Limiting expandable aortic valve conduit and preparation thereof

Abstract

The limiting expandable aortic valve pipeline comprises an aortic valve preliminary pipeline attached with a collagen fiber coating, and the aortic valve preliminary pipeline comprises a proximal pipeline, a valve connecting pipe and a telecentric pipeline. The invention also discloses a preparation method thereof. The limiting expandable aortic valve pipeline provided by the invention is used for replacing an aortic artificial blood vessel and a Bentall type operation of an aortic valve, and after the artificial bioprosthetic valve declines, the limiting expandable aortic valve pipeline provided by the invention provides a condition for embedding the artificial bioprosthetic valve with the same size as an original valve in an interventional manner, so that the limiting expandable aortic valve pipeline can be used for replacing the Bentall type operation of the aortic valve and the artificial bioprosthetic valve. In this way, after the bioprosthetic valve declines, the valve with the same size as the original valve can be placed in an interventional mode, and the patient does not need to open the chest to replace the bioprosthetic valve with the same size.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedical materials, and particularly relates to a limited-expandable aortic valve conduit and its preparation. Background Art

[0002] Surgeries for replacing the aortic artificial blood vessel and aortic valve include Bentall surgery, Mini-Bentall surgery, Cabrol surgery, Wheat’s surgery, David surgery, Ross surgery, etc. Among them, Bentall surgery was first reported by cardiac surgeons named Bentall and DeBoNo in 1968, so it is called "Bentall surgery". Cabrol surgery is a modified surgical procedure based on Bentall surgery. Wheat’s surgery is an aortic valve and ascending aorta replacement surgery that retains the aortic sinus. This surgical procedure was designed and completed by Wheat et al. in 1964. For Bentall-type surgeries for replacing the aortic artificial blood vessel and aortic valve:

[0003] The heart valves used in the aortic valve conduit are divided into mechanical valves and biological valves. Mechanical valves are artificial valves made of non-metallic materials and metallic materials. Biological valves refer to artificial heart valves made of materials from other animals (such as bovine pericardium and porcine pericardium) after processing. Mechanical valves have good durability, but patients need lifelong anticoagulant therapy. The patients undergoing Bentall-type surgeries are relatively young. The 2020 American Heart Association / American College of Cardiology Guidelines for the Management of Valvular Heart Disease recommend that patients over 50 years old can consider using aortic biological valves (Class IIa recommendation). However, biological valve deterioration (such as calcification) will occur 10 - 15 years after biological valve replacement, resulting in problems such as aortic valve stenosis or aortic valve insufficiency, and valve replacement needs to be performed again.

[0004] The existing aortic valve conduits have the following problems: (1) The suture margin of the artificial heart valve is connected to the left ventricular outflow tract. After biological valve deterioration, when replacing the valve again, thoracotomy is required for valve replacement, or only an artificial heart valve smaller than the previous size can be intervened through an interventional method; (2) Most of the materials of the conduit are polyester, and the conduit is coated with a coating that plays a role in preventing bleeding, leakage, and increasing the speed of endothelialization. This coating cannot adapt to the high pulsatile pressure of the aorta (especially the aortic root), is easy to fall off, and the effects of preventing bleeding and leakage need to be further improved; (3) Poor biocompatibility and slow endothelialization speed. Failure to rapidly endothelialize will cause hemolysis or generate thrombus and local long-term calcification; (4) The thickness of the conduit is relatively large (>0.5 mm), resulting in insufficient surgical operability and compliance, and poor mechanical properties. Summary of the Invention

[0005] The limited-expandable aortic valve conduit provided by the present invention is used for replacing the aortic artificial blood vessel and the Bentall-type surgery of the aortic valve (which may include classic Bentall surgery, modified Bentall surgery, Mini-Bentall surgery, Cabrol surgery, Wheat’s surgery, David surgery, Ross surgery, etc.). Moreover, after the artificial biological valve in the limited-expandable aortic valve conduit deteriorates, the limited-expandable aortic valve conduit provided by the present invention provides conditions for implanting an artificial biological valve of the same size as the original valve in an interventional manner, without the need to perform thoracotomy on the patient to replace the artificial biological valve, greatly reducing the damage to the patient, and is particularly suitable for patients who do not have the conditions for thoracotomy to perform secondary valve replacement treatment.

[0006] The limited-expandable aortic valve conduit provided by the present invention is prepared from a preliminary aortic valve conduit coated with a collagen fiber coating. In the process of completing the present invention, the inventor first optimized the preparation method of the collagen fiber coating, and then coated the preliminary aortic valve conduit with the optimized preparation method to obtain a preliminary aortic valve conduit with a collagen fiber coating attached thereto, and then prepared a limited-expandable aortic valve conduit that can withstand high pulsatile pressure, has sutures that are not easily detached, has good anti-bleeding effect, fast endothelialization speed, stable coating, anti-degradation, good biocompatibility, excellent mechanical properties, and good compliance.

[0007] The preliminary aortic valve conduit with a collagen fiber coating attached thereto is obtained through two chemical cross-linking steps, including the first chemical cross-linking and the second chemical cross-linking. The first chemical cross-linking is to cross-link collagen molecules or collagen fibers to obtain collagen fibers cross-linked in the first step. The second cross-linking is to attach the collagen fibers cross-linked in the first step to the internal voids of the preliminary aortic valve conduit and the inner and outer surfaces of the preliminary aortic valve conduit, and cross-link to form a collagen fiber coating.

[0008] During the research process, the inventor unexpectedly found that the melting point of the collagen fiber coating and the melting point of the collagen fibers cross-linked in the first step need to satisfy a certain difference relationship. By optimizing and adjusting the difference in the change of the collagen melting point, a preliminary aortic valve conduit with a stable coating and good anti-bleeding effect can be obtained.

[0009] In addition, the inventor unexpectedly found that by controlling the suture method, the maximum circumferential tensile elongation, elastic deformation rate, maximum tensile force, the value of the elastic deformation rate accounting for the maximum circumferential tensile elongation, and the ratio of the corrugation width to the corrugation height, the bleeding conditions at the connection between the proximal conduit and the left ventricular outflow tract, the connection between the proximal conduit and the valve connecting tube, and the connection between the valve connecting tube and the distal conduit can be effectively controlled.

[0010] As an aspect of the present invention, it relates to a limited-expandable aortic valve conduit, which includes a preliminary aortic valve conduit attached with a collagen fiber coating. The preliminary aortic valve conduit includes a proximal conduit, a valve connecting tube, and a distal conduit;

[0011] The collagen fiber coating is formed by chemically cross-linking collagen fibers with a melting point of 68.54 - 71.24 °C that are attached to the internal voids and surfaces of the preliminary aortic valve conduit. The melting point of the collagen fiber coating is 77.59 - 79.84 °C, and the difference range between the melting point of the collagen fiber coating and the melting point of the collagen fibers cross-linked for the first time is 7.39 - 11.30 °C.

[0012] Preferably, in the natural state of the preliminary aortic valve conduit, the axial length of the proximal conduit is not less than 5 mm and axially includes at least 2 corrugations; the axial length of the valve connecting tube is 23 - 29 mm and circumferentially includes 24 - 36 corrugations; the axial length of the distal conduit is not less than 70 mm and axially includes at least 30 corrugations.

[0013] Preferably, the proximal conduit, the valve connecting tube, and the distal conduit are made of polyester corrugated pipes of the same specification, and the ratio of the corrugation width to the corrugation height of the polyester corrugated pipe is 1.24 - 1.36.

[0014] Preferably, the maximum circumferential tensile elongation rate range of the limited-expandable aortic valve conduit is 2.2 - 4.8%, the elastic deformation rate range is 1.0 - 2.3%, the value range of the elastic deformation rate accounting for the maximum circumferential tensile elongation rate is 38 - 68%, and the maximum pulling force range is 13.5 - 55.9 N.

[0015] Preferably, the range of the outer diameter at the maximum bulging part of the valve connecting tube is 28 - 38 mm, and the range of the outer diameter at the connection parts at both ends of the valve connecting tube is 24 - 33 mm.

[0016] Preferably, it further includes a limited-expandable biological valve, which is sewn on the inner surface of the valve connecting tube, or the limited-expandable biological valve is sewn on the inner surface at the connection of the valve connecting tube and the proximal conduit.

[0017] Preferably, it further includes a valve holder connected to the limited-expandable biological valve.

[0018] Preferably, two symmetrically arranged knotting protrusions are integrally connected to the rod body of the valve holder, and a suture cutting groove is formed between the two knotting protrusions.

[0019] Preferably, the connection between the centripetal conduit / centrifugal conduit and the valve connecting tube is turned outwards, the ends of the valve connecting tube are respectively sleeved on the outer sides of the centripetal conduit / centrifugal conduit, and the suture reciprocally passes through the inner and outer side walls of the connection between the valve connecting tube and the centripetal conduit / centrifugal conduit.

