Limiting expandable aortic valvular conduit and preparation therefor

Abstract

Disclosed in the present invention is a limiting expandable aortic valvular conduit. The limiting expandable aortic valvular conduit comprises a preliminary aortic valvular conduit attached with a collagen fiber coating, wherein the preliminary aortic valvular conduit comprises a proximal pipeline, a valve connecting conduit, and a distal conduit. Further disclosed in the present invention is a preparation method therefor. The limiting expandable aortic valvular conduit provided in the present invention is used for Bentall-type surgeries. Moreover, after the bioprosthetic valve deterioration, the limiting expandable aortic valvular conduit provided in the present invention provides the conditions for implanting a bioprosthetic valve of the same size as the original valve via an interventional approach; that is, after the biological valve deterioration, a valve of the same size as the original valve can be implanted via an interventional approach, without opening the chest of a patient to replace the biological valve of the same size.

Description

Limiting dilatable aortic valve conduit and its preparation Technical Field

[0001] This invention belongs to the field of biomedical materials technology, and particularly relates to the confined expandable aortic valve conduit and its preparation. Background Technology

[0002] Surgical procedures used to replace aortic prostheses and aortic valves include the Bentall procedure, Mini-Bentall procedure, Cabrol procedure, Wheat's procedure, David procedure, and Ross procedure (collectively referred to as "Bentall-type procedures"). The Bentall procedure was first reported in 1968 by cardiac surgeons Bentall and DeBoNo, hence the name "Bentall procedure." The David procedure is short for Valve-Sparing Aortic Root Replacement (VSRR). The Cabrol procedure is a modified version of the Bentall procedure. Wheat's procedure is a replacement of the aortic valve and ascending aorta while preserving the aortic sinus. This procedure was designed and performed by Wheat et al. in 1964.

[0003] For Bentall-type surgeries requiring valve replacement, the heart valves used in the aortic valve conduit are divided into mechanical valves and bioprosthetic valves. Mechanical valves are artificial valves made of non-metallic and metallic materials. Bioprosthetic valves are artificial heart valves made using materials from other animals (such as bovine and porcine pericardium) through processing. Mechanical valves have good durability, but patients require lifelong anticoagulation therapy. Bioprosthetic valves may deteriorate (e.g., calcify) 10–15 years after replacement, leading to aortic stenosis or aortic regurgitation, requiring further valve replacement.

[0004] The existing aortic valve conduit has the following problems: (1) The suture edge of the artificial heart valve is connected to the left ventricular outflow tract. After the bioprosthetic valve fails, a second open-heart valve replacement is required, or only a smaller artificial heart valve can be used through intervention; (2) The conduit is mostly made of polyester and coated with a coating that prevents bleeding, seepage and increases the rate of endothelialization. This coating cannot adapt to the high pulsatile pressure of the aorta (especially the aortic root) and is easy to fall off. The effect of preventing bleeding and seepage needs to be further improved; (3) Poor biocompatibility and slow endothelialization. The inability to quickly endothelialize can lead to hemolysis or thrombosis and long-term local calcification; (4) The thickness of the conduit is large (>0.5mm), which makes the operation and compliance of the surgery insufficient and the mechanical properties poor. Summary of the Invention

[0005] The limiting expandable aortic valve conduit provided by this invention is used for Bentall-type surgeries (including classic Bentall surgery, modified Bentall surgery, Mini-Bentall surgery, Cabrol surgery, Wheat's surgery, David surgery, Ross surgery, etc.). Furthermore, after the artificial bioprosthetic valve in the limiting expandable aortic valve conduit fails, the limiting expandable aortic valve conduit provided by this invention provides the means to insert an artificial bioprosthetic valve of the same size as the original valve via interventional methods, eliminating the need for open-heart surgery to replace the artificial bioprosthetic valve, greatly reducing trauma to the patient, and is especially suitable for patients who are not suitable for open-heart surgery to undergo secondary valve replacement treatment.

[0006] The limiting expandable aortic valve conduit provided by this invention is made from a preliminary aortic valve conduit coated with collagen fibers. In completing this invention, the inventors first optimized the preparation method of the collagen fiber coating, and then used the optimized preparation method to coat the preliminary aortic valve conduit, obtaining a preliminary aortic valve conduit coated with collagen fibers. This resulted in a limiting expandable aortic valve conduit capable of withstanding high pulsating pressure, with sutures that are not easily dislodged, excellent hemorrhage prevention, rapid endothelialization, stable coating, resistance to degradation, good biocompatibility, excellent mechanical properties, and good compliance.

[0007] The aortic valve pre-conduit coated with collagen fibers is obtained through two chemical cross-linking steps, including a first chemical cross-linking and a second chemical cross-linking. The first chemical cross-linking involves cross-linking collagen molecules or collagen fibers to obtain cross-linked collagen fibers. The second cross-linking involves attaching the cross-linked collagen fibers to the internal voids and the inner and outer surfaces of the aortic valve pre-conduit, thus forming a collagen fiber coating.

[0008] During the research process, the inventors unexpectedly discovered that the melting point of the collagen fiber coating and the melting point of the collagen fibers after the first chemical cross-linking need to meet a certain difference relationship. By optimizing and adjusting the difference in the melting point of collagen, a preliminary aortic valve conduit with a stable coating and good anti-bleeding effect can be obtained.

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

[0010] As one aspect of the present invention, there is a limitation-expandable aortic valve conduit, including a preliminary aortic valve conduit with a collagen fiber coating, the preliminary aortic valve conduit including a proximal conduit, a valve connecting tube and a distal conduit.

[0011] The collagen fiber coating is formed by a second chemical cross-linking of collagen fibers that have undergone a first chemical cross-linking process, resulting in a melting point of 68.54-71.24°C. The collagen fiber coating is attached to the internal voids and surface of the aortic valve pre-conduit. The melting point of the collagen fiber coating is 77.59-79.84°C, and the difference between the melting point of the collagen fiber coating and the melting point of the collagen fibers after the first chemical cross-linking process is 7.39-11.30°C.

[0012] Preferably, in its natural state, the aortic valve pre-conduit has the following characteristics: the axial length of the proximal conduit is not less than 5 mm, and it includes at least 2 corrugations in the axial direction; the axial length of the valve connecting tube is 23-29 mm, and it includes 24-36 corrugations in the circumferential direction; the axial length of the distal conduit is not less than 70 mm, and it includes at least 30 corrugations in the axial direction.

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

[0014] Preferably, the distal conduit of the limiting dilatational aortic valve conduit has a maximum circumferential elongation range of 2.2-4.8%, an elastic deformation rate range of 1.0-2.3%, an elastic deformation rate as a percentage of the maximum circumferential elongation range of 38-68%, and a maximum tensile force range of 13.5-55.9 N.

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

[0016] Preferably, it also includes a limiting expandable bioprosthetic valve, which is sewn onto the inner surface of the valve connecting tube, or the limiting expandable bioprosthetic valve is sewn onto the inner surface of the connection between the valve connecting tube and the proximal conduit.

[0017] Preferably, it also includes a valve holder connected to the limited expandable bioprosthetic valve.

[0018] Preferably, the rod of the valve holder has two symmetrically arranged knotted protrusions integrally connected, with a suture cutting groove formed between the two knotted protrusions.

[0019] Preferably, the connection between the proximal / distal conduit and the valve connecting tube is folded outward, and the end of the valve connecting tube is respectively fitted onto the outside of the proximal / distal conduit. The suture passes back and forth through the inner and outer walls of the connection between the valve connecting tube and the proximal / distal conduit.

[0020] As another aspect of the present invention, a method for preparing a confined, dilatable aortic valve conduit is provided, comprising:

[0021] Step 1: Cutting and connecting:

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

[0023] The proximal aortic valve conduit is obtained by sequentially connecting the proximal conduit, valve connecting cannula, and distal conduit with sutures.

[0024] The second step involves attaching a collagen fiber coating to the internal gaps and inner and outer surfaces of the aortic valve pre-conduit:

[0025] S1. Preparation of collagen fibers;

[0026] S2. Using bio-derived collagen as raw material and glutaraldehyde as a cross-linking agent, collagen fibers with a melting point of 68.54-71.24℃ are obtained through the first chemical cross-linking process.

