A tissue engineered valve and valve stent

Abstract

The application relates to a tissue engineering valve, which comprises at least two valve leaves, the valve leaves are sewn by threads to form a valve shape; each of the valve leaves comprises a base layer and a living tissue layer attached to the surface of the base layer, the base layer is made of a degradable high polymer material; the valve leaves of the tissue engineering valve are sewn by threads to form a valve structure, each valve leaf has a base layer made of a degradable high polymer material, the base layer of the structure can be gradually degraded after entering the patient's tissue, no residues are left, the risk of pulmonary valve surgery of the patient is reduced, the living tissue layer is formed by TE technology to have a life-supporting living tissue, the damaged tissue is reconstructed in shape, structure and function and reaches permanent replacement and perfect shaping, and the secondary risk of surgery is greatly reduced; the application further provides a valve support with the above tissue engineering valve.

Description

Technical Field

[0001] This invention relates to the field of interventional cardiac surgery devices, specifically to a tissue-engineered valve and valve stent. Background Technology

[0002] In recent years, due to the continuous increase in life expectancy, the number of elderly and high-risk patients with valvular heart disease has been steadily increasing. In the field of interventional cardiology, percutaneous heart valve surgery has developed rapidly due to its minimally invasive nature, low risk, and high patient acceptance. Currently, techniques applied clinically include percutaneous aortic valve replacement, percutaneous pulmonary valve replacement, and percutaneous mitral valve repair. Among these three techniques, percutaneous pulmonary valve replacement was the first to be applied clinically because the pulmonary valve region has a relatively simple anatomical structure and lower circulatory pressure. This technique involves delivering an artificial pulmonary valve stent via a catheter through a peripheral vein to the patient's own pulmonary valve to replace the dysfunctional pulmonary valve, thereby treating pulmonary valve disease.

[0003] In some common congenital heart disease surgeries, such as tetralogy of Fallot, right ventricular outflow tract stenosis, and pulmonary atresia, it is necessary to use artificial or biological valved conduits to reconstruct the right ventricular outflow tract, or to use pulmonary valve patching. For the former, postoperative calcification and deterioration of the artificial or biological valved conduit can lead to stenosis and / or insufficiency of the conduit and valve. For the latter, a transvalvular patch is used to address right ventricular outflow tract stenosis; however, this method damages the structure of the pulmonary valve, resulting in loss of pulmonary valve function and potentially leading to severe right ventricular dysfunction, increasing the risk of fatal arrhythmias and sudden death. Therefore, for children with these types of congenital heart disease, transvalvular patching to relieve right ventricular outflow tract obstruction is the most common procedure in my country. Many patients face the need for repeat pulmonary valve surgery in adulthood.

[0004] Tissue engineering (TE) is a newly emerging discipline in recent years, belonging to the field of biotechnology. The term TE was first proposed in 1987 by American chemical engineer Robert Langer and surgeon Joseph P. Vacanti at a bioengineering panel meeting held by the National Science Foundation in Washington, D.C. In 1988, it was formally defined as: an emerging discipline that applies the principles and technologies of life sciences and engineering to study and develop biological substitutes for repairing, maintaining, and promoting the function and morphology of various tissues or organs after injury, based on a correct understanding of the relationship between tissue structure and function in both normal and pathological states in mammals. It involves many fields such as cell biology, molecular biology, chemistry, biomaterials engineering, and clinical practice, belonging to a systematic, multidisciplinary research scope. The core of TE is to establish a three-dimensional spatial complex composed of cells and biomaterials. Its greatest advantage is that it can form living tissue with vitality, reconstructing the morphology, structure, and function of damaged tissues and achieving permanent replacement and perfect shaping.

[0005] In the prior art, there is no application of tissue engineering technology in the field of pulmonary valve replacement. In order to fill the technological gap in this field, this application proposes a tissue-engineered valve and valve stent. Summary of the Invention

[0006] Based on the above description, the present invention provides a tissue-engineered valve to fill the technical gap in the prior art where tissue engineering technology is not used in the structural or functional application of pulmonary valves.

[0007] The technical solution of the present invention to solve the above-mentioned technical problems is as follows: A tissue-engineered valve comprising at least two leaflets, the leaflets being sutured together to form a valve shape; Each of the leaflets includes a basal layer and a living tissue layer attached to the surface of the basal layer, the basal layer being made of a biodegradable polymer material.

[0008] Compared with the prior art, the technical solution of this application has the following beneficial technical effects: The tissue-engineered valve provided in this application has leaflets formed by suture closure. Each leaflet has a base layer made of biodegradable polymer material. This base layer gradually degrades after entering the patient's tissue, leaving no residue and reducing the risk of repeat pulmonary valve surgery. The living tissue layer is formed using TE technology to create living tissue, which reconstructs the morphology, structure, and function of the damaged tissue and achieves permanent replacement and perfect shaping, greatly reducing the secondary risks of surgery.

