Methods for manufacturing personalized natural design mitral valve prostheses

Abstract

A natural design personalized mitral valve prosthesis and a method for manufacturing the same to precisely fit the specific patient for whom the valve prosthesis is made are provided, which method involves measuring the size and shape of the specific patient's mitral valve using an imaging tool, constructing a 3D model of the personalized mitral valve prosthesis, optimizing the 3D model using a FEM method, and creating the personalized mitral valve prosthesis by cutting out and connecting the annulus, leaflets, and tendons to form the personalized prosthetic mitral valve.

Description

[Technical field]

[0001] The mitral valve, or left atrioventricular valve, is a bicuspid valve (i.e., a valve with two leaflets) located in the heart that separates the left atrium from the left ventricle. The mitral valve allows blood to flow from the left atrium to the left ventricle during ventricular diastole, but prevents blood from flowing back during systole. The naturally occurring mitral valve consists of an annulus, two leaflets (cusps), atrial muscle, chordae tendineae, papillary muscle, and ventricular muscle.

[0002] Mitral valve replacement is a procedure designed to be performed to replace a diseased or dysfunctional valve. In a mitral valve replacement procedure, a patient's mitral valve is removed and replaced with a prosthesis. Because of the unique composition of the mitral valve, creating a long-lasting and properly functioning mitral valve prosthesis is a challenge. [Background technology]

[0003] Both biological and mechanical mitral valve prostheses are commercially available. Both biological and mechanical prostheses are rigid and circular, in contrast to the soft tissue and asymmetric shape of the human mitral valve. Another disadvantage of mechanical valves is that blood tends to clot on the mechanical parts of the valve, causing the valve to function improperly. Patients with mechanical valves must take anticoagulants to reduce the risk of blood clots forming on the valve and causing a stroke. Although biological valves have a lower risk of clot formation than mechanical valves, they are less durable and require more frequent replacement. Biological valves have a rigid metal framework, like mechanical valves, and a metal ring covered with silicone or other synthetic material to allow for the passage of sutures for implantation. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] U.S. Patent No. 6,074,417 [Patent Document 2] U.S. Pat. No. 5,415,667 [Patent Document 3] U.S. Patent No. 6,358,277 Summary of the Invention [Problem to be solved by the invention]

[0005] Currently available mitral valve prostheses are usually constructed in an unnatural circular configuration and are often made of rigid materials. They also often have three symmetrical leaflets, whereas the natural human mitral valve has only two leaflets: a larger anterior leaflet (anterior leaflet) and a smaller posterior leaflet (posterior leaflet). Because of their rigid and unnatural configuration, such mitral valve prostheses distort the natural anatomy of the heart. The myocardium around the prostheses does not recover well after implantation. On average, such prostheses last only 7-10 years, forcing patients to undergo a second and sometimes a third surgery in their lifetime, subjecting them to high-risk open-heart surgery.

[0006] Commercially available prostheses do not achieve the hemodynamic performance associated with a healthy human native mitral valve, which results in significant energy loss in the left heart chamber, significant damage over time, and ultimately heart failure and other adverse events.

[0007] Certain other available mitral valve prostheses can be made by reinforcing an allograft as described in U.S. Patent No. 5,399,663, but this requires the physician to test different sizes of valves to find the best match for the patient and involves the sacrifice of the animal from which the valve is harvested. Still other available mitral valve prostheses can be made by sewing together multiple layers of the pericardium as described in U.S. Patent No. 5,399,663, but this can result in blood clotting in the areas where multiple sutures are present.

[0008] In other types of atrioventricular valves, such as the mitral valve, disclosed in US Pat. No. 5,399,433, a template made of a membrane material is sewn onto the patient's mitral annulus. This type of valve has a tall, unnaturally shaped annulus, which creates a bulky collar around the prosthetic valve. Furthermore, the template is provided in a standard size and must be trimmed to fit the patient. [Means for solving the problem]

[0009] A method for manufacturing a precisely fitted and functioning native design personalized mitral valve prosthesis for an individual patient is provided, which includes a series of operations or steps beginning with receiving a customization / personalization order for a mitral valve prosthesis along with diagnostic imaging and image analysis results, quantifying the geometry and dimensions of the valve prosthesis using a validated algorithm, producing a valve according to the geometry and dimensions of an individualized recipient patient, and assembling the valve into a personalized valve prosthesis specially manufactured to fit each specific patient's anatomy and clinical condition, packaging and sterilizing the personalized valve prosthesis into the final mitral valve prosthesis, shipping it for implantation in the specific patient, and implanting the personalized prosthetic mitral valve into the patient.

[0010] A method is provided for manufacturing a natural design personalized mitral valve prosthesis to be precisely fitted to the particular patient for whom the valve prosthesis is made, by measuring the size and shape of the patient's native mitral valve using imaging techniques, calculating the geometry and dimensions of the annular ring, anterior leaflets, posterior leaflets and chords for the particular patient using validated algorithms, and then cutting and connecting the annular ring, anterior leaflets, posterior leaflets and chords to form the personalized prosthetic mitral valve.

[0011] According to certain embodiments, the imaging may be by 2D or 3D echocardiography, computed tomography (CT), cardiac magnetic resonance (CMR), or any combination thereof.

[0012] According to certain embodiments, when measuring the size and shape of a patient's native mitral valve, mitral valve-related parameters can be measured, which can include annular circumference (AC), annular area (AA), anterior-posterior diameter (AP), anterolateral-posteromedial diameter (AL-PM), commissural diameter (CC), anterior leaflet length (AL), posterior leaflet length (PL), mitral valve geometry, and chordae tendineae length (ACL and PCL).

[0013] According to certain embodiments, the method further includes collecting physiological information about the particular patient for the calculation, which predicts the cardiac geometry of the implanted heart valve with improved function, the physiological information may include height, weight, age, race, and sex.

[0014] A personalized mitral valve prosthesis is provided, comprising a flexible annular ring sized to match a patient's native mitral valve annulus, flexible anterior and posterior leaflets sized to match the patient's native mitral valve leaflets, the leaflets being connected to the annular ring, and tendons sized to match the patient's native mitral valve leaflets, the tendons being attached to papillary muscles of the heart. The personalized mitral valve prosthesis comprises: measuring the size and shape of the patient's native mitral valve using imaging techniques; Calculating the geometry and dimensions of the annulus, leaflets, and tendons for that particular patient using a validated algorithm; and The annulus, leaflets and tendons are then excised and joined to form a personalized prosthetic mitral valve. It can be formed.

[0015] According to certain embodiments, the imaging may be by 2D or 3D echocardiography, computed tomography (CT), cardiac magnetic resonance (CMR), or any combination thereof.

[0016] In certain embodiments, mitral valve-related parameters can be measured to measure the size and shape of the patient's mitral valve, including annular circumference (AC), annular area (AA), anterior-posterior diameter (AP), anterior-lateral-posterior-medial diameter (AL-PM), coaptation span (CC), anterior leaflet length (ALL), posterior leaflet length (PLL), mitral valve geometry, and chordae lengths (ACL and PCL).

[0017] According to certain embodiments, the personalized mitral valve prosthesis can be further formed by collecting physiological information about the particular patient for computation, which computationally predicts a post-implant cardiac geometry with improved cardiac valve function, the physiological information including height, weight, age, race, and gender.

[0018] According to certain embodiments, the calculation may be performed by combining the anterior leaflet annular circumference (AAC) at the upper edge of the anterior leaflet with the posterior leaflet annular circumference (PAC) at the upper edge of the posterior leaflet, as shown in equation (iii) below. According to certain embodiments, the annular ring may be formed into a multi-layered reinforced structure by folding or overlapping the upper edges of the anterior and posterior leaflets.

[0019] According to certain embodiments, the upper edges of each of the anterior and posterior leaflets can be straight or curved to properly fit the personalized mitral valve prosthesis to the natural geometry of the left ventricle of that particular patient.

[0020] In certain embodiments, coupling can couple the anterior leaflet edge with the posterior leaflet edge to create a coaptation that can control the size of the valve orifice and thus affect the transmitral pressure gradient, thereby controlling the function and performance of the personalized mitral valve prosthesis.

[0021] According to certain embodiments, the joining step involves joining two leaflets together to form two sutures, and the two sutures are spaced apart by a cone angle (δ 1 ) to create a slight conical shape in the body of the personalized mitral valve prosthesis, thereby allowing the personalized mitral valve prosthesis to fit properly within the left ventricle of the particular patient's native shape and contour.

[0022] According to certain embodiments, the cone angle (δ 1 ) is calculated by the equation (x) and the inclination angle (δ 0 ) can be determined.

[0023] In certain embodiments, the connection can connect the anterior leaflet to the posterior leaflet by connecting anterolateral to anterolateral and posteromedial to posteromedial.

[0024] According to certain embodiments, the connection of the anterior leaflet to the posterior leaflet may be a suture.

[0025] In certain embodiments, measurements are taken based on the patient's native annulus size and shape, suture height (CH), inclination angle (δ) to calculate the length of each leaflet edge according to equation (xi) below. 0 ), anterior leaflet length (ALL) and posterior leaflet length (PLL) as well as junctional height (CoaptH) can be measured.

[0026] According to certain embodiments, the height of the reinforcing hoop may be between 1 mm and 4 mm.

[0027] According to certain embodiments, the height of the reinforcing hoop may be between 2mm and 3mm.

[0028] According to certain embodiments, the annular circumference (AC) can be a function of the anterior-posterior diameter (AP) and the anterior-lateral-posterior-medial diameter (AL-PM) according to equation (iii) below.

[0029] According to certain embodiments, measurements of the anterior-posterior diameter (AP) and anterior-lateral-posterior-medial diameter (AL-PM) can be taken during left ventricular systole and when the mitral valve is closed.

[0030] According to certain embodiments, calculation of the annular circumference (AC) of the prosthesis can be based on the annular width (d) of the native leaflet that was preserved during clinical surgery.

[0031] According to certain embodiments, the calculation of the annular circumference (AC) of the prosthesis can be made based on the ratio (λ) in equation (iii).

[0032] In some embodiments, the annular ring can be asymmetrical, and can be formed by a combination of an anterior leaflet ring and a posterior leaflet ring, with the anterior leaflet ring circumference (AAC) being smaller than the posterior leaflet ring circumference (PAC), and the ratio (R) of AAC / PAC can be between 49 / 51 and 30 / 70.

[0033] According to certain embodiments, the ratio (R) AAC / PAC may be between 35 / 65 and 42 / 58.

[0034] According to certain embodiments, the ratio (R) AAC / PAC may be 40 / 60.

[0035] In certain embodiments, the ratio (R) AAC / PAC can be the ratio between the anterior leaflet length (ALL) and the posterior leaflet length (PLL) and can be used to ensure proper opening and closing of the prosthetic valve.

[0036] According to certain embodiments, the calculation can be performed using equations (viii) and (ix) below, based on (a) the anterior-posterior diameter (AP), which is the theoretical minimum distance for junction, (b) the ratio of ALL to PL (r), (c) junction depth (Cd), (d) junction height (CoaptH), and (e) tendon length (Lc), to calculate the anterior leaflet length (ALL) and posterior leaflet length (PLL).

[0037] According to certain embodiments, upon coupling, two leaflets may be coupled together to form the body of the personalized mitral valve prosthesis.

[0038] In certain embodiments, each of the anterior and posterior leaflets can have two sets of tendons, an anterior lateral tendon and a posteromedial tendon, each of which can have three accessory tendons, providing an even distribution of tendons from each end along at least 3 / 8 of each edge.

[0039] According to certain embodiments, the calculation can include calculating the length of each tendon to ensure that the personalized mitral valve prosthesis can open and close properly, and the calculation of the length of each tendon can be based on several parameters, including leaflet length, coaptation height, and coaptation depth.

[0040] According to certain embodiments, measurements can include measuring the distance from the papillary muscle apex to the joint edge to indicate the prosthetic tendon length, and also include on-site measurement and adjustment of the pledget-like tendon caps into which the tendons are bundled and where the ends of each pair of tendons meet.

[0041] According to certain embodiments, the personalized mitral valve prosthesis can be further created by providing the calculated geometry and dimensions of the annular ring, anterior leaflet, posterior leaflet and tendons for that particular patient as inputs into engineering drafting software or tools.

[0042] According to certain embodiments, the engineering drawing software or tool can output a template for manual cutting of the leaflets of the valve prosthesis.

