Blood vessel closing device

Abstract

The invention discloses a blood vessel closing device which comprises an anchoring piece located in a blood vessel inner cavity, a fixing piece located outside a blood vessel wall and a connecting piece penetrating through the blood vessel wall to pull the anchoring piece and the fixing piece to be close to each other to close an opening of the blood vessel wall in the using state. The anchoring piece comprises a base body and a coating which is attached to the surface of the base body and used for making direct contact with the blood vessel wall, the base body is made of an acellular matrix, and the coating is made of collagen or gelatin. According to the blood vessel closing device, the anchoring piece and the blood vessel wall have good attaching sealing performance, meanwhile, bleeding can be stopped instantly, degradation is achieved in a slow enzymolysis mode, and the use safety is better.

Description

Technical Field

[0001] The present application relates to the technical field of medical devices, and particularly to a vascular closure device. Background Art

[0002] In the prior art, a vascular closure device is used to close an opened blood vessel wall. Commonly used vascular closure devices usually adopt a "sandwich" structure. For example, products such as Angio-seal and MANTA have a structure including an anchor located in the blood vessel lumen and fitting against the inner wall of the blood vessel, and a collagen sponge located outside the blood vessel wall and fitting against the outer wall of the blood vessel. The anchor and the collagen sponge are connected by a connecting member.

[0003] The anchor is usually prepared from a biodegradable polymer material, such as materials like polylactic acid (PLA). The degradation mechanism of such materials is hydrolysis, and the degradation process is uneven, and it is easy to generate hydrolysis products such as flakes, blocks, and granules due to disintegration or cracking. If these enter the blood circulation system, they will cause harm to the human body. At the same time, the acidic substances generated during the degradation of materials such as polylactic acid will cause local inflammation and affect the healing of the blood vessel wall. Summary of the Invention

[0004] Based on this, a vascular closure device is provided, which has good fitting and sealing performance between the anchor and the blood vessel wall, can stop bleeding immediately, degrades by a slow enzymatic hydrolysis method, and has better use safety.

[0005] A vascular closure device includes, in the use state, an anchor located in the blood vessel lumen, a fixing member located outside the blood vessel wall, and a connecting member that penetrates the blood vessel wall to pull the anchor and the fixing member closer to each other to close the opening of the blood vessel wall. The anchor includes a matrix and a coating attached to the surface of the matrix for direct contact with the blood vessel wall. The matrix is made of acellular matrix, and the material of the coating is collagen or gelatin.

[0006] The following also provides several optional ways, which are not additional limitations to the above overall solution, but are only further supplements or optimizations. Without technical or logical contradictions, each optional way can be combined with the above overall solution alone, or multiple optional ways can be combined with each other.

[0007] Optionally, the acellular matrix is obtained by performing acellular treatment on at least one of dermis, pericardium, peritoneum, and small intestinal mucosa as raw materials.

[0008] Optionally, after the pore adjustment of the acellular matrix, a coating is prepared on the acellular matrix.

[0009] Optionally, the pore adjustment method adopts at least one of vacuum freeze-drying, air-drying, and drying, the porosity of the acellular matrix is 10-99%, and the pore diameter of the acellular matrix is 10-500 μm.

[0010] Optionally, the thickness of the substrate is 0.1 mm - 2 mm, and the thickness of the coating is 10 μm - 1000 μm.

[0011] Optionally, the method for preparing the coating includes: dissolving the coating material in an acid to obtain a coating dispersion, spraying or dip-coating the coating dispersion on the surface of the acellular matrix, at least a part of the coating dispersion penetrates into the pore structure, and after drying, the coating is formed.

[0012] Optionally, the concentration of the coating material in the coating dispersion is 0.1 - 100 mg / mL.

[0013] Optionally, the coating includes a plurality of sub-coatings arranged in the thickness direction, and the crosslinking degree of each sub-coating decreases as the distance from the acellular matrix increases.

[0014] Optionally, each sub-coating of the coating is crosslinked with an aldehyde substance or a carbodiimide substance.

[0015] Optionally, at least two sprayings or dip-coatings of the coating dispersion are sequentially performed on the surface of the substrate. After each spraying or dip-coating of the coating dispersion is dried, after at least one spraying or dip-coating of the coating dispersion is dried, an aqueous solution of an aldehyde substance with a mass fraction of 0.001% - 10% or an aqueous solution of a carbodiimide substance with a mass fraction of 0.001% - 10% is sprayed for crosslinking.

