A method for manufacturing a personalized, naturally designed mitral valve prosthesis

Abstract

A personalized natural design mitral valve prosthesis and a method for manufacturing the personalized natural design mitral valve prosthesis to precisely fit a specific patient for which the valve prosthesis is manufactured are provided. The method includes measuring the size and shape of the mitral valve of the specific patient by using an imaging device, constructing a 3D model of the personalized mitral valve prosthesis, optimizing the 3D model using a FEM method, and manufacturing the personalized mitral valve prosthesis by cutting and connecting annular rings, leaflets, and a chordae to form the personalized prosthesis mitral valve.

Description

Background Technology

[0001] The mitral valve, or left atrioventricular valve, is a bicuspid valve (a valve composed of two leaflets) that separates the left atrium and left ventricle in the heart. During ventricular diastole, the mitral valve allows blood to flow from the left atrium to the left ventricle, while preventing retrograde flow during systole. A naturally formed mitral valve consists of a valve annulus, two leaflets, atrial myocardium, chordae tendineae, pupillary muscle, and ventricular myocardium.

[0002] Mitral valve replacement is a procedure designed to replace a diseased or nonfunctional valve. During mitral valve replacement surgery, the patient's mitral valve is removed and replaced with a prosthesis. The unique configuration of the mitral valve presents challenges in manufacturing durable and functional mitral valve prostheses.

[0003] Biological and mechanical mitral valve prostheses are commercially available. Compared to the soft tissue and asymmetrical shape of a human mitral valve, both biological and mechanical prostheses have a rigid, rounded shape. Another disadvantage of mechanical valves is that blood tends to clot on the mechanical components of the valve, leading to valvular dysfunction. Patients using mechanical valves must take anticoagulants to prevent blood clots from forming on the valve, which can cause stroke. Compared to mechanical valves, biological valves have a lower risk of blood clot formation, but their durability is more limited, requiring more frequent replacements. Like mechanical valves, biological valves consist of a rigid metal skeleton and have metal rings covered with silicone or other synthetic materials to allow implantation sutures to pass through.

[0004] Currently available mitral valve prostheses are typically constructed in an unnaturally round shape and are usually made of rigid materials. They also often have three symmetrical leaflets, whereas the natural human mitral valve consists of only two leaflets: a larger anterior leaflet and a smaller posterior leaflet. Due to their rigid and unnatural structure, these mitral valve prostheses distort the natural anatomy of the heart. The myocardium surrounding these prostheses does not recover well after implantation surgery. The average lifespan of these prostheses is only 7 to 10 years, leading to patients needing a second, and sometimes even a third, surgery during their lifespan. This repeated exposure exposes patients to a high risk of open-heart surgery.

[0005] Commercially available mitral valves cannot achieve the hemodynamic performance of a healthy, native human mitral valve. This leads to significant energy loss in the left ventricle, substantial strain over time, and ultimately, heart failure and other adverse effects.

[0006] Some other available mitral valve prostheses can be formed by enhanced allograft formation, as described in U.S. Patent No. 6,074,417. This means that physicians need to scan valves of various sizes to find the best match for each patient, while sacrificing the animal in which the valve will be removed. Other available mitral valve prostheses can be formed by suturing multiple pericardial layers together, as described in U.S. Patent No. 5,415,667. This can lead to coagulation in areas where multiple sutures are present.

[0007] Other forms of atrioventricular valves, including the mitral valve, are disclosed in U.S. Patent No. 6,358,277, in which a membrane material template is sutured to the patient's mitral valve annulus. This type of valve has a high and unnaturally shaped annulus, causing the prosthetic valve to have a large peripheral volume and bulge like a collar. Furthermore, the template is provided in a standard size and must then be trimmed to fit the patient. Summary of the Invention

[0008] A method is provided for manufacturing a personalized, naturally designed mitral valve prosthesis that precisely fits and functions in an individual patient. Specifically, the method includes a series of operations or procedures, beginning with receiving an order for a custom / personalized mitral valve prosthesis, diagnostic imaging and analysis of the imaging results, quantifying the geometry and size of the valve prosthesis using a validated algorithm, assembling the prosthesis according to the individualized geometry and size of the receiving patient, and further packaging and sterilizing the personalized valve prosthesis into the final mitral valve prosthesis, delivering it to the specific patient, and implanting the personalized prosthetic mitral valve into the patient to produce a valve.

[0009] A method is provided for manufacturing a personalized, naturally designed mitral valve prosthesis to precisely fit the specific patient for whom the valve prosthesis is being manufactured. The method may include: measuring the size and shape of the specific patient's natural mitral valve using imaging methods; calculating the geometry and dimensions of the annular ring, anterior leaflet, posterior leaflet, and umbilical cord for each specific patient based on a validated algorithm; and cutting and connecting the annular ring, anterior leaflet, posterior leaflet, and umbilical cord to form a personalized prosthetic mitral valve.

[0010] According to some implementations, imaging methods may include: 2D or 3D echocardiography, computed tomography (CT), cardiac magnetic resonance (CMR), or any combination thereof.

[0011] According to some implementations, measuring the size and shape of a patient’s natural mitral valve may include measuring mitral valve-related parameters, which may include: annular circumference (AC), annular area (AA), anterior-posterior (AP) diameter, anterolateral-posteromedial (AL-PM) diameter, commissural diameter (CC), anterior leaflet length (ALL), posterior leaflet length (PLL), mitral valve shape, and chordae tendineae length (ACL and PCL).

[0012] According to some implementations, the method may also include collecting physical information of a specific patient for use in the calculation process to predict the geometry of the implanted heart after the heart valve function has improved, said physical information including: height, weight, age, ethnicity, and sex.

[0013] A personalized mitral valve prosthesis includes a flexible annular ring whose size matches the patient's natural mitral valve annulus, flexible anterior and posterior leaflets whose sizes match the patient's natural mitral valve leaflets, and leaflets and an umbilical cord connected to the annular ring whose sizes match the patient's natural mitral valve leaflets, providing an umbilical cord connection to the cardiac papillary muscles. The personalized mitral valve prosthesis can be formed in the following ways: The size and shape of the natural mitral valve in a specific patient were measured using imaging methods; The geometry and dimensions of the annulus, lobule, and umbilical cord for each specific patient are calculated using a validated algorithm; and The annular ring, leaflets, and umbilical cord are cut and connected to form a personalized prosthetic mitral valve.

[0014] According to some implementations, imaging methods may include: 2D or 3D echocardiography, computed tomography (CT), cardiac magnetic resonance (CMR), or any combination thereof.

[0015] According to some implementations, measuring the size and shape of a patient's mitral valve may include measuring mitral valve-related parameters, which may include: annular circumference (AC), annular area (AA), anterior-posterior (AP) diameter, anterolateral-posteromedial (AL-PM) diameter, commissural diameter (CC), anterior leaflet length (ALL), posterior leaflet length (PLL), mitral valve shape, and chordae tendineae length (ACL and PCL).

[0016] According to some implementations, personalized mitral valve prostheses can also be formed by collecting specific patient body information for use in the calculation process to predict the geometry of the implanted heart after the heart valve function has improved. The body information includes: height, weight, age, race, and sex.

[0017] According to some embodiments, the calculation may include calculating the annular circumference (AC) as a combination of the annular circumference (AAC) of the anterior lobule as the top edge of the anterior lobule and the annular circumference (PAC) of the posterior lobule as the top edge of the posterior lobule, based on the following equation (iii). According to some embodiments, the annulus can be formed into a multi-layered reinforced structure by folding or overlapping the top edges of each of the anterior and posterior lobules.

[0018] According to some implementations, the top edge of each of the anterior and posterior leaflets can be straight or curved so that the personalized mitral valve prosthesis can properly fit the natural geometry of the left ventricle of a particular patient.

[0019] According to some embodiments, the connection may include connecting the edge of the anterior leaflet to the edge of the posterior leaflet, thereby forming an engagement between the anterior and posterior leaflets. According to some embodiments, the engagement can control the function and performance of a personalized mitral valve prosthesis by controlling the size of the valve orifice, thereby influencing the transmitral pressure gradient.

[0020] According to some implementations, the connection may include joining two leaflets together to form two commissures, wherein the two commissures are tilted inward at a cone angle (δ1) to form a slight cone shape on the body of the personalized mitral valve prosthesis to suitably fit the natural left ventricle of each patient’s individual shape and contour.

[0021] According to some implementations, the cone angle (δ1) can be determined based on the equation (x) by the tilt angle (δ0) of each merging edge of the two leaflets.

[0022] According to some implementations, the connection may include connecting the anterior lobule to the posterior lobule by connecting the anterolateral side to the anterolateral side and the posteromedial side to the posteromedial side.

[0023] According to some implementations, the anterior lobule can be connected to the posterior lobule by suturing.

[0024] According to some implementations, the measurement may include measurements of the size and shape of the natural annular ring of a particular patient, the commissural height (CH), the tilt angle (δ0), the anterior lobule length (ALL), and the posterior lobule length (PLL), based on the following equation (xi), and the coaptation height (CoaptH) used to calculate the length of each lobule edge.

[0025] According to some implementation methods, the height of the reinforcing ring can be between 1 mm and 4 mm.

[0026] According to some implementation methods, the height of the reinforcing ring can be between 2mm and 3mm.

[0027] According to some implementations, the annular circumference (AC) can be a function of the front-to-back diameter (AP) and the front-outer-back-inner diameter (AL-PM) based on the following equation (iii).

[0028] According to some implementation methods, the anterior-posterior diameter (AP) and anterolateral-posteromedial diameter (AL-PM) can be measured during mitral valve closure during left ventricular systole.

[0029] According to some implementations, the annular circumference (AC) of the prosthesis can be calculated based on the annular width (d) of the natural leaflet preserved during clinical surgery.

[0030] According to some implementations, the annular circumference (AC) of the prosthesis can be calculated based on the ratio (λ) in equation (iii).

[0031] According to some embodiments, the annular ring can be asymmetrical. According to some embodiments, the annular ring can be formed by a combination of an anterior lobule ring and a posterior lobule ring, wherein the anterior lobule annular circumference (AAC) can be smaller than the posterior lobule annular circumference (PAC), and the ratio (R) between AAC / PAC can be between 49 / 51 and 30 / 70.

[0032] According to some implementation methods, the ratio (R) between AAC / PAC can be between 35 / 65 and 42 / 58.

[0033] According to some implementation methods, the ratio (R) between AAC / PAC can be 40 / 60.

[0034] According to some implementations, the ratio (R) between AAC / PAC can be between the anterior leaflet length (ALL) and the posterior leaflet length (PLL), and may be crucial for ensuring proper opening and closing of the prosthetic valve.

[0035] According to some implementations, the calculation may include calculating the anterior lobule length (ALL) and posterior lobule length (PLL) based on equations (viii) and (ix), respectively, based on: (a) the anterior-posterior diameter (AP) as the theoretical minimum engagement distance, (b) the ratio (r) between AL and PL, (c) the engagement depth (Cd), (d) the engagement height (CoaptH), and (e) the umbilical cord length (Lc).

[0036] According to some implementations, the connection may include a body that connects two leaflets together to form a personalized mitral valve prosthesis.

[0037] According to some embodiments, each anterior lobule and each posterior lobule may include two sets of umbilical cords: an anterolateral umbilical cord and a posteromedial umbilical cord. According to some embodiments, each of the anterolateral and posteromedial umbilical cords may include three sub-umbilical cords, whereby the umbilical cords are evenly distributed from each end along at least 3 / 8 of each edge.

[0038] According to some implementations, the calculation may include calculating the length of each umbilical cord to ensure that the personalized mitral valve prosthesis opens and closes correctly, thereby calculating the length of each umbilical cord based on several parameters, including: leaflet length, junction height, and junction depth.

[0039] According to some implementations, the measurement may include measuring the distance from the apex of the papillary muscle to the junctional edge to indicate the length of the prosthetic umbilical cord, and also includes on-site measurement and adjustment of the defatted cotton umbilical cord cap so that the umbilical cord is integrated and merged at the end of each set of umbilical cords.

[0040] According to some implementations, personalized mitral valve prostheses can also be formed by implementing the geometry and dimensions of the annular ring, anterior leaflet, posterior leaflet, and umbilical cord, calculated for each specific patient as input for engineering drawing software or drawing tools.

[0041] According to some implementations, engineering drawing software or drawing tools can output templates for manually cutting the leaflets of a valve prosthesis.

[0042] According to some implementations, engineering drawing software or drawing tools can output templates for machine cutting of leaflets.

[0043] According to some implementation methods, personalized mitral valve prostheses can also be formed by packaging, labeling, and sterilizing the personalized mitral valve prosthesis before it is released for use.

[0044] According to some implementation methods, personalized mitral valve prostheses can also be formed by assembling the personalized mitral valve prosthesis onto a valve stent before packaging.

[0045] According to some implementation methods, personalized mitral valve prostheses can also be created by implanting a personalized mitral valve prosthesis into a specific patient.

[0046] A prosthetic valve designed to resemble a patient's natural mitral valve is provided. Two flexible leaflets and an asymmetrical, flexible ring can move with the natural deformation of the myocardium during the cardiac cycle. An umbilical cord, similar to a patient's natural chordae tendineae, is included in the prosthetic valve to mimic the natural prevention of blood return to the atria and to provide support for the left ventricle during systole.

[0047] According to some implementation methods, the mitral valve prosthesis to be transplanted into the heart includes: The asymmetric ring, whose size mimics the patient’s natural mitral valve annulus, is made of a flexible material that rolls outward toward itself onto the valve. Anterior flexible leaflet and posterior flexible leaflet, the anterior leaflet and posterior leaflet are suspended on an asymmetric ring and are configured to substantially engage with each other; Each of the anterior and posterior lobules is configured to mimic the shape of a natural mitral valve, with an orifice formed by the anterior and posterior lobules through which blood flows in one direction; and At least two sets of umbilical cords, each set of cords being connected at a first end to the anterior or posterior lobule and at a second end to a cap, the cap being configured to connect at the other end to the papillary muscle of the heart.

[0048] According to some embodiments, the mitral valve prosthesis may also include an engagement surface that is continuous with each of the anterior and posterior leaflets and attached to each set of umbilical cords, the engagement surface being configured to enhance the seal of the mitral valve prosthesis.

[0049] According to some implementations, the asymmetric loop may also include at least two strands configured as a coiled structure.

[0050] According to some implementations, an asymmetric ring may include two layers of material folded together to provide elasticity and a third layer to provide structural stability.

[0051] According to some implementations, the asymmetric ring may include two layers of bovine pericardium; and a third layer of glycine or proline to provide strength.

[0052] According to some implementations, these layers can be joined together by staples, glue, or any combination thereof.