[0043] According to certain embodiments, the engineering drawing software or tool can output a template for machine cutting of the leaflets.

[0044] According to certain embodiments, the personalized mitral valve prosthesis may further be in a form that is packaged, labeled and sterilized prior to being released for use.

[0045] According to certain embodiments, the personalized mitral valve prosthesis may further be configured to be assembled onto a valve holder prior to packaging.

[0046] According to certain embodiments, the personalized mitral valve prosthesis may be further configured to be implanted within the particular patient.

[0047] A prosthetic valve designed to mimic a patient's natural mitral valve is provided. It has two flexible leaflets and an asymmetric flexible ring that can move with the natural distortion of the myocardium during the cardiac cycle. The prosthetic valve incorporates tendons that mimic the patient's natural chordae tendineae, which can mimic the natural prevention of blood backflow into the atrium and provide support to the left ventricle during systole.

[0048] According to certain embodiments, a mitral valve prosthesis for implantation in the heart comprises: an asymmetric annulus sized to mimic a patient's native mitral valve annulus, the asymmetric annulus being constructed by wrapping a flexible material over itself toward the outside of the valve; a flexible anterior leaflet and a flexible posterior leaflet suspended from the asymmetric annulus and configured to be substantially interconnected; the anterior and posterior leaflets are configured such that their respective shapes mimic the shape of a native mitral valve and thus define an orifice through which blood flows in one direction; The cap has at least two sets of tendons, each set of tendons attached at a first end to an anterior or posterior leaflet and attached at a second end within a cap, and the cap is configured to be attached at its other end over a papillary muscle of the heart.

[0049] In certain embodiments, the mitral valve prosthesis can further include an interface surface that communicates with each one of the anterior and posterior leaflets and has a respective pair of tendons attached thereto, the interface surface being configured to enhance sealing of the mitral valve prosthesis.

[0050] In certain embodiments, the asymmetric ring may further comprise at least two strands arranged in a coiled-coil structure.

[0051] According to certain embodiments, the asymmetric ring can include two layers of material folded together to provide elasticity and a third layer to provide structural stability.

[0052] According to certain embodiments, the asymmetric ring may comprise two layers of bovine (cow) pericardium and a third layer of glycine or proline to provide strength.

[0053] According to certain embodiments, the two layers may be joined together by sutures, staples, glue, or some combination thereof.

[0054] According to certain embodiments, the asymmetric ring, the flexible anterior and posterior leaflets, the at least two sets of tendons, the cap, or any combination thereof may be made of bovine pericardium.

[0055] In certain embodiments, the leaflet shape may be elongated by 1-5 mm to allow for better coaptation and tendon attachment.

[0056] According to certain embodiments, the leaflet shape can be designed to follow a semicircular pattern along half the length of the flexible anterior and posterior leaflets such that an "S" shaped seal is created by both leaflets when joined.

[0057] According to certain embodiments, the mitral valve can further include at least one secondary tendon that can be attached to the middle of the posterior leaflet at one end and to the middle of the primary tendon at the other end.

[0058] According to certain embodiments, the at least two sets of tendons can be attached to the cap and the opening can be located in a central portion of the cap.

[0059] According to certain embodiments, each of the at least two sets of tendons can be attached to the middle of the anterior or posterior leaflet to mimic the naturally occurring mitral valve.

[0060] According to certain embodiments, the anterior and posterior leaflets can be fabricated as a single unit, connected to an asymmetric ring, and attached to at least two sets of tendons.

[0061] In certain embodiments, the mitral valve may further include an extension configured to connect to the flexible anterior leaflet on one end and to at least two sets of tendons on the other end, and to allow coaptation between the flexible anterior leaflet and the flexible posterior leaflet.

[0062] According to certain embodiments, a mitral valve prosthesis implanted in the heart comprises: an asymmetric annulus sized to mimic the patient's native mitral valve annulus, the asymmetric annulus being constructed by wrapping a flexible material over itself toward the outside of the valve; two leaflets suspended from the asymmetric ring, the leaflets being on opposite sides of a cut made in a material similar to the base material of the asymmetric ring, the cut creating an orifice through which blood flows in one direction; at least two pairs of tendons, each pair attached to one of the two leaflets at a first end and attached in a bundle at a second end; a cap connected to the at least two sets of tendons at one end thereof and configured to be sutured onto the papillary muscles of the heart at the other end thereof; The present invention may be provided with the following.

[0063] According to certain embodiments, each pair of tendons is attached to one of the two leaflets via an extension configured to allow for attachment between the two leaflets.

[0064] According to certain embodiments, a method of making a mitral valve prosthesis includes: measuring the size and shape of the patient's mitral valve using an imaging technique; A replica of the subject's mitral valve was cut from a single piece of material. cutting along the single piece of material to create an orifice for blood flow and two lobules, one lobules on each side of the orifice; The required tendon length is measured using imaging techniques. Attach the tendons to one of two caps, and By attaching flexible rings onto the leaflets, an overall mitral valve prosthesis can be created that mimics a particular patient's native mitral valve.

[0065] According to certain embodiments, measuring the required tendon length can be performed simultaneously with measuring the size and shape of the subject's mitral valve.

[0066] According to certain embodiments, the method can further include attaching extensions to each of the two leaflets to carry the tendons prior to attaching the tendons to one of the two caps.

[0067] A method is provided for manufacturing a natural design personalized mitral valve prosthesis to precisely fit the particular patient for whom the valve prosthesis is manufactured, the method comprising: measuring the size and shape of the patient's native mitral valve using imaging means; providing data on the materials from which the personalized mitral valve prosthesis is made; constructing a 3D model of the personalized mitral valve prosthesis based on the size and shape of the particular patient's native mitral valve and the material data; Optimize the 3D model using FEM method, and The personalized mitral valve prosthesis can be created based on the optimized FEM model.

[0068] According to certain embodiments, the method further includes visualizing the personalized mitral valve prosthesis model after the optimization operation.

[0069] According to certain embodiments, the imaging may be by 2D or 3D echocardiography, computed tomography (CT), cardiac magnetic resonance (CMR), or any combination thereof.

[0070] According to certain embodiments, when measuring the size and shape of the patient's native mitral valve, mitral valve related parameters are measured including annular circumference (AC), annular area (AA), anterior-posterior diameter (AP), anterior-lateral-posterior-medial diameter (AL-PM), coaptation span (CC), anterior leaflet length (AL), posterior leaflet length (PL), mitral valve geometry, and chordae lengths (ACL and PCL).

[0071] According to certain embodiments, the method further includes collecting physiological information about the particular patient to predict the cardiac geometry following implantation of the personalized mitral valve prosthesis, the physiological information including height, weight, age, race, and gender.

[0072] In certain embodiments, a personalized mitral valve prosthesis is provided, which may include a flexible annular ring sized to match a patient's native mitral valve annulus, flexible anterior and posterior leaflets sized to match the patient's native mitral valve leaflets, the leaflets connected to the annular ring, and tendons sized to match the patient's native mitral valve leaflets, the tendons connected to the flexible anterior and posterior leaflets, and configured to connect the flexible anterior and posterior leaflets to papillary muscles of the heart. According to certain embodiments, the personalized mitral valve prosthesis may be configured as follows: measuring the size and shape of the patient's native mitral valve using imaging means; providing data on the materials from which the personalized mitral valve prosthesis is made; constructing a 3D model of the personalized mitral valve prosthesis based on the size and shape of the particular patient's native mitral valve and the material data; Optimize the 3D model using FEM method, and cutting the material into an annular ring, flexible anterior and flexible posterior leaflets, and tendons, connecting the flexible anterior and flexible posterior leaflets to the annular ring, and connecting tendons to the flexible anterior and flexible posterior leaflets, thereby creating the personalized mitral valve prosthesis based on the optimized FEM model; According to certain embodiments, the personalized mitral valve prosthesis can optionally be created by further visualizing the personalized mitral valve prosthesis model prior to the creation operation.

[0073] According to certain embodiments, the imaging modality is 2D or 3D echocardiography, computed tomography (CT), cardiac magnetic resonance (CMR), or any combination thereof.

[0074] According to certain embodiments, when measuring the size and shape of a patient's mitral valve, mitral valve related parameters are measured including annular circumference (AC), annular area (AA), anterior-posterior diameter (AP), anterior-lateral-posterior-medial diameter (AL-PM), coaptation span (CC), anterior leaflet length (ALL), posterior leaflet length (PLL), mitral valve geometry, and chordae lengths (ACL and PCL).

[0075] According to certain embodiments, the personalized mitral valve prosthetic may be further constructed by collecting physiological information about the particular patient to predict the cardiac geometry following implantation of the personalized mitral valve prosthesis, and the physiological information may include height, weight, age, race, and gender.

[0076] In certain embodiments, the measurement is made by measuring the annular circumference (AC) as a combination of the anterior leaflet annular circumference (AAC) at the upper edge of the anterior leaflet and the posterior leaflet annular circumference (PAC) at the upper edge of the posterior leaflet, based on equation (iii).

[0077] According to certain embodiments, the annular ring is formed into a multi-layered reinforced structure by folding or overlapping the upper edges of each of the anterior and posterior leaflets.

[0078] According to certain embodiments, the upper edges of each of the anterior and posterior leaflets are straight or curved to properly fit the personalized mitral valve prosthesis to the native geometry of the left ventricle of that particular patient.

[0079] In certain embodiments, the joining involves joining an edge of the anterior leaflet with an edge of the posterior leaflet such that an anterior-posterior interlobular junction is formed.

[0080] According to certain embodiments, during coupling, two sutures are formed by joining the flexible anterior leaflet and the flexible posterior leaflet together, and the two sutures have a cone angle (δ) such that the personalized mitral valve prosthesis has a cone shape and fits within the specific patient's native left ventricle. 1 ) is tilted inward.

[0081] According to certain embodiments, the cone angle (δ 1 ) is calculated based on the equation (x) by the inclination angle (δ 0 ) is determined by

[0082] In certain embodiments, the connection includes connecting the anterior leaflet to the posterior leaflet by connecting anterolateral to anterolateral and posteromedial to posteromedial.

[0083] According to certain embodiments, the connection of the anterior leaflet to the posterior leaflet is by sutures.

[0084] In certain embodiments, the measurements are made based on the patient's native annular ring size and shape, suture height (CH), inclination angle (δ) to calculate the length of each leaflet edge according to equation (xi): 0 ), anterior leaflet length (ALL) and posterior leaflet length (PLL) as well as junctional height (CoaptH) are measured.

[0085] According to certain embodiments, the height of the reinforcing ring is between 1 mm and 4 mm.

[0086] According to certain embodiments, the height of the reinforcing ring is between 2mm and 3mm.

[0087] According to certain embodiments, the annular circumference (AC) is a function of the anterior-posterior diameter (AP) and the anterior-lateral-posterior-medial diameter (AL-PM) according to equation (iii).

[0088] According to certain embodiments, during measurement, the anterior-posterior diameter (AP) and anterior-lateral-medial diameter (AL-PM) measurements are performed during left ventricular systole and when the mitral valve is closed.

[0089] According to certain embodiments, the calculation of the annular circumference (AC) of the prosthesis is based on the ratio (λ) in equation (iii).

[0090] In certain embodiments, the annular ring is asymmetric and further formed by a combination of an anterior leaflet ring and a posterior leaflet ring, the anterior leaflet ring circumference (AAC) is smaller than the posterior leaflet ring circumference (PAC), and the ratio (R) of AAC / PAC is between 49 / 51 and 30 / 70.

[0091] According to certain embodiments, the ratio (R) AAC / PAC is between 35 / 65 and 42 / 58.

[0092] According to certain embodiments, the ratio (R) AAC / PAC is 40 / 60.

[0093] According to certain embodiments, the ratio (R) AAC / PAC is the ratio between the anterior lobule length (ALL) and the posterior lobule length (PLL).

[0094] According to certain embodiments, when constructing the 3D model of the personalized mitral valve prosthesis, the anterior leaflet annular circumference (AAC) and posterior leaflet annular circumference (PAC) are calculated based on suture locations A and B.

[0095] According to certain embodiments, when constructing a 3D model of the personalized mitral valve prosthesis, the anterior leaflet length (ALL) and posterior leaflet length (PLL) are calculated based on equations (viii) and (ix) based on (a) the anterior-posterior diameter (AP), which is the theoretical minimum distance for coaptation, (b) the ratio of ALL to PLL (r), (c) coaptation depth (Cd), (d) coaptation height (CoaptH), and (e) tendon length (Lc).