[0027] S3. The collagen fibers obtained from step S2, which have undergone the first chemical cross-linking, are sprayed onto the polyester corrugated pipe and dried to obtain a polyester corrugated pipe with adsorbed collagen fibers; the spraying density of the collagen fibers that have undergone the first chemical cross-linking on the surface of the polyester corrugated pipe is 1.5-6 mg / cm³. 2 ;

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

[0029] S5. Immerse the polyester corrugated tube obtained in step S4 in a collagen fiber solution of 3.5-5.5 mg / mL that has undergone the first chemical cross-linking for a second chemical cross-linking. Let it stand for more than 2 hours and then dry it to obtain a polyester bio-patch with a collagen fiber coating. The melting point range of the collagen fiber coating is 77.59-79.84℃.

[0030] The third step is to dry the limited expandable bioprosthetic valve to obtain a dried limited expandable bioprosthetic valve.

[0031] The fourth step involves assembling the valve holder, preparing the dry, expandable bioprosthetic valve, and the preliminary aortic valve conduit to obtain the expandable aortic valve conduit.

[0032] The collagen fiber coating of the limiting and expandable aortic valve conduit provided by this invention is stable, can withstand the high pulsating pressure of the aorta (especially the aortic root), is not easy to fall off, has good anti-bleeding effect, is not easily degraded, has good biocompatibility, good compliance, and excellent mechanical properties. It is used in Bentall-type surgeries to replace aortic prosthetic vessels and aortic valves.

[0033] The limited expandable aortic valve conduit provided by this invention is a Bentall type of surgery. Furthermore, after the failure of the artificial bioprosthetic valve, the limited expandable aortic valve conduit provided by this invention provides the conditions for inserting an artificial bioprosthetic valve of the same size as the original valve through interventional means. That is, after the bioprosthetic valve fails, a valve of the same size as the original valve can be inserted through interventional means without having to open the patient's chest to replace it with a bioprosthetic valve of the same size.

[0034] The inflow end of the proximal conduit of the limited expandable aortic valve conduit provided by this invention is connected to the patient's left ventricular outflow tract. When expanding the limited expandable bioprosthetic valve, there is no need to consider numerous factors at the left ventricular outflow tract. The valve seat of the limited expandable bioprosthetic valve is sutured within the limited expandable aortic valve conduit. Optimizing the relevant parameters of the proximal conduit, valve connecting canal, and distal conduit can provide conditions for expanding the limited expandable bioprosthetic valve. For patients with small aortic valves, to avoid prosthesis-patient mismatch (PPM), the proximal conduit can be directly cut open, and aortic root enlargement can be performed. Attached Figure Description

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

[0036] Figure 2 is a schematic diagram of the structure of a polyester corrugated pipe, where A: a schematic diagram of the structure of a polyester corrugated pipe; B: a magnified view of part C in A.

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

[0038] Figure 4 is a schematic diagram of the preliminary aortic valve conduit structure in Examples 1-3.

[0039] Figure 5 shows the sewing methods 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 Examples 1-3.

[0040] Figures 6A-6D are schematic diagrams of the structure of a confined expandable bioprosthetic valve.

[0041] Figure 7 is a schematic diagram of the structure of the limited expandable aortic valve conduit provided in Examples 4-7.

[0042] Figure 8 is a top view of the limited expandable aortic valve conduit provided in Examples 4-7.

[0043] Figure 9 is a perspective view of the mold in Examples 4-7.

[0044] Figure 10 is a schematic diagram of the preliminary aortic valve conduit structure in Examples 8-11.

[0045] Figure 11 is a schematic diagram of the preliminary aortic valve conduit structure in Example 12.

[0046] Figure labels: 1. Preliminary aortic valve conduit; 2. Proximal conduit; 3. Valve connecting cannula; 4. Distal conduit; 5. Expandable sinus connecting cannula; 6. Wavy suture; 7. Valve holder; 8. Suture cutting groove; 9. Thread hole; 10. Polyester corrugated tube; 12. Marking line; 13. Mold; 14. Valve leaflet; 15. Valve frame; 16. Valve seat; 17. Polyester sheath with suture edge; 18. Limiting expandable bioprosthetic valve. Detailed Implementation

[0047] Based on the practical application needs of Bentall-type surgeries, and considering the physiological environment of the aorta and aortic root, this invention provides a limited, expandable aortic valve conduit capable of withstanding high pulsating pressure, with sutures that are not prone to dislodgement, excellent bleeding prevention, rapid endothelialization, stable coating, resistance to degradation, good biocompatibility, superior mechanical properties, and good compliance. After the failure of an artificial bioprosthetic valve, the limited, expandable aortic valve conduit provided by this invention allows for the interventional placement of an artificial bioprosthetic valve of the same size as the original valve, eliminating the need for open-chest surgery to replace the bioprosthetic valve.

[0048] In the process of completing this 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") is 68.54-71.36℃, the melting point of the collagen fiber coating (denoted as "melting point 2") is 76.92-80.98℃. When the difference between melting point 2 and melting point 1 is within the range of 7.42-11.33℃, the collagen fiber coating is stable and has a better anti-bleeding effect.

[0049] As shown in Figures 1-11, the limited-position expandable aortic valve conduit provided by this invention includes a proximal conduit 2, a valve connecting tube 3, and a distal conduit 4. The inventors first used polyester corrugated tubing to form the proximal conduit 2, valve connecting tube 3, and distal conduit 4, and then sewed them together to obtain the preliminary aortic valve conduit 1. After coating the preliminary aortic valve conduit 1 with a collagen fiber coating that is stable and has a good anti-bleeding effect, the melting point range of the collagen fiber coating was measured to be: melting point 2 is 76.93-80.97℃, melting point 1 is 68.54-71.36℃, and the difference between melting point 2 and melting point 1 is 7.39-11.30℃. Finally, the preliminary aortic valve conduit 1, the valve holder 7, and the dried limited-position expandable bio-valve 18 are connected to obtain the limited-position expandable aortic valve conduit.

[0050] An overall water permeability test was conducted on the constricted expandable aortic valve conduit. The results showed that the overall water permeability was relatively high at the connection points of proximal conduit 2 and valve connecting tube 3, and at the connection points of valve connecting tube 3 and distal conduit 4. Comparison revealed that melting point 2 was 77.59-79.84℃, melting point 1 was 68.54-71.24℃, and the difference between melting points 2 and 1 was 7.39-11.30℃. Furthermore, the overall water permeability of the constricted expandable aortic valve conduit was low, with a corrugation width (Figure 2B, b) of 1.24-1.89 mm, a corrugation height (Figure 2B, a) of 0.93-1.44 mm, and a b / a ratio (the ratio of corrugation width (Figure 2B, b) to corrugation height (Figure 2B, a)) within the range of 1.24-1.36, indicating good anti-hemorrhagic effect.

[0051] Animal experiments on the confined expandable aortic valve conduit revealed that the confined expandable aortic valve conduit exhibited strong shear resistance and no kinking, effectively preventing bleeding at the junction of the proximal conduit and the left ventricular outflow tract, demonstrating excellent mechanical properties. The maximum circumferential elongation of the distal conduit ranged from 2.2% to 4.8%, the elastic deformation rate from 1.0% to 2.3%, the elastic deformation rate as a percentage of the maximum circumferential elongation from 38% to 68%, and the maximum tensile force from 13.5% to 55.9 N.

[0052] Melting point 2 is 77.59-79.84℃, melting point 1 is 68.54-71.24℃, and the difference between melting point 2 and melting point 1 is 7.39-11.30℃; the maximum circumferential tensile elongation of the distal pipe ranges from 2.2-4.8%, the elastic deformation rate ranges from 1.0-2.3%, the elastic deformation rate as a percentage of the maximum circumferential tensile elongation ranges from 38-68%, and the maximum tensile force ranges from 13.5-55.9N; the corrugation width (b in Figure 2B) is 1.24-1.89mm, the corrugation height (a in Figure 2B) is 0.93-1.44mm, and the b / a ratio (the ratio of corrugation width (b in Figure 2B) to corrugation height (a in Figure 2B)) is between 1.24 and 1.36.