[0053] According to some implementations, the asymmetric ring, anterior flexible lobule and posterior flexible lobule, at least two umbilical cords, cap or any combination thereof can be made from bovine pericardium.

[0054] According to some implementation methods, the leaflet shape can be extended by 1-5 mm to achieve better fusion and umbilical connection.

[0055] According to some implementations, the leaflet shape can be designed as a semi-circle along half the length of the front flexible leaflet and the rear flexible leaflet, so that the two leaflets form an "S"-shaped seal when they are joined.

[0056] According to some embodiments, the mitral valve may also include at least one secondary umbilical cord; wherein the at least one secondary umbilical cord may be attached at one end to the middle portion of the posterior leaflet and at the other end to the middle portion of the primary umbilical cord.

[0057] According to some implementations, at least two sets of umbilical cords can be attached to an opening in the cap, which is located in the middle of the cap.

[0058] According to some implementations, each of at least two sets of umbilical cords can be attached to the middle portion of the anterior or posterior lobule, thereby mimicking a naturally occurring mitral valve.

[0059] According to some implementations, the anterior and posterior lobules can be made from a single unit, connected to an asymmetric ring, and attached to at least two sets of umbilical cords.

[0060] According to some embodiments, the mitral valve may also include an extension that is connected at one end to the anterior flexible leaflet and at the other end to at least two sets of umbilical cords, and is configured to allow engagement between the anterior and posterior flexible leaflets.

[0061] According to some implementation methods, a mitral valve prosthesis to be transplanted into the heart may include: The asymmetric ring is sized to mimic the patient's natural mitral valve annulus; the asymmetric ring is made of a flexible material that rolls outward toward itself onto the valve. Two leaflets are suspended on an asymmetric ring, the leaflets being constructed on opposite sides of an incision made of a material similar to that constituting the asymmetric ring, wherein the incision forms an orifice through which blood flows in one direction. At least two sets of umbilical cords, each set connected at the first end to one of the two lobes and joined together at the second end; and The cap will be attached to at least two sets of umbilical cords at one end and configured to be sewn to the papillary muscles of the heart at the other end.

[0062] According to some implementations, each set of umbilical cords is attached to one of the two leaflets by an extension configured to allow engagement between the two leaflets.

[0063] According to some implementation methods, a method for manufacturing a mitral valve prosthesis may include: The size and shape of the patient's mitral valve were measured using imaging methods; A replica of the subject's mitral valve was cut from a single piece of material; An incision is made along the monolithic material to form an opening for blood flow and two leaflets, one on each side of the opening; The required umbilical cord length is measured using imaging methods; Connect the umbilical cord to one of the two caps; and A flexible ring is attached to the leaflet to form a complete mitral valve prosthesis that mimics the natural mitral valve of a specific patient.

[0064] According to some implementation methods, the required umbilical cord length can be measured simultaneously with the measurement of the size and shape of the subject's mitral valve.

[0065] According to some implementations, the method may also include attaching an extension to each of the two leaflets to carry the umbilical cord before attaching the umbilical cord to one of the two caps.

[0066] A method is provided for manufacturing a personalized, naturally designed mitral valve prosthesis to precisely fit the specific patient for whom the valve prosthesis is to be manufactured. The method may include: By using imaging devices to measure the size and shape of a specific patient's natural mitral valve, data can be provided for the materials used to manufacture personalized mitral valve prostheses. Based on data on the size, shape, and materials of a specific patient's natural mitral valve, a personalized 3D model of a mitral valve prosthesis is constructed. Optimize 3D models using the FEM method, and Personalized mitral valve prostheses are fabricated based on the optimized FEM model.

[0067] According to some implementations, the method may also include visualizing a personalized mitral valve prosthesis model after optimization operations.

[0068] According to some embodiments, the imaging device may include: 2D or 3D echocardiography, computed tomography (CT), cardiac magnetic resonance (CMR), or any combination thereof.

[0069] According to some implementations, measuring the size and shape of a patient's natural mitral valve includes measuring mitral valve-related parameters, including: annular circumference (AC), annular area (AA), anterior-posterior (AP) diameter, anterolateral-posteromedial (AL-PM) diameter, commissural diameter (CC), anterior leaflet length (ALL), posterior leaflet length (PLL), mitral valve shape, and chordae tendineae length (ACL and PCL).

[0070] According to some implementations, the method also includes collecting physical information of a specific patient to predict the geometry of the heart after implantation of a personalized mitral valve prosthesis, said physical information including height, weight, age, ethnicity, and sex.

[0071] In some embodiments, a personalized mitral valve prosthesis is provided. The personalized mitral valve prosthesis may include a flexible annular ring whose size matches the natural mitral valve annulus of a particular patient, flexible anterior and posterior leaflets whose size matches the natural mitral valve leaflets of a particular patient, the leaflets connected to the annular ring, and an umbilical cord whose size matches the natural mitral valve leaflets of a particular patient, the umbilical cord being connected to the flexible anterior and posterior leaflets, the umbilical cord being further configured to connect the flexible anterior and posterior leaflets to the papillary muscles of the heart. In some embodiments, the personalized mitral valve prosthesis may be formed in the following manner: The size and shape of a patient's natural mitral valve were measured using an imaging device. Provide data on materials for manufacturing personalized mitral valve prostheses; Based on data on the size, shape, and materials of a specific patient's natural mitral valve, a personalized 3D model of a mitral valve prosthesis is constructed. Optimize 3D models using the FEM method; as well as Personalized mitral valve prostheses are fabricated based on an optimized FEM model by cutting material into annular rings, flexible anterior and posterior leaflets, and an umbilical cord, and attaching the flexible anterior and posterior leaflets to the annular rings, and attaching the umbilical cord to the flexible anterior and posterior leaflets. In some embodiments, the personalized prosthetic mitral valve may optionally be further formed by including visualizing the personalized mitral valve prosthesis model prior to the manufacturing operation.

[0072] According to some embodiments, the imaging device includes: 2D or 3D echocardiography, computed tomography (CT), cardiac magnetic resonance (CMR), or any combination thereof.

[0073] According to some implementations, measuring the size and shape of a patient's mitral valve includes measuring mitral valve-related parameters, including: annular circumference (AC), annular area (AA), anterior-posterior (AP) diameter, anterolateral-posteromedial (AL-PM) diameter, commissural diameter (CC), anterior leaflet length (ALL), posterior leaflet length (PLL), mitral valve shape, and chordae tendineae length (ACL and PCL).

[0074] According to some implementations, a personalized prosthetic mitral valve can also be formed by collecting specific patient information to predict the geometry of the heart after implantation of a personalized mitral valve prosthesis, including height, weight, age, ethnicity, and sex.

[0075] According to some implementations, the measurement includes measuring the annular circumference (AC) based on equation (iii) as a combination of the annular circumference (AAC) of the anterior lobule as the top edge of the anterior lobule and the annular circumference (PAC) of the posterior lobule as the top edge of the posterior lobule.

[0076] According to some implementations, the annular ring forms a multi-layered reinforced structure by folding or overlapping the top edges of each of the anterior and posterior lobes.

[0077] According to some implementations, the top edge of each of the anterior and posterior leaflets is straight or curved in order to properly fit the personalized mitral valve prosthesis to the natural geometry of the left ventricle of a particular patient.

[0078] According to some implementations, the connection includes joining the edge of the anterior lobule to the edge of the posterior lobule, thereby forming a connection between the anterior and posterior lobules.

[0079] According to some implementations, the connection includes connecting the flexible anterior leaflet and the flexible posterior leaflet together to form two commissures, wherein the two commissures are tilted inward at a cone angle (δ1) to form a cone-shaped personalized mitral valve prosthesis to fit the native left ventricle of a particular patient.

[0080] According to some implementations, the cone angle (δ1) is determined based on the equation (x) by the tilt angle (δ0) of each merging edge of the flexible anterior leaflet and the flexible posterior leaflet.

[0081] According to some implementations, the connection includes connecting the anterior lobule to the posterior lobule by connecting the anterolateral side to the anterolateral side and the posteromedial side to the posteromedial side.

[0082] According to some implementations, connecting the anterior lobule to the posterior lobule includes suturing.

[0083] According to some implementations, the measurements include, based on equation (xi), the following measurements: the size and shape of the natural annular ring of a particular patient, the commissural height (CH), the tilt angle (δ0), the anterior lobule length (ALL), and the posterior lobule length (PLL), and the coaptation height (CoaptH) used to calculate the length of each lobule edge.

[0084] According to some implementation methods, the height of the reinforcing ring is between 1 mm and 4 mm.

[0085] According to some implementation methods, the height of the reinforcing ring is between 2mm and 3mm.

[0086] According to some implementations, based on equation (iii), the annular circumference (AC) is a function of the front-to-back diameter (AP) and the front-outer-back-inner diameter (AL-PM).

[0087] According to some implementations, the measurements include measuring the anterior-posterior diameter (AP) and the anterolateral-posteromedial diameter (AL-PM) during left ventricular systole when the mitral valve is closed.

[0088] According to some implementations, the annular circumference (AC) of the prosthesis is calculated based on the ratio (λ) in equation (iii).

[0089] According to some embodiments, the annular ring is asymmetrical, and the annular ring is further formed by a combination of anterior lobule ring and posterior lobule ring, wherein the anterior lobule ring circumference (AAC) is smaller than the posterior lobule ring circumference (PAC), and the ratio (R) between AAC / PAC is between 49 / 51 and 30 / 70.

[0090] According to some implementations, the ratio (R) between AAC / PAC is between 35 / 65 and 42 / 58.

[0091] According to some implementation methods, the ratio (R) between AAC / PAC is 40 / 60.

[0092] According to some implementations, the ratio (R) between AAC / PAC is between the anterior leaflet length (ALL) and the posterior leaflet length (PLL).

[0093] According to some implementation methods, constructing a personalized 3D model of a mitral valve prosthesis involves calculating the anterior lobule circumference (AAC) and posterior lobule circumference (PAC) based on suture locations A and B.

[0094] According to some implementations, constructing a personalized 3D model of a mitral valve prosthesis involves calculating the anterior lobule length (ALL) and posterior lobule length (PLL) based on equations (viii) and (ix), using: (a) the anterior-posterior diameter (AP) as the theoretical minimum engagement distance; (b) the ratio (r) between ALL and PLL; (c) engagement depth (Cd); (d) engagement height (CoaptH); and (e) umbilical cord length (Lc).

[0095] According to some implementations, the connection includes a body that connects the anterior and posterior leaflets together to form a personalized mitral valve prosthesis.

[0096] According to some implementations, each anterior lobule and each posterior lobule includes two sets of umbilical cords: anterior lateral umbilical cords and posteromedial umbilical cords, wherein each anterior lateral umbilical cord and posteromedial umbilical cord includes three sub-umbilical cords, wherein the umbilical cords are evenly distributed from each side along at least 3 / 8 of each side.

[0097] According to some implementations, constructing a 3D model includes calculating the length of each umbilical cord, wherein the calculation of the length of each umbilical cord is based on parameters including: lobule length, junction height, and junction depth.

[0098] According to some implementations, the measurement includes measuring the distance from the apex of the papillary muscle to the junctional edge to indicate the length of the prosthetic umbilical cord, and also includes on-site measurement and adjustment of the defatted cotton umbilical cord cap so that the umbilical cord is integrated and merged at the end of each set of umbilical cords.

[0099] According to some implementations, constructing a 3D model includes providing each specific patient with calculated geometry and dimensions of the annular ring, anterior lobule, posterior lobule, and umbilical cord as input for engineering drawing software or drawing tools.

[0100] According to some implementations, engineering drawing software or drawing tools output templates for manually cutting the leaflets of the valve prosthesis.

[0101] According to some implementations, engineering drawing software or drawing tools output templates for machine cutting of leaflets.

[0102] According to some implementations, the method may also include packaging, labeling, and sterilizing the personalized mitral valve prosthesis before it is released for use.

[0103] According to some implementations, the method may also include assembling a personalized mitral valve prosthesis onto a valve stent prior to packaging.

[0104] According to some implementations, the method may also include implanting a personalized mitral valve prosthesis into a specific patient. Attached Figure Description

[0105] Figure 1A and 1B This is a schematic diagram of an embodiment of the present invention. Figure 1A A prosthetic mitral valve in the open position according to some embodiments of the present disclosure is depicted, and the chordae tendineae before attachment to the leaflets are shown. Figure 1B A prosthetic mitral valve in the closed position according to some embodiments of the present disclosure is depicted and the chordae tendineae attached to the leaflets are shown.

[0106] Figure 2 This is a schematic diagram of an embodiment of the present invention implanted in the heart according to some embodiments of this disclosure;

[0107] Figure 3 These are 3D reconstructed images of the mitral valve region in 3D CT image analysis software according to some embodiments of this disclosure;

[0108] Figure 4 These are photographs of a 3D-printed valve mold and a porcine pericardial mitral valve leaflet according to some embodiments of this disclosure;

[0109] Figure 5 These are photographs of prosthetic valves in in vitro testing according to some embodiments of this disclosure;

[0110] Figures 6A to 6B These are schematic side views of the anterior and posterior leaflets of a prosthetic mitral valve according to some embodiments of the present disclosure, and a top view of the leaflets when they are engaged with each other.

[0111] Figure 6C This is a schematic diagram of a top view of a mitral valve prosthesis viewed from the left atrium down toward the left ventricle according to an embodiment of the present disclosure (during diastole, when the valve opens to allow blood to enter the left ventricle);

[0112] Figure 6D This is a schematic diagram of a single-piece material including anterior and posterior lobes according to an embodiment of the present disclosure;

[0113] Figures 7A to 7B This is a schematic diagram of a cap for connecting the umbilical cord to the papillary muscle of the heart and a mitral valve prosthesis having two caps attached to the umbilical cord, according to an embodiment of the present disclosure.

[0114] Figures 8A to 8B These are schematic diagrams showing possible positions of the umbilical cord relative to the leaflet according to some embodiments of this disclosure, and a cross-section of the umbilical cord when attached to the leaflet;

[0115] Figures 9A to 9B These are schematic diagrams of a prosthetic mitral valve with two attached leaflets according to some embodiments of the present disclosure, the prosthetic mitral valve employing an alternative design with a curved (ellipsoidal / droplet) configuration to enlarge the engagement surface, and possible engagement surface configurations.

[0116] Figure 10 This is a schematic diagram of a measurement copy of a patient's mitral valve derived from a 2D or 3D echocardiographic image according to some embodiments of this disclosure;

[0117] Figure 11 This is a schematic diagram illustrating the formation of a bilobal prosthesis according to some embodiments of the present disclosure;

[0118] Figure 12 This is a schematic diagram of an opening formed along the leaflet portion according to some embodiments of the present disclosure;

[0119] Figure 13 This is a schematic diagram of an echocardiogram or MRI scan of a patient's left ventricular chamber or ventricle according to some embodiments of this disclosure;

[0120] Figures 14A to 14B These are schematic diagrams of the left ventricle of a patient during diastole and systole, respectively, according to some embodiments of this disclosure;

[0121] Figures 15A to 15B These are schematic diagrams of extensions attached to the anterior and posterior leaflets according to some embodiments of the present disclosure.