[0020] As another aspect of the present invention, it relates to a method for preparing a limited-expandable aortic valve conduit, including:

[0021] The first step, cutting and connecting:

[0022] Select a polyester corrugated pipe with a corrugation width of 1.24 - 1.89 mm, a corrugation height of 0.93 - 1.44 mm, and a ratio of corrugation width to corrugation height of 1.24 - 1.36. Cut it along its axial direction to obtain a centrifugal conduit, a valve intermediate pipe, and a centripetal conduit; Cut the valve intermediate pipe along its axial direction to obtain a rectangular corrugated pipe material, so that the corrugations are arranged along the axial direction of the entire limited-expandable aortic valve conduit, and then sew it into a valve connecting tube;

[0023] Sequentially connect the centripetal conduit, the valve connecting tube, and the centrifugal conduit with sutures to obtain a preliminary aortic valve conduit;

[0024] The second step, attaching a collagen fiber coating to the inner void and the inner and outer surfaces of the preliminary aortic valve conduit:

[0025] S1. Prepare collagen fibers;

[0026] S2. Using biogenic collagen as the raw material and glutaraldehyde as the cross-linking agent, through the first chemical cross-linking, obtain collagen fibers cross-linked for the first time with a melting point of 68.54 - 71.24 °C;

[0027] S3. Spray the collagen fibers cross-linked for the first time obtained in step S1 on the polyester corrugated pipe, and dry it to obtain a polyester corrugated pipe adsorbed with collagen fibers; The spraying density of the collagen fibers cross-linked for the first time on the surface of the polyester corrugated pipe is 1.5 - 6 mg / cm 2 ;

[0028] S4. Immerse the polyester corrugated pipe adsorbed with collagen fibers in the cross-linking agent solution to obtain a polyester corrugated pipe adsorbed with collagen fibers and impregnated with the cross-linking agent; The cross-linking agent solution is a compound solution of N-hydroxysuccinimide and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, compounded in a mass ratio of 1:1, and the concentration is 27 - 40 mg / mL;

[0029] S5. Immerse the polyester corrugated pipe obtained in step S4 in a collagen fiber solution with 3.5 - 5.5 mg / mL of collagen fibers that have undergone the first chemical cross-linking, let it stand for more than 2 h, and then dry it to obtain a polyester biological patch with a collagen fiber coating. The melting point range of the collagen fiber coating is 77.59 - 79.84 °C;

[0030] Step 3. Dry the limited-expandable biological valve to obtain a dried limited-expandable biological valve;

[0031] Step 4. Assemble a valve holder, a dried limited-expandable biological valve, and a preliminary aortic valve conduit to obtain a limited-expandable aortic valve conduit.

[0032] The collagen fiber coating of the limited-expandable aortic valve conduit provided by the present invention is stable, can withstand the high pulsatile pressure of the aorta (especially the aortic root), is not easy to fall off, has a good anti-bleeding effect, is not easy to degrade, has good biocompatibility, good compliance, and excellent mechanical properties. It is used in Bentall surgeries for replacing the aortic artificial blood vessel and the aortic valve.

[0033] The limited-expandable aortic valve conduit provided by the present invention is used in Bentall surgeries for replacing the aortic artificial blood vessel and the aortic valve. Moreover, after the artificial biological valve deteriorates, the limited-expandable aortic valve conduit provided by the present invention provides conditions for implanting an artificial biological valve of the same size as the original valve in an interventional manner, that is, after the biological valve deteriorates, a valve of the same size as the original valve can be implanted through an interventional method without thoracotomy for the patient to replace the biological valve of the same size.

[0034] The inflow end of the proximal conduit of the limited-expandable aortic valve conduit provided by the present invention is connected to the left ventricular outflow tract of the patient. When expanding the limited-expandable biological valve, many factors at the left ventricular outflow tract do not need to be considered. The valve seat of the limited-expandable biological valve is sewn in the limited-expandable aortic valve conduit. By optimizing the relevant parameters of the proximal conduit, the valve connecting pipe, and the distal conduit, conditions can be provided for expanding the limited-expandable biological valve. For patients with a small aortic valve, in order to avoid the prosthesis-patient mismatch (PPM) problem, the proximal conduit can be directly cut open and an aortic root enlargement operation can be performed. Description of the Drawings

[0035] Figure 1 It is a schematic structural diagram of the limited-expandable aortic valve conduit provided for Examples 1 - 3.

[0036] Figure 2 It is a schematic structural diagram of the polyester corrugated pipe, where A: schematic structural diagram of the polyester corrugated pipe; B: partial enlarged view of C in A.

[0037] Figure 3 It is a schematic structural diagram of a valve holder.

[0038] Figure 4 It is a schematic structural diagram of the preliminary aorta valve conduit in Embodiments 1-3.

[0039] Figure 5 It is the sewing method at the connection between the proximal conduit and the valve connecting tube, and at the connection between the valve connecting tube and the distal conduit in Embodiments 1-3.

[0040] Figure 6 A- Figure 6 D is a schematic structural diagram of a limit-expandable biological valve.

[0041] Figure 7 It is a schematic structural diagram of the limit-expandable aorta valve conduit provided in Embodiments 4-7.

[0042] Figure 8 It is a top view of the limit-expandable aorta valve conduit provided in Embodiments 4-7.

[0043] Figure 9 It is a three-dimensional view of the mold in Embodiments 4-7.

[0044] Figure 10 It is a schematic structural diagram of the preliminary aorta valve conduit in Embodiments 8-11.

[0045] Figure 11 It is a schematic structural diagram of the preliminary aorta valve conduit in Embodiment 12.

[0046] Reference numerals: preliminary aorta valve conduit 1, proximal conduit 2, valve connecting tube 3, distal conduit 4, expandable sinus connecting tube 5, wavy routing 6, valve holder 7, suture cutting groove 8, threading hole 9, polyester bellows 10, identification line 12, mold 13, valve leaflet 14, valve frame 15, valve seat 16, polyester sleeve with suture edge 17, limit-expandable biological valve 18. Detailed implementation manners

[0047] Based on the actual application scenario requirements of the Bentall-like operation for replacing the aortic artificial blood vessel and the aortic valve, aiming at the physiological environment of the aorta and the aortic root, a limit-expandable aorta valve conduit is provided, which can withstand high pulsating pressure, the suture is not easy to fall off, has a good anti-bleeding effect, a fast endothelialization speed, a stable coating, anti-degradation, good biocompatibility, excellent mechanical properties, and good compliance. After the artificial biological valve deteriorates, the limit-expandable aorta valve conduit provided by the present invention provides conditions for implanting an artificial biological valve with the same size as the original valve in an interventional manner, without the need to perform thoracotomy on the patient to replace the artificial biological valve surgically.

[0048] In the process of completing the present invention, the inventors first optimized the preparation method of the collagen fiber coating. During the optimization process, it was found that when the melting point of the collagen fiber after the first chemical cross-linking (denoted as "melting point 1") was 68.54 - 71.36 °C, the melting point of the collagen fiber coating (denoted as "melting point 2") was 76.92 - 80.98 °C, and when the difference between melting point 2 and melting point 1 was within the range of 7.42 - 11.33 °C, the collagen fiber coating was stable and had a better anti-bleeding effect.

[0049] As Figures 1 - 11 shown, the limited-expandable aortic valve conduit provided by the present invention includes a proximal conduit 2, a valve connecting tube 3, and a distal conduit 4. The inventors first made the proximal conduit 2, the valve connecting tube 3, and the distal conduit 4 from a polyester corrugated tube, and after sewing them in sequence, obtained a preliminary aortic valve conduit 1. After coating the preliminary aortic valve conduit 1 with a preparation method for the collagen fiber coating that is stable and has a better anti-bleeding effect, the measured melting point range of the collagen fiber coating is: melting point 2 is 76.93 - 80.97 °C, melting point 1 is 68.54 - 71.36 °C, and the difference between melting point 2 and melting point 1 is 7.39 - 11.30 °C. Finally, after connecting the preliminary aortic valve conduit 1, the valve holder 7, and the dried limited-expandable biological valve 18, the limited-expandable aortic valve conduit is obtained.

[0050] For the overall water leakage experiment of the limited-expandable aortic valve conduit, it was found that: at the connection between the proximal conduit 2 and the valve connecting tube 3, and at the connection between the valve connecting tube 3 and the distal conduit 4, the overall water leakage was relatively large. By comparison, it was found that melting point 2 was 77.59 - 79.84 °C, melting point 1 was 68.54 - 71.24 °C, the difference between melting point 2 and melting point 1 was 7.39 - 11.30 °C, and the corrugation width ( Figure 2 b in Figure 2 B) was 1.24 - 1.89 mm, the corrugation height ( Figure 2 a in Figure 2 B) was 0.93 - 1.44 mm, and the b / a ratio (the ratio of the corrugation width ( Figure 2 b in Figure 2 B) to the corrugation height ( Figure 2 a in Figure 2 B)) within the range of 1.24 - 1.36 had a relatively small overall water permeability for the limited-expandable aortic valve conduit, indicating a good anti-bleeding effect.

[0051] For the animal experiment of the limited-expandable aortic valve conduit, it was found that: the maximum circumferential tensile elongation rate range was 2.2 -

[0052] 4.8%, the elastic deformation rate range was 1.0 - 2.3%, and the value range of the elastic deformation rate accounting for the maximum circumferential tensile elongation rate was 38 -

[0053] The shear resistance of the limited-expandable aortic valve conduit with 68% and a maximum tensile force range of 13.5 - 55.9 N is strong, and there is no kinking phenomenon. It can prevent bleeding at the connection between the proximal conduit and the left ventricular outflow tract, and has excellent mechanical properties. The relevant parameters of the finally obtained limited-expandable aortic valve conduit are as follows:

[0054] The melting point 2 is 77.59 - 79.84 °C, the melting point 1 is 68.54 - 71.24 °C, and the difference between the melting point 2 and the melting point 1 is 7.39 - 11.30 °C; the maximum circumferential tensile elongation rate range is 2.2 - 4.8%, the elastic deformation rate range is 1.0 - 2.3%, the value range of the elastic deformation rate accounting for the maximum circumferential tensile elongation rate is 38 - 68%, and the maximum tensile force range is 13.5 - 55.9 N; the corrugation width ( Figure 2 b in B) is 1.24 - 1.89 mm, and the corrugation height ( Figure 2 a in B) is 0.93 - 1.44 mm, and the b / a ratio (the ratio of the corrugation width ( Figure 2 b in B) to the corrugation height ( Figure 2 a in B)) is 1.24 - 1.36.