[0096] According to certain embodiments, upon coupling, the anterior leaflet and the posterior leaflet are coupled together to form the body of the personalized mitral valve prosthesis.

[0097] According to certain embodiments, each anterior leaflet and each posterior leaflet comprises two sets of tendons, anterior lateral tendons and posteromedial tendons, each of which comprises three accessory tendons, which are evenly distributed along at least 3 / 8 of each edge from each side.

[0098] According to certain embodiments, the length of each tendon is calculated when constructing the 3D model, and the calculation of the length of each tendon is based on parameters including leaflet length, junction height, and junction depth.

[0099] According to certain embodiments, measurements include measuring the distance from the papillary muscle apex to the commissure edge to indicate the prosthetic tendon length, and also includes on-site measurement and adjustment of pledget-like tendon caps into which the tendons are bundled and where the ends of each pair of tendons meet.

[0100] According to certain embodiments, in constructing the 3D model, the calculated geometry and dimensions of the annulus, anterior leaflet, posterior leaflet and tendon for that particular patient are provided as input to engineering drafting software or tools.

[0101] According to certain embodiments, the engineering drawing software or tool outputs a template for manual cutting of the leaflets of the valve prosthesis.

[0102] According to certain embodiments, the engineering drawing software or tool outputs a template for machine cutting of the leaflets.

[0103] According to certain embodiments, the method further includes packaging, labeling and sterilizing the personalized mitral valve prosthesis before it is released for use.

[0104] According to certain embodiments, the method may further include assembling the personalized mitral valve prosthesis onto a valve holder prior to packaging.

[0105] According to certain embodiments, the method may further include implanting the personalized mitral valve prosthesis in the particular patient. [Brief description of the drawings]

[0106] [Figure 1A]1 is a schematic diagram of embodiments of the present invention, illustrating a prosthetic mitral valve in an open position and showing the tendons prior to attachment to the leaflets, in accordance with certain embodiments of the present disclosure. [Figure 1B] 1 is a schematic diagram of embodiments of the present invention, depicting a prosthetic mitral valve in a closed position and showing the tendons after attachment to the leaflets, in accordance with certain embodiments of the present disclosure. [Diagram 2] FIG. 1 is a schematic diagram of an embodiment of the present disclosure implanted in a heart, in accordance with certain embodiments of the present disclosure. [Diagram 3] FIG. 1 illustrates a 3D reconstruction of the mitral valve area in 3D CT image analysis software, according to certain embodiments of the present disclosure. [Figure 4] FIG. 1 shows photographs of 3D printed valve molds and porcine pericardial mitral valve leaflets according to certain embodiments of the present disclosure. [Diagram 5] 1A-1C show photographs of prosthetic valves under in vitro testing according to certain embodiments of the present disclosure. [Figure 6A] FIG. 2 is a schematic diagram of a side view of the anterior and posterior leaflets of a prosthetic mitral valve according to certain embodiments of the present disclosure. [Figure 6B] FIG. 13 is a schematic diagram of a top view of leaflets coapted according to certain embodiments of the present disclosure. [Figure 6C] FIG. 1 is a schematic diagram of a top view of a mitral valve prosthesis according to various embodiments of the present disclosure, looking down from the left atrium into the left ventricle (during diastole when the valve is open and blood is able to enter the left ventricle). [Figure 6D] FIG. 2 is a schematic diagram of a single piece of material including an anterior leaflet and a posterior leaflet according to embodiments of the present disclosure. [Figure 7A] FIG. 1 is a schematic diagram of a cap that may connect tendons to papillary muscles of the heart, according to embodiments of the present disclosure. [Figure 7B] FIG. 1 is a schematic diagram of a mitral valve prosthesis with two caps attached to tendons according to embodiments of the present disclosure. [Figure 8A] 1A-1C are schematic diagrams of possible locations of tendons relative to leaflets according to certain embodiments of the present disclosure; [Figure 8B]1 is a schematic diagram of a cross section of a tendon upon leaflet attachment according to certain embodiments of the present disclosure. [Figure 9A] FIG. 1 is a schematic diagram of a prosthetic mitral valve with two leaflets attached according to an alternative design featuring a curved (ellipsoid / droplet) configuration, such as that for coaptation expansion, according to certain embodiments of the present disclosure. [Figure 9B] 1A-1D are schematic diagrams of potential interface configurations according to certain embodiments of the present disclosure. [Figure 10] 1A-1C are schematic diagrams of measured copies of a patient's mitral valve derived from 2D or 3D echocardiograms, according to certain embodiments of the present disclosure. [Figure 11] 1A-1D are schematic diagrams of bileaflet prosthesis formation according to certain embodiments of the present disclosure. [Figure 12] 1A-1C are schematic diagrams of apertures formed in the surfaces of leaflet sections according to certain embodiments of the present disclosure. [Figure 13] FIG. 1 is a schematic diagram illustrating an echocardiogram or MRI scan of a patient's left heart chamber or ventricle, according to certain embodiments of the present disclosure. [Figure 14A] 1 is a schematic diagram illustrating a patient's left ventricle during diastole, in accordance with certain embodiments of the present disclosure. [Figure 14B] 1 is a schematic diagram illustrating a patient's left ventricle during systole, in accordance with certain embodiments of the present disclosure. [Figure 15A] 13 is a schematic diagram of an extension attached to the anterior leaflet according to certain embodiments of the present disclosure. FIG. [Figure 15B] 13 is a schematic diagram of an extension attached to the posterior leaflet according to certain embodiments of the present disclosure. FIG. [Figure 16A] FIG. 2 is a schematic diagram showing a diastolic side view of a mitral valve prosthesis having extensions and tendons attached according to certain embodiments of the present disclosure. [Figure 16B] FIG. 2 is a schematic diagram showing a systolic side view of a mitral valve prosthesis having extensions and tendons attached according to certain embodiments of the present disclosure. [Figure 17]1A-1C are schematic diagrams of the attachment of an asymmetric flexible ring around the circumference of a valve prosthesis to mimic the natural annulus, according to certain embodiments of the present disclosure. [Figure 18A] 1 is a schematic diagram of an elastic material incorporated into a rolled valve annulus before rolling, according to certain embodiments of the present disclosure. FIG. [Figure 18B] 1 is a schematic diagram of an elastic material incorporated into a rolled-type valve annulus after rolling, according to certain embodiments of the present disclosure. FIG. [Figure 19] 1 is a schematic flow chart illustrating a method of making a mitral valve prosthesis according to certain embodiments of the present disclosure. [Figure 20A] 1A-1D are schematic diagrams illustrating a method for manufacturing a personalized mitral valve prosthesis according to certain embodiments of the present disclosure. [Figure 20B] 1 is a schematic flow chart illustrating a method for manufacturing a personalized mitral valve prosthesis according to certain embodiments of the present disclosure. [Figure 21A] FIG. 1 is a schematic diagram of the annular pericardial rim preserved when the native mitral valve is removed in clinical practice, according to certain embodiments of the present disclosure. [Figure 21B] FIG. 1 is a schematic diagram of an elliptical ring model used to calculate the annular circumference (AC) of a valve prosthesis, with the major axis being the diameter (AL-PM) and the minor axis being the diameter (AP), according to certain embodiments of the present disclosure. [Figure 22A] 1A-1D are schematic diagrams of example anterior leaflet designs according to certain embodiments of the present disclosure. [Figure 22B] 1A-1D are schematic diagrams of example posterior leaflet designs according to certain embodiments of the present disclosure. [Figure 22C] 1A-1D are schematic diagrams of example mitral valve prosthesis assembly designs according to certain embodiments of the present disclosure. [Figure 22D] FIG. 1 is a schematic diagram of a ring model showing two papillary muscles according to certain embodiments of the present disclosure. [Figure 22E] FIG. 1 is a schematic diagram of a pre-customized leaflet model according to certain embodiments of the present disclosure. [Figure 22F] FIG. 1 is a schematic diagram of a customized leaflet model according to certain embodiments of the present disclosure. [Figure 23A]1 is a schematic diagram of an example anterior or posterior leaflet illustrating the theoretical length of the free edge of the leaflet according to certain embodiments of the present disclosure. [Figure 23B] FIG. 2 is a schematic diagram of another example anterior or posterior leaflet illustrating the theoretical length of the free edge of the leaflet according to certain embodiments of the present disclosure. [Figure 23C] FIG. 2 is a schematic diagram illustrating the relationship between several parameters that affect prosthesis leaflet coaptation, according to certain embodiments of the present disclosure. [Figure 23D] 1 is a schematic flow chart illustrating a method for custom mitral valve design using FEM according to certain embodiments of the present disclosure. [Figure 24A] FIG. 1 is a schematic diagram of a side view of mitral valve leaflet coaptation according to certain embodiments of the present disclosure. [Figure 24B] FIG. 1 is a schematic diagram of a perspective view of mitral valve leaflet coaptation according to certain embodiments of the present disclosure. [Diagram 25] FIG. 1 shows an echocardiogram of an ovine (sheep) heart implanted with a natural design personalized mitral valve prosthesis manufactured according to the methods of the present disclosure. [Figure 26A] FIG. 2 is a schematic diagram of a posterior leaflet according to certain embodiments of the present disclosure. [Figure 26B] FIG. 2 is a schematic diagram of the anterior leaflet according to certain embodiments of the present disclosure. [Figure 27] FIG. 1 is a schematic diagram of a final customized 3D model of a prosthetic mitral valve according to certain embodiments of the present disclosure. [Figure 28] 1A-1C are schematic diagrams of FEM simulation optimization results of a customized prosthetic mitral valve model according to certain embodiments of the present disclosure. [Figure 29A] 1 is a schematic diagram of a prosthetic mitral valve in an open configuration within a fluid dynamic test chamber according to certain embodiments of the present disclosure. FIG. [Figure 29B] 1 is a schematic diagram of a prosthetic mitral valve in a fluid dynamic test chamber in a closed configuration according to certain embodiments of the present disclosure. FIG. [Diagram 30] FIG. 13 is an echocardiogram of a customized prosthetic mitral valve implanted in a porcine heart in the closed configuration. [Diagram 31]FIG. 13 is a blood pressure gradient diagram in a porcine heart implanted with a customized prosthetic mitral valve. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0107] These and other aspects will become apparent from the following more particular description of exemplary embodiments of the invention, which are illustrated in the accompanying drawings, in which like reference numerals refer to like parts throughout the various viewing angles of the drawings. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating embodiments of the invention.

[0108] 1A and 1B show a mitral valve prosthesis of the present invention. The mitral valve prosthesis 100 has a physiological shape similar to the natural human mitral valve. The mitral valve prosthesis has a flexible asymmetric ring 1 and two flexible membranous leaflets 2 suspended from the asymmetric ring 1. The mitral valve prosthesis also has two sets of tendons 3 that mimic the chordae tendineae of the heart. Each set of tendons 3 is adapted to be attached at one end to the margins and / or bodies of the leaflets 2 and at the other end to be gathered in a fixation cap 8. The fixation cap 8 is adapted to be sewn onto the papillary muscles of the left ventricle.

[0109] Of the mitral valves 100 shown in the figures, the one in FIG. 1A has the tendons 3 not attached to the leaflets 2, and the one in FIG. 1B has them attached. The tendons 3 may be attached to the leaflets 2 prior to surgery or during surgery. For example, the attachment device 9 between the tendons 3 and the leaflets 2 may be a suture, or they may be en bloc (integrally) produced. Of the mitral valves 100 shown in the figures, the one in FIG. 1A is in an open state, and the one in FIG. 1B is in a closed state. In the closed state, the leaflets 2 may be coapted as shown.

[0110] Figure 2 shows a mitral valve 100 implanted in the heart, implanted at the location of the natural mitral annulus 12, adjacent on one side to the aortic valve 6, which connects the root of the aorta 7 to the left ventricle, and facing on the other side to the opposite ventricular wall 5. The tendons 3 are attached to the papillary muscles 4.

[0111] The flexible ring 1 can be custom fabricated based on an ultrasound examination of the patient's heart. In particular, a 3D echocardiographic study can be performed to obtain detailed anatomical measurements and / or render a 3D model of the patient's heart from which a customized or personalized mitral valve can be produced. The leaflets 2 and tendons 3 can also be customized based on ultrasound imaging of the subject's native mitral valve and surrounding anatomy. A customized / personalized mitral valve can also be produced based on data obtained by other imaging modalities that provide 3D information, such as cardiac CT and cardiac MRI. Thus, the mitral valve prosthesis of the present invention can be selected or designed to match the individual anatomy of the patient.