[0122] Figures 16A to 16B These are schematic side views of a mitral valve prosthesis having an extension and an attached umbilical cord during diastole and systole, according to some embodiments of the present disclosure.

[0123] Figure 17 This is a schematic diagram of attaching an asymmetric flexible ring to the periphery of a valve prosthesis to simulate a natural valve annulus, according to some embodiments of this disclosure.

[0124] Figures 18A to 18B These are schematic diagrams of elastic material inserted into a rolling valve ring before and after it rolls on the ring, according to some embodiments of the present disclosure.

[0125] Figure 19 This is a schematic flowchart illustrating a method for manufacturing a mitral valve prosthesis according to some embodiments of the present disclosure;

[0126] Figure 20A This is a schematic diagram illustrating a method for manufacturing a personalized mitral valve prosthesis according to some embodiments of the present disclosure;

[0127] Figure 20B This is a schematic flowchart illustrating a method for manufacturing a personalized mitral valve prosthesis according to some embodiments of the present disclosure;

[0128] Figure 21A This is a schematic diagram of the annular valve edge retained during the removal of a natural mitral valve in clinical practice, according to some embodiments of this disclosure;

[0129] Figure 21B This is a schematic diagram of an elliptical ring model for calculating the annular circumference (AC) of a valve prosthesis according to some embodiments of the present disclosure, wherein the AL-PM diameter is the major axis and the AP diameter is the minor axis;

[0130] Figures 22A to 22C These are, respectively, example designs of the anterior leaflet, example designs of the posterior leaflet, and schematic diagrams of an example mitral valve prosthesis assembly according to some embodiments of this disclosure;

[0131] Figure 22D This is a schematic diagram of a ring model of two nipple muscles according to some embodiments of this disclosure;

[0132] Figures 22E to 22F This is a schematic diagram of a customized anterior and posterior leaflet model according to some embodiments of this disclosure;

[0133] Figures 23A to 23B These are schematic diagrams of two examples of leaflets (front or rear) according to some embodiments of this disclosure, illustrating the theoretical length of the free edge of the leaflet;

[0134] Figure 23C This is a schematic diagram illustrating the relationship between multiple parameters that influence each other when the prosthesis's leaflets are engaged, according to some embodiments of this disclosure.

[0135] Figure 23D This is a schematic flowchart illustrating a method for customizing mitral valve design using FEM according to some embodiments of the present disclosure;

[0136] Figures 24A to 24B These are schematic diagrams of a side view and a perspective view of a mitral valve leaflet conjoint according to some embodiments of the present disclosure;

[0137] Figure 25These are echocardiographic photographs of sheep hearts implanted with personalized, naturally designed mitral valve prostheses manufactured according to the methods of this disclosure; and

[0138] Figures 26A to 26B These are schematic diagrams of the posterior and anterior lobes according to some embodiments of this disclosure;

[0139] Figure 27 This is a schematic diagram of a final customized 3D model of a prosthetic mitral valve according to some embodiments of the present disclosure;

[0140] Figure 28 This is a schematic diagram of the FEM simulation optimization results of a customized prosthetic mitral valve model according to some embodiments of this disclosure;

[0141] Figures 29A to 29B These are schematic diagrams of a prosthetic mitral valve in an open and closed configuration within a hydrodynamic test chamber, according to some embodiments of this disclosure.

[0142] Figure 30 Echocardiography of a custom-made prosthetic mitral valve during its closure configuration after implantation in a pig heart; and

[0143] Figure 31 This is the blood pressure gradient in a pig's heart after a custom-made prosthetic mitral valve is implanted.

[0144] The foregoing will be readily understood from the following more detailed description of exemplary embodiments of the invention, as illustrated in the accompanying drawings, wherein the same reference numerals refer to the same parts in different views. The drawings are not necessarily drawn to scale; rather, the focus is on illustrating embodiments of the invention. Detailed Implementation

[0145] The mitral valve prosthesis of the present invention is shown in Figure 1A and Figure 1B The mitral valve prosthesis 100 has a physiological shape similar to that of a natural human mitral valve. The mitral valve prosthesis includes a flexible, asymmetrical ring 1 and two flexible, membranous leaflets 2, which are suspended from the asymmetrical ring 1. The mitral valve prosthesis also includes two sets of umbilical cords 3 mimicking the chordae tendineae of the heart. Each set of umbilical cords 3 is configured to attach at one end to the edge and / or body of the leaflet 2 and converge at the other end to form a fixation cap 8. The fixation cap 8 is configured to suture to the papillary muscles of the left ventricle.

[0146] Mitral valve 100 indicates it is not attached. Figure 1A Leaflet 2 and attached to Figure 1B The umbilical cord 3 is attached to the lobule 2 in the mitral valve. The umbilical cord 3 can be attached to the lobule 2 before surgery, or it can be attached during surgery. For example, the attachment 9 between the umbilical cord 3 and the lobule 2 can be a suture or they can be an integral design. The mitral valve 100 is... Figure 1A It is displayed as open in the middle, and in Figure 1B The middle section shows the closed state. In the closed state, leaflet 2 is shown as joined.

[0147] Figure 2 A mitral valve 100 implanted in the heart is shown. The mitral valve 100 is shown as being implanted in the natural mitral valve annulus 12, one side close to the aortic valve 6, where the aortic root 7 connects to the left ventricle, and the other side against the opposing ventricular wall 5. The umbilical cord 3 is shown attached to the papillary muscle 4.

[0148] The flexible ring 1 can be customized after an ultrasound examination of the patient's heart. Specifically, a three-dimensional echocardiographic study can be performed to obtain detailed anatomical measurements and / or present a three-dimensional model of the patient's heart from which a customized or personalized mitral valve can be generated. The leaflets 2 and umbilical cord 3 can also be customized based on ultrasound imaging of the subject's natural mitral valve and surrounding anatomy. Customized / personalized mitral valves can also be generated from data obtained from other imaging modalities that provide three-dimensional information, including cardiac CT and cardiac MRI. Therefore, the mitral valve prosthesis of the present invention can be selected or designed to match the specific anatomy of a patient.

[0149] The flexible ring 1 can be formed, for example, by an elastic annulus angioplasty ring. The leaflet 2 can be formed from a natural material or a biocompatible composite material, which is resistant to clotting and functions similarly to the patient's natural anterior and posterior leaflets. At least two sets of umbilical cords are provided, one attached to one of the two leaflets at a first end and the other to the papillary muscle at a second end, functioning similarly to the patient's natural chordae tendineae. The umbilical cord 3 tethers the leaflet 2 to the patient's papillary muscle, providing support to the left ventricular wall throughout the cardiac cycle and preventing the leaflet from opening into the atrial cavity.

[0150] The mitral valve prosthesis 100, comprising a flexible ring 1, leaflets 2, and umbilical cord 3, resembles a healthy natural mitral valve in appearance and behavior. Furthermore, the mitral valve prosthesis of the present invention can be manufactured using natural materials and can avoid the inclusion of foreign bodies, such as absorbent cotton. Allogeneic and / or composite materials, including various combinations of allogeneic, xenogeneic, and / or autologous transplant materials, can be used to manufacture the flexible ring, leaflets, umbilical cord, and cap. Materials forming the valve annulus and leaflets can include, but are not limited to, human, bovine, or porcine pericardium, decellularized bioprosthetic materials, cell-bound woven biodegradable polymers, and extracellular materials. Biodegradable natural polymers can include, but are not limited to, fibrin, collagen, chitosan, gelatin, hyaluronic acid, and similar materials. Biodegradable synthetic polymer scaffolds that can be infiltrated with cell and extracellular matrix materials can include, but are not limited to, poly(L-lactide), polyglycolic acid, poly(lactic-co-glycolic acid), poly(caprolactone), polyorthoester, poly(dioxanone), poly(acid anhydride), poly(trimethylene carbonate), polyphosphazene, and similar materials. The flexible ring can be further customized to provide patients with personalized flexibility or rigidity. Furthermore, some components of the mitral valve prosthesis, including the umbilical cord 3, can be formed intraoperatively from the patient's own pericardium.

[0151] For example, a mitral valve prosthesis can be made from the patient's own pericardium. Alternatively, a mitral valve prosthesis can be made from xenogeneic materials (e.g., animal tissue, such as existing valves) with a layer of the patient's own cultured cells applied on top through tissue engineering.

[0152] Artificial valves are often fixed with glutaraldehyde, a known toxin that promotes regeneration. The mitral valve prosthesis of this invention can be fixed using non-glutaraldehyde-based methods, such as dye-mediated photofixation. The mitral valve of this invention can also be fixed using optional crosslinking agents, such as epoxy compounds, carbodiimides, diglycidyl, reuterin, genipin, diphenylphosphohydrazine, acyl azide, and cyanamide, or by physical methods such as ultraviolet light and dehydration.

[0153] Mitral valve prostheses or some components thereof can be produced directly using biomaterials via bio-3D printing. Alternatively, mitral valve prostheses or some components thereof can be produced using templates or molds constructed by 3D printing, based on detailed dimensions obtained from preoperative 3D imaging.

[0154] A method for implanting a mitral valve prosthesis is also provided. Prior to implantation, an echocardiographic study (or other imaging study) of the patient is obtained. Through this imaging study, the size and motion of the heart chambers are measured. Detailed dimensions of the patient's mitral valve annulus, leaflets, and umbilical cord are also measured from the acquired images. Furthermore, a three-dimensional depiction of the valve to be replaced can be presented. Based on the measurements and three-dimensional modeling of the patient's natural valve, a mitral valve prosthesis that closely matches the patient's natural mitral valve, corrected for existing pathology, can be produced.

[0155] Three-dimensional echocardiographic studies can be performed using probes such as transesophageal echocardiography (TEE) or transthoracic echocardiography (TTE). Three-dimensional and four-dimensional modeling and measurements of various parts of the mitral valve can be performed using software such as eSieValves.TM (Siemens Medical Solutions USA, Inc., Malvern, Pa.). Relevant measurements can include the outer and inner diameters of the valve annulus, the annular area, the intertrigonal and intercommunication distances, and the lengths along the axes of the anterior and posterior leaflets.

[0156] Alternatively, three-dimensional studies of the mitral valve can be performed using computed tomography (CT) or magnetic resonance imaging (MRI). For example, as Figure 3 As shown, a 3D reconstruction of a pig heart was obtained using CT imaging (SOMATOM.RTM.Definition Flash, Siemens Healthcare, Erlangen, Germany). The mitral valve region of the heart is visible on the right side of the image. Image analysis software can be used to segment the mitral valve region and obtain relevant measurements.

[0157] Mitral valve prostheses can be completely custom-made for the patient, with each component (e.g., annulus, leaflet, umbilical cord, cap) manufactured to a size that matches the patient's natural valve. For example, as Figure 4 As shown, a 3D printed mold for the mitral valve is created based on the 3D reconstruction of the imaging valve. Figure 4 The 3D-printed valve shown is modeled during either the diastolic or adduction phase of the cardiac cycle. Prosthetic valves based on 3D molds are also shown. Figure 4 The mold guides the pig pericardium to be incised at the attachment sites of the leaflets and chordae tendineae. Alternatively, a prefabricated mitral valve or a prefabricated mitral valve assembly can be selected for implantation of a valve or natural valve assembly that best approximates the patient's natural valve or natural valve assembly in shape and size.

[0158] Figure 5Images of a prosthetic valve prototype sutured in an in vitro testing system are shown. The valve prototype shown is sutured to the entire explanted heart. A saline pill is injected into the left ventricle of the heart through a tube, and the aorta is clamped to contain the saline in the left ventricle and generate pressure. The injection pressure can be monitored, for example, on a pressure gauge connected to the injection line. The ability of the valve prototype to function under physiological pressure (e.g., without regurgitation and leaflet prolapse) can then be monitored. The valve's ability can be measured or monitored under the systolic pressure of left ventricular contraction and natural valve closure.

[0159] Figures 6A to 6B These are schematic diagrams of the anterior and posterior leaflets of a prosthetic mitral valve according to some embodiments of the present disclosure, and when these leaflets are joined together. Figure 6A and 6B A prosthetic mitral valve may be a prosthetic mitral valve 600. According to some embodiments, valve 600 may include two leaflets, for example, an anterior leaflet 602A and a posterior leaflet 602P. Each of the posterior leaflet 602P and the anterior leaflet 602A may be designed and created preoperatively as a monolithic shell (monopiece) to fit the patient's specific physiology and anatomy based on a cross-sectional image of the patient's heart. Measurements taken from the patient's own heart may be used to determine the length, width, and height of each leaflet, for example, 602A, 602P, such that each leaflet is substantially identical to the patient's natural leaflets. Each leaflet may be shaped to include chordae tendineae (e.g., chordae tendineae 604, 606, 608, 610) and additional material to form annular portions (e.g., anterior annular portion 601A and posterior annular portion 601P). As further described below, the surgeon may determine the length of the chordae tendineae to fit the patient. The leaflet can be cut from a single piece of material using a knife or scissors and can be sutured by a surgeon during mitral valve replacement surgery to form a mitral valve similar to the patient's natural mitral valve.

[0160] For example, the anterior leaflet (AL) height might be approximately 30 mm, the AL length might be approximately 45 mm, the posterior leaflet (PL) height might be approximately 15 mm, and the posterior leaflet length might be approximately 60 mm. Figure 6A As shown, in the medical field, 630A is referred to as the height of the anterior lobule 602A, and 630P is referred to as the height of the posterior lobule 602P. The length of each lobule is referred to as a portion of the lobule circumference. For example, 632A refers to the length of the anterior lobule 602A, and 632P refers to the length of the posterior lobule 602P.

[0161] According to some embodiments, cutting each of the leaflets 602A and 602P separately from the same or different material sheets, and cutting each of the annular portions 601A and 601P separately, can reduce the burden on the person (e.g., a surgeon) preparing a prosthetic mitral valve for implantation. Cutting the leaflets into two separate portions and the annular portions into two separate portions, attaching the leaflets to the annulus, and further attaching the umbilical cord to each leaflet, reduces preparation time and the time required for the surgical procedure of implanting the prosthetic valve compared to cutting the leaflets and umbilical cord from a single piece of material as a single unit. Because high precision is required when cutting the leaflets and each umbilical cord while maintaining the connection between the leaflet portions and the integrity of the umbilical cord portion, cutting the leaflets and umbilical cord as a single unit and implanting a single prosthesis is more complex and time-consuming than the methods disclosed herein.