[0055] I. Experiments 1 - 60: Optimize the preparation method of the collagen fiber coating on the conduit

[0056] 1. Preparation method of the collagen fiber coating

[0057] S1. Prepare porcine-derived type I collagen fibers

[0058] (1) Pretreatment of animal-derived tissue: After scraping the surface fat from fresh pigskin tissue, immerse it in an acetone solution. After soaking at room temperature for 16 h, wash it with deionized water 3 - 5 times to remove excess acetone. Then put the material into a 2.0 M NaOH solution and stir at room temperature for 16 h. After the treatment, soak it in deionized water and wash the material until it is neutral. (2) Preparation of crude collagen molecule extract: Put the washed material into 0.5 M acetic acid for crushing and homogenization. The homogenized tissue is used for collagen molecule extraction at a ratio of 20:1 (tissue weight / pepsin weight). Control the temperature at 18 °C and stir for extraction for 72 h. Centrifuge the extract to collect the supernatant, stir it evenly and then perform clarification filtration, controlling the turbidity to be less than 30 to obtain the crude collagen molecule extract. (3) Purification: Ultrafilter the crude collagen molecule extract using a tangential flow filtration system. After concentrating to 3 mg / ml, perform dialysis with a 20 mM acetic acid solution. After dialysis with 20 times the volume, collagen molecules are obtained. (4) Fibrosis of collagen molecules: Take a certain volume of the purified collagen molecules, add 1 / 10 volume of phosphate buffer (0.2 M Na2HPO4: 0.2 M NaH2PO4 = 7:3, v:v). Mix well and adjust the pH to 7.0, and place it at 30 °C for 6 h to obtain collagen fibers. Steps (1)-(4) are collagen fibers obtained from biogenic collagen. Any means disclosed in the prior art can be used for the above steps (1)-(4) as long as the corresponding technical purposes can be achieved.

[0059] S2, First chemical cross-linking:

[0060] Add the collagen fibers obtained in steps (1)-(4) to aqueous glutaraldehyde solutions with different concentrations, mix well, stir overnight at 30 °C, centrifuge to collect the precipitate, and wash it 2 - 3 times with a pH 7.0 phosphate buffer to obtain the collagen fibers subjected to the first chemical cross-linking. The concentration range of the aqueous glutaraldehyde solution is 0.004% - 0.035%.

[0061] The concentrations of the glutaraldehyde aqueous solutions used in Experiments 1-10 are shown in Table 1 below. The difference among Experiments 1-10 lies in the different concentrations of the glutaraldehyde aqueous solutions used. The melting points of the first chemically cross-linked collagen fibers obtained from Experiments 1-10 (denoted as "Melting Point 1") were measured by differential scanning calorimetry (DSC). Specifically, the first chemically cross-linked collagen fibers obtained from Experiments 1-10 were transferred to the test aluminum crucible of the differential scanning calorimeter, sealed in the differential scanning calorimeter, and scanned and measured under a nitrogen atmosphere with a heating rate of 10 K / min in the temperature range of 25-100 °C (the temperature range covers the melting point range of the substance). It can be seen from Table 1 that the range of Melting Point 1 of the first chemically cross-linked collagen fibers obtained from Experiments 1-10 is 68.54-71.36 °C. The main differences among Experiments 1-10 and the measured Melting Point 1 are shown in Table 1:

[0062] Table 1: Main differences among Experiments 1-10 and the measured Melting Point 1

[0063] Group Concentration of Aqueous Glutaraldehyde Solution Melting Point 1 (°C) Group Concentration of Aqueous Glutaraldehyde Solution Melting Point 1 (°C) Experiment 1 0.004％ 68.54±0.13 Experiment 6 0.016％ 70.77±0.02 Experiment 2 0.009％ 69.82±0.10 Experiment 7 0.018％ 70.83±0.12 Experiment 3 0.011％ 70.17±0.05 Experiment 8 0.025％ 71.08±0.01 Experiment 4 0.012％ 70.36±0.09 Experiment 9 0.03％ 71.24±0.03 Experiment 5 0.014％ 70.61±0.02 Experiment 10 0.035％ 71.36±0.02

[0064] S3. Preparation of the coating

[0065] Select polyester bellows with the following parameters: inner diameter 20-22 mm, outer diameter 23-25 mm, thickness 0.15-0.45 mm, corrugation height ( Figure 2 a) in B 0.5-2.0 mm, corrugation width ( Figure 2 b) in B 0.5-3.0 mm. Uniformly spray the first chemically cross-linked collagen fibers obtained in Step S2 on the inner and outer surfaces of the polyester bellows, with a spraying density of 1-6 mg / cm 2 (i.e., 1-6 mg is uniformly sprayed on the inner and outer surfaces of each square centimeter of the pipeline). After spraying, dry it in an oven at 30-35 °C to obtain a pipeline adsorbed with collagen fibers.

[0066] Table 2: Main differences in S3 among Experiments 11-60

[0067]

[0068]

[0069] It can be seen from the above table that the corrugation height ( Figure 2 a) in B of the pipelines obtained from Experiments 11-60 ranges from 0.65-1.99 mm, and the corrugation width ( Figure 2 b) in B ranges from 0.51-2.73 mm, and the b / a range is 0.61-2.57.

[0070] S4. Immerse the pipeline adsorbed with collagen fibers fully in the second cross-linking agent solution, and let it stand at room temperature for 20 min to obtain a pipeline adsorbed with collagen fibers immersed with the cross-linking agent. Preparation method of the second cross-linking agent solution: Weigh N-hydroxysuccinimide (NHS) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) in a centrifuge tube according to a mass ratio of 1:1, and add a pH 7.2 phosphate (PBS) solution to obtain a cross-linking agent solution. The concentration ranges of NHS and EDC are both 10 - 60 mg / mL.

[0071] Table 3: Concentration of S4 in Experiments 11 - 60

[0072]

[0073] S5. Second chemical cross-linking

[0074] Use a pH 7.2 phosphate (PBS) solution to prepare a collagen fiber solution with a concentration of 1 - 8.5 mg / mL from the collagen fibers obtained by the first chemical cross-linking in S2. Immerse the pipeline adsorbed with collagen fibers immersed with the cross-linking agent in the collagen fiber solution, and let it stand at room temperature for more than 2 h (preferably stand overnight), and dry it thoroughly at 30 - 35 °C. At this time, the collagen fibers that have undergone two chemical cross-linkings form a collagen fiber coating, which exists in the internal voids and on the inner and outer surfaces of the pipeline, and a pipeline with a collagen fiber coating attached is obtained.

[0075] Measure the melting point of the collagen fiber coating (denoted as "melting point 2") by differential scanning calorimetry DSC. Specifically, transfer the pipeline with a collagen fiber coating attached and the pipeline raw material (or called: polyester bellows) to the test aluminum crucible of the differential scanning calorimeter, seal it in the differential scanning calorimeter, under a nitrogen atmosphere, heat at a rate of 10 K / min, and perform a scan measurement under the condition of a heating range of 25 - 100 °C (the temperature range covers the melting point range of the substance). The melting point of the collagen fiber coating is the melting point of the collagen fiber coating after removing the background peak of the pipeline raw material. It can be seen from Table 4 that when the melting point 1 is 68.54 - 71.36 °C, the melting point 2 range of the pipeline collagen fiber coating obtained in Experiments 11 - 60 is 71.36 - 85.53 °C, and the difference between the melting point 2 and the melting point 1 is 0.65 - 15.71 °C.

[0076] Table 4: Differences and related melting points of S5 in Experiments 11 - 60

[0077]

[0078]

[0079] S6. Drying

[0080] Dry the pipeline with a collagen fiber coating attached. Specifically, immerse the pipeline with a collagen fiber coating attached in 100% glycerol to fully displace the water molecules in the pipeline with a collagen fiber coating attached with glycerol, and obtain a dried pipeline.

[0081] 2. Pipeline coating peeling situation obtained from Experiment 11 - 60

[0082] The stability of the coating is reflected by the collagen content and collagen infrared transmittance before and after the pulsatile flow experiment. Specifically, take the pipelines prepared in the above Experiment 11 - 60 and conduct pulsatile flow experiments respectively. Specifically, according to the ISO 5840 standard, cut the pipelines into sheet samples with a length of 4 cm and a width of 1 cm, sew them on the pulsatile flow platform, and under standard physiological conditions, after 90 days of pulsation, compare the collagen content and collagen infrared transmittance of the sheet samples before and after the pulsatile flow test to evaluate the stability of the collagen fiber coating under pulsatile flow. The test results are shown in Table 5. It can be seen from Table 5 that the collagen fiber coatings of the pipelines obtained from Experiments 12 - 13, 15, 18 - 19, 27 - 28, 33, 54, 58 - 59 are relatively stable.