[0112] The flexible ring 1 can be made, for example, of an elastic annuloplasty ring. The leaflets 2 can be made of natural materials or biocompatible composite materials, which resist blood clotting and allow them to function similarly to the patient's natural anterior and posterior leaflets. At least two pairs of tendons are provided, with a first end attached to one of the two leaflets and a second end attached to the papillary muscles, allowing them to function similarly to the patient's natural chordae tendineae. The tendons 3 thus anchor the leaflets 2 to the patient's papillary muscles, providing support to the left ventricular wall throughout the cardiac cycle and preventing the leaflets from opening into the atrial sinus.

[0113] The mitral valve prosthesis 100 has flexible ring 1, leaflets 2, and tendons 3, and looks and behaves similarly to a healthy native mitral valve. In addition, the mitral valve prosthesis of the present invention can be produced from natural materials, avoiding the introduction of foreign bodies such as pledgets. The flexible ring, leaflets, tendons, and caps can be made from various combinations of allograft and / or composite materials, such as allograft, xenograft, and / or autograft materials. Possible materials for forming the valve ring and leaflets include, but are not limited to, human, bovine, or porcine pericardium, decellularized bioprosthetic materials, biodegradable woven polymers with cells incorporated therein, and extracellular materials. Possible biodegradable natural polymers include, but are not limited to, fibrin, collagen, chitosan, gelatin, hyaluronic acid, and similar materials. Biodegradable synthetic polymer scaffolds that can be infiltrated with cells and extracellular matrix materials include, but are not limited to, poly(L-lactide), polyglycolic acid, poly(lactic-co-glycolic acid), polycaprolactone, polyorthoesters, polydioxanone, polyanhydrides, polytrimethylene carbonate, polyphosphazenes, and the like. The flexible rings can be further customized to provide personalized flexibility or stiffness for the patient. Additionally, some components of the mitral valve prosthesis, such as tendon 3, can be tailored intraoperatively with the patient's own pericardium.

[0114] For example, a mitral valve prosthesis can be made from the patient's own pericardium, or alternatively, the mitral valve prosthesis can be made from a xenogeneic material (e.g., animal tissue such as an existing valve) onto which a layer of the patient's own cultured cells is applied via tissue engineering.

[0115] Artificial valves are often fixed with glutaraldehyde, a known toxin that promotes regeneration. The mitral valve prosthesis of the present invention can be fixed by methods that do not rely on glutaraldehyde, such as dye-mediated photofixation. The mitral valve of the present invention can also be fixed using alternative crosslinking agents, such as epoxy compounds, carbodiimides, diglycidyl, reuterin, genipin, diphenylphosphoryl azide, acyl azides, and cyanamides, or by physical methods, such as ultraviolet light and dehydration.

[0116] Mitral valve prostheses, or some of their components, can be directly produced by biological three-dimensional (3D) printing using biological materials. Alternatively, mitral valve prostheses, or some of their components, can be produced by performing 3D imaging before surgery to obtain detailed dimensions, constructing a template or mold by 3D printing based on the detailed dimensions, and using the template or mold.

[0117] A method of mitral valve prosthesis implantation is also provided. Prior to implantation, an echocardiogram (or other imaging) is obtained for the patient. The imaging is used to measure the size and motion of the heart chambers. Detailed dimensions of the patient's mitral valve annulus, leaflets, and tendons are also measured from the images obtained. In addition, a three-dimensional representation of the valve to be replaced can be rendered. Based on the measurements and three-dimensional modeling of the patient's native valve, a mitral valve prosthesis can be produced that closely matches the patient's native mitral valve and is corrected for any existing pathology.

[0118] Three-dimensional echocardiographic examination can be performed, for example, with a transesophageal echocardiography (TEE) probe or a transthoracic echocardiography (TTE) probe. The segments of the mitral valve can be modeled and measured in three and four dimensions using software such as eSieValves™ (Siemens Medical Solutions USA, Inc., Malvern, PA, USA). Potential relevant measurements include the outer and inner diameters of the annulus, the annulus area, the intertrigonal and intercomm distances, and the lengths along the axes of the anterior and posterior leaflets.

[0119] Additionally or alternatively, three-dimensional diagnosis of the mitral valve can be performed by computed tomography (CT) or magnetic resonance imaging (MRI). For example, as shown in FIG. 3, a 3D reconstruction of a pig heart was obtained using CT imaging (SOMATOM® Definition Flash, Siemens Healthcare, Erlangen, Germany), and the mitral valve area of ​​the heart was visible on the right side of the image. Segmentation of the mitral valve area can be performed using image analysis software, and related measurements can be obtained.

[0120] The mitral valve prosthesis can be fully customized for a patient, allowing each component (e.g., annulus, leaflets, tendons, cap) to be sized to match that of the patient's native valve. As an example, a 3D printed mold of a mitral valve was created based on a 3D reconstruction of an imaged valve, as shown in FIG. 4. The 3D printed valve shown in FIG. 4 was modeled during the diastole or open phase of the cardiac cycle. A prosthetic valve based on this 3D mold is also shown in FIG. 4. This mold can be used to guide the cutting of the porcine pericardium to form the leaflets and tendon attachment sites. Alternatively, a prefabricated mitral valve or prefabricated mitral valve components closest in shape and size to the patient's native valve or native valve components can be selected for implantation.

[0121] In FIG. 5, an image of a sewn prosthetic valve prototype in an ex vivo test system is shown. The valve prototype is shown sewn to an explanted whole heart. A salt bolus is injected into the left ventricle of the heart via a tube, and the aorta is clamped so that the salt is trapped in the left ventricle and pressure is created. The injection pressure can be monitored, for example, on a pressure gauge connected to the injection line. The fitness of the valve prototype (e.g., no regurgitation and no valve leaflet prolapse) can then be monitored under physiological pressure. Valve fitness can be measured and monitored while the left ventricle is contracting at systolic pressure, i.e., the pressure at which the native valve closes.

[0122] 6A and 6B are schematic representations of the anterior and posterior leaflets of a prosthetic mitral valve according to certain embodiments of the present disclosure, and the leaflets when coapted. According to FIGS. 6A and 6B, the prosthetic mitral valve may be a prosthetic mitral valve 600. According to certain embodiments, the valve 600 may comprise two leaflets, e.g., an anterior mitral leaflet 602A and a posterior mitral leaflet 602P. The posterior mitral leaflet 602P and the anterior leaflet 602A may each be pre-operatively designed and fabricated as a monocoque (single piece) to fit the individual physiology and anatomy of the patient 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, e.g., 602A, 602P, such that each leaflet is substantially identical to the patient's natural leaflets. Each leaflet can be shaped to incorporate tendons (e.g., tendons 604, 606, 608, 610) and additional material to form annulus (e.g., anterior annulus 601A and posterior annulus 601P). The length of the tendons can be determined by the surgeon to fit the patient, as described in more detail below. The leaflets can be cut from a single piece of material with a knife or scissors and sewn together by the surgeon during mitral valve replacement surgery to form a mitral valve that resembles the patient's natural mitral valve.

[0123] For example, the anterior leaflet (AL) height may be about 30 mm, the AL length may be about 45 mm, the posterior leaflet (PL) height may be about 15 mm, and the posterior leaflet length may be about 60 mm. As depicted in Figure 6A, the medical community refers to 630A as the height of the anterior leaflet 602A and 630P as the height of the posterior leaflet 602P, while the length of each leaflet is referred to as the circumference of that leaflet, e.g., 632A as the length of the anterior leaflet 602A and 632P as the length of the posterior leaflet 602P.

[0124] According to certain embodiments, cutting each leaflet 602A and 602P separately from the same or different pieces of material, and cutting each annulus 601A and 601P separately, can facilitate personnel, e.g., a surgeon, preparing the prosthetic mitral valve for implantation. By cutting the leaflets as two separate pieces and cutting the annulus as two separate pieces, attaching the leaflets to the annulus, and attaching the tendons to each leaflet, the preparation time and the time required to perform the surgical implantation of the prosthetic valve is reduced compared to cutting the leaflets and tendons as a single unit from a single piece of material. Cutting the leaflets and tendons as a single unit and implanting a single-piece prosthesis would be more complicated and time consuming than the disclosed method, given the high degree of precision required to cut the leaflets and tendons while keeping the leaflet-to-tendon connections intact.

[0125] In certain embodiments, each annulus 601A and 601P is created through wrapping of the posterior side of each leaflet such that the posterior side of each leaflet folds or rolls over itself (e.g., anterior rolled portion 605A and posterior rolled portion 605P) toward the outside of valve 600. According to this embodiment, the size of the posterior end of each leaflet can be increased by 5-10 mm of additional material that can be used to roll the posterior end of the leaflet over itself to create an annulus (e.g., anterior mitral leaflet annulus 601A and posterior mitral leaflet annulus 601P). The rolling or folding of the ring (or each ring portion 601A and 601P) over itself towards the outside of the valve 600 helps to prevent blood clots from forming within the valve 600, and poses little risk of compromising the efficient operation of the valve 600, since any blood clots that do form will only likely appear in the folded or rolled areas of the ring or ring portion on the outside surface of the valve 600. According to certain additional embodiments, the ring (or each ring portion 601A and 601P) may be further strengthened by the addition of strips of material (not shown), such as a suitable biomedical fiber or polymer. Such strips may be fabricated from the same piece of material that the valve 600 is fabricated from, and may be sized to fit within each ring portion 601A, 601P. Preferably, the strips are 1-3 mm wide and 10-20 mm long. The strips of material may be placed within each of the rings 601A, 601P by adding them to the valve 600 as the rings 601A, 601P are rolled. Such strips of material may be resilient and may be made of a variety of compositions, such as biocompatible rubber, recoil metal wire, or synthetic materials.

[0126] According to FIG. 6B, the leaflet 602A may be semi-ellipsoidal or plano-convex, while the leaflet 602P may be plano-concave. In certain embodiments, the valve 600 may include at least two sets of tendons. In certain embodiments, the at least two sets of tendons may be attached to the middle of each leaflet to mimic the native mitral valve. For example, in certain embodiments, the leaflet 602A may include at least one set of tendons 603A, which may be connected to the middle of the leaflet 602A at one end and typically connected to the annular portion 601A at the opposite end. In certain embodiments, the at least one set of tendons 603A may include at least two tendon subsets, such as tendon subset 604 and tendon subset 606. In certain embodiments, the tendon subsets 604 and 606 may be spaced apart to provide a gap of about 3-5 millimeters between the two tendon subsets to allow for more efficient coaptation. The gaps between the tendon subsets 604-606 also allow for a more even distribution of tension on the leaflets, potentially reducing wear and tear. As will be described in detail in connection with Figures 7A and 7B, the tendon subsets 604 and 606 can be connected to distinct, separate caps that connect the tendons of the subsets to the papillary muscles of the heart.

[0127] In certain embodiments, the leaflet 602P can include at least one set of tendons 603P that are connected to the middle portion of the leaflet 602P at one end of the leaflet 602P and typically connected to the annular portion 601P at the opposite end.

[0128] According to certain embodiments, the at least one set of tendons 603P can include at least two tendon subsets, such as tendon subset 608 and tendon subset 610. The tendon subsets 608 and 610 can be spaced apart to allow for a more efficient attachment, with a gap of about 5-8 millimeters between the two tendon subsets. As will be described in more detail in connection with Figures 7A and 7B, the tendon subsets 608 and 610 can be connected to different, separate caps that connect the tendons of the subsets to the papillary muscles of the heart.

[0129] In certain embodiments, tendons 603A and / or tendons 603P can be 1-2 mm wide or other widths. In certain embodiments, posterior mitral leaflet 602P can be connected on one side to annular portion 601P of an asymmetric ring. Through attachment of annular portion 601A to annular portion 601P, e.g., by sutures, fasteners, etc., a complete asymmetric flexible ring can be formed.

[0130] According to certain embodiments, the tendon distance 634A at the anterior mitral leaflet can be between 8-10 mm. According to certain embodiments, the tendon distance 634A at the posterior mitral leaflet can be between 10-15 mm. According to certain embodiments, the tendon distance between the anterior and posterior leaflets at the suture area, designated distance 636 and / or 638, can be between 5-7 mm.