[0162] In some embodiments, each of the annular portions 601A and 601P is formed by rolling the posterior side of each leaflet such that the posterior side of each leaflet folds or rolls onto itself (e.g., the rolled anterior portion 605A and the rolled posterior portion 605P) toward the outer side of the valve 600. According to this embodiment, the posterior end of each leaflet can be augmented with an additional 5-10 mm of material, which can be used to form the annular portion (e.g., the annular portion 601A in the anterior leaflet of the mitral valve and the annular portion 601P in the posterior leaflet of the mitral valve). Rolling or folding the annulus (or each annular portion 601A and 601P) toward the outer side of the valve 600 helps to prevent clot formation on the inner side of the valve 600, and if clots do form, they will only appear on the outer side of the valve 600 in the folded or rolled area of ​​the annulus or annular portion, posing a lower risk of impairing the effective operation of the valve 600. According to some additional embodiments, the rings (or each ring portion 601A and 601P) can be further reinforced by additional material strips (not shown), such as suitable biomedical fibers or polymers. Such strips can be made from a sheet of material used to manufacture the valve 600, and their dimensions are designed to fit within each ring portion 601A, 601P. Preferably, such strips have a width of 1-3 mm and a length of 10-20 mm. These material strips can be added to the valve 600 when each ring portion 601A, 601P is rolled up, the strips being placed within each ring portion 601A, 601P. These material strips can be elastic and can be made from various compositions, such as biocompatible rubber, recoil wire, or synthetic materials.

[0163] according to Figure 6BLeaflet 602A may be semi-elliptical or plano-convex, while leaflet 602P may be plano-concave. In some embodiments, valve 600 may include at least two sets of umbilical cords. In some embodiments, each of the at least two sets of umbilical cords is attached to the middle portion of the corresponding leaflet, thereby mimicking the natural mitral valve. For example, in some embodiments, leaflet 602A may include at least one set of umbilical cords 603A, which may be attached to the middle portion of leaflet 602A at one end, which is generally opposite to the end of leaflet 602A in which the annular portion 601A is attached. In some embodiments, at least one set of umbilical cords 603A may include at least two subsets of umbilical cords, such as subset 604 and subset 606. According to some embodiments, these subsets 604 and 606 are spaced apart such that a gap of about 3-5 mm is maintained between the two subsets of umbilical cords for more effective fusion. The gap between umbilical cord subsets 604 and 606 also serves to create a more uniform tension distribution on the lobule and potentially reduce abrasion. These umbilical cord subsets 604 and 606 can be attached to different and separate caps for connecting the umbilical cord subset to the papillary muscles of the heart, as will be referred to... Figures 7A-7B A detailed explanation.

[0164] In some embodiments, the leaflet 602P may include at least one set of umbilical cords 603P, which may be connected to the middle portion of the leaflet 602P at one end, the end of the leaflet 602P generally opposite the end of the leaflet 602P in which the involute portion 601P is connected.

[0165] In some embodiments, at least one set of umbilical cords 603P may include at least two subsets of umbilical cords, such as umbilical cord subset 608 and umbilical cord subset 610. These umbilical cord subsets 608 and 610 are spaced apart such that a gap of approximately 5-8 mm is maintained between the two subsets for more efficient ligation. These umbilical cord subsets 608 and 610 may be connected to different and separate caps for connecting the umbilical cord subsets to the papillary muscles of the heart, as will be referred to... Figures 7A to 7B A detailed explanation.

[0166] In some embodiments, the width of umbilical cord 603A and / or umbilical cord 603P can be between 1 mm and 2 mm, although other widths are possible. In some embodiments, the posterior mitral leaflet 602P can be attached to the annular portion 601P of the asymmetric ring on one side. Once the annular portion 601A is attached to the annular portion 601P, for example by sutures, fasteners, etc., a complete asymmetric and flexible ring can be formed.

[0167] According to some embodiments, the intersegmental distance in the anterior mitral leaflet 634A can be between 8 and 10 mm. In some embodiments, the intersegmental distance in the posterior mitral leaflet 634A can be between 10 and 15 mm. In some embodiments, the intersegmental distance between the anterior and posterior leaflets in the commissural region, designated as distances 636 and / or 638, can be between 5 and 7 mm.

[0168] According to some implementation methods, and as Figure 6B As shown, the anterior leaflet 602A can be connected to the posterior leaflet 602P, and the annular portion 601A can be connected to the annular portion 601P to construct a prosthetic mitral valve 600. Once leaflet 602A is connected to leaflet 602P, an orifice 620 created between leaflets 602A and 602P allows blood to flow in one direction, i.e., from the left atrium to the left ventricle. Therefore, the orifice 620 created between leaflets 602A and 602P can be configured to prevent backflow, i.e., from the left ventricle to the left atrium. Leaflets 602A, leaflets 602P, and these leaflets are connected to each other in a certain manner of engagement, and the annular portions 601A and 601P can be configured to mimic the shape, size, and therefore function of a natural human mitral valve. Specifically, annular portion 601A can be configured to mimic the anterior leaflet annulus, while annular portion 601P can be configured to mimic the posterior leaflet annulus of a natural mitral valve. In some implementations, each leaflet may include a shape extending approximately 1-5 mm between the ring portion and the umbilical cord to allow for better engagement between the two leaflets and better umbilical cord attachment to each leaflet.

[0169] In some embodiments, the anterior leaflet 602A may include at least two subsets of umbilical cord, such as umbilical cord subsets 604 and 606, which may be attached to different ends of the leaflet 602A. In some embodiments, the posterior leaflet 602P may include at least two subsets of umbilical cord, such as umbilical cord subsets 608 and 610, which may be attached to different ends of the leaflet 602P. Similar to the natural mitral valve, the umbilical cord should be attached to the papillary muscles of the heart. More specifically, in the natural human mitral valve, each subset of umbilical cord is attached to a different region of the papillary muscle. Therefore, the prosthetic valve 600 may include at least two subsets of umbilical cord for each leaflet, whereby each subset of umbilical cord will be attached to a different region of the papillary muscle to closely mimic the structure and operation of the natural mitral valve. (See below for further details.) Figure 6C and Figures 7A to 7B As explained, each umbilical cord subset can be capped to the papillary muscle to ensure easy, yet sufficiently stable and durable attachment between any umbilical cord subset and the papillary muscle. The number of umbilical cords in each umbilical cord subset (e.g., 604, 606, 608, and 610) can be different or the same. In some embodiments, each umbilical cord subset may include at least two umbilical cords.

[0170] Figure 6C This is a schematic diagram of a top view of a mitral valve prosthesis viewed from the left atrium down towards the left ventricle, according to an embodiment of this disclosure. Figure 6C The posterior lobule 602P can be connected to the anterior lobule 602A via a connecting line (e.g., suture 609). In some embodiments, the annular portion 601A can be connected to the annular portion 601P, for example along line 609, and can roll onto itself towards the outer side of the valve 600. In some embodiments, the anterior lobule 602A may include two umbilical cord subsets, such as subsets 604 and 606, whereby each of these umbilical cord subsets can be connected to a different papillary muscle 720 via a separate cap element 700. Therefore, the posterior lobule 602P may include two umbilical cord subsets 608 and 610, whereby each umbilical cord subset can be attached to the papillary muscle 720 via a different cap element 700. For example, the anterior umbilical cord 604 can be connected to the first papillary muscle 720 via a first cap 700, and the posterior umbilical cord 608 can also be connected to the same first papillary muscle via the same first cap 700. Similarly, the anterior umbilical cord 606 can be connected to the second nipple muscle 720 via the second cap 700, and the posterior umbilical cord 610 can also be connected to the same second nipple muscle via the same second cap 700.

[0171] according to Figure 6D In some embodiments, leaflets 602P and 602A can be cut from a single monopod and connected along suture 609, for example, by suturing to form a complete valve. According to some embodiments, the umbilical cord length can be adjusted based on the patient's preoperative scan, according to the recipient / patient's individual optimal umbilical cord length.

[0172] Figures 7A to 7BThese are schematic diagrams of a cap for connecting the umbilical cord to the papillary muscle of the heart, according to embodiments of the present disclosure, and a mitral valve prosthesis having two caps attached to the umbilical cord. In some embodiments, the cap 700 may be arc-shaped in its layout configuration. In some embodiments, the shape of the cap 700 in a closed configuration may resemble a cone shape having a small opening 730 at its top 702 and a wider opening at its bottom 704, whereby the ends of the arc can be sutured to each other or one over the other using surgical sutures 706, thereby forming a closed configuration. The sutures 706 may be placed before the cap 700 is placed on top of the pupillary muscle 720. In some embodiments, the diameter of the cap 700 may be between 5 mm and 10 mm, and the height between 5 and 10 mm. According to some embodiments, the cap 700 may be made of a single piece of material having a cap shape, while according to other embodiments, the cap 700 may be made of two open leaflets or sheets of the same material to be sutured together and immediately reach the papillary muscle. For example, the suture can start from one side of the two pieces of material of the cap 700, pass through a part of the cap 700 and exit, so as to attach the cap 700 to the papillary muscle, and so on, until the two parts of the cap 700 are fully connected to each other and fully connected to the papillary muscle of the heart.

[0173] According to some embodiments, the cap 700 of the prosthetic valve 600 can be formed by rolling a pericardium (e.g., from a human, bovine, or porcine source) into the closure structure. In some other configurations, the cap can be formed from a biomedical polymer. In some embodiments, the size of the cap 700 can be 5 mm or more. In some embodiments, the chordae tendineae of the prosthetic mitral valve can be made of the same material as the leaflets and / or the cap. In some embodiments, the chordae tendineae can be chordae tendineae taken from the same source, and the cap 700, anterior leaflet 602A, and posterior leaflet 602P can be taken from, for example, the same animal, such as the same cow, to increase the advantage of having the same cellular structure and homology as the cap 700, anterior leaflet 602A, and posterior leaflet 602P.

[0174] Once the cap 700 is placed on the pupillary muscle 720, umbilical cords such as umbilical cord subsets 604, 608 can be connected to the cap 700 using sutures 710, which connect the umbilical cord, cap 700, and pupillary muscle 720 together. According to some embodiments, a cap opening 730 allows for a good fit between the cap 700 and the papillary muscle 720 because the cap opening 730 allows the shape of the cap to be adjusted to the shape of the papillary muscle 720. In some embodiments, the cap 700 can be attached to one end of the umbilical cord subsets 604, 608, for example, via sutures 710, while the cap 700 can be attached to the papillary muscle of the heart from the other end, for example, via sutures 706, typically with the opposite end of the cap 700 close to the bottom end 704. The cap 700 can be connected to the papillary muscle 720 via the entire circumference of the bottom end 704 of the cap 700, but in some embodiments, the cap 700 can be connected to the papillary muscle 720 via a specific portion along the circumference of the bottom end 704 of the cap 700.

[0175] According to some embodiments, the umbilical cords can be connected to each other to form an umbilical cord bundle. The umbilical cord can be attached as a bundle to the end of the umbilical cord to be connected to the cap 700 (e.g., the ends of umbilical cord subsets 604 and 608, connected to the leaflet 602). According to some embodiments, connecting the umbilical cord (e.g., umbilical cord subsets 604 and 608) to the papillary muscle 720 via the cap 700 is easier than directly connecting the umbilical cord to the papillary muscle 720 because it requires a more extensive attachment procedure. For example, if the attachment method is suture, then suturing each umbilical cord to the papillary muscle 720 is more complex and time-consuming than suturing the umbilical cord to the unfolded cap 700 and suturing the cap 700 (which is a single large piece) to the papillary muscle 720. Since patients receiving the prosthesis of this disclosure are connected to a cardiopulmonary bypass, also commonly referred to as a cardiopulmonary bypass machine, mitral valve replacement is preferably conveniently performed.

[0176] although Figure 7A Only two umbilical cord subsets 604 and two umbilical cord subsets 608 attached to the cap 700 are shown; however, it should be understood that additional umbilical cords may be attached to the cap 700. Umbilical cord subsets 604 and 608 may include one or more umbilical cords. In some embodiments, such as Figure 6C As shown, four umbilical cords 604 from the right sector of the anterior mitral leaflet 602A and four umbilical cords 608 from the left sector of the posterior mitral leaflet 602P are connected to the cap 700.

[0177] In some embodiments, each of the subsets 604, 606, 608, and 610 of the umbilical cord may be attached to the outer side of the cap 700. In other embodiments, the umbilical cord, or the umbilical cord of at least some of the prosthetic valves, may be attached to the cap 700 through an opening 730, which may be located in the middle of the cap 700. That is, the umbilical cord may pass through the opening 730 and may be attached to the inner side of the cap 700.

[0178] In some implementations, each of the umbilical cord subsets 604, 606, 608, and 610 may first be connected to each other to form a bundle, and then may be connected to the cap 700.

[0179] like Figure 7B As shown, the prosthetic mitral valve 600 may include a flexible asymmetric ring 601 attached to two leaflets (e.g., leaflets 602A and 602P). In some embodiments, each of the two leaflets may have a set of attached umbilical cords, such as subsets 604 (not shown), 606 (not shown), 608, and 610. In some embodiments, depending on each of the two leaflets, each set of umbilical cords may be attached to a single cap 700, and each cap 700 may connect the mitral valve prosthesis 600 to the papillary muscles 720 of the heart by connecting each subset of umbilical cords 610 to their respective cap 700.

[0180] As described above, according to some embodiments, each of the umbilical cord subsets 604 (not shown), 606 (not shown), 608, and 610 can be made from the same piece of material used to form the anterior and posterior lobules. Each of these umbilical cords can be considered an extension of lobules 602A and 602P and can be referred to as a primary umbilical cord. According to some embodiments, additional umbilical cords can be attached to both the anterior lobule 602A and the posterior lobule 602P. Each of these secondary umbilical cords can be made from a different and separate material than the material used to construct the lobules and primary umbilical cord. The secondary umbilical cords can be configured to connect the underside of each of lobules 602A and 602P to a point along the primary umbilical cord. The connection point of the secondary umbilical cord along the primary umbilical cord can be the middle of the primary umbilical cord, although other locations along the primary umbilical cord can be implemented as connection points to achieve better lobule fusion. The secondary umbilical cord can typically be sutured to either the anterior lobule 602A or the posterior lobule 602P at one end, and to the primary umbilical cord at the other end. When the secondary umbilical cord is attached, for example, to the anterior leaflet 602A or the posterior leaflet 602P via sutures, damage to the outer surface of either leaflet 602A or posterior leaflet 602P should be avoided to prevent coagulation along the connection line (e.g., the suture). For example, the chance of damaging leaflets 602A and 602P is less when using microsurgical sutures. The purpose of the secondary umbilical cord is to provide additional support to the prosthetic valve against the pressure exerted on the ventricular side of the prosthetic valve during systole.