[0083] Table 5: Changes in collagen coating content of pipelines obtained from Experiment 11 - 60 before and after pulsation

[0084]

[0085]

[0086] 3. Overall water leakage experiment

[0087] Execute according to YYT0500 - 2021 to measure the flow rate of water leakage through the pipeline wall under a pressure of 16 kPa (120 mmHg). The specific test steps are as follows:

[0088] Before the test, wet the pipeline with clean filtered water at room temperature (or specified temperature). Conduct the experiment on the pipeline in an implantable state. Seal the distal end of the test sample with a plug or adapter suitable for the inner diameter of the pipeline. Connect the proximal end of the pipeline to an adapter with a specific inner diameter to ensure sealing. Connect the adapter and the pipeline to a fixed device for pressure generation and measurement. Gradually increase the pressure in the lumen of the sample to expel the trapped air. Make the pressure reach 16.0 kPa ± 0.3 kPa (120 mmHg ± 2 mmHg), keep the pressure or flow rate stable, and measure the amount of water leaking through the wall of the pipeline within 60 s and calculate the overall water permeability. The overall water permeability is expressed as ml / (cm 2 ·min).

[0089] Table 6: Overall water leakage of pipelines obtained from Experiment 11 - 60

[0090]

[0091] As can be seen from the above, the overall water seepage of the pipeline coatings obtained in Experiments 12-13, 15, 18-19, 27-28, 33, 54, 58-59 is relatively low, and the overall water permeability range is 0.08-0.47 ml / (cm 2 ·min).

[0092] Considering the coating peeling situation and the overall water seepage situation, the inventor surprisingly found that when the melting point 1 is 68.54-71.36 °C and the melting point 2 is 76.92-80.98 °C, the coating with the difference between the melting point 2 and the melting point 1 in the range of 7.42-11.33 °C is more stable, has a relatively low overall water seepage, and has a good anti-bleeding effect.

[0093] Experiments 12-13, 15, 18-19, 27-28, 33, 54, 58-59 are hereinafter referred to as 11 optimized experiments.

[0094] II. Embodiments 1-12: Limited-expandable aortic valve conduit

[0095] 1. Structure of the limited-expandable aortic valve conduit in Embodiments 1-12

[0096] As Figures 1 - 11 shown, Embodiments 1-12 provide a limited-expandable aortic valve conduit, which includes a proximal conduit 2, a valve connecting conduit 3, a distal conduit 4, and a limited-expandable biological valve 18.

[0097] The materials of the proximal conduit 2, the valve connecting conduit 3, and the distal conduit 4 are the same or different specifications of polyester bellows 10. As Figure 2 shown, the relevant parameters of the polyester bellows 10 are as follows: inner diameter 20-22 mm, outer diameter 23-25 mm, thickness 0.15-0.45 mm, corrugation height ( Figure 2 a) in B) 0.5-2.0 mm, corrugation width ( Figure 2 b) in B) 0.5-3.0 mm. The parameters of the polyester bellows 10 in Embodiments 1-12 are shown in Table 8 below.

[0098] The proximal conduit 2, the valve connecting conduit 3, and the distal conduit 4 are sewn in sequence to obtain a preliminary aortic valve conduit 1.

[0099] After the proximal conduit 2, the valve connecting conduit 3, and the distal conduit 4 are connected, except for the sewing operations such as folding at the connection, according to Figure 1 , Figure 4 , Figure 7 , Figure 10 and Figure 11 the structure presented, the relevant specifications of the three are as follows:

[0100] In the natural state, the axial length of the proximal conduit 2 is not less than 5 mm and axially includes at least 2 corrugations. The axial length of the valve connecting tube 3 is 23 - 29 mm and circumferentially includes 24 - 36 corrugations. In the natural state, the axial length of the distal conduit 4 is not less than 70 mm and axially includes at least 30 corrugations. The main specifications of the aortic valve preliminary conduit 1 in Examples 1 - 12 are shown in Table 7 below.

[0101] Table 7: Differences in the main specifications of the aortic valve preliminary conduit 1 obtained in Examples 1 - 12

[0102]

[0103] Table 8: Parameters of the polyester bellows 10 in Examples 1 - 12

[0104] Group Pipeline of the Corresponding Optimized Experiment Ripple width( Figure 2 b in B) Ripple height( Figure 2 a) in B b / a Ratio Example 1 Experiment 12 1.48±0.02 1.13±0.02 1.31 Example 2 Experiment 13 1.56±0.01 1.26±0.04 1.24 Example 3 Experiment 15 1.89±0.16 1.44±0.04 1.31 Example 4 Experiment 18 1.65±0.03 1.25±0.01 1.32 Example 5 Experiment 19 1.24±0.02 0.93±0.04 1.33 Example 6 Experiment 27 1.38±0.02 1.03±0.01 1.34 Example 7 Experiment 28 1.27±0.02 0.94±0.01 1.35 Example 8 Experiment 33 1.54±0.04 1.13±0.03 1.36 Example 9 Experiment 54 1.58±0.01 1.16±0.03 1.36 Example 10 Experiment 58 1.62±0.01 1.15±0.06 1.41 Example 11 Experiment 59 1.11±0.01 0.84±0.05 1.32 Example 12 Experiment 12 1.48±0.02 1.13±0.02 1.31

[0105] As can be seen from Table 8, the corrugation width ( Figure 2 B in b) of the polyester bellows 10 in Examples 1 - 12 is 1.11 - 1.89 mm, and the corrugation height ( Figure 2 B in a) is 0.84 - 1.44 mm, and the b / a ratio is 1.24 - 1.41.

[0106] The valve connecting tube 3 is in a regular lantern shape, or imitates the structure of the physiological sinus of the human body, and its outer diameter gradually increases from the two ends to the middle. Specifically, the range of the outer diameter at the maximum bulging part of the valve connecting tube 3 is 28 - 38 mm, and the range of the outer diameter at the two ends of the valve connecting tube 3 is 24 - 33 mm.

[0107] The sewing method at the connection between the proximal conduit 2 and the valve connecting tube 3 and at the connection between the valve connecting tube 3 and the distal conduit 4 can refer to Figure 5 , the connections between the proximal conduit 2 / distal conduit 4 and the valve connecting tube 3 are turned outwards, the ends of the valve connecting tube 3 are respectively sleeved outside the proximal conduit 2 / distal conduit 4, and the suture reciprocally passes through the inner and outer side walls of the connection between the valve connecting tube 3 and the proximal conduit 2 / distal conduit 4. This sewing method helps to prevent bleeding at the connection between the valve connecting tube 3 and the proximal conduit 2 / distal conduit 4, helps to increase the durability of the conduit connection, and reduces the difficulty of manual sewing.

[0108] The preparation method of the collagen fiber coating with 11 optimized experiments attaches the collagen fiber coating to the inner void and the inner and outer surfaces of the preliminary aortic valve conduit 1. The melting point 1 of the preliminary aortic valve conduit 1 obtained in Examples 1 - 12 is the melting point of the collagen fibers cross-linked chemically for the first time (the collagen fibers cross-linked chemically for the first time are obtained from Experiment 1 - 60: the preparation method of the collagen fiber coating for the optimized conduit), and the melting point 2 is the melting point of the collagen fiber coating. The melting points 1 and 2 are measured by DSC. For the preparation method of the relevant collagen fiber coating and the detection method of the melting point, refer to "Experiment 1 - 60: the preparation method of the collagen fiber coating for the optimized conduit". The specific melting points 1 and 2 are shown in the following table:

[0109] Table 9: Relevant melting points of Examples 1 - 12

[0110]

[0111]

[0112] In summary, the melting point 2 obtained in Examples 1 - 12 is 76.93 - 80.97 °C, the melting point 1 is 68.54 - 71.36 °C, and the difference between the melting point 2 and the melting point 1 is 7.39 - 11.30 °C.

[0113] After coating, the limited-expandable biological valve 18 is connected to the limited-expandable aortic valve conduit to obtain the limited-expandable aortic valve conduit. Specifically, the limited-expandable aortic valve conduit further includes a valve holder 7 and sutures. The structure of the limited-expandable biological valve 18 refers to CN116196150B, and the schematic diagram is as Figure 6 shown. The specific structure of the valve holder 7 is as Figure 1 and Figure 3 shown. The limited-expandable biological valve 18 includes valve leaflets 14, a valve frame 15, a valve seat 16, and a polyester sleeve 17 with a suture margin. The valve leaflets 14 are made of bovine pericardium or porcine pericardium. The valve leaflets 14 are connected to the valve frame 15, the valve seat 16 is externally sleeved with the polyester sleeve 17 with a suture margin, and then these two parts are connected by sutures to obtain the limited-expandable biological valve 18. The specific connection method can refer to the prior art. After the limited-expandable biological valve 18 fails, since the valve seat 16 is expandable, a valve of the same size as the original artificial biological valve can be intervened without thoracotomy for the patient.

[0114] The suture is specifically a polyester suture, and the number is two to three. The polyester suture is used to connect the limited-expandable biological valve 18 and the valve holder 7. Two symmetrically arranged knotting protrusions are integrally connected to the rod body of the valve holder 7, and a suture cutting groove 8 is formed between the two knotting protrusions. After one end of the polyester suture is knotted on one knotting protrusion, it runs downward along the rod body of the valve holder 7 to be connected to the limited-expandable biological valve 18, then runs upward along the rod body of the valve holder 7 to cross the suture cutting groove 8, and then is knotted on the knotting protrusion again. That is, after being connected to the limited-expandable biological valve 18, crossing the suture cutting groove 8, and then being knotted on the knotting protrusion. During the operation, when the suture is cut at the suture cutting groove 8, the valve holder 7 and the limited-expandable biological valve 18 can be separated. This way of leading the suture can facilitate the operation of the doctor. And after cutting the suture, the free end lengths of the three sutures are not very different. When the doctor separates the valve holder 7 and the limited-expandable biological valve 18, the separation times of the free ends of the three sutures from the valve holder 7 are quite the same, without the doctor having to wait for the separation of the valve holder 7 and the suture in sequence, which facilitates the doctor's operation and saves the operation time.