[0131] According to certain embodiments, as depicted in FIG. 6B, a prosthetic mitral valve 600 can be constructed by connecting anterior leaflet 602A to posterior leaflet 602P and annular portion 601A to annular portion 601P. When leaflet 602A is connected to leaflet 602P, an orifice 620 is created between leaflets 602A and 602P, allowing blood flow in one direction, i.e., from the left atrium to the left ventricle. Thus, by appropriately configuring orifice 620 between leaflets 602A and 602P, backflow, i.e., from the left ventricle to the left atrium, can be prohibited. By appropriately configuring leaflets 602A, 602P, and the manner in which they are interconnected by certain joints, as well as annular portions 601A and 601P, the shape, size, and therefore function of the natural human mitral valve can be mimicked. Specifically, annular portion 601A can be configured to mimic the anterior annulus of the natural mitral valve, while annular portion 601P can be configured to mimic the posterior annulus. In certain embodiments, the shape of each leaflet can be elongated to provide approximately 1-5 mm between the annulus and tendon to provide better coaptation between the two leaflets, as well as better tendon attachment to each leaflet.

[0132] According to certain embodiments, the anterior leaflet 602A may have at least two tendon subsets, such as tendon subset 604 and tendon subset 606, which may be connected to the leaflet 602A on different sides of the leaflet 602A. According to certain embodiments, the posterior leaflet 602P may have at least two tendon subsets, such as tendon subset 608 and tendon subset 610, which may be connected to different sides of the leaflet 602P. As in the natural mitral valve, the tendons should be attached to the papillary muscles of the heart. More specifically, in the natural human mitral valve, each tendon subset is attached to a different area of ​​the papillary muscles. Thus, by providing the prosthetic valve 600 with at least two tendon subsets per leaflet, with each tendon subset attached to a different papillary muscle area, the structure and therefore operation of the natural mitral valve may be closely mimicked. As will be explained in connection with Figures 6C, 7A and 7B, each tendon subset is connected to the papillary muscle by a cap to ensure easy attachment between any tendon subset and the papillary muscle, yet sufficiently stable and strong. The number of tendons in each tendon subset, e.g., 604, 606, 608 and 610, may be different or the same. According to certain embodiments, each tendon subset may include at least two tendons.

[0133] FIG. 6C is a schematic depiction of a top view of a mitral valve prosthesis according to embodiments of the present disclosure, looking down from the left atrium towards the left ventricle. According to FIG. 6C, the posterior leaflet 602P can be attached to the anterior leaflet 602A via an attachment line, e.g., suture line 609. According to certain embodiments, the annular portion 601A can be attached to the annular portion 601P, e.g., along line 609, and can be wrapped over itself towards the outside of the valve 600. According to certain embodiments, the anterior leaflet 602A can have two tendon subsets, e.g., subsets 604 and 606, each of which can be connected to a different papillary muscle 720 via a different cap element 700. Similarly, the posterior leaflet 602P can have two tendon subsets 608 and 610, each of which can be attached to a papillary muscle 720 via a different cap element 700. For example, the anterior tendon 604 can be connected to a first papillary muscle 720 by a first cap 700, while the posterior tendon 608 can also be connected to the first papillary muscle by the same first cap 700. Similarly, the anterior tendon 606 can be connected to a second papillary muscle 720 by a second cap 700, while the posterior tendon 610 can also be connected to the second papillary muscle by the same second cap 700.

[0134] 6D, according to certain embodiments, leaflets 602P and 602A can be cut from a single monocoque and joined, e.g., sutured, to form a complete valve along suture line 609. According to certain embodiments, the tendons can be adjusted in relation to the recipient / patient's individual optimal tendon length based on the pre-op scan results for the patient.

[0135] 7A and 7B are schematic depictions of a cap connecting a tendon to a papillary muscle of the heart and a mitral valve prosthesis with two caps attached to the tendons according to embodiments of the present disclosure. In certain embodiments, the cap 700 may have an arcuate shape in its deployed configuration. In certain embodiments, the cap 700 may have a tapered cone shape in its closed configuration with a small opening 730 at its top end 702 and a larger opening at its bottom end 704, and the arcuate ends may be sutured together or overlapping with surgical sutures 706 to create the closed configuration. The sutures 706 may be performed prior to placing the cap 700 on top of the papillary muscle 720. In certain embodiments, the cap 700 may have dimensions ranging from 5 mm to 10 mm in diameter at various points and 5 to 10 mm in length. In some embodiments, the cap 700 can be made from a single piece of material in the shape of a cap, while in other embodiments, the cap 700 can be made from two spread leaflets or pieces of material that are sewn together and then sewn onto the papillary muscle at the same time, for example by starting a suture on one side of the two cap 700 pieces of material and repeating the process of sewing the two cap 700 pieces together, such as the portion of the cap 700 that is intended to be attached onto the papillary muscle, until the two cap 700 pieces are fully interconnected and attached to the papillary muscle of the heart.

[0136] In certain embodiments, the cap 700 of the prosthetic valve 600 can be formed by rolling pericardium (e.g., of human origin, bovine or porcine origin) into a closed configuration. In certain other configurations, the cap can be formed of a biomedical polymer. In certain embodiments, the size of the cap 700 can be 5 mm or greater. In certain embodiments, the mitral valve tendon can be made of the same material as the leaflets and / or cap. In certain embodiments, the tendon can be from the same source, e.g., the same animal, e.g., the same cow, as the cap 700, anterior leaflet 602A and posterior leaflet 602P, with the added advantage of having the same cellular structure and the same origin as the cap 700, anterior leaflet 602A and posterior leaflet 602P.

[0137] After the cap 700 is placed over the papillary muscle 720, the tendons, e.g., tendon subsets 604, 608, can be connected to the cap 700 using sutures 710, thereby binding the tendons, cap 700, and papillary muscle 720 together. According to certain embodiments, the cap openings 730 allow the cap shape to be adjusted to match that of the papillary muscle 720, thereby achieving a good fit between the cap 700 and the papillary muscle 720. According to certain embodiments, one end of the cap 700 can be attached to the tendon subsets 604 and 608, such as with sutures 710, while the other end of the cap 700, typically the opposite end of the cap 700 near the bottom end 704, can be attached to the papillary muscle of the heart, such as with sutures 706. The cap 700 may be connected to the papillary muscles 720 around the entire circumference of the bottom end 704 of the cap 700, however, in some embodiments, the cap 700 is connected to the papillary muscles 720 along a specific portion along the circumference of the bottom end 704 of the cap 700.

[0138] According to certain embodiments, tendons can be tied together to form tendon bundles. The resulting bundles can be connected to the cap 700 at their ends (e.g., the ends of the tendon subsets 604 and 608 connected to the leaflets 602). According to certain embodiments, attaching tendons, such as the tendon subsets 604 and 608, to the papillary muscle 720 with the cap 700 can be easier than directly attaching the tendons to the papillary muscle 720, which can require a more extensive attachment procedure. For example, if the attachment method is suturing, sewing the individual tendons to the papillary muscle 720 can be more complicated and time consuming than sewing the tendons to the deployed cap 700 and sewing a single large piece of the cap 700 onto the papillary muscle 720. Because a patient receiving the prosthesis of the present disclosure is on cardiopulmonary bypass, it is desirable to perform the mitral valve replacement quickly.

[0139] 7A shows only two tendon subsets 604 and two tendon subsets 608 attached to the cap 700, it should be appreciated that additional tendons can be connected to the cap 700. The tendon subsets 604, 608 can include one or more tendons. In certain embodiments, as shown in FIG. 6C, four tendons 604 originating from the right scallop of the anterior mitral leaflet 602A and four tendons 608 originating from the left scallop of the posterior mitral leaflet 602P are connected to the cap 700.

[0140] According to certain embodiments, each of the tendon subsets 604, 606, 608, and 610 may be coupled to the cap 700 along the outer surface of the cap 700. According to other embodiments, the tendons of the prosthetic valve, or some of the tendons, may be attached to the cap 700 via openings 730, which may be located in the middle of the cap 700, i.e., the tendons may pass through the openings 730 and be attached to the inner surface of the cap 700.

[0141] According to certain embodiments, each of the subsets 604 , 606 , 608 and 610 may be tied together into a bundle that is connected to the cap 700 .

[0142] As depicted in FIGURE 7B, the prosthetic mitral valve 600 can include a flexible, asymmetric ring 601 that is attached to two leaflets (e.g., leaflets 602A and 602P). According to certain embodiments, each of the two leaflets can be attached to a set of tendons, such as tendon subsets 604 (not shown), 606 (not shown), 608, and 610. According to certain embodiments, each set of tendons for each of the two leaflets can be attached to a single cap 700, with each cap 700 connecting the mitral valve prosthesis 600 to the papillary muscles 720 of the heart via a connection between each tendon subset 610 and its corresponding cap 700.

[0143] As discussed above, in certain embodiments, each of the tendon subsets 604 (not shown), 606 (not shown), 608, and 610 can be fabricated from the same piece of material from which the anterior and posterior leaflets are fabricated. Such tendons can be considered extensions of the leaflets 602A and 602P, respectively, and can be referred to as primary tendons. In certain embodiments, additional tendons can be attached to both the anterior and posterior leaflets 602A and 602P. These secondary tendons can be fabricated from a different piece of material than that used to construct the leaflets and primary tendons, respectively. These secondary tendons can be configured to connect the underside of each leaflet 602A and 602P to a point along the primary tendon. The secondary tendon attachment point along the primary tendon can be the middle of the primary tendon, although in practice attachment points can be located elsewhere along the primary tendon to achieve better leaflet attachment. The secondary tendons are typically sewn at one end to the anterior leaflet 602A or posterior leaflet 602P and at the other end to the primary tendon. When the secondary tendons are attached to the anterior leaflet 602A or posterior leaflet 602P, respectively, by, for example, suturing, trauma to the outer surface of the anterior leaflet 602A or posterior leaflet 602P should be avoided to prevent blood clotting along the attachment line, for example, the suture line. For example, when microsutures are used, there is less chance of trauma to the leaflet 602A or leaflet 602P. The purpose of the secondary tendons is to provide additional support to the prosthetic valve against pressure on the ventricular side of the prosthetic valve during systole.

[0144] 8A and 8B are schematic representations of possible locations of secondary tendons relative to the posterior leaflet and cross-sections of primary and secondary tendons at the anterior leaflet attachment in certain embodiments of the present disclosure. As depicted in FIG. 8A, the posterior leaflet 602P can be wrapped over its posterior end to form annulus 601. According to certain embodiments, the posterior mitral leaflet 602P can be divided into several areas. Areas 812 and 814 can be areas to which secondary tendons, such as tendon 603, can be attached. On the other hand, an area 816 along the posterior leaflet 602P can be an area that should be tendon-free, i.e., area 816 should not be attached to secondary tendons. This is because area 816 is an area that will be exposed to high pressure during ventricular systole after the posterior leaflet 602P is attached to the heart as part of a prosthetic valve. According to certain embodiments, area 816 can include approximately 2-5 mm to the right of midline 810 of the posterior leaflet 602P and approximately 2-5 mm to the left of midline 810 of the posterior leaflet 602P. According to certain embodiments, area 816 can be approximately 3 mm to the right and approximately 3 mm to the left of midline 810 of the posterior leaflet 602P. Appropriate design of the secondary tendons can help provide additional support to the posterior leaflet 602P during the rising pressure gradient during ventricular systole.

[0145] In some embodiments, the secondary tendons 603 should not reach the ends of areas 812 and 814 of the posterior leaflet 602P in the deployed configuration. In some embodiments, the tendons should not be connected too close to the ends of areas 812 and 814, i.e., to the annulus 601. For example, the tendons may be located along areas 812 and 814 about 20°-70° of the overall layout of the posterior leaflet 602P relative to the midline 810 of the posterior leaflet 602P. The remaining areas of the posterior leaflet 602P, i.e., between the midline 810 and about 15-20° on either side of the midline 810, may be kept free of secondary tendons.

[0146] FIG. 8B is a schematic representation of a posterior mitral valve cross section showing the primary and secondary tendons as they are attached to the posterior leaflet 602P. The primary tendons 608 depicted in FIG. 8B are made from the same piece of material as the leaflets. The primary tendons 608 extend from the posterior leaflet 602P at one end and are attached to the cap 700 at the other end. In certain embodiments, the primary tendons 608 can be tied together into a bundle (not shown) that can then be connected to the outer surface of the cap 700. The cap 700 can then be connected to the papillary muscles 720.