[0016] For the vascular closure device provided in this application, the anchor uses an acellular matrix as the substrate, a coating is prepared on the acellular matrix, and the coating is gradient-crosslinked, so that the part with a lower crosslinking degree of the coating has good fitting and sealing with the blood vessel and plays a role in stopping bleeding in a timely manner. The part with a higher crosslinking degree of the coating forms a structure with a stronger binding force with the acellular matrix to maintain the binding strength between the two. The acellular matrix degrades by a slow enzymatic hydrolysis method, and the safety in use is better. Description of the Drawings

[0017] Figure 1 is a schematic diagram of the vascular closure device of this application;

[0018] Figure 2 is Figure 1 the enlarged view of part A in

[0019] Figure 3 is Figure 2 the enlarged view of part B in

[0020] Figure 4a Fluorescence image of a tissue section before decellularization treatment;

[0021] Figure 4b Fluorescence image of a tissue section after decellularization treatment;

[0022] Figure 5 Scanning electron microscope photograph of the decellularized matrix after lyophilization treatment in Example 1;

[0023] Figure 6 Staining photograph of the anchor prepared in Example 1 after degradation in vivo. Detailed implementation manners

[0024] Next, the technical solutions in the embodiments of the present application will be clearly and completely described in conjunction with the accompanying drawings in the embodiments of the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present application.

[0025] For better description and illustration of the embodiments of the present application, one or more accompanying drawings can be referred to, but the additional details or examples used to describe the drawings should not be considered as limiting the scope of any one of the invention creations, the currently described embodiments, or the preferred modes of the present application.

[0026] It should be noted that when a component is referred to as being "connected" to another component, it can be directly connected to the other component or there may also be an intermediate component. When a component is considered to be "disposed on" another component, it can be directly disposed on the other component or there may be an intermediate component at the same time.

[0027] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the technical field to which this application belongs. The terms used in the specification of this application herein are only for the purpose of describing specific embodiments and are not intended to limit this application.

[0028] See Figure 1 、 Figure 2 As shown, a vascular closure device includes, in the use state, an anchor 1 located in the vascular lumen, a fixing member 2 located outside the vascular wall, and a connecting member 3 passing through the vascular wall to pull the anchor 1 and the fixing member 2 closer to each other to close the opening of the vascular wall. The anchor 1 includes a matrix 11 and a coating 12 attached to the surface of the matrix for direct contact with the vascular wall. The matrix 11 is made of a decellularized matrix, and the material of the coating is collagen or gelatin.

[0029] In this application, the matrix of the anchor is made of acellular matrix, and the degradation mechanism of the acellular matrix is enzymatic hydrolysis. Collagenase is a protease that exists in the human body itself. When it contacts specific sites on the collagen peptide chain with a triple helix structure, it cuts the peptide chain. When a large number of peptide chains are cut, the peptide chains will fall off from the fibers, forming a degradation process. When the body's own collagenase adsorbs on the porous acellular matrix and penetrates layer by layer inward, it will gradually degrade collagen layer by layer, ultimately achieving controllable enzymatic hydrolysis rather than bursting or disintegrating hydrolysis.

[0030] Since the acellular matrix has a uniform and controllable degradation rate and will not produce large-sized substances that are free in the blood vessels due to disintegration or lysis, and at the same time, the acellular matrix is rich in collagen and has the functions of promoting blood coagulation and tissue repair, which can further accelerate the healing of the blood vessel wall wound.

[0031] In the prior art, the polylactic acid material used is relatively hard and cannot fit well with the inner wall of the blood vessel. In this application, the acellular matrix needs to have appropriate mechanical properties, be soft enough to adhere to the inner wall of the blood vessel, and not be too soft to provide effective support.

