[0170] The cross-linked porcine pericardium material after double bond copolymerization was immersed in 70% ethanol aqueous solution for 20 min, and then immersed in a drying solution (80% glycerol, 2% water, 18% ethanol) at room temperature for 1.5 h. Excess glycerol was removed from the surface of the porcine pericardium material, and it was sterilized with ethylene oxide and designated as sample 11.

[0171] Example 12

[0172] Fresh porcine pericardium was placed in a PS solution containing 0.5% sodium deoxycholate (surfactant) and shaken at room temperature for 4 hours, then washed three times with a 0.9% sodium chloride aqueous solution (i.e., physiological saline).

[0173] After cleaning, the pig pericardium was washed with distilled water for 2 hours under the condition of 4℃ and 100RPM oscillation. It was then soaked in 0.30% (w / w) glutaraldehyde solution at room temperature for 48 hours to obtain glutaraldehyde cross-linked pig pericardium for biological valve treatment.

[0174] The glutaraldehyde-crosslinked porcine pericardium was further washed with deionized water and then immersed in a 5% (v / v) propanol aqueous solution of glycidyl methacrylate at room temperature for double bond modification. The reaction time was 72 hours, and the solvent used for the double bond modification solution was a 20% (v / v) propanol aqueous solution.

[0175] After the double bond modification was completed, the double-bonded glutaraldehyde cross-linked porcine pericardium was washed with deionized water; then the double-bonded glutaraldehyde cross-linked porcine pericardium was immersed in a mixture of 20 mM potassium persulfate and 10 mM sodium bisulfite to further initiate the polymerization reaction of the double bonds on the double-bonded glutaraldehyde cross-linked porcine pericardium. After reacting at 37°C for 8 hours, the double-bonded cross-linked porcine pericardium was obtained and was designated as sample 12.

[0176] The embodiments described above are merely illustrative of several implementation methods of this application, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the patent application. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this application, and these all fall within the protection scope of this application. Therefore, the protection scope of this patent application should be determined by the appended claims.

Claims

1. A method for preparing biological valve materials by double bond polymerization after aldehyde crosslinking, characterized in that, include: Step S110: The biomaterial is cross-linked by contacting the aldehyde cross-linking agent solution; Step S120: Immerse the biomaterial treated in step S110 in a solution containing a first functional monomer, wherein the first functional monomer has a first carbon-carbon double bond and an ethylene oxide group, and the biomaterial chemically reacts with the ethylene oxide group to attach the first carbon-carbon double bond. In step S200, the first carbon-carbon double bond undergoes a polymerization reaction under the action of an initiator to obtain a biological valve material.

2. The method according to claim 1, characterized in that, The aldehyde crosslinking agent is glutaraldehyde or formaldehyde.

3. The method according to claim 1, characterized in that, The biological material is animal tissue, which is selected from one or more of the following: pericardium, valves, intestinal membrane, meninges, pulmonary membrane, blood vessels, skin, and ligaments.

4. The method according to claim 3, characterized in that, The animal tissue is either fresh animal tissue or biological tissue that has undergone decellularization.

5. The method according to claim 1, characterized in that, In step S200: the initiator is added to the system treated in the previous step; or the biological material treated in the previous step is taken out and directly or after washing is immersed in a solution containing the initiator.

6. The method according to claim 1, characterized in that, The initiator can be a single initiator or a mixture of initiators.

7. The method according to claim 6, characterized in that, The mixed initiator is: A mixture of ammonium persulfate and sodium bisulfite, or a mixture of ammonium persulfate and sodium bisulfite, or a mixture of sodium persulfate and sodium bisulfite, or a mixture of potassium persulfate and sodium bisulfite, or a mixture of potassium persulfate and sodium bisulfite, or a mixture of potassium persulfate and tetramethylethylenediamine, or a mixture of ammonium persulfate and tetramethylethylenediamine, or a mixture of sodium persulfate and tetramethylethylenediamine; wherein the concentration of each component in the mixture is 1~100 mM.

8. The method according to claim 7, characterized in that, The single initiator can be any component of the mixed initiators.

9. The method according to claim 1, characterized in that, In step S200, the polymerization reaction takes 3 to 24 hours.

10. The method according to claim 1, characterized in that, The first functional monomer is selected from at least one of allyl glycidyl ether, glycidyl methacrylate, and glycidyl acrylate.

11. The method according to claim 1, characterized in that, In step S110: The w / w concentration of the aldehyde-based crosslinking agent solution is 0.1%~5%; the crosslinking time is 0.5h-120h.

12. The method according to claim 1, characterized in that, In step S120: The w / w concentration of the first functional monomer in the solution containing the first functional monomer is 1% to 10%; the reaction time is 2 to 120 hours.

13. The method according to claim 1, characterized in that, The solution containing the first functional monomer contains only the first functional monomer and a solvent that does not participate in the chemical reaction.

14. The method according to claim 1, characterized in that, The solvent in the solution containing the first functional monomer is one or more of the following: an aqueous solution of methanol, ethanol, ethylene glycol, propanol, 1,2-propanediol, 1,3-propanediol, isopropanol, butanol, isobutanol, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, glycerol, water, physiological saline, and pH neutral buffer.

15. A biological valve material, characterized in that, It is prepared by the method described in any one of claims 1 to 14.

16. A biological valve material, characterized in that, include: Step S110: The biomaterial is cross-linked by contacting the aldehyde cross-linking agent solution; Step S120: Immerse the biomaterial treated in step S110 in a solution containing a first functional monomer. The first functional monomer has a first carbon-carbon double bond and an ethylene oxide group. The biomaterial reacts chemically with the ethylene oxide group to attach the first carbon-carbon double bond. In step S200, the first carbon-carbon double bond undergoes a polymerization reaction under the action of an initiator to obtain a biological valve material.

17. A biological valve, comprising a scaffold and leaflets, characterized in that, The leaflet is the biological valve material as described in claim 15 or 16.

18. The bioprosthetic valve according to claim 17, characterized in that, The bioprosthetic valve is a heart valve.

19. An interventional system comprising a heart valve and a catheter assembly, wherein the heart valve is delivered via the catheter assembly after folding, characterized in that, The heart valve includes a stent and leaflets, wherein the leaflets are the bioprosthetic valve material as described in claim 15 or 16.

Images