[0115] The inflow end of the proximal conduit 2 is connected to the left ventricular outflow tract of the patient. The polyester sleeve 17 with a suture margin outside the valve seat 16 of the limited-expandable biological valve 18 is sewn on the inner surface of the connection between the valve connecting tube 3 and the proximal conduit 2, or on the inner surface of the valve connecting tube 3 (near the inflow end of the valve connecting tube 3). The present invention can provide conditions for expanding the limited-expandable biological valve 18 by optimizing the sewing method at the connection between the valve connecting tube 3 and the proximal conduit 2, the number of folds of the valve connecting tube 3, and the bulging size of the valve connecting tube 3. And the setting of the proximal conduit 2 facilitates the doctor to connect the proximal conduit 2 and the left ventricular outflow tract of the patient. When the limited-expandable biological valve 18 is expanded, since the inflow end of the proximal conduit 2 is connected to the left ventricular outflow tract of the patient, many factors at the left ventricular outflow tract do not need to be considered, and the problem of damaging the left ventricular outflow tract will not occur. For the convenience of the doctor's operation, marking lines 12 are provided on the proximal conduit 2, the valve connecting tube 3 and / or the distal conduit 4 along their axial directions. The marking lines 12 are preferably provided on the proximal conduit 2, the valve connecting tube 3 and the distal conduit 4, and can also be provided only on the proximal conduit 2 and the valve connecting tube 3, or only on the valve connecting tube 3 and the distal conduit 4. The number of the marking lines 12 is preferably three, and the three marking lines 12 are respectively aligned with the positions of the protrusions of the valve frame 15 (or the connection between the valve leaflets 14 and the valve leaflets 14).

[0116] The specific structural schematic diagrams of the aortic valve preliminary conduit 1 provided in Embodiments 1-3 are as Figure 4 shown. The specific structural schematic diagrams of the aortic valve preliminary conduit 1 provided in Embodiments 4-7 are as Figure 7 shown. The specific structural schematic diagrams of the aortic valve preliminary conduit 1 provided in Embodiments 8-11 are as Figure 10As shown. The specific structural schematic diagram of the preliminary aortic valve conduit 1 provided in Example 12 is as Figure 11 shown.

[0117] Specifically, in another preferred Example 4-7, the valve connecting tube 3 includes a sinus structure, and the "valve connecting tube 3" is renamed as the "expandable sinus connecting tube 5". Specifically, as Figures 7 - 8 shown, three sinuses are evenly distributed circumferentially on the valve connecting tube 3. In the natural state, each sinus includes 8-12 corrugations. On the one hand, the sinus structure can imitate the human physiological structure, and blood vortices are formed in each sinus, which is more convenient for the opening and closing of the valve leaf 14. On the other hand, the setting of the sinus structure can better match the limited-expandable biological valve 18 before expansion, and can also match the limited-expandable biological valve 18 after expansion.

[0118] In another preferred Example 8-11, as Figure 10 shown, the connection between the expandable sinus connecting tube 5 and the proximal conduit 2 is a wavy wire 6 that is consistent with the bottom direction of the limited-expandable biological valve 18. In addition to the corrugations on the corrugated conduit, the sewing method of the wavy wire 6 can reserve more space for the outflow end of the proximal conduit 2 (or the inflow end of the expandable sinus connecting tube 5) and the expanded biological valve seat 16.

[0119] In another preferred Example 12, as Figure 11 shown, compared with the limited-expandable aortic valve conduit provided in the above Example 11, the longitudinal section of the proximal conduit 2 of the limited-expandable aortic valve conduit provided in this example is trumpet-shaped, which is more convenient for the proximal conduit 2 to be laid on the left ventricular outflow tract of the patient during the operation and facilitates the doctor's suture.

[0120] 2. Preparation method of the limited-expandable aortic valve conduit of Examples 1-12

[0121] The first step, cutting and connecting:

[0122] Select an inner diameter of 20-22 mm, an outer diameter of 23-25 mm, a thickness of 0.15-0.45 mm, and a corrugation height ( Figure 2 B in a) 0.5-2.0 mm, and a corrugation width ( Figure 2In b) of B, a polyester corrugated pipe 10 with a length of 0.5 - 3.0 mm is axially cut to obtain a distal conduit 4, a valve intermediate tube, and a proximal conduit 2. The valve intermediate tube is axially cut open to obtain a rectangular corrugated pipe material, with the corrugations arranged along the axis of the entire limited-expandable aortic valve conduit, and then sewn into a valve connecting tube 3. The size of the valve connecting tube 3 should be able to match the limited-expandable biological valve 18 before expansion and the limited-expandable biological valve 18 after expansion. The proximal conduit 2, the valve connecting tube 3, and the distal conduit 4 are sequentially connected in this order to obtain a preliminary aortic valve conduit 1.

[0123] In another preferred embodiment 4 - 7, the valve connecting tube 3 is sleeved on a mold 13 ( Figure 9 ) and heat-set to obtain an expandable sinus connecting tube 5 with three sinuses circumferentially distributed. The proximal conduit 2, the valve connecting tube 3, and the distal conduit 4 are sequentially sewn to obtain a preliminary aortic valve conduit 1. Alternatively, the proximal conduit 2, the valve connecting tube 3, and the distal conduit 4 are first sequentially sewn to obtain a preliminary aortic valve conduit 1, and then the preliminary aortic valve conduit 1 is sleeved on the mold 13 for heat-setting, so that the valve connecting tube 3 becomes an expandable sinus connecting tube 5 with three sinuses circumferentially distributed.

[0124] In another preferred embodiment 12, the valve intermediate tube is axially cut open to obtain a rectangular corrugated pipe material, with the corrugations arranged along the axis of the entire limited-expandable aortic valve conduit, and then sewn into a valve connecting tube 3. The proximal intermediate conduit is axially cut open and then appropriately cut to obtain a trapezoidal corrugated pipe material, which is sewn into a proximal conduit 2 with a longitudinally sectioned trumpet shape.

[0125] Second step: The preparation method of 11 optimized experimental collagen fiber coatings is used to attach collagen fiber coatings to the internal voids, inner and outer surfaces of the preliminary aortic valve conduit 1. The specific steps are as follows:

[0126] S1: Prepare porcine-derived type I collagen fibers

[0127] Prepare with reference to "I. Examples 1 - 60: Preparation method of optimized conduit collagen fiber coating".

[0128] S2: First chemical cross-linking:

[0129] The obtained collagen fibers are added to aqueous glutaraldehyde solutions with different concentrations, mixed evenly, stirred overnight at 30 °C, the precipitate is collected by centrifugation, and after washing 2 - 3 times with a pH 7.0 phosphate buffer solution, the collagen fibers subjected to the first chemical cross-linking are obtained. The melting point of the collagen fibers subjected to the first chemical cross-linking is measured by DSC (denoted as "melting point 1"). The main differences in S2 of Examples 1 - 12 are as follows:

[0130] Table 10: Differences in S2 of Examples 1-12

[0131]

[0132] As can be seen from Table 10, the concentration of the glutaraldehyde aqueous solution in Examples 1-12 is 0.004-0.35%, and the melting point 1 is 68.54-71.36 °C.

[0133] S3. Preparation of the coating

[0134] The first chemically cross-linked collagen fibers obtained in step S2 are evenly sprayed on the inner and outer surfaces of the aortic valve preliminary conduit 1, and the spraying density is 1.5-6 mg / cm 2 (that is, 1.5-6 mg is evenly sprayed on the inner and outer surfaces of each square centimeter of the conduit). After spraying, it is dried in an oven at 31-33 °C to obtain the aortic valve preliminary conduit 1 adsorbed with collagen fibers. The main differences in S3 of Examples 1-12 are as follows:

[0135] Table 11: Differences in S3 of Examples 1-12

[0136]

[0137] S4. The aortic valve preliminary conduit 1 adsorbed with collagen fibers is fully immersed in the second cross-linking agent solution and left standing at room temperature for 20 min to obtain the aortic valve preliminary conduit 1 adsorbed with collagen fibers and impregnated with the cross-linking agent.

[0138] Preparation method of the second cross-linking agent solution: N-hydroxysuccinimide (NHS) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) are weighed in a centrifuge tube according to a mass ratio of 1:1, and a cross-linking agent solution is obtained by adding a pH 7.2 phosphate (PBS) solution. The concentration ranges of NHS and EDC are both 27-40 mg / mL.

[0139] Table 12: Differences in S4 of Examples 1-12

[0140]

[0141] S5. Second chemical cross-linking

[0142] The collagen fibers obtained by the first chemical cross-linking in S2 were formulated into a collagen fiber solution with a concentration of 3.5 - 5.5 mg / mL using a pH 7.2 phosphate (PBS) solution. The preliminary aortic valve conduit 1 adsorbed with collagen fibers and impregnated with a cross-linking agent was immersed in the collagen fiber solution, and left standing at room temperature for more than 2 h (preferably standing overnight), and then dried thoroughly at 31 - 35 °C. At this time, the collagen fibers cross-linked twice formed a collagen fiber coating, which existed in the internal voids and on the inner and outer surfaces of the preliminary aortic valve conduit 1, and the preliminary aortic valve conduit 1 with the attached collagen fiber coating was obtained. The melting point of the collagen fiber coating was measured by differential scanning calorimetry (DSC) (denoted as "melting point 2").