[0032] The surface of the anchor is provided with a coating. The coating is in direct contact with the blood vessel wall in the use state. The coating has better adhesion to the blood vessel wall and can play an immediate hemostasis role. The material of the coating is collagen or gelatin. In particular, when collagen is used as the coating, although the acellular matrix itself contains collagen, its structure is a large molecular weight collagen fiber bundle, and its immediate hemostasis effect is not as good as that of small molecular weight collagen. Therefore, a collagen coating is added to the surface layer of the acellular matrix. In the use state, the collagen coating is in direct contact with the blood vessel wall. The collagen coating enhances the immediate hemostasis effect and can also improve the adhesion and sealing performance between the acellular matrix and the blood vessel wall, that is, the collagen coating can adhere to the inner wall of the blood vessel, making the sealing performance between the anchor and the blood vessel wall better.

[0033] In this application, the acellular matrix is obtained by performing acellular treatment on at least one of the dermis, pericardium, peritoneum, and small intestinal mucosa as raw materials. The tensile strength of the acellular matrix is 10 - 50 MPa, and the elastic modulus is 50 - 150 MPa. Further preferably, the tensile strength of the acellular matrix is 20 - 40 MPa, and the elastic modulus is 80 - 120 MPa.

[0034] The following takes the dermis as the raw material as an example to elaborate on the acellular operation in detail, and the acellular treatment of the other materials refers to this operation.

[0035] The acellular matrix is obtained by performing acellular treatment on the dermis as the raw material. The dermis raw material can be directly purchased. The dermis can be the dermis of pigskin or cowhide. The acellular treatment can be carried out by the following method:

[0036] First, remove the fat and irrelevant tissues on the dermis layer mechanically and wash it clean with water. Then, wash it in pure water at room temperature for 2 hours. After decanting the water, place the dermis layer in 3% (volume fraction) TRITONX-100TM and incubate it at room temperature for 7 hours. Decant the TRITONX-100TM solution and then incubate the dermis layer in the DNA enzyme solution for 18 hours. The amount of DNA enzyme used is 8 active units / cm 2 membrane. Then, incubate it three times with anhydrous isopropanol at room temperature (the incubation times are 3, 18, and 24 hours respectively) to degrease the dermis layer extracted by the detergent and enzyme.

[0037] Then, extract the degreased dermis layer in an acid solution containing Na2SO4 at room temperature for 6 hours. The acid solution contains 0.5M Na2SO4 and 0.5M HCl. Then, neutralize the acid solution to a pH of about 7 with 3M NaOH. Further extract the dermis layer in the neutralized salt solution for 18 hours and decant the solution. Subsequently, extract the acid-extracted dermis layer in an alkaline solution containing Na2SO4 at room temperature for 6 hours. The alkaline solution contains 1.2M Na2SO4 and 1M NaOH. Neutralize the alkaline solution to a pH of about 7 with 3M HCl. Further extract the dermis layer in the neutralized salt solution for 18 hours and decant the solution.

[0038] Finally, after the salt solution extraction, wash the dermis layer 4 times with purified water to remove the residual salts associated with the purified dermis layer. Freeze-dry the purified dermis layer and store it for later use.

[0039] In the above process, during the isopropanol extraction, the amount of isopropanol used is 2.7 mL of isopropanol per square centimeter of the dermis layer. Except for the isopropanol extraction, the amount of the other extraction solutions used is 3.0 mL of the extraction solution per square centimeter of the dermis layer.

[0040] After decellularization treatment, fluorescence staining is usually used to qualitatively characterize the residual cells. DAPI is a fluorescent dye that can penetrate the cell membrane and bind to the double-stranded DNA in the nucleus to play a labeling role and can produce blue fluorescence more than 20 times stronger than DAPI itself. See the fluorescence image of the tissue section before decellularization treatment in Figure 4a as shown. See the fluorescence image of the tissue section after decellularization treatment in Figure 4b as shown. Figure 4a The blue fluorescence in Figure 4b is the fluorescence produced by the binding of DAPI to the DNA in the nucleus, indicating the presence of a large number of cells;

[0041] See Figure 2As shown, the anchor 1 includes a matrix 11 and a coating 12 attached to the surface of the matrix. The thickness of the matrix is 0.1 mm to 2 mm, and the thickness of the coating is 10 μm to 1000 μm. Further preferably, the thickness of the matrix is 0.3 mm to 2 mm, and the thickness of the coating is 100 μm to 1000 μm.

[0042] The acellular matrix has appropriate flexibility and can adhere to the inner wall of the blood vessel. At the same time, it can also provide appropriate support force and cooperate with the fixing part to achieve the closure of the opening of the blood vessel wall. The thickness of the coating should not be too thick to prevent excessive occupation of the thickness of the acellular matrix and inability to provide effective support.