[0009] Based on the above technical solution, the present invention can be further improved as follows.

[0010] Furthermore, the degradation rates of the biodegradable material used in the base layer of all the petals are not all the same.

[0011] Furthermore, the living tissue layer is formed by culturing autologous cells, allogeneic cells, or xenogeneic cells in a culture dish; the thread is formed by culturing autologous cells, allogeneic cells, or xenogeneic cells in a culture dish.

[0012] Furthermore, the base layer is made by weaving or 3D printing.

[0013] This application also provides a valve stent, which includes a stent body and a tissue-engineered valve as described above; The sidewalls of the stent are grid-like and have a valve receiving cavity in the middle. The tissue-engineered valve is disposed in the valve receiving cavity and is sutured to the inner wall of the stent on the outside. The stent has a connector for detachable connection with an external delivery system.

[0014] Furthermore, the support body includes an upper part, a waist part, and a lower part; the upper part and the waist part are partially disconnected; or The waist and lower part are partially disconnected.

[0015] Furthermore, the vertices of the upper sidewall mesh near the waist are disconnected from the corresponding vertices of the waist sidewall mesh near the upper part; and / or The vertices of the sidewall mesh of the waist near the lower part are disconnected from the corresponding vertices of the sidewall mesh of the lower part near the waist.

[0016] Furthermore, at least two vertices of the upper sidewall mesh near the waist are fixedly connected to the corresponding vertices of the waist sidewall mesh near the upper part using connecting ribs; and / or At least two vertices of the sidewall mesh of the waist section near the lower part are fixedly connected to the corresponding vertices of the sidewall mesh of the lower part near the waist section using connecting ribs.

[0017] Furthermore, the support body includes an upper part, a waist part, and a lower part; the upper part and the waist part are completely disconnected and connected by a wire; and / or The waist and the lower part are completely disconnected and connected by a line.

[0018] Furthermore, the support body is made of a biodegradable material, and the biodegradable material used in the waist part degrades at a slower rate than the biodegradable materials used in the upper and lower parts. Attached Figure Description

[0019] Figure 1 This is a schematic diagram of the structure of a tissue-engineered valve provided in Embodiment 1 of the present invention; Figure 2 This is a cross-sectional schematic diagram of a leaflet according to an embodiment of the present invention; Figure 3 This is a schematic diagram of a valve stent provided in Embodiment 2 of the present invention; Figure 4 This is a schematic diagram of the integrally formed support structure in Embodiment 2 of the present invention; Figure 5 This is a schematic diagram of the first structure of the support body in Embodiment 2 of the present invention; Figure 6 This is a schematic diagram of the second structure of the support body in Embodiment 2 of the present invention. Detailed Implementation

[0020] To facilitate understanding of this application, a more complete description will be provided below with reference to the accompanying drawings, which illustrate embodiments of the present application. However, the present application can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that the disclosure of this application will be thorough and complete.

[0021] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application.

[0022] It is understood that spatial relation terms such as "below," "under," "below," "below," "above," "above," etc., can be used here to describe the relationship between one element or feature shown in the figure and other elements or features. It should be understood that, in addition to the orientation shown in the figure, spatial relation terms also include different orientations of the device in use and operation. For example, if the device in the figure is flipped, the element or feature described as "below" or "below" of the other element or feature will be oriented "above" the other element or feature. Therefore, the exemplary terms "below" and "below" can include both upper and lower orientations. Furthermore, the device may also include other orientations (e.g., rotated 90° or other orientations), and the spatial descriptive terms used herein will be interpreted accordingly.

[0023] It should be noted that when one element is considered to be "connected" to another element, it can be directly connected to the other element or connected to the other element through an intermediary element. In the following embodiments, "connection" should be understood as "electrical connection," "communication connection," etc., if the connected circuits, modules, units, etc., have the transmission of electrical signals or data between them.

[0024] When used herein, the singular forms of “a,” “an,” and “the” may also include the plural forms unless the context clearly indicates otherwise. It should also be understood that the terms “comprising,” “including,” or “having,” etc., specify the presence of the stated feature, whole, step, operation, component, part, or combination thereof, but do not preclude the possibility of the presence or addition of one or more other features, wholes, steps, operations, components, parts, or combinations thereof.

[0025] Example 1 like Figure 1 and Figure 2 As shown, this application provides a tissue-engineered valve, which includes at least two leaflets 10, the leaflets 10 being formed into a valve shape by suture stitching; in optional embodiments of this application, the number of leaflets 10 can be two or three, preferably three.