[0053] I. Experiment 1-60: Optimization of the preparation method of collagen fiber coating for pipes

[0054] 1. Preparation method of collagen fiber coating

[0055] S1. Preparation of porcine type I collagen fibers

[0056] (1) Pretreatment of animal-derived tissue: After scraping off the surface fat of fresh pig skin tissue, soak it in acetone solution at room temperature for 16 hours. Then wash it with deionized water 3-5 times to remove excess acetone. Then put the material into 2.0M NaOH solution and stir at room temperature for 16 hours. After 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 0.5M acetic acid for crushing and homogenization. The homogenized tissue is extracted for collagen molecules at a ratio of 20:1 (tissue weight / pepsin weight). The temperature is controlled at 18℃ and the extraction is stirred for 72 hours. The extract is centrifuged to collect the supernatant, stirred evenly, and then clarified and filtered to control the turbidity to be less than 30 to obtain crude collagen molecule extract. (3) Purification: Ultrafiltration of crude collagen molecule extract is carried out using a tangential flow filtration system. After concentration to 3mg / ml, dialyze it with 20mM acetic acid solution. After dialyzing 20 times the volume, collagen molecules are obtained. (4) Collagen molecule fibrillation: Take a certain volume of purified collagen molecules and add 1 / 10 volume of phosphate buffer (0.2M Na2HPO4:0.2M NaH2PO4 = 7:3, v:v). Mix well and adjust the pH to 7.0. Incubate at 30℃ for 6 hours to obtain collagen fibers. Steps (1)-(4) are collagen fibers obtained from biological collagen. Any means disclosed in the prior art can be used in steps (1)-(4) as long as the corresponding technical purpose can be achieved.

[0057] S2, First chemical cross-linking:

[0058] The collagen fibers obtained in steps (1)-(4) were added to glutaraldehyde aqueous solutions of different concentrations, mixed well, stirred overnight at 30°C, and the precipitate was collected by centrifugation. After washing 2-3 times with pH 7.0 phosphate buffer, collagen fibers with the first chemical cross-linking were obtained. The concentration range of the glutaraldehyde aqueous solution was 0.004%-0.035%.

[0059] The concentrations of glutaraldehyde aqueous solutions used in Experiments 1-10 are shown in Table 1 below. The difference between Experiments 1-10 lies in the different concentrations of the glutaraldehyde aqueous solution used. The melting point (denoted as "melting point 1") of the collagen fibers obtained in Experiments 1-10 after the first chemical cross-linking was determined by differential scanning calorimetry (DSC). Specifically, the collagen fibers obtained in Experiments 1-10 after the first chemical cross-linking were transferred to the test aluminum crucible of the differential scanning calorimeter, sealed in the DSC, and the temperature was increased at 10 K / min under a nitrogen atmosphere, with the temperature range of 25-100℃ (covering the melting point range of the substance). Table 1 shows that the melting point 1 range of the collagen fibers obtained in Experiments 1-10 after the first chemical cross-linking is 68.54-71.36℃. The main differences between Experiments 1-10 and the determined melting point 1 are shown in Table 1.

[0060] Table 1: Main differences between Experiments 1-10 and the measured melting point 1

[0061] S3, Coating Preparation

[0062] Select polyester corrugated tubing with the following parameters: inner diameter 20-22mm, outer diameter 23-25mm, thickness 0.15-0.45mm, corrugation height (Figure 2Ba) 0.5-2.0mm, and corrugation width (Figure 2Bb) 0.5-3.0mm. Uniformly spray the first chemically cross-linked collagen fibers obtained in step S2 onto the inner and outer surfaces of the polyester corrugated tubing at a spray density of 1-6 mg / cm³. 2 (i.e., 1-6 mg is evenly sprayed on the inner and outer surfaces of the pipe per square centimeter). After spraying, the pipe is dried in an oven at 30-35℃ to obtain a pipe with adsorbed collagen fibers.

[0063] Table 2: Main differences in S3 of Experiments 11-60

[0064] As can be seen from the table above, the corrugation height (a in Figure 2B) of the pipe obtained in Experiments 11-60 ranges from 0.65 to 1.99 mm, the corrugation width (b in Figure 2B) ranges from 0.51 to 2.73 mm, and the b / a ratio ranges from 0.61 to 2.57.

[0065] S4. Fully immerse the tube containing adsorbed collagen fibers in the second cross-linking agent solution and let it stand at room temperature for 20 minutes to obtain a tube containing adsorbed collagen fibers and impregnated 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 at a mass ratio of 1:1, and add pH 7.2 phosphate (PBS) solution to obtain the cross-linking agent solution. The concentration range of NHS and EDC is 10-60 mg / mL.

[0066] Table 3: Concentration of S4 in Experiments 11-60

[0067] S5, Second Chemical Crosslinking

[0068] The collagen fibers obtained in S2 after the first chemical cross-linking were prepared into a collagen fiber solution with a concentration of 1-8.5 mg / mL using a pH 7.2 phosphate PBS solution. The tube containing the collagen fibers and impregnated with the cross-linking agent was immersed in the collagen fiber solution and allowed to stand at room temperature for at least 2 hours (preferably overnight). Then, it was thoroughly dried at 30-35°C. At this point, the collagen fibers, after two chemical cross-linking processes, form a collagen fiber coating that exists in the internal pores and on the inner and outer surfaces of the tube, resulting in a tube with an attached collagen fiber coating.

[0069] The melting point of the collagen fiber coating (denoted as "melting point 2") was determined by differential scanning calorimetry (DSC). Specifically, the pipe with the collagen fiber coating and the pipe material (or polyester corrugated pipe) were transferred to the test aluminum crucible of the differential scanning calorimeter, sealed in the DSC, and heated at a rate of 10 K / min under a nitrogen atmosphere. The temperature was measured within a range of 25-100℃ (covering 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 peaks of the pipe material. Table 4 shows that when melting point 1 is 68.54-71.36℃, the melting point 2 range of the collagen fiber coating obtained in experiments 11-60 is 71.36-85.53℃, and the difference between melting point 2 and melting point 1 is 0.65-15.71℃.

[0070] Table 4: Differences in S5 and related melting points in Experiments 11-60

[0071] S6, Drying

[0072] The tubes coated with collagen fibers are dried by immersing them in 100% glycerol to fully replace the water molecules in the tubes with the glycerol, thus obtaining dried tubes.

[0073] 2. The peeling of the pipe coating obtained in Experiment 11-60

[0074] The stability of the coating was assessed by examining the collagen content and infrared transmittance of collagen before and after a pulsating flow experiment. Specifically, the pipes prepared in experiments 11-60 were subjected to pulsating flow experiments. Following ISO 5840 standards, the pipes were cut into sheet-like samples 4 cm long and 1 cm wide, sewn onto a pulsating flow platform, and subjected to pulsating flow for 90 days under standard physiological conditions. The collagen content and infrared transmittance of the sheet-like samples before and after the pulsating flow test were compared to evaluate the stability of the collagen fiber coating under pulsating flow. The test results are shown in Table 5. Table 5 shows that the collagen fiber coatings of the pipes obtained in experiments 12-13, 15, 18-19, 27-28, 33, 54, and 58-59 were relatively stable.

[0075] Table 5: Changes in collagen coating content before and after pipeline pulsation in Experiments 11-60

[0076] 3. Overall seepage volume test

[0077] Perform the test according to YYT0500-2021, measuring the flow rate of water leaking through the pipe wall under a pressure of 16 kPa (120 mmHg). The specific test procedures are as follows:

[0078] Before testing, wet the tubing with clean, filtered water at room temperature (or a specified temperature). Perform the experiment with the tubing in an implantable state. Seal the distal end of the test sample using a plug or adapter suitable for the tubing's inner diameter. Connect the proximal end of the tubing to an adapter of a specific inner diameter, ensuring a seal. Connect the adapter and tubing to a fixed device for pressure generation and measurement. Gradually increase the pressure within the sample's tubing cavity, expelling trapped air. Maintain a pressure of 16.0 kPa ± 0.3 kPa (120 mmHg ± 2 mmHg), keeping the pressure or flow rate stable, and measure the amount of water seeping through the tubing wall over 60 seconds to calculate the overall water permeability. Overall water permeability is expressed as ml / (cm²). 2 ·min).

[0079] Table 6: Overall water seepage volume of the pipeline obtained from Experiment 11-60

[0080] In summary, experiments 12-13, 15, 18-19, 27-28, 33, 54, and 58-59 showed that the overall water permeability of the pipe coatings was relatively low, ranging from 0.08 to 0.47 ml / (cm²). 2 ·min).

[0081] Based on a comprehensive analysis of coating peeling and overall water seepage, the inventors were surprised to find that coatings with a melting point of 68.54-71.36℃ and a melting point of 76.92-80.98℃, where the difference between melting point 2 and melting point 1 is within the range of 7.42-11.33℃, are more stable and have lower overall water seepage, resulting in better anti-bleeding effects.

[0082] Experiments 12-13, 15, 18-19, 27-28, 33, 54, and 58-59, hereinafter referred to as the 11 optimization experiments.

[0083] II. Examples 1-12: Limiting dilatable arterial valves

[0084] 1. The structure of the limiting dilatable aortic valve conduit in Examples 1-12

[0085] As shown in Figures 1-11, Examples 1-12 provide a limiting expandable aortic valve conduit, which includes a proximal conduit 2, a valve connecting tube 3, a distal conduit 4, and a limiting expandable bio-valve 18.