[0043] There needs to be sufficient bonding strength between the acellular matrix and the coating to prevent peeling between the acellular matrix and the coating. In order to make the coating have a stronger bonding force with the cell matrix, in this application, after the acellular matrix is adjusted for porosity, a coating is prepared on the acellular matrix.

[0044] The porosity adjustment method adopts at least one of vacuum freeze-drying, air-drying, and drying. The porosity of the acellular matrix is 10 - 99%, and the pore diameter of the acellular matrix is 10 - 500 μm. Further preferably, the porosity of the acellular matrix is 30 - 99%, and the pore diameter of the acellular matrix is 10 - 300 μm. Further preferably, the porosity of the acellular matrix is 60 - 95%, and the pore diameter of the acellular matrix is 100 - 300 μm.

[0045] The steps of vacuum freeze-drying include the following steps carried out in sequence:

[0046] Pre-freeze to -40°C to -50°C and keep warm for 1 - 2 hours;

[0047] Heat up to -10°C to -20°C and keep warm for 5 - 7 hours;

[0048] Heat up to -5°C to -4°C and keep warm for 1.5 - 2.5 hours;

[0049] Heat up to 20°C to 30°C and keep warm for 3.5 - 4.5 hours.

[0050] During the vacuum freeze-drying process, the pre-freezing rate affects the pore diameter. The faster the freezing speed, the higher the porosity. During the heating process, the residence time at different temperatures affects the pore structure.

[0051] The preparation method of the coating includes: dissolving the coating material in an acid to obtain a coating dispersion liquid, spraying or dip-coating the coating dispersion liquid on the surface of the acellular matrix, at least a part of the coating dispersion liquid penetrates into the pore structure, and after drying, the coating is formed.

[0052] The collagen concentration in the coating dispersion is 0.1 - 100 mg / mL. More preferably, the collagen concentration in the coating dispersion is 0.1 - 10 mg / mL. Even more preferably, the collagen concentration in the coating dispersion is 0.1 - 5 mg / mL.

[0053] The material of the coating is soluble in an acid with a pH of 2 - 4, and hydrochloric acid or sulfuric acid can be used.

[0054] The following takes collagen as the coating material to elaborate on the coating preparation operation in detail, and the coating preparation of other materials refers to this operation.

[0055] The coating is a collagen coating, and the preparation method of the collagen coating includes: dissolving the collagen lyophilized powder in an acid to obtain a collagen dispersion, spraying or dip-coating the collagen dispersion on the surface of the acellular matrix, at least a part of the collagen dispersion penetrates into the pore structure, and a collagen coating is formed after drying.

[0056] The collagen lyophilized powder uses fibrous collagen with relatively high strength. In the collagen lyophilized powder, the water content ≤ 12% w / w, the hydroxyproline content ≥ 10%, the fat content < 1%, and the nitrogen content ≥ 15%. For example, the fibrous collagen uses type I bovine collagen powder, which is extracted from bovine flexor tendons using acid and alkali, and is obtained as a white or off-white powder through freezing, freeze-drying, and grinding.

[0057] The collagen lyophilized powder is dissolved in an acid with a pH of 2 - 4, and hydrochloric acid or sulfuric acid can be used.

[0058] The collagen concentration in the collagen dispersion is 0.1 - 100 mg / mL. More preferably, the collagen concentration in the collagen dispersion is 0.1 - 10 mg / mL. Even more preferably, the collagen concentration in the collagen dispersion is 0.1 - 5 mg / mL.

[0059] The collagen coating can be formed by dip-coating or spraying. When using the dip-coating method, the acellular matrix is placed in the collagen dispersion for 10 - 60 s, taken out and air-dried, and repeated several times to obtain the desired coating thickness. When using the spraying method, the collagen dispersion is sprayed on the surface of the acellular matrix for 10 - 60 s, and then air-dried, and repeated several times to obtain the desired coating thickness.

[0060] See Figure 3 As shown, the coating includes multiple sub-coatings arranged in the thickness direction, and the crosslinking degree of each sub-coating decreases as the distance from the sub-coating to the acellular matrix increases.