[0147] In certain embodiments, the primary tendons 608 can be connected to the secondary tendons 603 by connecting one end of each secondary tendon 603, e.g., end 823, to the posterior leaflet 602P and connecting the opposite end of each secondary tendon 603, e.g., 825, to a contact point along the primary tendon. In some embodiments, the secondary tendons 603 should be approximately 30-40% thicker and wider than the primary tendons 608. Depending on the desired prosthesis, anywhere from 1-4 secondary tendons can be used for each leaflet scallop of the posterior mitral leaflet (602P).

[0148] 9A and 9B are schematic depictions of a prosthetic mitral valve with two leaflets attached according to an alternative design featuring a curved (ellipsoid / droplet) configuration, such as that for coaptation expansion, according to certain embodiments of the present disclosure, and potential coaptation surface configurations. According to FIG. 9A, the prosthetic mitral valve 1100 can be provided with two leaflets, such as an anterior leaflet 1602A and a posterior leaflet 1602P, each leaflet 1602A and 1602P can be semicircular in shape, and the two leaflets can cooperate to generate a "yin-yang" shape. According to certain embodiments, the leaflet shape can be designed in a semicircular manner along the half length of each leaflet, such that an "S" shaped seal is generated by both leaflets when coapted.

[0149] This unique shape allows for sufficient anterior 1602A-posterior 1602P coaptation, particularly in area 1120. According to certain embodiments, there may be a coaptation or overlap between the anterior 1602A-posterior 1602P leaflets along area 1120. Symmetrically, there may be a similar coaptation or overlap area between the posterior 1602P-anterior 1602A leaflets (not shown). As with valve 600 detailed above, each leaflet may include a separate ring, e.g., ring 601A and ring 601P, which may be formed by rolling an end of the material from which each leaflet is made over itself.

[0150] According to FIG. 9B, a joint structure between the two anterior leaflets 1602A and the posterior leaflets 1602P can be provided in the immediate vicinity of the joint area. According to certain embodiments, as with the prosthetic valve 600, the prosthetic valve 1100 can also comprise two types of tendons: primary tendons and secondary tendons. According to certain embodiments, the primary tendons can be configured as an extension of the anterior or posterior leaflets 1602A and 1602P, respectively. That is, the primary tendons, e.g., the primary tendons 1102A and 1102P, can be configured from the same piece of material as the corresponding leaflets, i.e., the anterior leaflet 1602A and the posterior leaflet 1602P. The primary tendons 1102A and / or 1102P can extend from the middle of the respective leaflets at one end and be connected to a cap at the other end. According to certain embodiments, the secondary tendons, e.g., the tendons 1104P, can be attached only to the posterior leaflet 1602P. A secondary tendon, such as tendon 1104P, can be connected at one end to the middle of the posterior leaflet 1602P and at the other end to the middle of the primary tendon 1102P. According to certain embodiments, the addition of secondary tendons 1104P can better mimic a native mitral valve, which has an additional, shorter tendon connecting the posterior leaflet to the posterior primary tendon. The addition of secondary tendons allows the posterior leaflet to withstand subsequent pressures on the leaflet during systole, allows proper coaptation of the leaflets (i.e., closing) during the systole phase of the cardiac cycle, and allows the leaflets to open during diastole.

[0151] For example, the posterior leaflet 1602P may have a secondary tendon 1104P attached to it, the secondary tendon 1104P may be attached to the posterior edge of the leaflet 1602P, which may in turn be connected to the middle of the primary tendon 1102P.

[0152] According to certain embodiments, each tendon bundle and / or each tendon may be attached to a cap, such as cap 700, which may connect the tendons to the papillary muscles of the heart.

[0153] 10 is a schematic depiction of a measured copy of a patient's mitral valve according to certain embodiments of the present disclosure. According to certain embodiments, measurements of the length, width and height of the leaflet sections can be obtained by echocardiography, and other imaging techniques can also be used, such as cardiac CT, cardiac MRI, etc. That is, the size and shape of the prosthetic mitral valve 1200 can be a substantially exact copy of the patient's natural or native mitral valve.

[0154] Figure 11 is a schematic illustrating the formation of a bileaflet prosthesis according to certain embodiments of the present disclosure. According to certain embodiments, the basic portion or leaflet section of the valve can be cut from a single blank 1210 based on a cross-sectional image of the intended recipient heart as depicted in Figure 12. The leaflet section can be cut in a manner that replicates the prosthesis image at 1:1 scale, and an incision 1220 can be made along the middle of the leaflet section in a crescent or semicircular configuration to provide an opening 1230 and the outline of two leaflets, e.g., anterior leaflet 1202A and posterior leaflet 1202P, as depicted in Figure 12.

[0155] 12 is a schematic depiction of openings formed along the leaflet sections according to certain embodiments of the present disclosure. According to certain embodiments, an opening or orifice 1230 can be formed (e.g., cut) in the single piece of material 1210, and two leaflets 1202A and 1202P can be formed on opposite sides of the opening 1230. After the orifice 1230 is created by cutting in the single piece of material 1210, two leaflets in the form of flaps, e.g., anterior leaflet 1202A and posterior leaflet 1202P, can be invaginated into the orifice 1230, further creating unidirectional blood flow through the orifice 1230, i.e., from the left atrium to the left ventricle of the heart.

[0156] 13 is a schematic depiction of an echocardiogram or MRI scan of a patient's left heart chamber or ventricle in accordance with certain embodiments of the present disclosure. According to certain embodiments, the patient's left ventricle 1500 can be imaged or scanned by echocardiogram, CT or MRI, or other imaging techniques. Such an image or scan of the left ventricle 1500 can provide the exact or substantially exact lengths of the patient's tendons required from the tips of the papillary muscles 1520 to the valve leaflets 1502A and 1502P. This allows for the creation of a customized prosthetic mitral valve that meets the anatomical and physiological requirements of the patient.

[0157] 14A and 14B are schematic depictions of a patient's left ventricle during diastole and systole, respectively, according to certain embodiments of the present disclosure. According to certain embodiments, the annular diameter 1640 of the left ventricle 1610, which is the systolic left ventricle, as depicted in FIG. 14B, may be smaller than the annular diameter 1650 of the left ventricle 1612, which is the diastolic left ventricle, depicted in FIG. 14A. During diastole, blood enters the left ventricle and the left ventricle 1612 fills with blood, resulting in a larger annular diameter 1650. During systole, blood leaves the left ventricle 1610 after it has flowed from the left ventricle into the blood system of the patient's body, e.g., as it is reaching tissues. That is, 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 systolic annular diameter 1640 compared to the diastolic annular diameter 1650.

[0158] Since it is desired that the annulus and leaflets 1502A and 1502P be flexible as their diameter and size repeatedly change during the recurrent phases of cardiac function (i.e., systole and diastole), it is evident that it is desirable to fabricate the annulus and leaflets from an elastic material similar to the constituent tissue of the native mitral valve. Thus, since a stent-free, metal-ring-free and rigid-material-free prosthesis is disclosed, the material selected for the manufacture of the leaflets 1502A and 1502P and annulus must have a degree of compliance and elasticity.

[0159] 15A and 15B are schematic depictions of extensions attached to the anterior and posterior leaflets, respectively, according to certain embodiments of the present disclosure. According to certain embodiments, as depicted in FIG. 15A, the anterior leaflet 1202A may include an extension 1703 that may include additional material to increase the size of the anterior leaflet 1202A. The extension 1703 may be sized to be approximately 1-5 mm long and substantially the same width as the incision (e.g., incision 1220, FIG. 11) made to form the anterior leaflet. In some embodiments, one end of the extension 1703 may be sewn to the edge of the anterior leaflet 1202A (see incision 1220, FIG. 11) and the other end may include a tendon 1704, such as tendons 604, 606, similar to FIG. 6A.

[0160] As depicted in FIG. 15B, the posterior leaflet 1202P may include an extension 1709 that may include additional material to increase the size of the anterior leaflet 1202P. The extension 1709 may be sized to be approximately 1-5 mm long and substantially the same width as the incision (e.g., incision 1220, FIG. 11) made to form the anterior leaflet. In some embodiments, one end of the extension 1709 may be sewn to the edge of the anterior leaflet 1202P (see incision 1220, FIG. 11) and the other end may include a tendon 1708, such as tendons 608, 610, similar to FIG. 6A.

[0161] As depicted in Figure 15B, posterior leaflet 1202P has extension 1709 attached to one end (leaflet end) and tendon 1708 attached to the other end. Tendon 1708 is connected to extension 109 at one end and to cap 1870 at the other end, e.g., a cap structurally similar to the cap described in connection with Figure 7A. Anterior leaflet 1202A has extension 1703 attached to one end (leaflet end) and tendon 1704 attached to the other end. Tendon 1704 is connected to extension 1703 at one end and to cap 1870 at the other end, e.g., a cap structurally similar to the cap described in connection with Figure 7A.

[0162] Each tendon 1704 and 1708 may be comprised of several tendons, also referred to herein as primary tendons, for example, four primary tendons, although other numbers of tendons may be implemented depending on the specific requirements of each patient. According to certain embodiments, the tendons may also include secondary tendons (not shown) as described above.

[0163] 16A and 16B are schematic illustrations of the side view of a mitral valve prosthesis having extensions and tendons attached thereto according to certain embodiments of the present disclosure, in diastole and systole, respectively. With reference to FIG. 16A, which shows the profile of the mitral valve prosthesis when the heart is in diastole, and FIG. 16B, which shows the side view of the mitral valve prosthesis when the heart is in diastole, respectively. When the anterior leaflet 1202A and the posterior leaflet 1202P are positioned at a distance from each other, blood can flow into the left ventricle through the orifice between the leaflets 1202A-1202P. The extensions 1703, 1709 allow the valve prosthesis to exhibit an enhanced coaptation profile. Extensions 1703, 1709 are attached to each leaflet 1202A and 1202P, providing additional material to the anterior and posterior leaflets to provide the necessary coaptation during systole to prevent backflow of blood into the atrium and assist the left ventricle during systole.

[0164] In some embodiments, extensions 1703 and 1709 are prepared to be different sizes (e.g., lengths, widths, and shapes). According to some embodiments, tendons 1704, 1708 can be tied together with sutures prior to attachment to cap 1870.

[0165] Each of the extensions 1703 and 1709 is adapted to carry a corresponding tendon (1704, 1708) that resembles a natural heart valve tendon and is intended for insertion into a heart chamber and attachment onto a heart wall muscle or papillary muscle. For example, extension 1703 can carry tendon or pair of tendons 1704 and extension 1709 can carry tendon or pair of tendons 1708. The other end of each of the at least two tendons (opposite the end connected to each extension) can be connected to a cap 1870 that is adapted to attach the valve to a papillary muscle.

[0166] According to certain embodiments, as depicted in FIG. 16A, during diastole, leaflets 1202A and 1202P and their corresponding extensions 1703 and 1709 can be positioned a distance apart from one another to allow blood to flow in one direction, from the left atrium to the left ventricle.

[0167] According to certain embodiments, as depicted in Figure 16B, during systole, leaflets 1202A and 1202P and corresponding extensions 1703 and 1709 can be positioned in close proximity to one another to inhibit leakage or backflow of blood in the reverse direction, i.e., from the left ventricle to the left atrium. According to certain embodiments, extensions, such as extensions 1703 and 1709, can provide the necessary coaptation or closure for the valve to preclude backflow or leakage of blood from the left ventricle to the left atrium.

[0168] In certain embodiments, the extensions can be cut to fit the edge of the leaflet and can be set to different widths to ensure adequate adhesion, but not less than 5 mm. Attachment of the extensions to the leaflets can be accomplished by suturing, gluing, stapling, or otherwise attaching them to the edge of the leaflet.

[0169] According to certain embodiments, the tendons, e.g., tendons 1704 and 1708, can be individually attached, e.g., by suturing, to the heart chamber wall or papillary muscles and can be bundled together, e.g., in pairs, quadrants, etc., according to a design determined to be optimal for that particular patient.

[0170] In certain embodiments, the tendons can be asymmetric, i.e., the tendons can be different sizes between the two papillary muscles in the left heart chamber, and the tendons originating at different points in the leaflet extension can have different lengths and distances from the upper edge of those muscles, i.e., the length of each tendon or tendon bundle can be individualized and different from the others, thus ensuring full closure of the prosthetic valve and sufficient coaptation length.