[0086] The materials for the proximal conduit 2, valve connecting tube 3, and distal conduit 4 are polyester corrugated tubing 10 of the same or different specifications, as shown in Figure 2. The relevant parameters of the polyester corrugated tubing 10 are as follows: inner diameter 20-22 mm, outer diameter 23-25 ​​mm, thickness 0.15-0.45 mm, corrugation height (Figure 2B a) 0.5-2.0 mm, and corrugation width (Figure 2B b) 0.5-3.0 mm. The parameters of the polyester corrugated tubing 10 in Examples 1-12 are shown in Table 8 below.

[0087] The proximal conduit 2, valve connecting tube 3, and distal conduit 4 are sewn together in sequence to obtain the preliminary aortic valve conduit 1.

[0088] After the proximal conduit 2, valve connecting tube 3, and distal conduit 4 are connected, excluding the folds and other sewing operations at the connection points, the relevant specifications of the three are as follows, based on the structures shown in Figures 1, 4, 7, 10, and 11:

[0089] In its natural state, the proximal conduit 2 has an axial length of not less than 5 mm and includes at least 2 corrugations axially. The valve connecting tube 3 has an axial length of 23-29 mm and includes 24-36 corrugations circumferentially. In its natural state, the distal conduit 4 has an axial length of not less than 70 mm and includes at least 30 corrugations axially. The main specifications of the aortic valve preliminary conduit 1 in Examples 1-12 are shown in Table 7 below.

[0090] Table 7: Main dimensional differences of the preliminary aortic valve conduit 1 obtained in Examples 1-12

[0091] Table 8: Parameters of Polyester Corrugated Pipes in Examples 1-12

[0092] As can be seen from Table 8, the corrugated width (b in Figure 2B) of the polyester corrugated pipe 10 in Examples 1-12 is 1.11-1.89 mm, the corrugated height (a in Figure 2B) is 0.84-1.44 mm, and the b / a ratio is 1.24-1.41.

[0093] The valve connecting tube 3 is shaped like a regular lantern, or mimics the structure of the human physiological sinus, with its outer diameter gradually increasing from the two ends to the middle. Specifically, the outer diameter of the maximum bulge of the valve connecting tube 3 ranges from 28 to 38 mm, and the outer diameter of the two ends of the valve connecting tube 3 ranges from 24 to 33 mm.

[0094] The suturing methods for the connections between the proximal conduit 2 and the valve connecting tube 3, and between the valve connecting tube 3 and the distal conduit 4, can be referred to Figure 5. The connections between the proximal conduit 2 / distal conduit 4 and the valve connecting tube 3 are folded outwards, with the ends of the valve connecting tube 3 fitted over the outer sides of the proximal conduit 2 / distal conduit 4. The sutures are passed back and forth through the inner and outer walls of the connections between the valve connecting tube 3 and the proximal conduit 2 / distal conduit 4. This suturing method helps prevent bleeding at the connections between the valve connecting tube 3 and the proximal conduit 2 / distal conduit 4, increases the durability of the connections, and reduces the difficulty of manual suturing.

[0095] A collagen fiber coating was applied to the internal voids and inner and outer surfaces of the preliminary aortic valve conduit 1 using a method optimized through 11 experiments. Melting point 1 of the preliminary aortic valve conduit 1 obtained in Examples 1-12 is the melting point of the collagen fibers after the first chemical cross-linking (the first chemical cross-linking collagen fibers were obtained from the method described in "I. Experiments 1-60: Optimization of the Preparation Method of Collagen Fiber Coating for the Conduit"), and melting point 2 is the melting point of the collagen fiber coating. Melting points 1 and 2 were determined by DSC. For details on the preparation method of the collagen fiber coating and the melting point detection method, please refer to "I. Examples 1-60: Optimization of the Preparation Method of Collagen Fiber Coating for the Conduit". Specific melting points 1 and 2 are shown in the table below.

[0096] Table 9: Relevant melting points of Examples 1-12

[0097] In summary, the melting point 2 obtained in Examples 1-12 is 76.93-80.97℃, the melting point 1 is 68.54-71.36℃, and the difference between melting point 2 and melting point 1 is 7.39-11.30℃.

[0098] After coating, the limiting expandable bioprosthetic valve 18 is connected to the limiting expandable aortic valve conduit to obtain the limiting expandable aortic valve conduit. Specifically, the limiting expandable aortic valve conduit also includes a valve holder 7 and sutures. The structure of the limiting expandable bioprosthetic valve 18 is shown in CN116196150B, and a schematic diagram is shown in Figure 6. The specific structure of the valve holder 7 is shown in Figures 1 and 3. The limiting expandable bioprosthetic valve 18 includes leaflets 14, a valve frame 15, a valve seat 16, and a polyester sheath with sutured edges 17. The leaflets 14 are made from bovine or porcine pericardium. The leaflets 14 and valve frame 15 are connected, the valve seat 16 is fitted with the polyester sheath with sutured edges 17, and these two parts are then connected with sutures to obtain the limiting expandable bioprosthetic valve 18. The specific connection method is described in existing technology. After the limiting expandable bioprosthetic valve 18 fails, because the valve seat 16 is expandable, a valve of the same size as the original artificial bioprosthetic valve can be inserted without open-chest surgery.

[0099] The sutures are specifically polyester sutures, numbering two to three. These polyester sutures are used to connect the limiting expandable bioprosthetic valve 18 to the valve holder 7. Two symmetrically arranged knotting protrusions are integrally connected to the rod of the valve holder 7, forming a suture cutting groove 8 between them. One end of the polyester suture is knotted at one of the knotting protrusions, then runs down the rod of the valve holder 7 to connect with the limiting expandable bioprosthetic valve 18, then runs up the rod of the valve holder 7, crosses the suture cutting groove 8, and is knotted again at the knotting protrusion. After connecting to the expandable bioprosthetic valve 18, the suture is passed over the suture cutting groove 8 and then tied on the knotting protrusion. During the operation, the suture is cut at the suture cutting groove 8, which allows the valve holder 7 to be separated from the expandable bioprosthetic valve 18. This suture method facilitates the doctor's operation, and after the suture is shortened, the free ends of the three sutures are of similar length. When the doctor separates the valve holder 7 from the expandable bioprosthetic valve 18, the separation time of the free ends of the three sutures is approximately the same as that of the valve holder 7. The doctor does not need to wait for the valve holder 7 and the sutures to separate sequentially, which facilitates the doctor's operation and saves surgical time.

[0100] The inflow end of the proximal conduit 2 connects to the patient's left ventricular outflow tract. A polyester sleeve 17 with sutured edges is sewn onto the inner surface of the connection between the valve connecting tube 3 and the proximal conduit 2, or onto the inner surface of the valve connecting tube 3 (near the inflow end). This invention optimizes the sewing method, the number of folds, and the bulge size of the valve connecting tube 3 at the connection between the valve connecting tube 3 and the proximal conduit 2, providing conditions for expanding the limited expandable biovalve 18. Furthermore, the proximal conduit 2 facilitates the connection between the proximal conduit 2 and the patient's left ventricular outflow tract. When the limited expandable biovalve 18 is expanded, since the inflow end of the proximal conduit 2 is connected to the patient's left ventricular outflow tract, there is no need to consider various factors at the left ventricular outflow tract, and there is no risk of damage to the left ventricular outflow tract. To facilitate surgical procedures, the proximal conduit 2, valve connecting tube 3, and / or distal conduit 4 are provided with axial marking lines 12. These marking lines 12 are preferably located on the proximal conduit 2, valve connecting tube 3, and distal conduit 4, but may also be located only on the proximal conduit 2 and valve connecting tube 3, or only on the valve connecting tube 3 and distal conduit 4. Preferably, there are three marking lines 12, each aligned with a protrusion on the valve frame 15 (or the leaflet 14 and its connection point).

[0101] Figure 4 shows a schematic diagram of the specific structure of the preliminary aortic valve conduit 1 provided in Examples 1-3. Figure 7 shows a schematic diagram of the specific structure of the preliminary aortic valve conduit 1 provided in Examples 4-7. Figure 10 shows a schematic diagram of the specific structure of the preliminary aortic valve conduit 1 provided in Examples 8-11. Figure 11 shows a schematic diagram of the specific structure of the preliminary aortic valve conduit 1 provided in Example 12.