[0061] For example, there are two sub-coatings, namely sub-coating 121 and sub-coating 122, and the crosslinking degree of sub-coating 122 is less than that of sub-coating 121.

[0062] The coating with a lower degree of crosslinking is in direct contact with the blood vessel wall, which can provide sufficient flexibility and a fitting seal with the blood vessel wall. At the same time, when the blood vessel wall tissue is repaired, the coating with a lower degree of crosslinking degrades, providing space for tissue growth.

[0063] Each sub-coating of the coating is crosslinked with an aldehyde substance or a carbodiimide substance. The aldehyde substance can be substances such as formaldehyde, glyoxal, glutaraldehyde, etc.; the carbodiimide substance can be EDC / NHS [N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) / N-hydroxysuccinimide (NHS)], and formaldehyde is preferably used.

[0064] The sub-coatings have different degrees of crosslinking, which can be achieved in the following ways:

[0065] At least two sprayings or dip coatings of the coating dispersion liquid are sequentially carried out on the substrate surface. After at least one spraying or dip coating of the coating dispersion liquid is dried, an aqueous solution of an aldehyde substance with a mass fraction of 0.001% - 10% or an aqueous solution of a carbodiimide substance with a mass fraction of 0.001% - 10% is sprayed for crosslinking.

[0066] Crosslinking can be carried out after each spraying or dip coating of the coating dispersion liquid is dried, or several times can be selected for crosslinking. Crosslinking is carried out after each spraying or dip coating of the coating dispersion liquid is dried, that is, after each layer of the coating dispersion liquid is dried, an aldehyde or carbodiimide substance is used for crosslinking, and finally a structure with a higher degree of crosslinking is formed closer to the substrate surface due to more crosslinking times.

[0067] Preferably, the mass fraction of the aqueous solution of the aldehyde substance or the carbodiimide substance is 0.001% - 1%. Further preferably, the mass fraction of the aqueous solution of the aldehyde substance or the carbodiimide substance is 0.01% - 1%.

[0068] After each crosslinking is completed, the collagen coating can be washed as needed. After removing the residual aldehyde or carbodiimide substance, the next spraying or dip coating of the coating dispersion liquid is carried out.

[0069] Although for the convenience of expression, the collagen coating is divided into several sub-coatings, there is no clear interface distinction between two adjacent sub-coatings. When preparing the collagen coating, after the next coating dispersion liquid is sprayed or dip-coated, it will also partially immerse into the sub-coating formed by the previous coating dispersion liquid. Similarly, when the next aqueous solution of the aldehyde or carbodiimide substance is sprayed, it will also partially immerse into the sub-coating formed by the previous coating dispersion liquid. The formed collagen coating is an integral coating structure, and its degree of crosslinking will form a gradient change.

[0070] The thickness of the collagen coating is small, and the thickness of each sub-coating is also thin. The aqueous solutions of aldehydes or carbodiimides sprayed subsequently will affect the cross-linking of several previous sub-coatings, resulting in a gradient difference in the cross-linking degree of the collagen coating as a whole.

[0071] During the preparation of the collagen coating, part of the coating dispersion enters the pore structure of the acellular matrix. And the acellular matrix in this bonded part has the highest cross-linking degree with the collagen coating. A microscopic interlocking structure is formed between the acellular matrix and the collagen coating, improving the bonding strength between the acellular matrix and the collagen coating. The surface collagen coating has a low cross-linking degree or is not cross-linked, with better flexibility, and can better fit the inner wall of the blood vessel, improving the sealing and hemostasis effects.

[0072] Uncross-linked collagen usually degrades completely within 2 - 4 weeks. This part of the collagen is in direct contact with the blood vessel wall, which can provide sufficient flexibility and the fitting tightness with the blood vessel wall. At the same time, when the blood vessel wall tissue repairs, the collagen coating with a lower cross-linking degree degrades, providing space for tissue growth. The acellular matrix usually degrades within 3 - 6 months. The acellular matrix degrades relatively fast in the first 0.5 - 1 month, and is stable in the middle 1 - 4 months, matching the healing speed of the blood vessel wall. The cross-linked collagen can be adjusted to degrade within 1 - 6 months.