[0171] In certain embodiments, the tendons, e.g., tendons 1704 and 1708, originating from leaflet extensions, e.g., extensions 1703 and 1709, respectively, can be distributed along the edges of the anterior and posterior leaflet extensions to evenly distribute tension along the margins of the leaflets when the valve is moved in vivo, thus reducing wear and tear on the prosthetic valve.

[0172] 17 is a schematic depiction of the application of an asymmetric flexible ring around a valve prosthesis in accordance with certain embodiments of the present disclosure to mimic the natural annulus. According to certain embodiments, a long piece of material can be wrapped over itself to close the annulus, or a piece of material with a hole in the middle can be wrapped over itself toward the outside of the material to form the flexible ring 1901. According to certain embodiments, the rolled ring 1901 can be attached around the mitral valve prosthesis 1200 to provide a more rigid ring that can be surgically attached, for example, sewn to the patient's annulus, and, if an elastic material is used, to provide better elasticity during systolic and diastolic changes in the cardiac cycle. The rolled ring 1901 can be fitted around the initially cut valve 1200 (FIG. 10).

[0173] In certain embodiments, the outer reinforcement ring 1901 can be made of an elastic material exhibiting variable elasticity, allowing for variable expansion and contraction of the prosthetic valve during the diastole and systole of the cardiac cycle. In certain embodiments, the elasticity of the ring 1901 can be derived from continuous assessment of the patient's native ring motion, relying on 3D echocardiography assessment.

[0174] According to certain embodiments, the reinforcement ring 19010 can be exposed to the intracardiac blood environment or it can be rolled into an elastic sandwich and made from the same material as the surrounding leaflets.

[0175] As depicted in Figure 17, the prosthetic valve 1200 can include tendons 1704 and 1706 that can be attached (with or without extensions) to the anterior leaflet 1202A, and tendons 1708 and 1710 that can be attached (with or without extensions) to the posterior leaflet 1202P. Attaching the tendons to at least two caps, as depicted in Figures 16A and 16B, and configured to attach the valve 1200 to the papillary muscles of the heart, allows for the proper placement of the prosthetic mitral valve 1200 in the patient's left ventricle based on the specific anatomical and physiological requirements of that particular patient.

[0176] 18A and 18B are schematic depictions of elastic material incorporated into a wound valve annulus, before and after winding, respectively, according to certain embodiments of the present disclosure. According to certain embodiments, as depicted in FIG. 18A and 18B, the valve annulus 2201 can be provided with additional elastic material 2205 that can be incorporated into the annulus 2201, thus wrapping the annulus 2201 over the elastic material 2205 to "sandwich" the elastic material 2205 within the annulus 2201. The additional elastic material 2205 within the annulus 2201 provides additional elasticity to the annulus 2201, which can help better mimic the elastic properties of the native mitral valve. According to certain embodiments, the elastic material 2205 can be rubber or any other biocompatible synthetic material. In certain embodiments, the shape of the elastic material 2205 can mimic the shape of the ring 2201 into which it is inserted, thus facilitating the incorporation of the elastic material 2205 into the ring 2201 .

[0177] According to certain embodiments, as depicted in Fig. 18B, a ring 2201 (e.g., made from the same material as the leaflets or made from an extension of an alternative material attached to the outer annulus of the leaflets) can be wrapped over the elastic material 2205 inwardly of the synthetic valve, e.g., toward the notch 2220, and the notch can be made along the middle of the leaflet section in a crescent or semicircular configuration, to provide an opening between two leaflets, e.g., anterior leaflet 2202A and posterior leaflet 2202P, delineated by the notch 2220. The notch 2220 is actually the actual mitral valve prosthesis orifice through which blood flows from the left atrium to the left ventricle. Thus, the outer margin of the mitral valve prosthesis may be provided with annulus 2201, to which may be connected the major surfaces of the leaflets, e.g., leaflets 2201A and 2202P, which may be attached to the papillary muscles via caps 2270 by tendons, e.g., tendon 2204.

[0178] FIG. 19 is a schematic flow chart illustrating a method of making a mitral valve prosthesis according to certain embodiments of the present disclosure. According to certain embodiments, a method 2000 of making a customized mitral valve prosthesis for a patient can include measuring the size and shape of the patient's mitral valve by imaging 2002. The imaging method by which the shape and size of the mitral valve of a particular patient is measured can be any imaging method such as echocardiography, cardiac CT, cardiac MRI, or the like. The method 2000 can further include cutting a replica of the patient's mitral valve from a single piece of material at 1:1 scale 2004. According to certain embodiments, the method 2000 can include cutting a flow orifice and two leaflets, one leaflet on each side of the orifice, by cutting along the single piece of material 2006. Method 2000 may include an operation 2008 of measuring the required tendon length using an imaging technique, which may be similar to the imaging technique in which the shape and size of the mitral valve is measured, such as that in operation 2002.

[0179] According to certain embodiments, the method 2000 may further include an operation 2010 of attaching the tendons to one of two caps configured to attach the tendons to the papillary muscles of the heart.

[0180] According to certain embodiments, the method 2000 can include an operation 2012 of creating an overall mitral valve prosthesis that mimics the particular patient's native mitral valve by attaching flexible rings over the leaflets.

[0181] According to certain embodiments, method 2000 can further include the optional step of attaching extensions to each of the two leaflets for carrying the tendons as measured in operation 2008, which can assist in proper coaptation and closure during the systole phase of the cardiac cycle.

[0182] The motivation for implementing the method of manufacturing a natural design personalized mitral valve prosthesis according to the embodiments of the present disclosure is that the personalized valve is expected to last longer than current valve prostheses because it is manufactured to fit each patient's exact anatomical dimensions and limitations. The personalized prosthesis will perform better than any of the best quality prostheses available because it is tailored to fit the patient and can provide superior hemodynamic performance and faster or better cardiac recovery after prosthesis implantation.

[0183] Referring now to FIG. 20A, a schematic diagram illustrates a method 2020 for manufacturing a personalized mitral valve prosthesis according to certain embodiments of the present disclosure. The valve prosthesis according to the method 2020 is not an off-the-shelf product as is the current practice. Instead, a remote diagnostic imaging scan is performed in operation 2024 after ordering the personalized mitral valve prosthesis in operation 2022, and used as a basis for personalizing the mitral valve prosthesis dimensions in operation 2026, so that a more accurate personalized valve prosthesis can be manufactured for an individual patient in operation 2028. According to certain embodiments, the method 2020 can include an operation 2030 of packaging and shipping the native design personalized mitral valve prosthesis for implantation in the particular patient. According to certain embodiments, a very short scan can be performed prior to manufacturing 2028 to fully fit the personalized mitral valve prosthesis to the patient.

[0184] Referring now to FIG. 20B, a schematic flow chart illustrates a method 2040 for manufacturing a personalized mitral valve prosthesis according to certain embodiments of the present disclosure. Method 2040 is similar to method 2020, but may include additional operations. According to certain embodiments, method 2040 may include an operation 2042 of measuring the size and shape of the patient's native mitral valve by imaging. The diagnostic imaging techniques include, but are not limited to, current imaging techniques, including 2D and 3D echocardiography, computed tomography (CT) or cardiac magnetic resonance (CMR).

[0185] According to certain embodiments, method 2040 can further include operation 2044 of calculating the geometry and dimensions of the annulus, leaflets and tendons of the mitral valve prosthesis for the patient based on validated algorithms, such as calculations that aid in determining appropriate mitral valve prosthesis dimensions for each particular patient, as described below.

[0186] According to certain embodiments, method 2040 can include operation 2046 of cutting and connecting all components of a personalized prosthetic mitral valve, i.e., the annular ring, leaflets, and tendons, based on the calculations, and can be performed for each patient based on the patient's specific anatomy and individual physiology to form a personalized prosthetic mitral valve.

[0187] According to certain embodiments, the method 2040 may include an operation 2048 of implanting the personalized mitral valve prosthetic in the heart of the patient for whom the personalized mitral valve prosthesis is manufactured.

[0188] Referring now to Figures 21A and 21B, there are shown, respectively, a schematic representation of the annular pericardial rim that is preserved when the native mitral valve is removed in clinical practice in accordance with certain embodiments of the present disclosure, and a schematic representation of an elliptical ring model with the major axis being diameter (AL-PM) and the minor axis being diameter (AP) that is used to calculate the annular circumference (AC) of a valve prosthesis.

[0189] In some embodiments, the following abbreviations are used with respect to mitral valve prosthesis ring components: Mitral annulus (MA), Circumferential annulus (AC); Anterior-posterior diameter (AP), Front outer / rear inner diameter (AL-PM), Seam width (CC) and Ring area (AA).

[0190] Mitral valve prosthesis: According to certain embodiments, the dimensions of the flexible annular ring of the personalized mitral valve prosthesis of the present disclosure can be matched to the patient's native mitral valve annulus. According to the present disclosure, the mitral valve prosthesis can be personalized or customized based on the following characteristics:

[0191] The first property is that the prosthesis' annular ring is manufactured without the constraints of a rigid frame, whatever that may be, and is therefore malleable to the patient's mitral annulus.

[0192] A second characteristic is that the prosthesis annular ring dimension, referred to as the circumference, is personalized based on diagnostic imaging results for that particular patient, such as the results of performing operation 2022 in Figure 20B. In certain embodiments, the prosthesis annular ring dimension is calculated as a function of the anterior-posterior diameter (AP) in the Figure 21A view and the anterior-lateral-medial diameter (AL-PM) in the Figure 21A view during left ventricular systole and when the mitral valve is closed.

[0193] The third property is that in clinical practice, when the native mitral valve is removed, the annular pericardial rim is preserved (FIG. 21A), and the annular ring of the present prosthesis is sewn onto the native pericardial rim, or in other words, onto the nape-shaped native ring. The annular ring dimension of the present personalized prosthesis, referred to as the annular circumference (AC), is given by equation (i): (i) AC=f(diameter(AP),diameter(AL-PM),d) However, the calculation can be made according to the following: AP is the anterior-posterior diameter, Diameter (AL-PM) is the front-to-back diameter, d is the width of the edge of the annulus.

[0194] Using an approximation derived from an elliptical ring with the major axis being the diameter (AL-PM) and the minor axis being the diameter (AP) (Figure 21B), equation (ii) (ii) AC(1)=2π(diameter(AP)-2d) / 2+4((diameter(AL-PM)-2d) / 2-(diameter(AP)-2d) / 2) Based on this, the AC(1) of the valve prosthesis can be calculated.

[0195] In some embodiments, the annular circumference (AC) of the mitral valve prosthesis may require further adjustment compared to the patient's natural annulus, which usually involves a reduction in the size of the annular circumference (AC). In such circumstances, the annular circumference of the mitral valve prosthesis may be used as an annuloplasty procedure for the dilated annulus in some patients suffering from the problem. In some embodiments, the AC reduction ratio may be in the range of 0% to 20%, and the actual value may be suitably determined by existing clinical diagnostic methods or by mathematical models established by big data analysis, or simply and more practically, by comparison with the body surface area (BSA) of healthy individuals. In some embodiments, the AC reduction is also necessitated by the tendency of annular remodeling after prosthesis implantation when the leaflet coaptation is removed by the new valve prosthesis, so that the reduction ratio (λ) also depends on the patient's expected cardiac recovery. In conclusion, a more accurate value for the AC(2) of the mitral valve prosthesis, i.e., the circumference of the personalized mitral valve prosthesis, can be calculated using equation (iii): (iii) AC(2)=[2π(Diameter(AP)-2d) / 2+4((Diameter(AL-PM)-2d) / 2-(Diameter(AP)-2d) / 2)]×(1-λ) where λ is the AC reduction ratio (from the natural annulus circumference to the personalized prosthesis annulus circumference).

[0196] According to certain embodiments, an annular crimping technique can be used when AC reduction is required. The annular crimping can be uniform along the annulus, rather than the localized annular crimping typically performed during annuloplasty. Annular crimping according to the presently disclosed embodiments will favor the posterior leaflet annulus more since it constitutes a larger portion of the mitral valve circumference. In addition, the posterior annulus of the human heart lacks a fibrous scaffold and is therefore prone to symmetric or asymmetric dilation, allowing the posterior annulus to widen and allow for leaflet divergence and leakage.