[0026] Each leaflet 10 includes a basal layer 11 and a living tissue layer 12 attached to the surface of the basal layer 11. Leaflets 10 cultured from living tissue cells lack sufficient mechanical strength, making them difficult to suture properly when forming a valve. Therefore, the basal layer 11 is needed to facilitate the formation of a complete valve. The basal layer 11 is made of a biodegradable polymer material. This type of basal layer 11 gradually degrades over time after entering the patient's tissue, leaving no residue and reducing the risk of repeat surgery. The living tissue layer 12 is attached to both sides of the basal layer 11. It is formed into a living tissue using TE technology, which reconstructs the morphology, structure, and function of the damaged tissue and achieves permanent replacement and perfect shaping, greatly reducing the secondary risks of surgery.

[0027] The degradation rates of the biodegradable materials used in the base layers 11 of the three leaflets 10 are not all the same; for example, the base layers 11 within the three leaflets 10 may use materials with different degradation rates. This is because the base layer of a tissue-engineered valve has a certain mechanical strength. If the base layers 11 of the three leaflets 10 degrade simultaneously during degradation, the mechanical strength of the leaflets will disappear at the same time, causing changes in the blood flow through the leaflets during opening and closing. If this change is too large, it can have adverse effects on the human body. Different degradation rates can mitigate this change. It is understandable that the base layers 11 may use materials with different degradation rates but similar initial mechanical strength, such as PDO and PL. A, where PDO, also known as 1,3-propanediol, is a high-molecular-weight material with excellent polymer monomer synthesis performance. It is a colorless, transparent, and odorless liquid that is miscible with water, alcohols, and a variety of organic solvents, and slightly soluble in benzene and chloroform, possessing the typical properties of alcohols and glycols; PLA, or polylactic acid, also known as polylactide, is a polyester polymer obtained by polymerizing lactic acid as the main raw material. It is a new type of biodegradable material. Both of these materials are biodegradable materials that can be applied in the surgical field, and the degradation rate and mechanical strength can be controlled in various ways, such as by controlling the ratio of copolymers within the material or the content of additives. Based on the above structural characteristics, the base layer 11 is made by weaving or 3D printing.

[0028] The living tissue layer 12 is formed by culturing autologous cells, allogeneic cells, or xenogeneic cells in a culture dish; the suture used to sew the leaflets is also formed by culturing autologous cells, allogeneic cells, or xenogeneic cells in a culture dish. During fabrication, the cells are introduced into an environment subjected to cyclic pressure and attached to the basal layer 11, wherein the cyclic pressure causes pulsating motion in the aforementioned environment.

[0029] Example 2 like Figure 3 As shown, this embodiment provides a valve stent based on the above-mentioned tissue-engineered valve, used to replace a dysfunctional arterial valve in diseased tissue. In this embodiment, the pulmonary valve is preferred.

[0030] The valve stent includes a stent body 210 and a tissue-engineered valve 220 disclosed in Example 1.

[0031] Similar to existing valve stent structures, the stent body 210 is generally cylindrical in shape. The sidewalls of the stent body 210 have a mesh-like structure to facilitate compression and self-expansion. The central part is configured as a valve receiving cavity. The tissue-engineered valve 220 is disposed in the valve receiving cavity and its outer side is sutured and fixed to the inner wall of the stent body 210. It can be understood that, in order to facilitate the suturing and fixing of the tissue-engineered valve 220, a skirt is connected to the inner wall of the stent body 210. The tissue-engineered valve 220 is sutured to the skirt to ensure stability and reliability.

[0032] The support body 210 has a connector 211 for detachable connection with an external conveying system. The connector 211 is a protrusion or an annular component. If the connector 211 is a protrusion, a corresponding groove is provided on the corresponding structure of the external conveying system. If the connector 211 is an annular component, a corresponding protrusion is provided on the corresponding structure of the external conveying system to ensure that the annular component can elastically hold the protrusion. In the preferred embodiment of this application, the connector 211 is a protrusion, and three are evenly provided circumferentially at the end of the support body 210 to ensure a stable connection with the external conveying system.

[0033] In this application, as Figure 4 and Figure 5 As shown, the support body 210 includes three parts: an upper part 21a, a waist part 21b, and a lower part 21c. According to a general design, the inner diameter of the upper part 21a and the lower part 21c is larger than that of the waist part, forming a shape similar to the joint of two funnel openings.

[0034] In some alternative embodiments, the three parts of the support body can be integrally molded, such as Figure 3 As shown, when the pulmonary valve stent provided in this application is compressed inside the sheath of the external delivery system, because the pulmonary valve stent is relatively long, if the upper part 21a, the waist part 21b, and the lower part 21c are made into a completely connected integral structure after compression, the inflexible part of the sheath will be longer. This makes it difficult to operate the sheath when the pulmonary valve stent passes through the blood vessel during implantation. Since the structure of the upper part 21a and the lower part 21c also serves to fix the stent, a split structure can be used to deliver the stent. On the other hand, because the pulmonary valve stent is very large, it will generate a large radial tension, which can easily enlarge the pulmonary artery. Therefore, in some preferred embodiments, a split structure design can be used to effectively reduce the radial tension.