[0073] Example 1

[0074] The preparation method of the anchor of the blood vessel closure device includes:

[0075] (1) Perform acellular treatment on bovine pericardium to obtain an acellular matrix, and the thickness of the acellular matrix is 0.5 mm;

[0076] (2) Perform vacuum freeze-drying treatment on the acellular matrix. The steps of the vacuum freeze-drying treatment include: pre-freezing to -40°C and keeping warm for 1 hour; heating to -10°C and keeping warm for 5 hours; heating to -5°C and keeping warm for 1.5 hours; heating to 20°C and keeping warm for 3.5 hours.

[0077] Figure 5 For the pore structure of the acellular matrix after vacuum freeze-drying treatment, as Figure 5 can be seen, the pore size is less than 50 μm and is evenly distributed.

[0078] (3) At room temperature, dissolve the fibrous collagen lyophilized powder in hydrochloric acid with a pH of 2 to obtain a coating dispersion, and the concentration of the coating dispersion is 0.5 mg / mL;

[0079] (4) At room temperature, soak the acellular matrix in the coating dispersion for 30 s, take it out and air-dry it, spray an aqueous solution of glutaraldehyde with a mass fraction of 0.1% for cross-linking. After the cross-linking is completed, wash to remove the residual glutaraldehyde;

[0080] (5) Step (4) is repeated 3 times to obtain a collagen coating with a thickness of 50 μm;

[0081] (6) Trim the shape to obtain the anchor.

[0082] Test the degradation status of the anchor of this embodiment in vivo. See the tissue stained sections in Figure 6 as shown in Figure 6 The red area with larger unit structures in the lower middle is the tissue itself. The blue area above it is the residual substance after the degradation of the anchor. The dark red dots represent newly grown tissue cells. The new tissue cells have good biocompatibility with the anchor. As the anchor gradually degrades and is absorbed, new tissue gradually grows and occupies the area of the anchor, realizing the repair of the tissue.

[0083] Example 2

[0084] The preparation method of the anchor of the vascular closure device includes:

[0085] (1) Decellularize the dermis of porcine skin to obtain a decellularized matrix with a thickness of 1.0 mm;

[0086] (2) Perform vacuum freeze-drying treatment on the decellularized matrix. The steps of the vacuum freeze-drying treatment include: pre-freezing to -40 °C and holding for 1 hour; raising the temperature to -10 °C and holding for 5 hours; raising the temperature to -5 °C and holding for 1.5 hours; raising the temperature to 20 °C and holding for 3.5 hours.

[0087] (3) At room temperature, dissolve the gelatin freeze-dried powder in hydrochloric acid with a pH of 2 to obtain a coating dispersion with a concentration of 0.5 mg / mL;

[0088] (4) At room temperature, fix the decellularized matrix on a scaffold, spray the coating dispersion on the decellularized matrix for 30 s, air-dry it, spray a 0.1% aqueous formaldehyde solution for cross-linking, and after the cross-linking is completed, wash to remove the residual formaldehyde;

[0089] (5) Step (4) is repeated 10 times to obtain a gelatin coating with a thickness of 100 μm;

[0090] (6) Trim the shape to obtain the anchor.

[0091] Example 3

[0092] The preparation method of the anchor of the vascular closure device includes:

[0093] (1) Decellularize the dermis of porcine skin to obtain a decellularized matrix with a thickness of 1.0 mm;

[0094] (2) Perform vacuum freeze-drying treatment on the acellular matrix. The steps of the vacuum freeze-drying treatment include successively: pre-freezing to -50°C and holding for 2 hours; heating to -20°C and holding for 7 hours; heating to -4°C and holding for 2.5 hours; heating to 30°C and holding for 3.5 - 4.5 hours.

[0095] (3) At room temperature, dissolve collagen in hydrochloric acid with a pH of 2 to obtain a coating dispersion. The concentration of the coating dispersion is 0.5 mg / mL.

[0096] (4) At room temperature, immerse the acellular matrix in the coating dispersion for 30 s, take it out and air-dry it, then spray an EDC / NHS solution (using MES buffer as the solvent) for cross-linking. The EDC / NHS solution contains 1 mg / mL EDC and 0.5 mg / mL NHS. After the cross-linking is completed, wash to remove the remaining EDC and NHS.

[0097] (5) Repeat step (4) three times to obtain a collagen coating with a thickness of 50 μm.

[0098] (6) Trim the shape to obtain the anchor.