[0102] Specifically, in other preferred embodiments 4-7, the valve connecting tube 3 includes a sinus structure, and the "valve connecting tube 3" is further named "expandable sinus connecting tube 5". Specifically, as shown in Figures 7-8, three sinuses are evenly distributed around the circumference of the valve connecting tube 3. In its natural state, each sinus includes 8-12 corrugations. On the one hand, the sinus structure can mimic the physiological structure of a human body, forming blood vortices within each sinus, which facilitates the opening and closing of the leaflet 14. On the other hand, the design of the sinus structure can better match the pre-expansion limited expandable bio-valve 18, and can also match the post-expansion limited expandable bio-valve 18.

[0103] In another preferred embodiment 8-11, as shown in Figure 10, the connection between the expandable sinus connecting tube 5 and the proximal conduit 2 is a wavy line 6 that runs in the same direction as the bottom of the limiting expandable bioprosthetic valve 18. In addition to the corrugations on the corrugated conduit, the stitching method of the wavy line 6 allows for more space to be reserved for the outflow end of the proximal conduit 2 (or the inflow end of the expandable sinus connecting tube 5) and the enlarged bioprosthetic valve seat 16.

[0104] In another preferred embodiment 12, as shown in FIG11, compared with the limiting expandable aortic valve conduit provided in the above embodiment 11, the longitudinal section of the proximal conduit 2 of the limiting expandable aortic valve conduit provided in this embodiment is funnel-shaped, which makes it more convenient for the proximal conduit 2 to be laid onto the patient's left ventricular outflow tract during surgery, and facilitates the doctor's suturing.

[0105] 2. Preparation method of the confined dilatable aortic valve conduit in Examples 1-12

[0106] Step 1: Cutting and connecting:

[0107] A polyester corrugated tube 10 with an inner diameter of 20-22 mm, an outer diameter of 23-25 ​​mm, a thickness of 0.15-0.45 mm, a corrugation height (Figure 2Ba) of 0.5-2.0 mm, and a corrugation width (Figure 2Bb) of 0.5-3.0 mm is selected and cut along its axial direction to obtain the distal conduit 4, the valve intermediate tube, and the proximal conduit 2. The valve intermediate tube is cut along its axial direction to obtain a rectangular corrugated tube, with the corrugations arranged along the axial direction of the entire limiting expandable aortic valve conduit, and then sewn into a valve connecting tube 3. The dimensions of the valve connecting tube 3 should be able to match the limiting expandable bioprosthetic valve 18 before expansion, and also be able to match the limiting expandable bioprosthetic valve 18 after expansion. The proximal conduit 2, the valve connecting tube 3, and the distal conduit 4 are connected sequentially to obtain the preliminary aortic valve conduit 1.

[0108] In another preferred embodiment 4-7, the valve connecting tube 3 is fitted onto the mold 13 (Figure 9) and subjected to high-temperature shaping to obtain an expandable sinus connecting tube 5 with three sinuses evenly distributed circumferentially. The proximal conduit 2, valve connecting tube 3, and distal conduit 4 are sewn sequentially to obtain the aortic valve preliminary conduit 1. Alternatively, the proximal conduit 2, valve connecting tube 3, and distal conduit 4 are first sewn sequentially to obtain the aortic valve preliminary conduit 1, and then the aortic valve preliminary conduit 1 is fitted onto the mold 13 and subjected to high-temperature shaping to make the valve connecting tube 3 become the expandable sinus connecting tube 5 with three sinuses evenly distributed circumferentially.

[0109] In another preferred embodiment 12, the valve intermediate tube is cut along its axial direction to obtain a rectangular corrugated tube, with the corrugations arranged axially along the entire limiting expandable aortic valve conduit, and then sewn into a valve connecting tube 3. The proximal intermediate tube is cut along its axial direction and then appropriately trimmed to obtain a trapezoidal corrugated tube, which is then sewn into a proximal tube 2 with a trumpet-shaped longitudinal section.

[0110] The second step involves attaching a collagen fiber coating to the internal voids and inner and outer surfaces of the aortic valve pre-conduit 1 using a method developed through 11 optimized experiments. The specific steps are as follows:

[0111] S1. Preparation of porcine type I collagen fibers

[0112] The preparation method was carried out in accordance with "I. Examples 1-60: Optimized preparation method of collagen fiber coating for pipes".

[0113] S2, First chemical cross-linking:

[0114] The obtained collagen fibers were added to glutaraldehyde aqueous solutions of different concentrations, mixed well, stirred overnight at 30°C, and the precipitate was collected by centrifugation. After washing 2-3 times with pH 7.0 phosphate buffer, collagen fibers with the first chemical cross-linking were obtained. The melting point of the collagen fibers with the first chemical cross-linking was determined by DSC (denoted as "melting point 1"). The main differences between S2 in Examples 1-12 are as follows:

[0115] Table 10: Differences in S2 between Examples 1-12

[0116] As can be seen from Table 10, the concentration of glutaraldehyde aqueous solution in Examples 1-12 is 0.004-0.35%, and the melting point is 68.54-71.36℃.

[0117] S3, Coating Preparation

[0118] The collagen fibers obtained in step S2, which have undergone the first chemical cross-linking, are uniformly sprayed onto the inner and outer surfaces of the aortic valve preliminary conduit 1 at a spray density of 1.5-6 mg / cm³. 2 (That is, 1.5-6 mg is evenly sprayed onto the inner and outer surfaces of the conduit per square centimeter). After spraying, it is dried in an oven at 31-33℃ to obtain the preliminary aortic valve conduit 1 with adsorbed collagen fibers. The main differences between S3 in Examples 1-12 are as follows:

[0119] Table 11: Differences in S3 between Examples 1-12

[0120] S4. Immerse the aortic valve preliminary conduit 1 with adsorbed collagen fibers in the second cross-linking agent solution and let it stand at room temperature for 20 minutes to obtain the aortic valve preliminary conduit 1 with adsorbed collagen fibers impregnated with the cross-linking agent.

[0121] Preparation method of the second crosslinking agent solution: Weigh N-hydroxysuccinimide (NHS) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) in a centrifuge tube at a mass ratio of 1:1, and add pH 7.2 phosphate (PBS) solution to obtain the crosslinking agent solution. The concentration range of NHS and EDC is 27-40 mg / mL.

[0122] Table 12: Differences in S4 between Examples 1-12

[0123] S5, Second Chemical Crosslinking

[0124] The collagen fibers obtained in S2 after the first chemical cross-linking were prepared into a collagen fiber solution with a concentration of 3.5-5.5 mg / mL using a pH 7.2 phosphate PBS solution. The aortic valve preliminary conduit 1, which was impregnated with the cross-linking agent and adsorbed with collagen fibers, was immersed in the collagen fiber solution and allowed to stand at room temperature for at least 2 hours (preferably overnight). It was then thoroughly dried at 31-35°C. At this point, the collagen fibers, after two chemical cross-linking processes, formed a collagen fiber coating, existing in the internal voids and on the inner and outer surfaces of the aortic valve preliminary conduit 1, resulting in the aortic valve preliminary conduit 1 with a collagen fiber coating. The melting point of the collagen fiber coating (denoted as "melting point 2") was determined by differential scanning calorimetry (DSC).

[0125] Table 13: Differences in S5 between Examples 1-12

[0126] Step 3: Drying

[0127] Immersing the expandable bioprosthetic valve 18 in 100% glycerol allows for complete displacement of water molecules by the glycerol, resulting in a dried expandable bioprosthetic valve 18. As shown in Figure 6, the tissue ring diameter of the expandable bioprosthetic valve 18 ranges from 19.0 to 29.0 mm, and the expandable diameter ranges from 2 to 3 mm. After expansion, the tissue ring diameter ranges from 21.0 to 31.0 mm.

[0128] Step 4: Assembly

[0129] One end of the valve holder 7 is connected to the limiting expandable bioprosthetic valve 18 by sutures, and then the limiting expandable bioprosthetic valve 18 is connected to the aortic valve preliminary conduit 1 obtained in the third step by sutures to obtain the limiting expandable aortic valve conduit.

[0130] III. Relevant Tests in Examples 1-12

[0131] 1. Physical properties

[0132] Visual observation of Examples 1-12 revealed that the limited-size expandable aortic valve conduit exhibited symmetrical and neatly aligned valve leaflets, free from wrinkles and scratches; the suture stitches were neat and uniform, without cracks or exposed thread ends; the valve conduit joints and free ends had no exposed thread ends or knots, and there were no burrs, broken threads, or pulled threads; the conduit had a pleated structure, exhibiting elasticity and stretchability. Using a thickness gauge and general measuring tools, the thickness of the limited-size expandable aortic valve conduit obtained in Examples 1-12 was 0.33±0.08 mm. The valve of the limited-size expandable aortic valve conduit can be fully expanded with balloon assistance under conditions of 607.9±101.3 kPa (6±1 atm), without any damage to its appearance after expansion.