[0143] Table 13: Differences in S5 of Examples 1 - 12

[0144]

[0145] Step 3: Drying

[0146] The limit-expandable biological valve 18 was immersed in 100% glycerol to fully displace water molecules with glycerol, and the dried limit-expandable biological valve 18 was obtained. As Figure 6 shown, the tissue ring diameter range of the limit-expandable biological valve 18 is 19.0 - 29.0 mm, the expandable diameter range is 2 - 3 mm, and the tissue ring diameter range after expansion is 21.0 - 31.0 mm.

[0147] Step 4: Assembly

[0148] One end of the valve holder 7 was connected to the limit-expandable biological valve 18 by sutures, and then the limit-expandable biological valve 18 was connected to the preliminary aortic valve conduit 1 obtained in the third step by sutures to obtain a limit-expandable aortic valve conduit.

[0149] III. Related Tests of Examples 1 - 12

[0150] 1. Physical Properties

[0151] Visually observing the limit-expandable aortic valve conduits obtained in Examples 1 - 12, the valve leaflets are symmetrical, neatly opposed, without wrinkles or scratches; the suture needle stitches are neat and uniform, without cracks or exposed thread ends; there are no exposed thread ends or knots at the joints and free ends of the valve conduits, without burrs, broken wires or wire drawing; the conduit is a folded structure and is elastic and stretchable. Measured with a thickness gauge and a general measuring tool, the thickness of the limit-expandable aortic valve conduits obtained in Examples 1 - 12 is 0.33 ± 0.08 mm. The valve of the limit-expandable aortic valve conduit can be expanded with the assistance of a balloon and can be fully expanded under the condition of 607.9 ± 101.3 kPa (6 ± 1 atm), and the appearance is not damaged after expansion.

[0152] 2. Chemical properties

[0153] Prepare the leaching test solution according to GB / T 14233.1. Specifically, add water to the sample at a ratio of 0.2 g of sample to 1 mL, leach at 37°C ± 1°C for 72 h, separate the sample from the liquid, and cool to room temperature to obtain the test solution. Detect the heavy metal content according to the methods in 5.6.1 and 5.9.2 of GB / T 14233.1-2022. The experimental results show that the total content of barium, chromium, copper, lead, and tin in the test solutions of the limited-expandable aortic valve conduits obtained in Examples 1-12 does not exceed 1 μg / mL, and the content of cadmium does not exceed 0.1 μg / mL. The heavy metal content (calculated as lead) does not exceed 1 mg / L.

[0154] Detect the ethylene oxide residue of the limited-expandable aortic valve conduits obtained in Examples 1-12 according to the method of GB / T 14233.1-2022. After measurement, the ethylene oxide residue of the limited-expandable aortic valve conduits obtained in Examples 1-12 does not exceed 10 μg / g.

[0155] 3. Mechanical experiments

[0156] Refer to YY_T 0500-2021. Specifically, place two circular pins inside the limited-expandable aortic valve conduit, and stretch the limited-expandable aortic valve conduit circumferentially at a stable rate of 100 mm / min until the limited-expandable aortic valve conduit breaks, and obtain the inner diameter of the limited-expandable aortic valve conduit at the time of breakage. Calculate the maximum circumferential tensile elongation rate through ((inner diameter length of the limited-expandable aortic valve conduit at the time of breakage - original inner diameter length of the limited-expandable aortic valve conduit) / original inner diameter length of the limited-expandable aortic valve conduit)×100%. The determination of the elastic deformation rate uses the conventional determination methods in the art. Specifically, based on the tensile curve drawn when measuring the maximum circumferential tensile elongation rate, and based on the elastic deformation section of the tensile curve, calculate the elastic deformation rate.

[0157] Table 15: Related mechanical parameters of the limited-expandable aortic valve conduits in Examples 1-12

[0158]

[0159] In summary, the range of the maximum circumferential tensile elongation rate of the limited-expandable aortic valve conduits in Examples 1-12 is 2.2-4.8%, the range of the elastic deformation rate is 1.0-2.3%, the range of the value of the elastic deformation rate accounting for the maximum circumferential tensile elongation rate is 21-75%, and the range of the maximum pulling force is 13.5-55.9 N.

[0160] 4. Overall water leakage experiment

[0161] Execute in accordance with YYT0500-2021, and measure the water leakage flow rate through the pipe wall under a pressure of 16 kPa (120 mmHg). The specific test steps are as follows:

[0162] Before the test, specifically wet the limited-expandable aortic valve conduit with clean and filtered water at room temperature (or specified temperature). Conduct experiments on the limited-expandable aortic valve conduit in the implantable state. Seal the distal end of the limited-expandable aortic valve conduit with a plug or adapter suitable for the inner diameter of the conduit. Connect the proximal end of the limited-expandable aortic valve conduit to an adapter with a specific inner diameter to ensure sealing. Connect the adapter and the limited-expandable aortic valve conduit to the fixture for pressure generation and measurement. Gradually increase the pressure inside the lumen of the limited-expandable aortic valve conduit to expel the trapped air. Make the pressure reach 16.0 kPa ± 0.3 kPa (120 mmHg ± 2 mmHg), keep the pressure or flow rate stable, and measure the amount of water seeping through the wall within 60 s and calculate the overall water permeability. The overall water permeability is expressed as ml / (cm 2 ·min).

[0163] Table 14: Overall water seepage of the limited-expandable aortic valve conduits obtained in Examples 1-12

[0164] Group <![CDATA[Overall water permeability (ml / (cm 2 ·min)]]> Group <![CDATA[Overall water permeability (ml / (cm 2 ·min)]]> Example 1 2.24±0.09 Example 7 0.26±0.07 Example 2 0.18±0.03 Example 8 0.42±0.21 Example 3 0.35±0.05 Example 9 0.65±0.23 Example 4 0.97±0.21 Example 10 3.67±0.01 Example 5 0.12±0.04 Example 11 1.22±0.08 Example 6 0.34±0.01 Example 12 2.28±0.03

[0165] Since the overall water permeability of the conduits obtained from 11 optimization experiments is relatively small, while in Examples 1-12, the overall water seepage of the limited-expandable aortic valve conduits in Examples 1, 10-12 is relatively large, and the main water seepage parts of the limited-expandable aortic valve conduit are mainly the connection of the valve connecting tube 3 and the distal conduit 4, and the connection of the proximal conduit 2 and the valve connecting tube 3.

[0166] It can be seen from Table 14 that the overall water permeability of the limited-expandable aortic valve conduits obtained in Examples 2-9 is relatively small, indicating good anti-bleeding effect. Through comparison, it can be found that the melting point 2 of the limited-expandable aortic valve conduits obtained in Examples 2-9 is 77.59 - 79.84 °C, the melting point 1 is 68.54 - 71.24 °C, the difference between the melting point 2 and the melting point 1 is 7.39 - 11.30 °C, the corrugation width ( Figure 2 B in b) is 1.24 - 1.89 mm, the corrugation height ( Figure 2 B in a) is 0.93 - 1.44 mm, and the b / a ratio (the ratio of the corrugation width ( Figure 2 B in b) and the corrugation height ( Figure 2 B in a)) is between 1.24 - 1.36.

[0167] IV. Animal experiments

[0168] Sheep have hemodynamic characteristics and laboratory indicators similar to those of humans. In particular, the blood coagulation system characteristics of sheep are close to those of humans. Therefore, sheep are often selected as animal models for heart valve replacement and vascular replacement. Sheep are docile, easy to manage, less likely to develop infections after surgery, relatively easy to control during long-term feeding, and have a high long-term survival rate. Therefore, sheep were selected as experimental animals in this experiment.

[0169] Sheep were selected as experimental animals. The Bentall procedure was performed on the experimental animals to evaluate the safety and effectiveness of the limited-expandable aortic valve conduit in the animal body, as well as to evaluate the feasibility and safety of placing an interventional valve-in-valve in the limited-expandable biological valve after balloon dilation. After limited expansion, a valve-in-valve was implanted to simulate the future need for an interventional valve-in-valve. Animal experiments were conducted to evaluate the subsequent cardiac function of the animals after intervention, monitor blood routine, and assist in evaluating the safety and effectiveness of the limited-expandable aortic valve conduit.

[0170] 1. Inclusion criteria and feeding

[0171] The experimental animals were purchased from Xi'an Dilipu Biomedical Co., Ltd. The sheep used in this experiment were male, with an average preoperative body weight of 56.35 ± 6.911 kg, and the body weight range was between 42 kg and 75 kg; they were over 12 months old; they had normal body temperature, no symptoms such as cold, fever, or cough, passed normal quarantine, and blood samples were taken for testing during quarantine; the observation period was 7 days, and they were numbered after being confirmed qualified; the preoperative fasting time was 12 - 16 hours, and water was not restricted; animals with abnormal blood coagulation mechanisms were not eligible for selection; other animals that might affect the experimental results were also not eligible for selection. The experimental animals were acclimated to the environment and quarantined for one week before the operation. After the operation, the animals were housed in the animal house. The facility temperature was in the range of 16 - 26 °C, and each animal was housed in a single cage. The sheep's cages were cleaned twice a day. Standardized feed was fed, and they had free access to food and water.

[0172] 2. Grouping and quantity

[0173] A total of 24 sheep were used as experimental animals. The limited-expandable aortic valve conduits obtained from 8 examples were used for the experiment. The 8 examples were Examples 2 - 9, and 3 animals were used for each example.