[0099] Example 4

[0100] A method for preparing an anchor of a vascular closure device includes:

[0101] (1) Perform acellular treatment on the dermis layer of cowhide to obtain an acellular matrix. The thickness of the acellular matrix is 1.5 mm.

[0102] (2) Perform vacuum freeze-drying treatment on the acellular matrix. The steps of the vacuum freeze-drying treatment include successively: pre-freezing to -50°C and holding for 2 hours; heating to -20°C and holding for 7 hours; heating to -4°C and holding for 2.5 hours; heating to 30°C and holding for 3.5 - 4.5 hours.

[0103] (3) At room temperature, dissolve gelatin in hydrochloric acid with a pH of 2 to obtain a coating dispersion. The concentration of the coating dispersion is 0.5 mg / mL.

[0104] (4) At room temperature, fix the acellular matrix on a scaffold, spray the coating dispersion on the acellular matrix for 30 s, air-dry it, then spray an EDC / NHS solution (using MES buffer as the solvent) for cross-linking. The EDC / NHS solution contains 1 mg / mL EDC and 0.5 mg / mL NHS. After the cross-linking is completed, wash to remove the remaining EDC and NHS.

[0105] (5) Repeat step (4) ten times to obtain a gelatin coating with a thickness of 100 μm.

[0106] (6) Trim the shape to obtain the anchor.

[0107] The technical features of the above-described embodiments can be combined arbitrarily. For the sake of brevity of description, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, it should be considered as falling within the scope described in this specification.

[0108] The above-described embodiments merely represent several implementation manners of the present application. The description thereof is relatively specific and detailed, but it should not be construed as a limitation on the scope of the invention patent. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present application, several modifications and improvements can still be made, and these all belong to the protection scope of the present application. Therefore, the protection scope of the patent of the present application shall be subject to the appended claims.

Claims

1. A vascular closure device, comprising, in a use state, an anchor located in the lumen of a blood vessel, a fixing member located outside the blood vessel wall, and a connecting member passing through the blood vessel wall to pull the anchor and the fixing member closer to each other to close an opening in the blood vessel wall, characterized in that, The anchor includes a matrix and a coating attached to the surface of the matrix for direct contact with the blood vessel wall. The matrix is made of decellularized matrix, and the material of the coating is collagen or gelatin.

2. The vascular closure device according to claim 1, wherein The decellularized matrix is obtained by subjecting at least one of dermis, pericardium, peritoneum, and small intestinal mucosa to decellularization treatment.

3. The vascular closure device according to claim 1, characterized in that, After the pore adjustment of the decellularized matrix, a coating is prepared on the decellularized matrix.

4. The vascular closure device according to claim 1, characterized in that, The pore adjustment method adopts at least one of vacuum freeze-drying, air-drying, and drying. The porosity of the decellularized matrix is 10-99%, and the pore diameter of the decellularized matrix is 10-500 μm.

5. The vascular closure device according to claim 1, characterized in that, The thickness of the matrix is 0.1 mm to 2 mm, and the thickness of the coating is 10 μm to 1000 μm.

6. The vascular closure device according to claim 1, wherein The preparation method of the coating includes: dissolving the material of the coating in an acid to obtain a coating dispersion liquid, spraying or dip-coating the coating dispersion liquid on the surface of the decellularized matrix, at least a part of the coating dispersion liquid penetrates into the pore structure, and the coating is formed after drying.

7. The vascular closure device according to claim 6, characterized in that, The concentration of the coating material in the coating dispersion liquid is 0.1-100 mg / mL.

8. The vascular closure device according to claim 7, wherein, The coating includes a plurality of sub-coatings arranged in the thickness direction, and the crosslinking degree of each sub-coating decreases as the distance from the decellularized matrix increases.

9. The vascular closure device according to claim 8, wherein Each sub-coating of the coating is crosslinked with an aldehyde substance or a carbodiimide substance.

10. The vascular closure device according to claim 8, wherein, At least two sprayings or dip-coatings of the coating dispersion liquid are sequentially performed on the surface of the matrix. After at least one spraying or dip-coating of the coating dispersion liquid is dried, an aqueous solution of an aldehyde substance with a mass fraction of 0.001%-10% or an aqueous solution of a carbodiimide substance with a mass fraction of 0.001%-10% is sprayed for crosslinking.

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