[0133] 2. Chemical properties

[0134] The extraction test solution was prepared according to GB / T 14233.1, specifically by adding water at a ratio of 0.2 g sample to 1 mL, and extracting at 37℃±1℃ for 72 h. The sample was then separated from the liquid and cooled to room temperature to obtain the test solution. The heavy metal content was determined according to methods 5.6.1 and 5.9.2 of GB / T14233.1-2022. Experimental results showed that the total content of barium, chromium, copper, lead, and tin in the test solutions for the limited dilatable aortic valve conduit obtained in Examples 1-12 did not exceed 1 μg / mL, and the cadmium content did not exceed 0.1 μg / mL. The heavy metal content (calculated as lead) did not exceed 1 mg / L.

[0135] The residual ethylene oxide in the conduits of the limited dilatable aortic valve obtained in Examples 1-12 was tested according to the method of GB / T 14233.1-2022. After measurement, the residual amount of ethylene oxide in the conduits of the limited dilatable aortic valve obtained in Examples 1-12 did not exceed 10 μg / g.

[0136] 3. Mechanics Experiment

[0137] Referring to YY_T 0500-2021, two circular pins are placed inside the conduit of the expandable aortic valve. The conduit is then stretched circumferentially at a stable rate of 100 mm / min until it breaks. The inner diameter of the conduit at the point of breakage is obtained. The maximum circumferential elongation of the distal conduit is calculated by dividing the original inner diameter of the conduit by (the inner diameter at break - the original inner diameter) / the original inner diameter × 100%. The elastic deformation rate is determined using conventional methods in this field. Specifically, the elastic deformation rate is calculated based on the elastic deformation segment of the stretch curve plotted when the maximum circumferential elongation is measured.

[0138] Table 15: Relevant mechanical parameters of the distal conduit of the limited dilatable aortic valve conduit in Examples 1-12

[0139] In summary, the maximum circumferential tensile elongation of the distal conduit of the limited dilatational aortic valve conduit in Examples 1-12 ranges from 2.2% to 4.8%, the elastic deformation rate ranges from 1.0% to 2.3%, the elastic deformation rate as a percentage of the maximum circumferential tensile elongation ranges from 21% to 75%, and the maximum tensile force ranges from 13.5% to 55.9 N. The mechanical properties of the proximal and distal conduits are consistent.

[0140] 4. Overall water seepage test

[0141] Perform the test according to YYT0500-2021, measuring the flow rate of water leaking through the pipe wall under a pressure of 16 kPa (120 mmHg). The specific test procedures are as follows:

[0142] Prior to testing, the constricted expandable aortic valve conduit was specifically moistened with clean, filtered water at room temperature (or a specified temperature). The constricted expandable aortic valve conduit was then tested in an implantable state. The distal end of the constricted expandable aortic valve conduit was sealed using a plug or adapter with a suitable conduit inner diameter. The proximal end of the constricted expandable aortic valve conduit was connected to an adapter of a specific inner diameter, ensuring a seal. The adapter and the constricted expandable aortic valve conduit were connected to a pressure generating and measuring device. The intraluminal pressure of the constricted expandable aortic valve conduit was gradually increased to expel trapped air. The pressure was brought to 16.0 kPa ± 0.3 kPa (120 mmHg ± 2 mmHg), and the pressure or flow rate was kept stable. The amount of water permeating through the conduit wall was measured over 60 seconds, and the overall water permeability was calculated. Overall water permeability is expressed as ml / (cm²). 2 ·min).

[0143] Table 14: Overall leakage volume of the confined dilatable aortic valve conduit obtained in Examples 1-12

[0144] Because the overall water permeability of the pipes obtained from the 11 optimization experiments is relatively small, while in Examples 1-12, the overall water leakage of the limited expandable aortic valve conduit in Examples 1 and 10-12 is relatively large, and the main water leakage sites of the limited expandable aortic valve conduit are mainly the connection between the valve connecting tube 3 and the distal conduit 4, and the connection between the proximal conduit 2 and the valve connecting tube 3.

[0145] As shown in Table 14, the limiting expandable aortic valve conduits obtained in Examples 2-9 have low overall water permeability, indicating good anti-hemorrhagic effect. A comparison reveals that the melting point 2 of the limiting expandable aortic valve conduits obtained in Examples 2-9 is 77.59-79.84℃, the melting point 1 is 68.54-71.24℃, the difference between melting point 2 and melting point 1 is 7.39-11.30℃, the corrugation width (b in Figure 2B) is 1.24-1.89 mm, the corrugation height (a in Figure 2B) is 0.93-1.44 mm, and the b / a ratio (the ratio of corrugation width (b in Figure 2B) to corrugation height (a in Figure 2B)) is between 1.24 and 1.36.

[0146] IV. Animal Experiments

[0147] Sheep possess hemodynamic characteristics and laboratory parameters similar to humans, particularly their blood coagulation system, making them a common animal model for heart valve and vascular replacement. Sheep are docile, easy to manage, less prone to postoperative infection, easier to control with long-term care, and have a high long-term survival rate. Therefore, sheep were chosen as the experimental animal for this experiment.

[0148] Sheep were selected as experimental animals. The Bentall procedure was performed on these animals to evaluate the safety and efficacy of the confined expandable aortic valve conduit in vivo, and to assess the feasibility and safety of placing an interventional valve-in-valve within a confined expandable bioprosthetic valve after balloon dilation. By implanting a valve-in-valve after confined dilation to simulate the future need for an interventional valve-in-valve, animal experiments were conducted to evaluate subsequent observation of cardiac function and monitoring of blood routine tests, further supporting the evaluation of the safety and efficacy of the confined expandable aortic valve conduit.

[0149] 1. Selection criteria and feeding

[0150] The experimental animals were purchased from Xi'an Dilepu Biomedical Co., Ltd. The sheep used in this experiment were male, with an average preoperative weight of 56.35±6.911 kg, ranging from 42 kg to 75 kg; over 12 months old; normal body temperature, no colds, fevers, coughs, or other symptoms; and passed normal quarantine, with blood samples taken for testing during quarantine. The observation period was 7 days, and animals were numbered after passing the observation. Preoperative fasting was 12-16 hours, but water was allowed. Animals with abnormal blood clotting mechanisms were not selected; animals with other conditions that might affect the experimental results were also not selected. The experimental animals underwent environmental acclimatization and quarantine one week prior to surgery. Postoperatively, the animals were housed in the animal room. The facility temperature was maintained between 16-26℃, with each animal housed individually. The sheep monitoring cages were cleaned twice daily. Standardized feed was provided, with free access to food and water.

[0151] 2. Grouping and Quantity

[0152] A total of 24 sheep were used as experimental animals. The experiments were conducted using the limited dilatationable aortic valve conduit obtained in 8 examples, namely Examples 2-9, with 3 sheep used in each example.

[0153] Thirty days after Bentall surgery using a confined expandable aortic valve conduit, eight sheep (one from each of the eight experimental cases) reached the experimental endpoint. The remaining 16 sheep underwent balloon confined dilation of the implanted confined expandable bioprosthetic valve via a small thoracic incision. Preoperative ultrasound, dilation pressure, and DSA measurements of the dilated valve size were recorded to confirm confined positioning. A corresponding type of interventional valve was then inserted via catheter into the dilated valve to verify the reliability of the valve seat and the absence of paravalvular leakage. The animals were fed for another 30 days post-surgery until the experimental endpoint, during which ultrasound and anatomical examinations were performed. Animal information recorded during the experiment included weight, surgical time, survival days, and information on the confined expandable aortic valve conduit. Preoperative blood tests (complete blood count, blood biochemistry, coagulation function, and blood gas analysis) and postoperative blood tests (complete blood count, blood biochemistry, coagulation function, and blood gas analysis) were performed.

[0154] 3. Experimental Design

[0155] Preoperative preparation: One week of preoperative acclimatization: 12-hour light-dark cycle, room temperature 22±6℃, humidity 40-70%, fasting period 12-16 hours, water allowed. Aortic valve annulus diameter was measured in each animal using CT scan before surgery. Scopolamine hydrobromide injection (0.01 mg / kg, intramuscular injection) was administered to reduce respiratory secretions. Isoflurane was inhaled via face mask, and isoflurane was inserted through endotracheal intubation. Intravenous access was established, and a cardiac monitor was connected to monitor heart rate, blood pressure, and blood oxygen saturation.