[0174] Thirty days after Bentall surgery using a limited-expandable aortic valve conduit, 8 sheep (8 examples, 1 sheep per example) reached the end point of the experiment. The remaining 16 sheep underwent balloon limited dilation of the implanted limited-expandable biological valve through a minimally invasive small thoracotomy incision. Preoperative ultrasound, dilation pressure, and DSA were used to measure the size of the valve after dilation to confirm the limiting situation. Then, an interventional valve of the corresponding model was inserted through the catheter into the valve after dilation to verify the reliability of the valve seat firmness after dilation and the presence or absence of paravalvular leakage. The animals were continued to be fed for 30 days until the end point of the experiment, and examinations such as ultrasound and dissection were performed. Animal information was recorded during the experiment: body weight, operation time, survival days, information of the limited-expandable aortic valve conduit, etc. Blood routine, blood biochemistry, coagulation function, and blood gas were measured before the operation. Blood routine, blood biochemistry, coagulation function, and blood gas were measured after the operation.

[0175] 3. Experimental protocol

[0176] Preoperative preparation: Adaptation feeding for 1 week before the operation: 12-hour light-dark cycle, room temperature 22 ± 6°C, humidity 40 - 70%, preoperative fasting time 12 - 16 hours, water not prohibited. Before the operation started, the aortic valve annulus diameter of each animal was measured using CT. Injection of scopolamine hydrobromide injection (dose 0.01 mg / kg, intramuscular injection) was used to reduce respiratory secretions, isoflurane was inhaled through a mask, and tracheal intubation was connected to isoflurane. An intravenous access was established, and an electrocardiogram monitor was connected to monitor heart rate, blood pressure, and oxygen saturation.

[0177] Twenty-four experimental animals underwent Bentall surgery according to the conventional procedure. The specific procedure is as follows:

[0178] a. Perform transthoracic cardiac Doppler color ultrasound examination according to the requirements of routine examination and record the preoperative data; b. Place the animal in the right lateral decubitus position, routinely disinfect the chest, drape the sterile sheet, perform left thoracotomy, heparinize the whole body after taking the fourth rib, and expose the heart; c. Establish extracorporeal circulation routinely, place a left heart drainage tube, block the ascending aorta, perfuse cold cardioplegic solution through the aorta and (or) the left and right coronary arteries, and cool the heart surface with ice chips; d. Make an oblique incision in the ascending aorta, incise the ascending aorta and excise the diseased valve leaflets; e. Perform root replacement with a limited-expandable aortic valve conduit for proximal anastomosis, suture continuously or intermittently; f. Punch holes at the corresponding positions of the left and right coronary artery openings of the valve connecting tube of the limited-expandable aortic valve conduit, and directly suture the button-shaped left and right coronary artery openings to the valve connecting tube, and continuously suture the distal end of the limited-expandable aortic valve conduit and the ascending aorta; g. Examine the function of the artificial biological valve and the hemodynamic situation by transesophageal ultrasound; h. After checking that there is no active bleeding in the thoracic cavity, place a drainage tube in the thoracic cavity, close the chest layer by layer intermittently, and place a thoracic drainage tube to connect to the drainage bottle; i. Remove the jugular vein and femoral artery puncture sheath tubes and compress the hemostasis for at least 10 minutes; j. After the experimental animal's spontaneous breathing and corneal reflex recover and the blood pressure and heart rate are stable, remove the tracheal intubation and observe for 30 minutes in the natural position.

[0179] Thirty days after Bentall surgery, balloon dilation was performed on 13 experimental animals in a minimally invasive manner through a small transthoracic incision. The specific procedure is as follows:

[0180] a. The animals were fasted for 12 - 16 hours before surgery without water restriction. Blood samples were taken before surgery for laboratory tests as baseline values. Blood was drawn intravenously from the animals before surgery for testing. b. Injection of scopolamine hydrobromide injection (dose 0.03 mg, intramuscular injection) was used to reduce respiratory secretions. Isoflurane was inhaled through a face mask and tracheal intubation was connected to isoflurane. An intravenous access was established. c. Arterial puncture was performed to monitor the invasive blood pressure of the experimental animals. Electrodes were connected and the electrocardiogram was observed for normality. d. The administration of drugs during the preparation process was determined by the doctor. Isoflurane inhalation anesthesia was maintained, and the anesthetic state was monitored by observing the animal's blood pressure, whether the ears were moving, whether the jaw was opening and closing, eye reflexes, and whether the toes were clamped. Cefazolin sodium was administered before the start of the surgery, and cefazolin sodium was re-administered if the surgery time exceeded 5 hours. e. Transthoracic cardiac Doppler color ultrasound examination was performed according to the requirements of routine examinations, and preoperative data were recorded; f. The animals were placed in the right lateral position, and a small left chest incision was made. The skin of the chest and the left inguinal region was routinely disinfected. The left femoral vein was punctured and a sheath was inserted to establish a contrast pathway; g. Transthoracic or epicardial cardiac color ultrasound was performed according to the requirements of routine examinations, and data were recorded; h. The skin, subcutaneous tissue, and muscle were incised layer by layer. The sternum was carefully cut open with scissors, the pericardium was incised, and the heart was suspended with a 6×14 silk pericardial cradle. The corresponding specifications of the interventional bovine pericardial valve were selected in combination with the model specifications of the implanted M23 bovine pericardial valve. The apex of the heart was exposed, and a purse string was sutured at the apex of the heart with 5-0 prolene suture; i. The puncture sheath was inserted into the left ventricle from the center of the purse string towards the left ventricular outflow tract. A medical guide wire was inserted along the puncture sheath core. After confirming that the medical guide wire entered the left atrium, the puncture sheath was withdrawn; j. A 25-sized balloon was advanced along the medical guide wire. The balloon was advanced into the aortic valve position through DSA angiography. The balloon was inflated with a pressure pump to expand it, and the expansion of the expandable biological valve 18 was completed by maintaining the pressure at 5.0 - 6.0 atm for about 2 s; h. Then, a 24F delivery sheath pre-loaded with an interventional valve-in-valve was advanced along the medical guide wire. The interventional valve-in-valve was advanced to the mitral valve. After determining that the stent position was appropriate through DSA angiography, the valve stent was expanded with a balloon pressure pump. After the valve was fully expanded, the balloon was retrieved, the delivery sheath was withdrawn, and the guiding sheath and the medical guide wire were withdrawn. After the purse string was tightened and there was no bleeding at the apex wound, the purse string was ligated. i. The function of the interventional bovine pericardial valve and the hemodynamic situation were examined by ultrasound. After checking that there was no active bleeding in the thoracic cavity, the chest was closed layer by layer. After the sheep's spontaneous breathing and corneal reflex recovered, and the blood pressure and heart rate were stable, the tracheal intubation was removed, and the animals were observed in the natural position for 30 minutes

[0181] Post-operative treatment: After the successful operation, the experimental animals were sent back to the animal house for continued observation and feeding after recovery. Food and water were provided regularly. After chest closure, injection of bupivacaine hydrochloride was used for intercostal block analgesia. The status of the animals should be closely monitored during the entire post-operative care period. Within 7 days after the operation, cefotaxime sodium at a dose of 5 mg / kg was administered intramuscularly twice a day, and records were kept. Heparin sodium injection was given intravenously during the operation at a dose of 1.5 mg / kg or 100 - 200 U / kg to maintain ACT > 500 s. Warfarin sodium tablets and aspirin were given starting from the day after the operation, with an initial dose of 5 mg + 100 mg. The dose of warfarin sodium tablets was adjusted according to the INR results to maintain the INR value within the range of 1.5 - 2.5. When bleeding or other conditions occurred, the anticoagulation regimen was adjusted according to the doctor's requirements. When bleeding or other conditions occurred, the anticoagulation regimen was adjusted according to the doctor's requirements.

[0182] Experimental endpoint: In this experiment, all animals that reached the experimental endpoint and those that did not reach the experimental endpoint were subjected to gross dissection and pathological examination. After the animals that reached the endpoint were euthanized under anesthesia, the heart and other major organs were removed and dissected, including the brain, kidneys, spleen, lungs, and liver. The appearance of each organ, sectional examination, and thrombosis were observed macroscopically: The heart was incised to observe the thrombosis on the inflow and outflow surfaces of the valves, and photos were taken for archiving. Sections were made from the heart, brain, kidneys, spleen, lungs, liver, and other major organs for thrombus examination, valve changes, and secondary or other pathological examinations of each organ through the sections.