[0181] Figures 8A to 8B These are schematic diagrams showing the possible positions of the secondary umbilical cord relative to the posterior lobule according to some embodiments of this disclosure, and the cross-sections of the primary and secondary umbilical cords when attached to the posterior lobule. Figure 8AAs shown, the posterior leaflet 602P can roll along its posterior end to form a ring 601. In some embodiments, the posterior leaflet 602P of the mitral valve can be divided into several regions. Regions 812 and 814 can be regions to which a secondary umbilical cord (e.g., umbilical cord 603) can be attached. However, along the posterior leaflet 602P, there may be a region 816 that should be cordless, i.e., a secondary umbilical cord should not be attached to region 816. This is because during ventricular systole, region 816 is the region that applies high pressure after the posterior leaflet 602P is attached to the heart as part of a prosthetic valve. In some embodiments, region 816 may include approximately 2-5 mm to the right of the midline 810 of the posterior leaflet 602P and approximately 2-5 mm to the left of the midline 810 of the posterior leaflet 602P. In some embodiments, region 816 may be 3 mm to the right and 3 mm to the left of the midline 810 of the posterior leaflet 602P. When the pressure gradient increases during ventricular systole, the secondary umbilical cord can be designed to help provide additional support for the posterior lobule 602P.

[0182] In some embodiments, when in the deployed configuration, the secondary umbilical cord 603 should not reach the ends of regions 812 and 814 of the posterior lobule 602P. In some embodiments, the umbilical cord should not be attached to the ends of regions 812 and 814, which are very close to the loop 601. For example, the umbilical cord may be positioned along either of regions 812 and 814 along the entire posterior lobule 602P layout at an angle of approximately 20 to 70 degrees relative to the midline 810 of the posterior lobule 602P. Furthermore, regions of the posterior lobule 602P located between the midlines 810 and at approximately 15-20 degrees to either side of the midline 810 may remain without a secondary umbilical cord.

[0183] Figure 8B A schematic cross-section of the posterior mitral valve is shown, illustrating the primary and secondary umbilical cords when attached to the posterior leaflet 602P. Figure 8B A primary umbilical cord 608 is shown, which is made of the same material as the lobule. Extending from the posterior lobule 602P at one end, the primary umbilical cord 608 is attached to a cap 700 at the other end. In some embodiments, the primary umbilical cords 608 may be connected to each other to form a bundle (not shown), which can then be attached to the outside of the cap 700. The cap 700 can then be attached to the papillary muscle 720.

[0184] According to some embodiments, a primary umbilical cord 608 can be connected to secondary umbilical cords 603, each of which can be connected at one end (e.g., end 823) to the posterior lobule 602P and connected to a contact point at the opposite end (e.g., end 825) of the primary umbilical cord at each secondary umbilical cord 603. According to some embodiments, the secondary umbilical cord 603 should be about 30-40% thicker and about 30-40% wider than the primary umbilical cord 608. Depending on the required prosthesis, one to four secondary umbilical cords can be used for each scallop of the posterior lobule (602P).

[0185] Figures 9A to 9B These are schematic diagrams of a prosthetic mitral valve with two attached leaflets according to some embodiments of the present disclosure, the prosthetic mitral valve employing an alternative design with a curved (ellipsoidal / droplet) configuration to enlarge the engagement surface, and possible engagement surface configurations. Figure 9A The prosthetic mitral valve 1100 may include two leaflets, such as an anterior leaflet 1602A and a posterior leaflet 1602P, whereby each of leaflets 1602A and 1602P may be semicircular and the two leaflets together may produce a “yin and yang” shape. In some embodiments, the leaflet shape may be designed in a semicircular manner along half the length of each leaflet, such that the two leaflets form an “S”-shaped seal when joined.

[0186] This unique shape allows for full engagement between the anterior leaflet 1602A and the posterior leaflet 1602P, particularly in region 1120. In some embodiments, engagement or overlap may exist between the anterior leaflet 1602A and the posterior leaflet 1602P along region 1120. Symmetrically, similar engagement or overlap regions may exist between the posterior leaflet 1602P and the anterior leaflet 1602A (not shown). Similarly, for the valve 600 detailed above, each leaflet may include a corresponding ring, such as rings 601A and 601P, which can be formed by rolling one end of the material constituting each leaflet onto itself.

[0187] according to Figure 9BIn the immediate vicinity of the junction region, two junction configurations may exist between the anterior lobule 1602A and the posterior lobule 1602P. In some embodiments, with respect to the prosthetic valve 600, the prosthetic valve 1100 may include two types of umbilical cords: a primary umbilical cord and a secondary umbilical cord. According to some embodiments, the primary umbilical cord may be configured as an extension to the anterior lobule 1602A and the posterior lobule 1602P, respectively. That is, the primary umbilical cords, for example, primary umbilical cords 1102A and 1102P, may be constructed from the same single piece of material as the corresponding lobules, anterior lobule 1602A, and posterior lobule 1602P. The primary umbilical cords 1102A and / or 1102P may extend from the middle portion of the corresponding lobule at one end and may be connected to a cap at the other end. According to some embodiments, the secondary umbilical cord, such as umbilical cord 1104P, may be attached only to the posterior lobule 1602P. A secondary umbilical cord, such as umbilical cord 1104P, may be connected at one end to the middle portion of the posterior leaflet 1602P and at the other end to the middle portion of the primary umbilical cord 1102P. According to some embodiments, a secondary umbilical cord 1104P may be added to better mimic the natural mitral valve, comprising an additional shorter cord connecting the posterior leaflet and the posterior primary umbilical cord. Adding a secondary umbilical cord allows the posterior leaflet to withstand the pressure applied to it during systole and to produce proper leaflet engagement (or closure) during systole of the cardiac cycle, further allowing the leaflet to open during diastole.

[0188] For example, the posterior lobule 1602P may have attached the secondary umbilical cord 1104P to the posterior edge of the lobule 1602P. The secondary umbilical cord 1104P may further connect to the middle portion of the primary umbilical cord 1102P.

[0189] In some implementations, each bundle of umbilical cords and / or each umbilical cord may be attached to a cap, such as cap 700, which can connect the umbilical cord to the papillary muscles of the heart.

[0190] Figure 10 This is a schematic diagram of a measured copy of a patient's mitral valve according to some embodiments of this disclosure. In some embodiments, the measurements of the length, width, and height of the leaflet portions can be obtained by echocardiography, although other imaging methods, such as cardiac CT or cardiac MRI, may be used. Therefore, the size and shape of the prosthetic mitral valve 1200 can be substantially an exact copy of the patient's natural or natural mitral valve.

[0191] Figure 11 The formation of a bilobal prosthesis according to some embodiments of the present disclosure is illustrated schematically. In some embodiments, such as Figure 12As shown, the base of the valve, namely the lobular portion, can be cut from a monolithic material 1210 based on a cross-sectional image of the intended recipient's heart. The lobular portion can be sized to replicate the prosthesis image at a 1:1 scale, and an incision 1220 can be made along the middle of the lobular portion in a crescent or semi-circular shape to provide an opening 1230 and the definition of two lobes, such as the anterior lobule 1202A and the posterior lobule 1202P, as shown. Figure 12 As shown.

[0192] Figure 12 An opening formed along a leaflet portion according to some embodiments of the present disclosure is schematically shown. In some embodiments, the opening or aperture 1230 may be formed (e.g., cut) in a monolithic material 1210, and two leaflets 1202A and 1202P may be formed on opposite sides of the opening 1230. Once the aperture 1230 is formed by cutting the monolithic material 1210, the two leaflets, such as the anterior leaflet 1202A and the posterior leaflet 1202P, may exist in the form of a flap folded into the aperture 1230, thus further generating unidirectional blood flow through the aperture 1230, i.e., from the left atrium to the left ventricle of the heart.

[0193] Figure 13 An echocardiographic or MRI scan of a patient's left ventricle or chamber according to some embodiments of this disclosure is schematically illustrated. In some embodiments, the patient's left ventricle 1500 can be imaged or scanned by echocardiography, CT, MRI, or other imaging techniques. Such an image or scan of the left ventricle 1500 can provide the precise or substantially precise length of the patient's umbilical cord, from the tip of the papillary muscle 1520 to the leaflets 1502A and 1502P. This enables the fabrication of a custom-made prosthetic mitral valve based on the patient's anatomical and physiological requirements.

[0194] Figures 14A to 14B These are schematic diagrams showing the left ventricle of a patient during diastole and systole, according to some embodiments of this disclosure. In some embodiments, such as Figure 14B As shown, the left ventricle during systole, i.e., left ventricle 1610, may include a portion of the ventricle that is in systole. Figure 14A The diastolic annular diameter of the left ventricle 1612 shown is 1650, smaller than the annular diameter 1640. When blood flows into the left ventricle during diastole, the left ventricle 1612 may become full of blood, thus increasing the annular diameter 1650. After blood flows from the left ventricle into the patient's circulatory system to reach the organs, blood leaves the left ventricle 1610 during systole. Therefore, the volume of the left ventricle 1610 during systole is smaller than the volume of the left ventricle 1612 during diastole, resulting in a smaller annular diameter 1640 during systole compared to 1650 during diastole.

[0195] Because the valve annulus and leaflets 1502A and 1502P require flexibility as their diameter and size repeatedly change during the repetitive phases of cardiac function (i.e., systole and diastole), it should be clear that the valve annulus and leaflets are expected to be made of elastic materials, just like the tissue used to make the natural mitral valve. Therefore, a prosthesis without a stent, without a metal ring, and without rigid materials is disclosed, and the materials chosen for manufacturing the leaflets 1502A and 1502P, as well as the annulus, require a certain degree of compliance and elasticity.

[0196] Figures 15A to 15B These are schematic diagrams showing extensions attached to the anterior and posterior lobes according to some embodiments of this disclosure. In some embodiments, such as Figure 15A As shown, the anterior leaflet 1202A may include an extension 1703, which includes additional material to enlarge the size of the anterior leaflet 1202A. The extension 1703 is approximately 1-5 mm in length and generally forms a cutout for forming the anterior leaflet (e.g., Figure 11 The width of the incision 1220. In some embodiments, the extension 1703 is sutured at one end to the edge of the anterior leaflet 1202A (see...). Figure 11 The cut 1220), and at the other end will include what can be similar to Figure 6A Umbilical cords 604 and 606, and umbilical cord 1704.

[0197] like Figure 15B As shown, the posterior leaflet 1202P may include an extension 1709, which includes additional material to enlarge the size of the anterior leaflet 1202P. The extension 1709 is approximately 1-5 mm in length and generally forms a cutout for the anterior leaflet (e.g., Figure 11 The width of the incision 1220. In some embodiments, the extension 1709 is sutured at one end to the edge of the anterior leaflet 1202P (see...). Figure 11 The cut 1220), and at the other end will include what can be similar to Figure 6A The umbilical cords of 608 and 610 are 1708.

[0198] like Figure 15B As shown, the posterior lobule 1202P has an extension 1709 attached to one end (lobule end) and an umbilical cord 1708 attached to the other end. One end of the umbilical cord 1708 is connected to the extension 109, and the other end is connected to the cap 1870; structurally, it can be similar to a combination. Figure 7A The cap is described. An extension 1703 is attached to one end (the lobule end) of the anterior lobule 1202A, and an umbilical cord 1704 is attached to the other end. One end of the umbilical cord 1704 is connected to the extension 1703, and the other end is connected to the cap 1870; structurally, this can be similar to a combination. Figure 7A The hat described.

[0199] Each of umbilical cords 1704 and 1708 may include several umbilical cords, also described herein as primary umbilical cords, for example, four primary umbilical cords, but any other number of umbilical cords may be implemented depending on the specific requirements of each patient. In some embodiments, the umbilical cord may also include secondary umbilical cords (not shown) as described above.

[0200] Figures 16A to 16B These are schematic side views of a mitral valve prosthesis having an extension and umbilical cord attachment during diastole and systole, according to some embodiments of this disclosure. Referring now... Figure 16A The side view of the mitral valve prosthesis shows its outline when the heart is in diastole, and references... Figure 16B A side view of the mitral valve prosthesis during diastole. The anterior leaflet 1202A and posterior leaflet 1202P are spaced apart to allow blood to flow into the left ventricle through an orifice between leaflets 1202A and 1202P. Extensions 1703 and 1709 provide an enhanced engagement profile to the valve prosthesis. Each of leaflets 1202A and 1202P may have attached extensions 1703 and 1709 that provide additional material to the anterior and posterior leaflets, providing the necessary engagement during systole to prevent backflow of blood into the atria and to support the left ventricle during systole.

[0201] In some embodiments, extensions 1703 and 1709 are prepared to have different dimensions (e.g., length, width, and shape). In some embodiments, umbilical cords 1704 and 1708 can be sewn together and secured before being attached to cap 1870.

[0202] Extensions 1703 and 1709 are respectively configured to carry corresponding umbilical cords (1704, 1708), which are similar to the umbilical cords of natural heart valves and should be inserted into the heart chamber and attached to the heart wall muscle or papillary muscle. For example, extension 1703 may carry an umbilical cord or umbilical cord group 1704, while extension 1709 may carry an umbilical cord or umbilical cord group 1708. Each of at least two umbilical cords may be connected at the other end (opposite to the end connected to each extension) to a cap 1870, which is configured to attach a valve to the papillary muscle.

[0203] In some implementations, during diastole, such as Figure 16A As shown, leaflets 1202A and 1202P, as well as their respective extensions 1703 and 1709, are spaced a certain distance from each other so that blood can flow from the left atrium to the left ventricle in one direction.

[0204] In some implementations, during the contraction phase, such as Figure 16BAs shown, leaflets 1202A and 1202P, and their respective extensions 1703 and 1709, are very close to each other to prevent blood from flowing back or leaking in the opposite direction (i.e., from the left ventricle to the left atrium). According to some embodiments, the extensions (e.g., extensions 1703 and 1709) provide the necessary engagement or closure of the valve to prevent leakage of blood from the left ventricle back to the left atrium.

[0205] According to some implementations, the extension can be cut to fit the leaflet edge and different widths of not less than 5 mm can be measured to ensure adequate engagement. The extension will be attached to the leaflet edge by stitching, gluing, stapling, or other means.

[0206] According to some implementations, the umbilical cord (e.g., umbilical cords 1704 and 1708) can be attached individually, for example, sutured to the ventricular wall or sutured to the papillary muscle, or they can be bundled together, for example, in pairs, in quadruplicates, and so on, depending on the design determined to be optimal for a particular patient.