[0156] Twenty-four laboratory animals underwent Bentall surgery according to standard procedures, as follows:

[0157] a. Perform transthoracic Doppler color Doppler ultrasound of the heart as per routine examination requirements, and record preoperative data; b. Position the animal in right lateral decubitus position, routinely disinfect the chest, drape with sterile sheets, open the left thorax, remove the fourth rib, and perform systemic heparinization to expose the heart; c. Routinely establish cardiopulmonary bypass, place a left ventricular drainage tube, occlude the ascending aorta, and perfuse cold blood cardioplegic solution through the aorta and / or left and right coronary arteries, cooling the heart surface with ice chips; d. Make an oblique incision in the ascending aorta, cut open the ascending aorta, and remove the diseased valve leaflet; e. Perform proximal anastomosis to limit the dilatationable aortic valve duct and perform root replacement, suturing continuously or interrupted; f. [The text abruptly ends here, likely due to an incomplete sentence or missing information.] Drill holes corresponding to the openings of the left and right coronary arteries, and suture the button-shaped openings of the left and right coronary arteries directly to the valve connecting tube. Continuous suturing and limiting can expand the distal end of the aortic valve duct and the ascending aorta; g. Examine the function and hemodynamics of the artificial bioprosthetic valve via transesophageal ultrasound; h. After confirming that there is no active bleeding in the pleural cavity, place a drainage tube in the pleural cavity, close the chest intermittently layer by layer, and place the pleural drainage tube connected to the drainage bottle; i. Remove the puncture sheaths of the jugular vein and femoral artery, and apply pressure to stop bleeding for at least 10 minutes; j. After the experimental animal resumes spontaneous breathing, corneal radiation recovers, and blood pressure and heart rhythm stabilize, remove the endotracheal tube and observe it in a natural position for 30 minutes.

[0158] Thirty days after Bentall's surgery, balloon dilation was performed on 13 experimental animals using a minimally invasive transthoracic incision. The specific procedure is as follows:

[0159] a. Animals should be fasted for 12-16 hours before surgery, but water is allowed. Blood samples should be taken preoperatively as baseline values. Blood should be drawn intravenously before surgery. b. Scopolamine hydrobromide injection (0.03 mg, intramuscular injection) should be administered to reduce respiratory secretions. Isoflurane should be inhaled through a face mask, and isoflurane should be inserted through an endotracheal tube. Establish intravenous access. c. Arterial puncture should be performed to monitor the experimental animals' invasive blood pressure. Electrodes should be attached, and the electrocardiogram should be observed to ensure it is normal. d. Medication administration during preparation is determined by the veterinarian. Maintain isoflurane inhalation anesthesia, and monitor the anesthesia status by observing the animal's blood pressure, ear movement, jaw opening and closing, eye reflexes, and toe clenching. Cefazolin sodium should be administered before surgery. If the surgery lasts more than 5 hours, cefazolin sodium should be administered again. e. Perform transthoracic Doppler color Doppler ultrasound examination as required by routine examination, and record preoperative data; f. Position the animal in right lateral decubitus position, make a small incision in the left chest, routinely disinfect the chest and left groin area, puncture the left femoral vein, insert a sheath to establish angiographic access; g. Perform transthoracic or transcardiographic color Doppler ultrasound examination as required by routine examination, and record data; h. Incise the skin, subcutaneous tissue, and muscle layer by layer, carefully cut the sternum with scissors, open the pericardium, suspend the heart with a 6×14 gauge pericardial sling, and select the appropriate size of the interventional bovine pericardial valve based on the size and specifications of the implanted M23 bovine pericardial valve. Expose the apex of the heart, and suture the purse-string suture at the apex with 5-0 Prolene suture; i. Insert the puncture sheath into the left ventricle from the center of the purse-string suture towards the left ventricular outflow tract, insert a medical guidewire along the core of the puncture sheath, confirm that the medical guidewire has entered the left atrium, and withdraw the puncture sheath; j. Advance a 25 gauge balloon along the medical guidewire, and guide the balloon to the aortic valve position through DSA angiography. The balloon is inflated using a pressure pump to 5.0-6.0 atm and held for approximately 2 seconds to complete the expansion of the limited-position expandable bioprosthetic valve 18. h. A 24F delivery sheath pre-loaded with the interventional valve-in-valve is then inserted along the medical guidewire. The interventional valve-in-valve is positioned at the mitral valve. After confirming the stent's proper placement via DSA angiography, the valve stent is expanded using a balloon pressure pump. Once the valve is fully expanded, the balloon is retrieved, the delivery sheath is withdrawn, and the guide sheath and medical guidewire are removed. After tightening the purse-string closure, if there is no bleeding at the apex of the heart, the purse-string closure is ligated. i. Ultrasound examination of the function of the interventional bovine pericardial valve and hemodynamics is performed. After confirming the absence of active bleeding in the pleural cavity, the chest is closed layer by layer. Once the sheep's spontaneous breathing, corneal radiation recovery, and blood pressure and heart rhythm are stable, the endotracheal tube is removed, and the sheep is observed in a natural position for 30 minutes.

[0160] Postoperative Management: After successful surgery, the experimental animals were resuscitated and returned to the animal facility for continued observation and care. Food and water were provided regularly. After chest closure, intercostal nerve blocks were administered using bupivacaine hydrochloride injection for pain relief. The animal's condition should be closely monitored throughout the postoperative care period. For the first 7 days postoperatively, ceftiofur sodium was administered intramuscularly at 5 mg / kg twice daily, and records were kept. Heparin sodium was administered intravenously during the operation at 1.5 mg / kg or 100-200 U / kg, maintaining an ACT > 500 seconds. Warfarin sodium tablets plus aspirin were started on the day of surgery, with an initial dose of 5 mg + 100 mg. The warfarin sodium dosage was adjusted according to the INR results, maintaining an INR value within the range of 1.5-2.5. In case of bleeding or other complications, the anticoagulation regimen was adjusted according to the veterinarian's instructions.

[0161] Experimental endpoint: All animals that reached and did not reach the experimental endpoint underwent gross dissection and pathological examination. After euthanasia under anesthesia, the heart and other major organs were removed and dissected, including the brain, kidneys, spleen, lungs, and liver. The appearance, cross-sectional views, and thrombosis status of each organ were observed macroscopically. The heart was incised to observe thrombosis at the valve inflow and outflow surfaces, and photographs were taken for archiving. Sections were prepared from the heart, brain, kidneys, spleen, lungs, liver, and other major organs for thrombosis examination, valve changes, and secondary or other pathological examinations of each organ.

[0162] 4. Observation Indicators

[0163] General assessment: This includes anastomotic bleeding, as well as the animal's feeding, mental state, lifestyle, urination and defecation, and the presence of shortness of breath, oliguria, or abnormal behavior. Blood tests: These include blood gas analysis, complete blood count (including plasma free hemoglobin, white blood cells, neutrophils, lymphocytes, monocytes, eosinophils, basophils, red blood cell count, hemoglobin, hematocrit, and platelet count), blood biochemistry (including total bilirubin, direct bilirubin, alanine aminotransferase, aspartate aminotransferase, C-reactive protein, alkaline phosphatase, gamma-glutamyl transferase, total protein, albumin, creatinine, uric acid, and blood urea nitrogen), coagulation analysis (including prothrombin time, thrombin time, and activated partial thromboplastin time), and immunology; to evaluate hemolysis, inflammation, and immune responses in the animal's blood after implantation of the device. Transthoracic ultrasound examination: Observe for vegetations and abnormal blood flow within the valves and annulus; measure left ventricular volume, aortic valve blood flow velocity and pressure gradient, and left ventricular ejection fraction; observe and record the size of each heart chamber, degree of regurgitation, and regurgitation of each valve in the experimental animals. Gross anatomy and pathological examination: Gross anatomy and pathological examination were performed on all animals that reached and did not reach the experimental endpoint. General anesthesia, femoral vein puncture for blood sampling (complete blood count, liver and kidney function); systemic heparinization, 3 mg / kg (heparinization is to prevent blood clotting after animal sacrifice, which could be confused with thrombi formed within the limited expandable bioprosthetic valve); animals were sacrificed by exsanguination under general anesthesia; observe the tissue condition around the implanted limited expandable bioprosthetic valve and the presence of morphological changes, adhesions, fibrous cysts, etc., at the tissue junctions, and take photographs; observe the morphological changes of the leaflets, thrombus formation, and calcification of the limited expandable bioprosthetic valve with the naked eye and take photographs; if thrombi are present, record the weight of the thrombus (wet). The proportion of the implant surface to the total weight of the prosthesis; observe the morphology of the aortic valve conduit and record the deformation; collect the expandable bioprosthetic valve and surrounding tissue to prepare pathological sections and observe pathological changes under a microscope: sample the expandable bioprosthetic valve and the surrounding 3mm area, fix in 10% neutral formalin for 10-14 days, embed in paraffin, section the tissue, and stain with HE; organ anatomy: dissect the heart, lungs, spleen, liver, kidneys, brain and other organs, first perform a gross examination, observe the condition of the surgical (chest) incision, whether there are infarcts and abnormal lesions, and take pictures and record them. Processing and analysis of cardiac specimens: cut open the left atrium and left ventricle to observe the valve placement position from the endocardial surface. Then take the ventricular cavity wall and the tissue around the aortic valve, fresh or refrigerated at 4°C, and send the specimens for examination on the day of the experiment endpoint or within 24 hours of accidental death. A full organ examination was conducted, focusing on changes on the valve surface and the presence of thromboembolism, infection, and necrosis in various organs. Routine light microscopic sampling was performed, including sampling of the left ventricle, left atrium, confined dilatable aortic valve conduit, and peri-aortic valve tissue, as well as confined dilatable bioprosthetic valves.