[0183] 4. Observation indicators

[0184] General conditions: including the situation of anastomotic bleeding, as well as the feeding, mental state, living habits, urination and defecation of experimental animals, and whether there are symptoms such as shortness of breath, oliguria, and abnormal behavior. Blood tests: including blood gas, blood routine (including plasma free hemoglobin, white blood cells, neutrophils, lymphocyte count, monocyte count, eosinophils, basophils, red blood cell count, hemoglobin, hematocrit, platelet count), blood biochemistry (including total bilirubin, direct bilirubin, alanine aminotransferase, aspartate aminotransferase, C-reactive protein, alkaline phosphatase, glutamyl transferase, total protein, albumin, creatinine, uric acid, blood urea nitrogen), blood coagulation (including prothrombin time, thrombin time, activated partial thromboplastin time) and immunology, etc.; to evaluate the hemolysis, inflammation and immune reactions of animals after implanting the device. Trans-thoracic echocardiography: Observe whether there are vegetations, abnormal blood flow in the pipeline, etc. at the valve and valve annulus; measure the left ventricular volume, aortic valve blood flow velocity and pressure difference, and left ventricular ejection fraction; observe and record the size of each cardiac chamber, the degree of regurgitation of each valve and the regurgitation of experimental animals. Gross anatomy and pathological examination: All animals that reached the experimental endpoint and those that did not reach the experimental endpoint in this experiment were subjected to gross anatomy and pathological examination. General anesthesia, femoral vein puncture for blood sampling (blood routine, liver and kidney functions); systemic heparinization, 3 mg / kg (the purpose of heparinization is to prevent blood coagulation after the animal is sacrificed, which may be confused with the thrombus formed in the limited-expandable biological valve); sacrifice the animal by bleeding under general anesthesia; observe the tissue around the limited-expandable biological valve implanted in the animal and whether there are morphological changes, adhesions, fibrous cyst cavities, etc. at the tissue junction, and take pictures for record; macroscopically observe the morphological changes of the valve leaflets, thrombus formation and calcification of the limited-expandable biological valve and take pictures for record; if there is a thrombus, record the weight (wet weight) of the thrombus and its proportion on the surface of the implant; observe the morphology of the prosthetic limited-expandable aortic valve pipeline and record the deformation condition; take the limited-expandable biological valve and the surrounding tissue to make pathological sections and observe the pathological changes under the microscope: sample the limited-expandable biological valve and the surrounding 3 mm area, fix it in 10% neutral formalin for 10-14 days, paraffin embed, section the tissue, and stain with HE; Organ anatomy: Dissect organs such as the heart, lungs, spleen, liver, kidneys, and brain, first perform a gross examination, observe the condition of the surgical (chest) incision wound surface, whether there are infarcts and abnormal lesions, and take pictures for record. Treatment and analysis of heart specimens: Cut open the left atrium and left ventricle and observe the valve placement position from the endocardial surface. Subsequently, take the ventricular wall and the tissue around the aortic valve, fresh or preserved in a 4°C refrigerator, and send for inspection on the day of sacrifice at the experimental endpoint or within 24 hours of accidental death. Perform a comprehensive organ examination, focusing on understanding the surface changes of the valve and the thromboembolism, infection and necrosis conditions of each organ. Take samples routinely under a light microscope, including the left ventricle, left atrium, limited-expandable aortic valve pipeline and the tissue around the aortic valve, and include the limited-expandable biological valve.

[0185] 5. Results of animal experiments

[0186] (1) Among the 8 embodiments, during the Bentall operation using the limited-expandable aortic valve conduit of Embodiment 4, relatively severe bleeding occurred at the connection between the proximal conduit and the left ventricular outflow tract. It is speculated that the reason is that the value of the elastic deformation rate accounting for the maximum circumferential tensile elongation rate is relatively low. Therefore, the value of the elastic deformation rate accounting for the maximum circumferential tensile elongation rate should be greater than 21%, and it can be controlled within 38 - 68%.

[0187] (2) Among the 8 embodiments, using the limited-expandable aortic valve conduits obtained from Embodiments 2 - 3 and 5 - 9, no uncontrollable anastomotic bleeding occurred during and after the operation on animals. Moreover, the conduit has strong shear resistance, no kinking phenomenon occurred, and its mechanical properties are excellent.

[0188] After minimally invasive intervention, the experimental animals using the limited-expandable aortic valve conduits obtained from Embodiments 2 - 3 and 5 - 9 had good general conditions during the survival and feeding period. Their body temperature, diet, and excretion were normal, their spontaneous activities were good, and no abnormal behaviors such as shortness of breath, oliguria, significant weight loss, fever, anorexia, and mania occurred. They survived smoothly until the end, and no complications such as myocardial infarction, severe arrhythmia, embolism, and artificial valve dysfunction occurred. There were no abnormalities in blood routine, blood biochemistry, and blood coagulation. When checking electrolytes, liver and kidney function values were almost within the normal range during each follow-up period after extracardiac radiofrequency ablation surgery, and the coagulation INR value was around 1.0 before the operation and during the follow-up period. The quantity, morphology, and quality of whole blood cells were not abnormal; the test results of white blood cells, red blood cells, hemoglobin, platelets, etc. showed that the overall results were stable, and no important blood routine index abnormalities were found. No liver and kidney function abnormalities were seen.

[0189] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. The present disclosure is not limited to the exact structure described above and shown in the drawings, and various modifications and changes can be made without departing from its scope. The scope of the present disclosure is only limited by the appended claims. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalent technologies, the present invention also intends to include these changes and modifications.

Claims

1. A limited-expandable aortic valve conduit, characterized in that, It includes a preliminary aortic valve conduit with a collagen fiber coating attached. The preliminary aortic valve conduit includes a proximal conduit, a valve connecting tube, and a distal conduit. The collagen fiber coating is formed by chemically cross-linking collagen fibers with a melting point of 68.54 - 71.24 °C that are attached to the internal voids and surfaces of the preliminary aortic valve conduit. The melting point of the collagen fiber coating is 77.59 - 79.84 °C, and the difference range between the melting point of the collagen fiber coating and the melting point of the collagen fibers cross-linked for the first time is 7.39 - 11.30 °C.

2. The limited-expandable aortic valve conduit according to claim 1, wherein In the natural state of the preliminary aortic valve conduit, the axial length of the proximal conduit is not less than 5 mm and axially includes at least 2 corrugations; the axial length of the valve connecting tube is 23 - 29 mm and circumferentially includes 24 - 36 corrugations; the axial length of the distal conduit is not less than 70 mm and axially includes at least 30 corrugations.

3. The limit-expandable aortic valve conduit according to claim 2, wherein The proximal conduit, the valve connecting tube, and the distal conduit are made of polyester bellows of the same specification, and the ratio of the corrugation width to the corrugation height of the polyester bellows is 1.24 - 1.

36.

4. The limited-expandable aortic valve conduit according to claim 1, characterized in that, The maximum circumferential tensile elongation rate range of the limited-expandable aortic valve conduit is 2.2 - 4.8%, the elastic deformation rate range is 1.0 - 2.3%, the value range of the elastic deformation rate accounting for the maximum circumferential tensile elongation rate is 38 - 68%, and the maximum pulling force range is 13.5 - 55.9 N.

5. The limited-expandable aortic valve conduit according to claim 1, characterized in that, The range of the outer diameter of the maximum bulging part of the valve connecting tube is 28 - 38 mm, and the range of the outer diameter of the two ends of the valve connecting tube where it is connected is 24 - 33 mm.

6. The limit-expandable aortic valve conduit according to claim 1, characterized in that, It further includes a limited-expandable biological valve, and the limited-expandable biological valve is sewn on the inner surface of the valve connecting tube, or the limited-expandable biological valve is sewn on the inner surface of the connection between the valve connecting tube and the proximal conduit.

7. The limit-expandable aortic valve conduit according to claim 6, wherein It further includes a valve holder connected to the limited-expandable biological valve.

8. The limited-expandable aortic valve conduit according to claim 7, characterized in that, Two symmetrically arranged knotting protrusions are integrally connected to the rod body of the valve holder, and a suture cutting groove is formed between the two knotting protrusions.

9. The limit-expandable aortic valve conduit according to claim 1, wherein The connection between the proximal conduit / distal conduit and the valve connecting tube is turned outwards, the ends of the valve connecting tube are respectively sleeved outside the proximal conduit / distal conduit, and the suture reciprocally passes through the inner and outer side walls of the connection between the valve connecting tube and the proximal conduit / distal conduit.

10. A method for preparing a limited-expandable aortic valve conduit, characterized in that, It includes: The first step, cutting and connecting: Select a polyester bellows with a corrugation width of 1.24 - 1.89 mm, a corrugation height of 0.93 - 1.44 mm, and a ratio of corrugation width to corrugation height) of 1.24 - 1.36, and cut it along its axial direction to obtain a distal conduit, a middle valve tube, and a proximal conduit; cut the middle valve tube along its axial direction to obtain a rectangular corrugated pipe material, so that the corrugations are arranged along the entire axial direction of the limited-expandable aortic valve conduit, and then sew it into a valve connecting tube. Sequentially connect the proximal conduit, the valve connecting tube, and the distal conduit through sutures to obtain a preliminary aortic valve conduit. The second step, attaching a collagen fiber coating to the internal voids and inner and outer surfaces of the preliminary aortic valve conduit: S1. Prepare collagen fibers; S2. Using biogenic collagen as the raw material and glutaraldehyde as the crosslinking agent, through the first chemical crosslinking, collagen fibers after the first chemical crosslinking with a melting point of 68.54 - 71.24 °C are obtained; S3. Spray the collagen fibers obtained from the first chemical cross-linking in step S1 on the polyester corrugated pipe, and dry it to obtain a polyester corrugated pipe adsorbed with collagen fibers; the spraying density of the collagen fibers obtained from the first chemical cross-linking on the surface of the polyester corrugated pipe is 1.5-6 mg / cm 2 ; S4. Immerse the polyester corrugated pipe adsorbed with collagen fibers in the crosslinking agent solution to obtain a polyester corrugated pipe adsorbed with collagen fibers immersed with the crosslinking agent; the crosslinking agent solution is a compound solution of N-hydroxysuccinimide and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, compounded in a mass ratio of 1:1, and the concentration is 27 - 40 mg / mL; S5. Immerse the polyester corrugated pipe obtained in step S4 in a collagen fiber solution with a concentration of 3.5 - 5.5 mg / mL of collagen fibers after the first chemical crosslinking, let it stand for more than 2 h, and dry it to obtain a polyester biological patch with a collagen fiber coating, and the melting point range of the collagen fiber coating is 77.59 - 79.84 °C; The third step: Dry the limited-expandable biological valve to obtain a dried limited-expandable biological valve; The fourth step: Assemble the valve holder, the dried limited-expandable biological valve and the preliminary aorta valve pipeline to obtain a limited-expandable aorta valve pipeline.

Images