[0207] According to some implementations, the umbilical cord can be asymmetrical. That is, the size of the umbilical cord can vary because the left ventricle has two papillary muscles, and the umbilical cords originating from various points on the lobule extension can include different lengths and distances from the top edges of these muscles. Therefore, each umbilical cord or umbilical cord bundle can have a personalized, different length compared to other umbilical cords or umbilical cord bundles. This will ensure perfect closure and sufficient engagement length of the prosthetic valve.

[0208] In some embodiments, umbilical cords (e.g., umbilical cords 1704 and 1708) originating from the leaflet extensions (e.g., extensions 1703 and 1709) can be distributed along the edges of the anterior and posterior leaflet extensions so that tension is evenly distributed along the edges of these leaflets as the valve moves in the body, thereby reducing wear on the prosthetic valve.

[0209] Figure 17 This is a schematic diagram illustrating the attachment of an asymmetric flexible ring to the periphery of a valve prosthesis to mimic a natural valve annulus, according to some embodiments of this disclosure. According to some embodiments, the flexible ring 1901 can be formed by rolling an elongated piece of material onto itself and closing it into a loop, or by rolling a piece of material with a central hole onto itself, facing outwards. In some embodiments, the loop 1901 can be attached to the periphery of the mitral valve prosthesis 1200 to allow surgical attachment, such as suturing to the patient's valve annulus, to allow for better stiffness of the valve annulus and, in the case of using an elastic material, to provide better elasticity during the varying cardiac cycle between systole and diastole. The loop 1901 can be used in conjunction with the initial transection of the valve 1200 (…). Figure 10 The surrounding area.

[0210] According to some embodiments, the outer ring reinforcement 1901 may be made of an elastic material including variable elasticity to allow for variable expansion and contraction of the prosthetic valve during diastole and systole, respectively, in the cardiac cycle. In some embodiments, the elasticity of the ring 1901 may be derived from continuous studies of the motion of the patient's natural valve annulus based on 3D echocardiographic studies.

[0211] In some embodiments, the reinforcing ring 19010 may be exposed to the blood environment within the heart, or it may be rolled into a sandwich to surround an elastic material, which may be made of the same material as the leaflets surrounding it.

[0212] like Figure 17 As shown, the prosthetic valve 1200 may include umbilical cords 1704 and 1706, which may be attached to the anterior lobule 1202A (with or without extension), and umbilical cords 1708 and 1710, which may be attached to the posterior lobule 1202P (with or without extension). Figures 16A to 16B As shown, the umbilical cord can be attached to at least two caps configured to attach valve 1200 to the papillary muscles of the heart, thereby enabling the mitral valve prosthesis 1200 to be properly attached to the patient's left ventricle, according to the specific anatomical and physiological requirements of the particular patient.

[0213] Figures 18A to 18B These are schematic diagrams illustrating elastic material inserted into a rolling valve ring before and after it rolls on the ring, according to some embodiments of this disclosure. According to some embodiments, such as... Figures 18A to 18B As shown, the valve annulus 2201 may include an added elastic material 2205, which can be inserted into the annulus 2201 such that the annulus 2201 rolls on the elastic material 2205, and the elastic material 2205 is "clamped" within the annulus 2201. The addition of the elastic material 2205 within the annulus 2201 provides additional elasticity to the annulus 2201, which helps to better mimic the elastic properties of the natural mitral valve. In some embodiments, the elastic material 2205 may be rubber or any other biocompatible synthetic material. In some embodiments, the shape of the elastic material 2205 is similar to the shape of the annulus 2201 into which it is inserted, so that the elastic material 2205 can be easily inserted into the annulus 2201.

[0214] According to some implementation methods, such as Figure 18BAs shown, a ring 2201 (which may be made of the same material as the leaflets or may be made of an extension of alternative material attached to the outer edge of the leaflets) can roll on an elastic material 2205 toward the inner side of the synthetic valve, for example, toward an incision 2220, which may be formed along the middle of the leaflet portion in a crescent or semi-circular shape to provide an opening between the two leaflets defined by the incision 2220, for example, the anterior leaflet 2202A and the posterior leaflet 2202P. The incision 2220 is actually the actual mitral valve prosthesis orifice through which blood flows from the left atrium to the left ventricle. Thus, the outer edge of the mitral valve prosthesis may include the ring 2201, and then connected to the ring 2201 are the main surfaces of the leaflets, such as leaflets 2201A and 2202P, which are then connected to the papillary muscle via a cap 2270 through an umbilical cord (e.g., umbilical cord 2204).

[0215] Figure 19 This is a schematic flowchart illustrating a method for manufacturing a mitral valve prosthesis according to some embodiments of the present disclosure. According to some embodiments, method 2000 for manufacturing a mitral valve prosthesis customized for each patient may include operation 2002, which may include measuring the size and shape of the patient's mitral valve by an imaging method. The imaging method for measuring the shape and size of a particular patient's mitral valve may be echocardiography, cardiac CT, cardiac MRI, and any other imaging method. Method 2000 may also include operation 2004, cutting a replica of the patient's mitral valve from a monolithic material at a 1:1 scale. In some embodiments, method 2000 may include operation 2006, cutting an incision along the monolithic material to create an orifice for blood flow and to create two leaflets, one on each side of the orifice. Method 2000 may include operation 2008, measuring the desired umbilical cord length by an imaging method, which may be similar to the imaging method used in operation 2002 to measure the shape and size of the mitral valve.

[0216] In some embodiments, method 2000 may also include operation 2010 of attaching the umbilical cord to one of two caps configured to attach the umbilical cord to the papillary muscles of the heart.

[0217] In some implementations, method 2000 may include operation 2012, which may include attaching a flexible ring to the leaflet to create a complete mitral valve prosthesis that mimics the natural mitral valve of each particular patient.

[0218] In some embodiments, method 2000 may also include an optional operation that may include attaching extensions to each of the two leaflets to carry the umbilical cord, as measured in operation 2008. These extensions may help provide proper engagement and closure during the systolic phase of the cardiac cycle.

[0219] According to embodiments of this disclosure, the motivation for implementing a method for manufacturing a personalized, naturally designed mitral valve prosthesis is the expectation that the valve will last longer than current valve prostheses because the personalized valve is manufactured to fit the precise anatomical dimensions and limitations of each patient. A personalized prosthesis will provide better service than any of the best quality prostheses because it fits the patient, allowing for superior hemodynamic performance and faster or better cardiac recovery after prosthesis placement.

[0220] refer to Figure 20A This is a schematic diagram illustrating a method 2020 for manufacturing a personalized mitral valve prosthesis according to some embodiments of the present disclosure. According to method 2020, the valve prosthesis is not an off-the-shelf product in current practice. Instead, after ordering the personalized mitral valve prosthesis in operation 2022, a remote diagnostic imaging scan performed in operation 2024 can be used as a basis for the personalized mitral valve prosthesis size in operation 2026, thereby manufacturing a more accurate personalized valve prosthesis for the individual patient in operation 2028. In some embodiments, method 2020 may include packaging and shipping the personalized, naturally designed mitral valve prosthesis for implantation in a specific patient in operation 2030. In some embodiments, scanning is performed within a very short time prior to manufacturing 2028 to ensure that the personalized mitral valve prosthesis is fully compatible with the patient.

[0221] Now for reference Figure 20B This is a schematic flowchart illustrating a method 2040 for manufacturing a personalized mitral valve prosthesis according to some embodiments of the present disclosure. Method 2040 is similar to method 2020, but may include different operations. In some embodiments, method 2040 may include operation 2042, which may include measuring the size and shape of a patient's natural mitral valve by imaging methods. Diagnostic imaging techniques may be, but are not limited to, current imaging techniques, including 2D and 3D echocardiography, computed tomography (CT), or cardiac magnetic resonance (CMR).

[0222] In some implementations, method 2040 may further include operation 2044, which may include calculating the geometry and dimensions of the annular ring, leaflets, and umbilicus of the mitral valve prosthesis for each particular patient based on a validated algorithm. Validated algorithms, such as those used to help define the appropriate mitral valve prosthesis size for each particular patient, will be detailed below.

[0223] In some implementations, method 2040 may include operation 2046, which may include, based on calculations, cutting and connecting all parts of a personalized prosthetic mitral valve, namely, the annular ring, leaflets, and umbilical cord, which may be done according to each patient’s specific anatomy and individual physiology, thereby forming a personalized mitral valve prosthesis.

[0224] In some implementations, method 2040 may include operation 2048, which may include implanting a personalized prosthetic mitral valve into the heart of a patient for whom a personalized mitral valve prosthesis has already been manufactured.

[0225] Now for reference Figures 21A to 21B It shows a schematic diagram of the annular valve edge retained when a natural mitral valve is removed in clinical practice according to some embodiments of the present disclosure, and a schematic diagram of an elliptical valve annulus model, wherein the AL-PM diameter is the major axis and the AP diameter is the minor axis, used to calculate the annular circumference (AC) of the valve prosthesis.

[0226] In some implementations, the following abbreviations are used for the mitral valve prosthesis annulus component: Mitral annulus (MA); Circumference of the annulus (AC); Front-to-back diameter (AP); Anterior-lateral and posteromedial diameters (AL-PM); Union diameter (CC); and Circular region (AA).

[0227] Mitral valve prosthesis annulus: According to some embodiments, the personalized mitral valve prosthesis of this disclosure includes a flexible annular ring whose size matches the patient's natural mitral valve annulus. According to this disclosure, the mitral valve prosthesis can be individualized or personalized based on the following characteristics.

[0228] The first feature is that the annular ring of the prosthesis is manufactured without being constrained by any rigid frame, thus making it compatible with the patient's mitral valve annulus.

[0229] The second feature is that the circumference of the prosthetic annular ring is personalized based on the diagnostic imaging results of a specific patient, for example, as... Figure 20B This was performed in Operation 2022. In some implementations, the size of the prosthetic annular ring is calculated during left ventricular systolic mitral valve closure. Figure 21A The front-to-back diameter (AP) shown Figure 21A The anterolateral and posteromedial diameters (AL-PM) are shown as a function.

[0230] The third characteristic is the preservation of the annular valve margin when removing the natural mitral valve in clinical practice. Figure 21A The annular ring of the prosthesis is then sutured to the edge of the natural valve; in other words, to the constricted natural valve annulus. The personalized annular ring size of the prosthesis, measured in annular ring circumference (AC), can be calculated according to equation (i): (i) AC = f(AP diameter, AL - PM diameter, d) In this way The diameter of AP is the front-to-back diameter; The AL-PM diameter is the diameter of the anterolateral and posteromedial sides; and d is the width of the edge of the ring.

[0231] Based on equation (ii), using the diameter of AL-PM as the major axis and the diameter of AP as the minor axis ( Figure 21B An approximate formula derived from the elliptical valve annulus is used to calculate the AC(1) of the valve prosthesis: (ii)

[0232] In some implementations, the annular circumference (AC) of the mitral valve prosthesis needs further adjustment compared to the patient's natural annulus, and this adjustment typically refers to reducing the size of the annular circumference (AC). In these cases, the annular ring of the mitral valve prosthesis can serve as an annulusoplasty treatment for some patients with such problems. On the one hand, the percentage reduction in AC can range from 0% to 20%, and the actual value can preferably be determined through existing clinical diagnosis, or through mathematical models established by big data analysis, or based on a simpler and more practical comparison with the body surface area (BSA) index value of healthy individuals. On the other hand, when the new valve prosthesis improves leaflet engagement, the trend of annular remodeling after prosthesis implantation also requires a reduction in AC; therefore, the reduction rate (λ) also depends on the patient's potential for cardiac recovery. In summary, the AC (2) of the mitral valve prosthesis, i.e., a more accurate value for the annular circumference of the personalized mitral valve prosthesis, can be calculated according to equation (iii): (iii) Where λ is the rate of reduction of AC (from the circumference of a natural annular ring to the annular ring of a personalized prosthesis).

[0233] According to some embodiments, annular folding techniques can be used when AC reduction is required. Annular folding can be a uniform fold along the valve annulus, rather than the localized folding typically performed during annuloplasty. Because the posterior leaflet occupies a larger portion of the mitral valve circumference, the annular folding according to embodiments of this disclosure can be more focused on the posterior leaflet annulus. Furthermore, the posterior valve annulus of the human heart lacks a fibrous framework, making it prone to dilation, symmetrical or asymmetrical conditions, which can lead to leaflet separation and leakage.

[0234] The fourth characteristic can be based on the fact that, according to this disclosure, a mitral valve prosthesis refers to one consisting of an anterior lobule 2210 ( Figure 22A ) and Houxiaoye 2220 ( Figure 22BThe mitral valve prosthesis consists of two leaflets. Therefore, the annular ring of the prosthesis can also comprise two parts: the anterior leaflet ring and the posterior leaflet ring. The apical edges of the anterior and posterior leaflets can be joined together in an anterolateral to anterolateral and posteromedial to posteromedial direction to form the annular ring 2230 of the mitral valve prosthesis. Figure 22C That is, the anterolateral side of the anterior lobule 2210 is attached to the anterolateral side of the posterior lobule 2220, and the posteromedial side of the anterior lobule 2210 is attached to the posteromedial side of the posterior lobule 2220.

[0235] The annular ring 2230 may have a reinforcing structure and be made of multiple layers of leaflet material. The height of the annular ring 2230 may range from 1 mm to 4 mm, more preferably from 2 mm to 3 mm, which allows clinical surgeons to suture the annulus to the mitral valve annulus of the patient's heart. The number of layers may be two to four, by folding or overlapping the top edges of the anterior and posterior leaflets onto themselves. In some embodiments, the annular ring may include surgical sutures 2316 for reinforcing the annular ring.

[0236] The mitral valve prosthesis of this disclosure can have an asymmetrical annular ring formed by a combination of an anterior and posterior annular rings, which are reinforcing apical edges of the leaflets. An example of such an asymmetrical annular ring is shown in... Figure 22A and Figure 22B As shown, the anterior lobule annular circumference (AAC) 2212 is smaller than the posterior lobule annular circumference (PAC) 2222, and the AAC / PAC ratio (R) can range from 49 / 51 to 30 / 70, more preferably from 35 / 65 to 42 / 58. The anterior lobule annular circumference (AAC) 2212 and the posterior lobule annular circumference (PAC) 2222 can be calculated according to equations (iv) and (v), respectively:

[0237] (iv)

[0238] (v)

[0239] Now for reference Figure 22D and 22E to Figure 22F These illustrate, respectively, a valve ring model indicating the two papillary muscles, and customized anterior and posterior lobule models. In some embodiments, the anterior lobule annular circumference (AAC) and posterior lobule annular circumference (PAC) can be determined by using... Figure 22D The new suture locations A and B are defined as shown. New suture locations A and B can be selected based on the location of each of the two papillary muscles PM1 and PM2, which can define the anterior lobule, for example, anterior lobule 602A (…). Figure 6A ) and posterior leaflets, for example, the posterior leaflets of AAC and PAC that determine each other 602P ( Figure 6A In some implementations, when the umbilical cord is sutured to the papillary muscles PM1 and PM2, compared to prosthetic valves based on other suture locations (e.g., along the valve annulus), the valve umbilical cord (e.g., umbilical cords 604, 606, 608, 610) is more effective than that of prosthetic valves based on other suture locations (e.g., along the valve annulus). Figure 6A The anterior and posterior lobules, which can be fabricated based on the new suture sites A and B, exhibit less deformation after implantation. In some embodiments, Figures 22E to 22F The anterior and posterior lobule models are shown after the new suture sites A and B have been implemented. Based on the current valve annulus model, the anterior lobule annular circumference (AAC) may be slightly longer than the posterior lobule annular circumference (PAC), which may be related to... Figures 22A to 22B In contrast to the published model, the PAC is longer than the AAC. In the current valve annulus model, the surface areas of the anterior and posterior lobules are similar to each other, so they can provide proper lobular closure under blood pressure.