[0035] As a characteristic of the first type of split structure, such as Figure 4 As shown, the upper part 21a and the waist part 21b are partially disconnected, or the waist part 21b and the lower part 21c are partially disconnected.

[0036] The partial disconnection between the upper part 21a and the waist part 21b includes the disconnection of some vertices of the sidewall mesh of the upper part 21a near the waist part 21b from the corresponding vertices of the sidewall mesh of the waist part 21b near the upper part 21a; that is, the upper part 21a and the waist part 21b are not completely separated. Specifically, at least two vertices of the sidewall mesh of the upper part 21a near the waist part 21b are fixedly connected to the corresponding vertices of the sidewall mesh of the waist part 21a near the upper part 21a by connecting ribs 212. In a certain optional embodiment, there are 9 rhomboid meshes around the circumference, which means there are 9 vertices corresponding to the upper part 21a and the waist part 21b. Three connecting ribs 212 are arranged in a circular pattern around the circumference to ensure a stable connection between the upper part 21a and the waist part 21b while also achieving bending control, which is convenient for implantation.

[0037] Similarly, the partial disconnection of the waist 21b and the lower part 21c includes the disconnection of some vertices of the side wall mesh of the waist 21b near the lower part 21c from the corresponding vertices of the side wall mesh of the lower part 21c near the waist 21b; specifically, the three vertices of the side wall mesh of the waist 21b near the lower part 21c are fixedly connected to the corresponding vertices of the side wall mesh of the lower part 21c near the waist 21b by connecting ribs 212.

[0038] As a characteristic of the second type of split structure, such as Figure 5 As shown, the upper part 21a and the waist part 21b are completely disconnected and connected by a line, or the waist part 21b and the lower part 21c are completely disconnected and connected by a line.

[0039] The complete disconnection between the upper part 21a and the waist part 21b includes the disconnection of all vertices of the sidewall mesh of the upper part 21a near the waist part 21b and the corresponding vertices of the sidewall mesh of the waist part 21b near the upper part 21a. That is, the upper part 21a and the waist part 21b are completely separate and are flexibly connected by a line. Similarly, the complete disconnection between the waist part 21b and the lower part 21c includes the disconnection of all vertices of the sidewall mesh of the waist part 21b near the lower part 21c and the corresponding vertices of the sidewall mesh of the lower part 21c near the waist part 21b. Preferably, the line is a thread made of a biodegradable material.

[0040] The support body 210 is made of a biodegradable material, and the biodegradable material used in the waist part 21b degrades at a slower rate than the biodegradable material used in the upper part 21a and the lower part 21c.

[0041] The purpose of using biodegradable scaffold 210 is so that after final degradation, only the tissue-engineered valve that replaces the human valve remains, thus playing a regenerative role. However, the tissue-engineered valve is located on the inner side of the waist 21b, and the endothelial tissue needs to attach to the tissue-engineered valve. At this time, the upper part 21a and the lower part 21c of the scaffold can easily form an obstacle. If the degradation rate is the same or the degradation rate of the waist 21b is too fast, the tissue-engineered valve is prone to detachment. Therefore, by different degradation rates, valve regeneration can be achieved and tissue-engineered valve detachment can be prevented. Preferably, the scaffold 210 is made of zinc-magnesium alloy, which is a biodegradable alloy material. The degradation rate of the middle part can be slowed down by adjusting the content, for example, by adjusting the content to make the degradation rate different.

[0042] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A valve stent, characterized in that, It includes a scaffold and a tissue-engineered valve; the tissue-engineered valve includes at least two leaflets, which are formed into a valve shape by suture stitching. Each of the leaflets includes a basal layer and a living tissue layer attached to the surface of the basal layer, the basal layer being made of a biodegradable polymer material; the degradation rate of the biodegradable material used in the basal layer of all the leaflets is not entirely the same; The sidewalls of the stent are grid-like and have a valve receiving cavity in the middle. The tissue-engineered valve is placed in the valve receiving cavity and its outer side is sutured and fixed to the inner wall of the stent. The stent has a connector for detachable connection with an external delivery system. The support structure includes an upper part, a waist part, and a lower part; the upper part and the waist part are completely disconnected and connected by a wire; and / or The waist and the lower part are completely disconnected and connected by a line; The support body is made of a biodegradable material, and the biodegradable material used in the waist part degrades at a slower rate than the biodegradable material used in the upper and lower parts.

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