[0164] 5. Animal Experiment Results

[0165] (1) In the eight embodiments, during the Bentall procedure using the limited expandable aortic valve conduit of embodiment 4, severe bleeding occurred at the connection between the proximal conduit and the left ventricular outflow tract. It is speculated that the elastic deformation rate as a percentage of the maximum circumferential elongation was low. Therefore, the elastic deformation rate as a percentage of the maximum circumferential elongation should be greater than 21%, and can be controlled between 38-68%.

[0166] (2) In the eight embodiments, the limited dilatable aortic valve conduit obtained in embodiments 2-3 and 5-9 did not cause uncontrollable anastomotic bleeding in animals during or after the operation. Furthermore, the conduit has strong shear resistance and no kinking was observed, demonstrating excellent mechanical properties.

[0167] Following minimally invasive interventional procedures, the experimental animals using the limited-position dilatational aortic valve conduits obtained in Examples 2-3 and 5-9 generally maintained good health during the rearing period. Their body temperature, diet, and excretion were normal, and they exhibited good spontaneous activity. No abnormal behaviors such as shortness of breath, oliguria, significant weight loss, fever, anorexia, or mania were observed. They successfully reached the endpoint without complications such as myocardial infarction, severe arrhythmia, embolism, or prosthetic valve dysfunction. Complete blood counts, blood biochemistry, and coagulation tests were all normal. Electrolytes and liver and kidney function values ​​remained almost within the normal range during follow-up periods after the cardiac radiofrequency ablation procedure. The coagulation INR value was approximately 1.0 both preoperatively and during follow-up. No abnormalities were observed in the number, morphology, or quality of complete blood cells. Tests for white blood cells, red blood cells, hemoglobin, and platelets showed overall stability, with no significant abnormalities found in routine blood indicators. No abnormalities were observed in liver or kidney function.

[0168] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. This disclosure is not limited to the precise structures described above and shown in the accompanying drawings, and various modifications and changes can be made without departing from its scope. The scope of this disclosure is limited only by the appended claims. Thus, if these modifications and variations of the invention fall within the scope of the claims of the invention and their equivalents, the invention is also intended to include these modifications and variations.

Claims

1. A limited expansion aortic valve conduit, characterized in that, The aortic valve preliminary conduit includes a collagen fiber coating and includes a proximal conduit, a valve connecting cannula, and a distal conduit. The collagen fiber coating is formed by a second chemical cross-linking of collagen fibers whose melting point has changed to 68.54-71.24℃ after the first chemical cross-linking. The collagen fiber coating is attached to the internal voids and surface of the aortic valve preliminary conduit; the melting point of the collagen fiber coating is 77.59-79.84℃, and the difference between the melting point of the collagen fiber coating and the melting point of the collagen fiber after the first chemical cross-linking is in the range of 7.39-11.30℃.

2. The constrained expandable aortic valve conduit of claim 1, wherein, In its natural state, the aortic valve pre-conduit has an axial length of not less than 5 mm and includes at least 2 corrugations in the axial direction; the valve connecting tube has an axial length of 23-29 mm and includes 24-36 corrugations in the circumferential direction; and the distal conduit has an axial length of not less than 70 mm and includes at least 30 corrugations in the axial direction.

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

36.

4. The constrained expandable aortic valve conduit of claim 1, wherein, The maximum circumferential tensile elongation of the distal conduit of the limiting dilatational aortic valve conduit ranges from 2.2% to 4.8%, the elastic deformation rate ranges from 1.0% to 2.3%, the elastic deformation rate as a percentage of the maximum circumferential tensile elongation ranges from 38% to 68%, and the maximum tensile force ranges from 13.5% to 55.9 N.

5. The constrained expandable aortic valve conduit of claim 1, wherein, The outer diameter of the maximum bulge of the valve connecting tube ranges from 28 to 38 mm, and the outer diameter of the connection points at both ends of the valve connecting tube ranges from 24 to 33 mm.

6. The constrained expandable aortic valve conduit of claim 1, wherein, It also includes a limiting expandable bioprosthetic valve, which is sewn onto the inner surface of the valve connecting tube, or a limiting expandable bioprosthetic valve is sewn onto the inner surface of the connection between the valve connecting tube and the proximal conduit.

7. The constrained expandable aortic valve conduit of claim 6, wherein, It also includes a valve holder that connects to the limited expandable bioprosthetic valve.

8. The constrained expandable aortic valve conduit of claim 7, wherein, The valve holder has two symmetrically arranged knotted protrusions integrally connected to its rod, with a suture cutting groove formed between the two knotted protrusions.

9. The constrained expandable aortic valve conduit of claim 1, wherein, The connection between the proximal / distal conduit and the valve connecting tube is folded outward, and the ends of the valve connecting tube are respectively fitted onto the outside of the proximal / distal conduit. The suture passes back and forth through the inner and outer walls of the valve connecting tube and the connection between the proximal / distal conduit.

10. A method of making a constrained expandable aortic valve conduit, characterized by, include: Step 1: Cutting and connecting: Select a polyester corrugated tube with a corrugation width of 1.24-1.89 mm, a corrugation height of 0.93-1.44 mm, and a corrugation width-to-height ratio of 1.24-1.

36. Cut it along its axial direction to obtain the distal conduit, the valve intermediate conduit, and the proximal conduit. Cut the valve intermediate conduit along its axial direction to obtain a rectangular corrugated tube, so that the corrugations are arranged along the axial direction of the entire limiting expandable aortic valve conduit. Then sew it into a valve connecting tube. The proximal aortic valve conduit is obtained by sequentially connecting the proximal conduit, valve connecting cannula, and distal conduit with sutures. The second step involves attaching a collagen fiber coating to the internal gaps and inner and outer surfaces of the aortic valve pre-conduit: S1. Preparation of collagen fibers; S2. Using bio-derived collagen as raw material and glutaraldehyde as a cross-linking agent, collagen fibers with a melting point of 68.54-71.24℃ are obtained through the first chemical cross-linking process. S3. The collagen fibers obtained from step S2, which have undergone the first chemical cross-linking, are sprayed onto the polyester corrugated pipe and dried to obtain a polyester corrugated pipe with adsorbed collagen fibers; the spraying density of the collagen fibers that have undergone the first chemical cross-linking on the surface of the polyester corrugated pipe is 1.5-6 mg / cm³. 2 ; S4. Immerse the polyester corrugated pipe with adsorbed collagen fibers in a crosslinking agent solution to obtain a polyester corrugated pipe with adsorbed collagen fibers impregnated with a crosslinking agent; the crosslinking agent solution is a compound solution of N-hydroxysuccinimide and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, compounded in a 1:1 mass ratio, with a concentration of 27-40 mg / mL; S5. Immerse the polyester corrugated tube obtained in step S4 in a collagen fiber solution of 3.5-5.5 mg / mL that has undergone the first chemical cross-linking for a second chemical cross-linking. Let it stand for more than 2 hours and then dry it to obtain a polyester bio-patch with a collagen fiber coating. The melting point range of the collagen fiber coating is 77.59-79.84℃. The third step is to dry the limited expandable bioprosthetic valve to obtain a dried limited expandable bioprosthetic valve. The fourth step involves assembling the valve holder, preparing the dry, expandable bioprosthetic valve, and the preliminary aortic valve conduit to obtain the expandable aortic valve conduit.

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