[0240] Mitral valve prosthesis leaflet: Now for reference Figure 23C It is a schematic diagram illustrating the relationship between multiple parameters that influence each other when the prosthesis's lobules are engaged, according to some embodiments of this disclosure, now referred to Figures 24A-24B These are schematic side and perspective views of mitral valve leaflet engagement according to some embodiments of the present disclosure. According to some embodiments, the mitral valve prosthesis of the present disclosure may include two flexible membranous leaflets suspended from an asymmetrical annular ring 2230. The two leaflets open during diastole to allow blood to flow from the left atrium to the left ventricle, and then the two leaflets close tightly, allowing blood to flow through the heart in one direction, preventing backflow through the valve during systole. The size of the two leaflets is crucial to ensuring proper opening and closing of the prosthesis valve.

[0241] For a healthy mitral valve, the prosthesis can be custom-made, with its leaflet length replicated from diagnostic imaging results. However, for patients with mitral valve dysfunction requiring replacement, measurements of the anterior leaflet length (La) and posterior leaflet length (Lp) are neither feasible nor useful in individualized or personalized new prostheses. Instead, the anterior-posterior diameter (AP, which may be referred to as A2P2) can be used as a reference representing the minimum distance or length of the leaflet junction. The ratio (r) of the anterior leaflet length to the posterior leaflet length can vary between 1 / 1 and 2 / 1 (this is a reference ratio).

[0242] In some implementations, in addition to the anterior-posterior diameter (AP) and ratio (r), the lobule length is also affected by the conjugation depth (Cd), conjugation height (CoaptH), and umbilical length (Lc). Therefore, the anterior lobule length (ALL) and posterior lobule length (PLL) can be functions of all the aforementioned parameters, as shown in equations (vi) and (vii):

[0243] (vi)ALL = f(AP diameter, r, Cd, Ch, Lc)

[0244] (vii)PLL=f(AP diameter,r,Cd,Ch,Lc)

[0245] According to some implementations, when the anterior-posterior diameter (AP) is less than 28 mm, empirical formulas are used to calculate the anterior lobule length (ALL) and posterior lobule length (PLL) in animal models. These formulas have proven effective in both pig and sheep models, showing low mean transmitral mitral pressure gradients and acceptable lobule entropion (Figure 24). Formulas (viii) and (ix) are as follows:

[0246] (viii)ALL = (AP diameter) ÷ 2 + 10 (unit: millimeters)

[0247] (ix)PLL = (AP diameter) ÷ 2 + 5 (unit: millimeters)

[0248] In some implementations, the apical edges of the anterior and posterior leaflets form a multi-layered reinforcing annular ring of the valve prosthesis, such as an asymmetric annular ring 2230. The apical edges of the leaflets can be straight or curved, i.e., semi-elliptical, so that the completed valve prosthesis more accurately conforms to the natural geometry of the left ventricle. Downward from the annular ring, two sutures are formed when the two leaflets come together, such as sutures 2310 and 2312. Figure 22C The commissure is tilted inward, giving the valve prosthesis a slight cone shape, thus better conforming to the shape and contour of the left ventricle. The tilt angle (δ0) can range from 5 to 20 degrees. The cone angle (δ1) is determined by the tilt angle (δ0) of the leaflet commissure edge according to equation (x):

[0249] (x)

[0250] According to some implementations, the tilt angles (δ0) of the two leaflets are equal, and therefore the cone angles (δ1) of the two leaflets are equal.

[0251] According to some implementations, another element of the prosthetic leaflet, which should be individualized or personalized, is the free edge. The edge-to-edge engagement between the anterior and posterior leaflets controls the function and performance of the prosthetic valve. Geometrically, the free edge of the leaflet in this invention is semi-elliptical. The length of the free edge can be calculated according to equation (xi):

[0252] (xi) The length of the free edge = {2π×|ALL (or PLL)-b-CH×cosδ0-Coapt H+4a-CH×sinδ0-ALL or PLL-b-CH×cosδ0-Coapt H÷2}

[0253] Where CH represents the lengths of the connecting edges 2214 and 2216, as shown below: Figure 22A and 22B As shown.

[0254] Parameters "a" and "b" are the geometric parameters required to define and form the shape of the tip edge of the anterior or posterior lobule, which curves into a semi-ellipse with the major axis "a" and the minor axis "b", as shown below. Figure 23A As shown, or as Figure 23B The straight line shown.

[0255] Figure 23B This is an extreme example where the top edge of the leaflet is a straight line. Given "b=0", the free edge of the leaflet can be calculated using equation (xi):

[0256] Length of free edge = {2π×(ALL (or PLL)-CH×cos(δ0)-Coapt H+412AAC (or PAC)-CH×sinδ0-ALL or PLL-CH×cosδ0-Coapt H÷2}

[0257] According to some embodiments, improved algorithms can be provided for calculating the leaflet length of a custom mitral valve prosthesis. Leaflet length is a key factor affecting the effective closure and opening of the valve. In some embodiments of this disclosure, the finite element method (FEM) can be used to optimize and calculate the optimal anterior and posterior leaflet lengths to increase engagement and reduce valve leakage. In such embodiments, variations in incoming bovine pericardial data, or incoming data from any other material that can be used to fabricate the prosthetic mitral valve, such as thickness and material properties, are first introduced to calculate the custom valve design. The thickness and material properties of the bovine pericardium or other materials, as well as other properties, may also affect the manner in which the valve closes and opens.

[0258] Now for reference Figure 23D This is a schematic flowchart illustrating a method for customizing a mitral valve using FEM. According to some embodiments, method 2300 may include operation 2320, which may include providing patient mitral valve-related data, such as providing the size and shape of a particular patient's natural mitral valve. Patient mitral valve-related data may include, for example, annular circumference, annular diameter, papillary muscle location, etc. Method 2300 may also include operation 2330, which may include providing incoming bovine pericardial data describing the material properties of the supplied (or incoming) bovine pericardium. In some embodiments, incoming data may be data on the material used to fabricate the prosthetic mitral valve; for example, incoming bovine pericardial data may include, for example, bovine pericardial thickness, tensile test data such as Young's modulus, stress-strain curves, etc.

[0259] In some embodiments, method 2300 may include operation 2340, which may include constructing a custom 3D model of the prosthetic mitral valve and optimizing it via FEM analysis based on incoming bovine pericardial data and patient mitral valve data, both of which can be used as inputs. In some embodiments, optimal anterior leaflet length, optimal posterior leaflet length, optimal umbilical cord width, etc., can be determined via FEM optimization through valve parameter studies by selecting different anterior leaflet lengths, posterior leaflet lengths, umbilical cord widths, and additional parameters, and any combination thereof. Leaflet deformation, maximum principal stress, von Mises stress, leaflet contact detection area, etc., can be used to evaluate valve performance as said valve parameters and other valve parameters are changed until optimal parameters are selected to achieve optimal valve performance.

[0260] In some embodiments, method 2300 may optionally include operation 2350, which may include visualizing a customized prosthetic mitral valve. In some embodiments, method 2300 does not require operation 2350. Operation 2350 may include visualizing a 3D model of the customized prosthetic mitral valve after determining the dimensions of the prosthetic mitral valve (e.g., dimensions of the anterior leaflet, posterior leaflet, anterior periphery, posterior periphery, annular diameter, anterior and posterior leaflet heights, umbilical cord width, etc., performed during operation 2340). In some embodiments, method 2300 may include operation 2360, which includes manufacturing the prosthetic mitral valve based on the constructed 3D model and following the visualization of the model in operation 2350.

[0261] In some implementations, after the custom prosthetic mitral valve design is completed, visualized, and manufactured, method 2300 may include additional operation 2370, which includes performance verification testing of the custom prosthetic mitral valve, for example, in an extracorporeal hydrodynamic chamber.

[0262] According to some implementations, a customized valve design method may include providing patient mitral valve parameters and incoming bovine pericardial data according to operations 2320 and 2330, respectively. An example of such data is provided in Table 1 below. In this example, the patient valve commissure diameter is 36 mm.

[0263] Table 1: Patient mitral valve data and afferent pericardial data Joint diameter (CC) 36.0 Distance offset between PM and the center line of the annulus (DPM) 6.0 Distance between two PMs (DBPM) 24.0 Z-height (ZH) from PM to the lobe ring 30.0 Pericardium thickness (BPTH) 0.28 Young's modulus of bovine pericardium (BPYM) 30.0MPa

[0264] In this method, the customized posterior and anterior lobule parameters, which are appropriate for the patient and implemented through FEM parameter optimization according to operation 2340, are provided in Table 2 below.

[0265] Table 2: Customized leaflet parameters The combined diameter CC (CC) 36.0 Rear circumference (PAC) 51.6 Anterior circumference (AAC) 63.2 Posterior lobule length (PLL) 25.0 Anterior lobule length (ALL) 25.0

[0266] In some implementations, the anterior leaflet length (ALL) and posterior leaflet length (PLL) may be influenced by patient mitral valve data (e.g., commissural diameter, papillary muscle distance, etc.) and afferent bovine pericardial data (e.g., bovine pericardial thickness and Young's modulus). That is, according to formulas (xii) and (xiii), ALL and PLL can be functions of the aforementioned parameters and additional parameters, respectively:

[0267] (xii)ALL=f(CC,DBPM,ZH,BPTH,BPYM, etc.)

[0268] (xiii)PLL=f (CC, DBPM, ZH, BPTH, BPYM, etc.) In this way CC indicates the joint diameter; DBPM represents the distance between the nipple muscles; ZH represents the Z-height from the papillary muscle to the valve annulus; BPTH represents pericardial thickness; and BPYM represents Young's modulus of bovine pericardium.

[0269] In some implementations, empirical formulas can be developed to calculate the anterior lobule length (ALL) and posterior lobule length (PLL) for other patients based on the aforementioned CC 36.0mm FEM data. The final anterior and posterior lobule lengths need to be validated using FEM methods. In some implementations, ALL and PLL can be calculated using equations (xiv) and (xv), respectively:

[0270] (xiv) ALL=(CC*DBPM*ZH*BPTH / BPYM)*α

[0271] (xv)PLL=(CC*DBPM*ZH*BPTH / BPYM)*β In this way α is the anterior lobule length magnification factor, for example, 0.1033; and β is the posterior leaflet length magnification factor, for example, 0.1033.

[0272] Mitral valve prosthesis umbilical cord: In a normal mitral valve, the umbilical cord is fan-shaped, extending from the papillary muscle and inserting into the leaflet. Based on their attachment point, they are classified as primary, secondary, and tertiary umbilical cords.

[0273] The mitral valve prosthesis disclosed herein comprises only the primary umbilical cord attached to the free edge of the anterior or posterior lobule. Two sets of umbilical cords ( Figure 24A ) and three umbilical cords in each group ( Figure 24B They are evenly distributed along 3 / 8 of the free edge from both ends; they are the anterolateral umbilical cord and the posteromedial umbilical cord.

[0274] The umbilical cord plays a crucial role in ensuring the proper opening and closing of the mitral valve prosthesis. Compared to other geometric features of the mitral valve, the umbilical cord, particularly its length, is currently understudied during clinical prediagnosis, especially after each valve replacement. Umbilical cord measurements can be defined as the distance from the apex of the papillary muscle to the annular plane, from the apex of the papillary muscle to the suture margin, or from the apex of the papillary muscle to the annular plane.

[0275] For personalized prosthesis design, the umbilical cord length, lobule length (ALL or PLL), lobule fusion height (Coapt H), lobule fusion depth (Cd), and distance from the apex of the papillary muscle to the lobule fusion margin (Lc) need to be correlated to ensure the function of complex prostheses. Therefore, the anterolateral umbilical cord length (ACL) and posteromedial umbilical cord length (PCL) can be expressed as functions of multiple parameters according to the following equations (xvi) and (xvii):

[0276] (xvi)ACL=f(ALL,Coapt H,Cd,Lc(anterolateral))

[0277] (xvii)PCL=f(ALL,Coapt H,Cd,Lc(posterior medial side))

[0278] This disclosure also describes a simplified method for using the measured distance from the apex of the papillary muscle to the conjoining edge as the prosthetic umbilical cord length, i.e., ACL = Lc (anterolateral) and PCL = Lc (posteromedial); from a design perspective, the three umbilical cords in each group will merge at the free end and fuse into a piece of absorbent cotton similar to umbilical cord cap 2240. Figure 22A and Figure 22B Clinical surgeons can complete the final, personalized or custom-made part of the mitral valve prosthesis by performing on-site measurements and adjustments. Figure 25 The image is an echocardiogram of a sheep heart implanted with a personalized, naturally designed mitral valve prosthesis manufactured according to the method disclosed herein.

[0279] Now for reference Figures 26A to 26B These are schematic diagrams of the posterior and anterior lobules according to embodiments of the present disclosure, showing the umbilical cord width and umbilical cord distance. In some embodiments, the umbilical cord width (CW), the umbilical cord distance per posterior lobule (DCPL), and the umbilical cord distance per anterior lobule (DCAL) can be determined by the FEM method. For an example with a CC of 36.0 mm, the CW is 3 mm for both the anterior and posterior lobules. In some embodiments, the umbilical cord width (CW) can be calculated based on a 36.0 mm CC valve using equation (xviii):

[0280] (xviii)CW=(CC*DBPM*ZH*BPTH / BPYM)*γ In this way γ represents the umbilical cord width magnification factor, for example, 0.0124.

[0281] In some implementations, the final umbilical cord width needs to be verified using the FEM method.

[0282] According to some implementations, the posterior lobule-umbilical distance (DCPL) and the anterior lobule-umbilical distance (DCAL) may depend on the distance between the two papillary muscles (DBPM).

[0283] Figure 27 This is a schematic diagram of the final customized 3D model of the prosthetic mitral valve, including the D-shaped annular ring. The 3D model of the prosthetic mitral valve can be constructed based on the patient mitral valve data provided in operation 2320, and can be further based on the incoming bovine pericardial data provided in operation 2330 of method 2300.

[0284] Figure 28 This is a schematic diagram of the FEM simulation optimization results of the customized prosthetic mitral valve model based on operation 2340 of method 2300. Figure 28 A FEM model of a prosthetic mitral valve in a closed configuration is shown. It is evident that the annular ring of the valve model is D-shaped, resembling the annular ring shape of a natural mitral valve.

[0285] After visualizing the custom-designed prosthetic mitral valve, as in operation 2350, and after manufacturing the custom-designed prosthetic mitral valve, as in operation 2360, performance verification tests of the custom-designed prosthetic mitral valve can be performed, as in operation 2370. Figures 29A to 29B These are schematic diagrams of a prosthetic mitral valve in both open and closed configurations within a hydrodynamic test chamber.

[0286] Figure 30 and Figure 31 The images show echocardiograms during the closure configuration of the custom-designed prosthetic mitral valve after implantation in a pig heart, and images of the blood pressure gradient in the pig heart after implantation. The custom-designed prosthetic mitral valve can close and open in a very efficient and effective manner without any leakage. The maximum pressure gradient is likely 3.87 mmHg, and the average pressure gradient is likely only 1.61 mmHg, which is similar to the pressure experienced by a natural human mitral valve.

[0287] The personalized geometry and dimensions discussed above can be used as input for various engineering drawing software or drawing tools.

[0288] The drawings can be printed out as templates for manually cutting the leaflets of the valve prosthesis, for example, manually cutting them under a microscope.

[0289] Drawings can be programmed into machining tools, such as laser cutters, for cutting leaflets more precisely and efficiently than by hand.

[0290] Drawings can also be programmed into machining tools to create personalized mold cutters or die cutters for leaflet cutting at temperatures lower than laser cutting temperatures, in order to minimize the thermal impact on the valve prosthesis cutting material.

[0291] A mitral valve prosthesis can be formed by connecting the annulus and commissural margins of the anterior and posterior leaflets in an anterolateral to anterolateral and posteromedial to posteromedial direction. Figure 22C One way to join two leaflets together is by suturing them together with surgical sutures, for example... Figure 22C The suture line is 2314.

[0292] The aforementioned valve prostheses can be further packaged, labeled, and sterilized before being implanted into the patient for whom the valve prosthesis was manufactured.

[0293] For ease of handling, the aforementioned valve prostheses can be assembled onto the valve stent before packaging.

[0294] The valve prosthesis disclosed herein can be shipped as a complete product for individualized implantation in a particular patient or otherwise transferred.

[0295] According to some embodiments, any disclosed anterior and posterior leaflets, any ring, any umbilical cord (and any subset thereof), any cap, and / or any combination thereof can be produced from natural materials and can avoid containing foreign matter, such as absorbent cotton. Allogeneic materials and / or composite materials, including various combinations of allogeneic, xenogeneic, and / or autologous transplant materials, can be further used to manufacture flexible rings, leaflets, umbilical cords, and caps. Materials forming valve rings and leaflets can include, but are not limited to, human, bovine, or porcine pericardium, decellularized bioprosthetic materials, cell-bound woven biodegradable polymers, and extracellular materials. Biodegradable natural polymers can include, but are not limited to, fibrin, collagen, chitosan, gelatin, hyaluronic acid, and similar materials. Biodegradable synthetic polymer scaffolds that can be infiltrated with cellular and extracellular matrix materials can include, but are not limited to, poly(L-lactide), polyglycolic acid, poly(lactic-co-glycolic acid), poly(caprolactone), polyorthoesters, poly(dioxane), poly(anhydride), poly(trimethylene carbonate), polyphosphazene, and similar materials. The flexible ring can be further customized to provide patients with personalized flexibility or rigidity. Furthermore, some components of the mitral valve prosthesis, including the umbilical cord, can be formed intraoperatively from the patient's own pericardium.

[0296] According to some embodiments, any disclosed asymmetric flexible ring, which may include a front ring portion and a rear ring portion or can be fabricated as a single unit, can be formed by rolling or folding the edges of the leaflets onto itself. In other embodiments, the flexible ring may further include at least two strands or two layers of material, such as human, bovine, or porcine pericardium, or any of the materials listed above, whereby the at least two strands or two layers may be coiled, twisted, woven, or wrapped around another. A ring constructed with a coiled coil may have greater strength than a ring formed simply by rolling the edges of the leaflets onto itself; however, the coiled ring should retain its elasticity.

[0297] According to some embodiments, the ring may comprise two strands or two layers of material folded together to provide elasticity, and a third layer may be added to provide structural stability. In some embodiments, the ring may comprise two layers made of calf's heart, while the third strand or third layer may be made of glycine or proline to provide strength to the ring.

[0298] In some embodiments, at least two layers or strands may be attached, for example, by stitching them together. In some embodiments, a third layer may be attached, for example, by stitching it to at least two layers of the ring.

[0299] According to some implementations, the components of a prosthetic mitral valve can be attached or connected to each other using several connection methods. For example, the components of a prosthetic mitral valve can be connected to each other using sutures, staples, glue, or any other attachment method.

[0300] In some embodiments, the suture or thread may be made of a non-biodegradable synthetic material, such as nylon, propylene (polypropylene), Novalfil, polyester, etc. In some embodiments, the suture or thread may be made of a non-biodegradable natural material, such as surgical silk or surgical cotton.

[0301] In some implementations, the staples may be made of biocompatible materials, such as stainless steel or titanium.

[0302] In some embodiments, the adhesive may be made of biocompatible materials, such as aldehyde adhesives, fibrin sealants, collagen-based adhesives, polyethylene glycol polymers (hydrogels), or cyanoacrylates.

[0303] According to some implementations, any leaflet, any ring, any umbilical cord (and any subset thereof), and / or any combination thereof can be customized for each patient based on ultrasound imaging of the patient's natural mitral valve and surrounding anatomy. Customized mitral valves can also be produced based on data obtained from other imaging modalities that provide three-dimensional information, including echocardiography, cardiac CT, and cardiac MRI. Therefore, the mitral valve prosthesis of this disclosure can be selected or designed to match a patient's specific anatomy, thereby increasing the chances of high acceptance of the prosthesis by the patient's surrounding tissues (e.g., the myocardium surrounding the prosthesis).

[0304] In preparation for implantation, the patient's heart is stopped, which is common in mitral valve surgery. During implantation, the prosthesis's flexible ring is secured to the natural valve annulus with sutures, while the papillary cap is sutured to the natural papillary muscles. For example, two sutures may be applied to the tip of each natural papillary muscle to secure the cap to the muscle. Clinicians ensure the valve will open and close completely by filling the ventricular chambers with saline under appropriate pressure and examining the movement and ability of the replaced valve to close under pressure. After implantation, the valve is examined using transesophageal echocardiography (TEE) after the heart has closed and resumed beating.

[0305] If necessary, the subject may be placed on anticoagulants after implantation. Given the natural shape and materials used to construct the mitral valve prosthesis of the present invention, low doses of anticoagulants or no anticoagulants are expected for most patients.

[0306] Currently available biological and mechanical prostheses have several drawbacks: they contain bulky foreign bodies, require potent anticoagulants, have short lifespans, require subsequent surgery when replacement is necessary, and do not aid in effective recovery after cardiac implantation. This invention offers several advantages over the aforementioned biological and mechanical prostheses. The described mitral valve prosthesis is designed to better match the patient's natural mitral valve and is made from natural materials, is expected to require less patient recovery time, provide a longer lifespan, and reduce or eliminate the need for anticoagulants.

[0307] All teachings of the patents, published applications and references cited in this article are incorporated herein by reference in their entirety.

[0308] While the invention has been specifically shown and described with reference to exemplary embodiments thereof, those skilled in the art will understand that various changes in form and detail may be made without departing from the scope of the invention as defined in the appended claims.

Claims

1. A method for manufacturing a personalized mitral valve prosthesis for a specific patient, the method comprising the following steps: The size and shape of the natural mitral valve in the specific patient were measured using an imaging device; Provide data on the materials used to manufacture the personalized mitral valve prosthesis; Based on the size and shape of the natural mitral valve of the specific patient and the data of the material, a 3D model of the personalized mitral valve prosthesis is constructed; The 3D model was optimized using the FEM method. and The personalized mitral valve prosthesis is fabricated based on an optimized FEM model by cutting the material into a flexible annular ring, a flexible anterior leaflet, a flexible posterior leaflet, and an umbilical cord. Connect the flexible anterior leaflet and the flexible posterior leaflet to the flexible annular ring; The umbilical cord is connected to the flexible anterior lobule and the flexible posterior lobule, and the umbilical cord is configured to connect to the papillary muscles of the heart; and Adjusting the AC (annular circumference) of the personalized mitral valve prosthesis is characterized by measuring the size and shape of the natural mitral valve of the specific patient, including measuring mitral valve-related parameters such as: AC, AA (annular area), AP (anterior-posterior) diameter, AL-PM (anterolateral-posteromedial) diameter, CC (commissural diameter), ALL (anterior leaflet length), PLL (posterior leaflet length), ACL (mitral valve shape), and PCL (chordae tendineae length). Specifically, based on equation iii, AC is adjusted to be a combination of AAC (anterior lobule annular circumference) as the top edge of the anterior lobule and PAC (posterior lobule annular circumference) as the top edge of the posterior lobule: ； Where λ is the rate of AC reduction, from the circumference of the natural annular ring to the annular ring of the personalized mitral valve prosthesis, and d is the annular ring width of the natural leaflet.

2. The method of claim 1, wherein the apical edge of each of the anterior and posterior leaflets is straight or curved to allow the personalized mitral valve prosthesis to properly conform to the natural geometry of the left ventricle of the particular patient.

3. The method of claim 1, wherein the connection comprises connecting the edge of the anterior lobule to the edge of the posterior lobule, thereby forming an engagement between the anterior lobule and the posterior lobule.

4. The method according to any one of claims 1-3, wherein the connection comprises connecting the flexible anterior leaflet and the flexible posterior leaflet together to form two commissures, wherein the two commissures are inclined inward at δ1 (cone angle) to form a cone-shaped personalized mitral valve prosthesis to fit the natural left ventricle of the particular patient.

5. The method of claim 4, wherein δ1 is determined based on equation x by δ0 (tilt angle) of each joining edge of the flexible anterior leaflet and the flexible posterior leaflet: 。 6. The method of claim 1, wherein the connection comprises connecting the anterior lobule to the posterior lobule by connecting the anterolateral side to the anterolateral side and the posteromedial side to the posteromedial side.

7. The method of claim 6, wherein connecting the anterior lobule to the posterior lobule comprises suturing.

8. The method of claim 3, wherein the length of the free edge of the lobule is calculated based on equation xi, the size and shape of the natural annular ring, CH (commissural height), δ0 (tilt angle), ALL (anterior lobule length), and PLL (posterior lobule length) of the specific patient are measured, and CoaptH (commissural height) is used to calculate the length of each lobule edge: 。 9. The method according to any one of claims 1-3, wherein the height of the flexible annular ring is between 1 mm and 4 mm.

10. The method according to any one of claims 1-3, wherein the height of the flexible annular ring is between 2 mm and 3 mm.

11. The method according to any one of claims 1-3, wherein the AC is a function of the AP diameter and the AL-PM (anterolateral-retromedial) diameter based on equation iii.

12. The method of claim 11, wherein the measurement comprises measuring the AP diameter and the AL-PM diameter during mitral valve closure during left ventricular systole.

13. The method of claim 1, wherein the flexible annular ring is asymmetrical, and wherein the flexible annular ring has an annular circumference comprising AAC (anterior lobule annular circumference) and PAC (posterior lobule annular circumference), wherein the AAC is smaller than the PAC, and the ratio (R) between AAC / PAC is between 49 / 51 and 30 / 70 of the annular circumference.

14. The method of claim 13, wherein the ratio (R) between AAC / PAC is between 35 / 65 and 42 / 58 of the annular circumference.

15. The method of claim 13, wherein the ratio (R) between AAC / PAC is 40 / 60 of the annular circumference.

16. The method of claim 13, wherein the ratio (R) between AAC / PAC is the ratio between ALL (anterior lobule length) and PLL (posterior lobule length).

17. The method of claim 1, wherein constructing the 3D model of the personalized mitral valve prosthesis comprises calculating the AAC (anterior lobule circumference) and PAC (posterior lobule circumference) based on suture locations A and B, and selecting the suture locations A and B based on the location of each of the two papillary muscles of the anterior or posterior lobule.

18. The method of claim 8, wherein constructing the 3D model of the personalized mitral valve prosthesis comprises calculating the ALL and the PLL based on equations vi and vii, and based on: (a) the anterior-posterior (AP) diameter as the theoretical minimum engagement distance; (b) the ratio (r) between the ALL and the PLL; (c) Cd (engagement depth); (d) CoaptH; and (e) Lc (umbilical cord length). ； 19. The method of claim 1, wherein the connection comprises connecting the anterior leaflet and the posterior leaflet together to form the body of the personalized mitral valve prosthesis.

20. The method of claim 1, wherein each anterior lobule and each posterior lobule comprises two sets of umbilical cords: an anterolateral umbilical cord and a posteromedial umbilical cord, wherein each of the anterolateral umbilical cord and the posteromedial umbilical cord comprises three sub-umbilical cords, wherein the umbilical cords are evenly distributed along at least 3 / 8 of each free edge of the anterior lobule and the posterior lobule.

21. The method of claim 20, wherein constructing the 3D model includes calculating the length of each umbilical cord, wherein calculating the length of each umbilical cord is based on parameters including: lobule length, CoaptH (coagulation height), and Cd (coagulation depth).

22. The method of claim 1, wherein the measurement includes measuring the distance from the apex of the papillary muscle to the junctional edge to represent the umbilical cord length of the prosthesis, and further includes on-site measurement and adjustment of the absorbent cotton umbilical cord cap such that the umbilical cord is integrated and merged at the end of each set of umbilical cords.

23. The method of claim 1, wherein constructing the 3D model comprises providing each specific patient with calculated geometry and dimensions of the annular ring, the anterior lobule, the posterior lobule, and the umbilical cord as input for engineering drawing software or drawing tools.

24. The method of claim 23, wherein the engineering drawing software or drawing tool outputs a template for manually cutting the leaflets of the valve prosthesis.

25. The method of claim 23, wherein the engineering drawing software or drawing tool outputs a template for machine cutting of the leaflets.

26. The method of claim 1, further comprising packaging, labeling, and sterilizing the personalized mitral valve prosthesis prior to release for use.

27. The method of claim 1, further comprising assembling the personalized mitral valve prosthesis onto a valve stent prior to packaging.

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