[0197] The fourth characteristic may be based on the fact that the mitral valve prosthesis according to the present disclosure is, so to speak, a bileaflet prosthetic valve composed of an anterior leaflet 2210 (FIG. 22A) and a posterior leaflet 2220 (FIG. 22B). Therefore, the annular ring of the present valve prosthesis may also have two parts, an anterior leaflet ring and a posterior leaflet ring. The annular ring 2230 (FIG. 22C) of the present mitral valve prosthesis can be formed by integrally connecting the upper edges of the anterior leaflet and the posterior leaflet in a direction in which the anterior outer side is anterior outer side and the posterior inner side is posterior inner side. That is, the anterior outer side of the anterior leaflet 2210 is attached to the anterior outer side of the posterior leaflet 2220, and the posterior inner side of the anterior leaflet 2210 is attached to the posterior inner side of the posterior leaflet 2220.

[0198] The annular ring 2230 is made from a multi-layered leaflet material and can have a reinforced structure. The height of the annular ring 2230 can be in the range of 1 mm to 4 mm, more preferably in the range of 2 mm to 3 mm, so that the clinical surgeon can sew the annulus to the mitral annulus of the patient's heart. The number of layers can be 2 to 4, with the upper edges of the anterior and posterior leaflets folding or overlapping on themselves. According to certain embodiments, the annular ring can include surgical sutures 2316 for reinforcing the annular ring.

[0199] The mitral valve prosthesis of the present disclosure may have an asymmetric annular ring formed by a combination of anterior and posterior leaflet annulus that are reinforced leaflet superior margins. In one example of such an asymmetric annular ring, shown in Figures 22A and 22B, the anterior leaflet annular circumference (AAC) 2212 is smaller than the posterior leaflet annular circumference (PAC) 2222, and the ratio (R) of AAC / PAC may be within the range of 49 / 51 to 30 / 70, more preferably within the range of 35 / 65 to 42 / 58. The anterior leaflet annular circumference (AAC) 2212 and the posterior leaflet annular circumference (PAC) 2222, respectively, may be determined by equations (iv) and (v). (iv) AAC = AC × R / (1 + R) (v) PAC = AC × 1 / (1 + R) It can be calculated according to:

[0200] 22D, 22E, and 22F, respectively, depict an annulus model with two papillary muscles indicated, a customized anterior leaflet model, and a customized posterior leaflet model. According to certain embodiments, new suture locations A and B shown in FIG. 22D can be used to define an anterior leaflet annular circumference (AAC) and a posterior leaflet annular circumference (PAC). The new suture locations A and B can be selected based on the location of two papillary muscles PM1 and PM2, respectively, which can mutually define an anterior leaflet, e.g., anterior leaflet 602A (FIG. 6A), and a posterior leaflet, e.g., posterior leaflet 602P (FIG. 6A), to determine AAC and PAC. According to certain embodiments, the valve tendons, e.g., tendons 604, 606, 608, 610 (FIG. 6A), anterior and posterior leaflets can be manufactured based on new suture points A and B, so that the tendons are sewn to the papillary muscles PM1 and PM2, resulting in less post-implant distortion compared to prosthetic valves based on other suture locations, e.g., along the annular ring. According to certain embodiments, FIGS. 22E and 22F show the anterior and posterior leaflet models after the implementation of the new suture locations A and B. Although the anterior leaflet annular circumference (AAC) may be slightly longer than the posterior leaflet annular circumference (PAC) according to the current annulus model, this is contrary to the disclosure of FIGS. 22A and 22B, where the PAC is longer than the AAC. The surface areas of the anterior and posterior leaflets in the current annulus model are similar to each other, so that they can be responsible for proper closure of the leaflets under the action of blood pressure.

[0201] Mitral Valve Prosthesis Leaflets: Referring now to Fig. 23C, which is a schematic depiction of the relationship of several interrelated parameters during prosthetic leaflet coaptation according to certain embodiments of the present disclosure, Figs. 24A and 24B, respectively, are schematic depictions of side and perspective views of mitral valve leaflet coaptation according to certain embodiments of the present disclosure. According to certain embodiments, the mitral valve prosthesis of the present disclosure may have two flexible, membranous leaflets that may be suspended from an asymmetric annular ring 2230. The two leaflets open during the diastolic cycle to allow blood to flow from the left atrium to the left ventricle, and then close tightly during the systolic cycle to allow unidirectional blood flow through the heart, so that there is no backflow through the valve. The dimensions of the two leaflets are critical to ensure that the prosthetic valve opens and closes properly.

[0202] If replacing a healthy mitral valve, the leaflet length can be replicated from diagnostic imaging to customise the valve prosthesis. However, for patients with incompetent mitral valves that need to be replaced, the measurements of anterior leaflet length (La) and posterior leaflet length (Lp) are not adequate or useful for personalising or customising a new valve prosthesis. Instead, the anterior-posterior diameter (AP, also called A2P2) can be used as a reference to represent the minimum distance or length of leaflet coaptation. The ratio of anterior leaflet length to posterior leaflet length (r) can vary from 1 / 1 to 2 / 1 (these are reference ratios).

[0203] In some embodiments, leaflet length is affected by junction depth (Cd), junction height (CoaptH) and tendon length (Lc) in addition to anterior-posterior diameter (AP) and ratio (r). Thus, anterior leaflet length (ALL) and posterior leaflet length (PLL) are calculated using equations (vi) and (vii): (vi) ALL=f(diameter(AP),r,Cd,Ch,Lc) (vii) PLL=f(diameter(AP),r,Cd,Ch,Lc) It can be a function of all the above parameters, as represented by:

[0204] According to certain embodiments, when the anterior-posterior diameter (AP) is less than 28 mm, the anterior leaflet length (ALL) and posterior leaflet length (PLL) can be calculated using empirical formulas from animal models that have been shown to work well in porcine and ovine models, exhibiting low mean transmitral pressure gradients and acceptable leaflet coaptation (FIG. 24). The formulas (viii) and (ix) are (viii) ALL = (diameter (AP)) / 2 + 10 (in millimeters) (ix) PLL = (Diameter (AP)) / 2 + 5 (in millimeters) As stated above.

[0205] In certain embodiments, the upper edges of the anterior and posterior leaflets form a multi-layered reinforced annular ring of the valve prosthesis, e.g., asymmetric annular ring 2230. The upper edges of the leaflets may be straight or curved, i.e., semi-elliptical, to allow the finished valve prosthesis to fit more closely to the natural geometry of the left ventricle. Below the annular ring, two sutures, e.g., sutures 2310 and 2312 (FIG. 22C), are formed by joining the two leaflets together. The sutures are angled inwardly to give the body of the valve prosthesis a slight conical shape, which allows the valve prosthesis to better fit the left ventricle in terms of shape and contour. The angle of inclination (δ 0 The cone angle (δ) can be in the range of 5° to 20°. 1 ) is the equation (x) (x) δ 1 =arctan[(2·sin(δ 0 )) / (π cos(δ 0 ) )] According to the above, the inclination angle of the suture edge of the leaflet (δ 0 ) is determined.

[0206] According to certain embodiments, the inclination angle (δ 0 ) are made equal, and thus the cone angle (δ 1 ) are made equal.

[0207] According to certain embodiments, another element of the prosthetic leaflets that is to be personalized or individualized is the free edge. The anterior and posterior interleaflet edge coaptation controls the function and performance of the prosthetic valve. Geometrically, the leaflet free edge in the present invention is semi-elliptical. The length of the free edge is determined by equation (xi): (xi) Free edge length = {2π × |ALL (or PLL) - b - CH × cos(δ 0 )-CoaptH|+4[a-CH×sin(δ 0 )-|ALL (or PLL)-b-CH×cos(δ 0 )-CoaptH|]} / 2 where CH represents the length of the suture edges 2214 and 2216 shown in Figures 22A and 22B, respectively.

[0208] The parameters "a" and "b" are the geometric parameters required to define and form the upper edge shape of the anterior or posterior leaflet, which is either curved in the form of a semi-ellipse with "a" as the major axis and "b" as the minor axis as shown in Figure 23A, or straight as shown in Figure 23B.

[0209] FIG. 23B shows an extreme example in which the upper edge of the leaflet is a straight line with a=(1 / 2)·AAC(PAC) and b=0. The free edge of the leaflet is expressed by equation (xi). (xi) Free edge length = {2π × (ALL (or PLL) - CH × cos(δ 0 )-CoaptH)+4[(1 / 2)·AAC(or PAC)-CH×sin(δ 0 )-(ALL(or PLL)-CH×cos(δ 0 )-CoaptH)]} / 2 It can be calculated according to:

[0210] According to certain embodiments, an improved algorithm for calculating customized mitral valve prosthesis leaflet length can be provided. Leaflet length is a fundamental factor that affects valve opening and closing in an efficient and effective manner. According to certain embodiments of the present disclosure, the anterior and posterior leaflet lengths can be optimized using a finite element method (FEM) to calculate optimal anterior and posterior leaflet lengths, thereby enhancing coaptation and reducing valve leakage. According to such embodiments, incoming bovine pericardium data or any other material from which the prosthetic mitral valve may be made, such as variations in thickness and material properties, are first brought in, and a customized valve design is calculated from it. The thickness and material properties and other characteristics of the bovine pericardium or other material can also affect how the valve opens and closes.

[0211] Referring now to FIG. 23D, a schematic flow chart is depicted illustrating a method for designing a customized mitral valve using FEM. According to certain embodiments, the method 2300 can include an operation 2320 of providing patient mitral valve related data, such as the size and shape of a particular patient's native mitral valve. The patient mitral valve related data can include, for example, annular circumference, annular diameter, papillary muscle location, etc. The method 2300 can further include an operation 2330 of providing incoming bovine pericardium data relating to material properties of the supplied (i.e., incoming) bovine pericardium. According to certain embodiments, the incoming data for the material from which the prosthetic mitral valve is made, such as the incoming bovine pericardium data, can include, for example, bovine pericardium thickness, tensile test data, such as Young's modulus, stress strain curves, etc.

[0212] According to certain embodiments, the method 2300 can include an operation 2340 of constructing a customized 3D model of the prosthetic mitral valve and optimizing the model through FEM analysis based on both the incoming bovine pericardium data and the patient mitral valve data as inputs. According to certain embodiments, an optimal anterior leaflet length, an optimal posterior leaflet length, an optimal tendon width, etc. can be determined by performing a valve parameter study and FEM optimization through the selection of various anterior leaflet lengths, posterior leaflet lengths, tendon widths, and additional parameters and any combination thereof. The above and other valve parameters can be varied while evaluating valve performance using leaflet deformation, maximum principal stress, equivalent (von Mises) stress, leaflet contact detection area, etc., to select optimal parameters that achieve optimal valve performance.

[0213] According to certain embodiments, method 2300 can optionally include operation 2350 of visualizing the customized prosthetic mitral valve. In some embodiments, operation 2350 is not required in method 2300. Visualization of the customized prosthetic mitral valve 3D model in operation 2350 can be performed according to the formulation of the prosthetic mitral valve dimensions performed in operation 2340, such as anterior leaflet dimensions, posterior leaflet dimensions, anterior circumference, posterior circumference, annular diameter, anterior and posterior leaflet heights, tendon width, etc. According to certain embodiments, method 2300 can include operation 2360 of creating the prosthetic mitral valve according to the constructed 3D model and following visualization of the model in operation 2350.

[0214] According to certain embodiments, after the customized prosthetic mitral valve design has been completed, visualized, and created, method 2300 may perform an additional operation 2370 to perform performance validation testing on the customized prosthetic mitral valve, such as testing in an in vitro fluid dynamics chamber.

[0215] According to certain embodiments, the customized valve design method can incorporate the provision of patient mitral valve parameters and incoming bovine pericardium data for operations 2320 and 2330, respectively. An example of such data is provided below in Table 1. In this example, the suture span of the patient valve is determined to be 36 mm. [Table 1]

[0216] In this method, patient-fit customized posterior and anterior leaflet parameters, which are implemented according to operation 2340 by FEM parameter optimization, are derived as shown in Table 2 below. [Table 2]

[0217] According to certain embodiments, the anterior leaflet length (ALL) and posterior leaflet length (PLL) can be influenced by patient mitral valve data, such as suture span, papillary muscle distance, etc., and incoming bovine pericardial data, such as bovine pericardial thickness and Young's modulus. That is, ALL and PLL can be calculated by equations (xii) and (xiii), respectively: (xii) ALL=f(CC, DBPM, ZH, BPTH, BPYM, etc.) (xiii) PLL=f(CC, DBPM, ZH, BPTH, BPYM, etc.) can be a function of the above parameters and additional parameters according to CC stands for seam span, DBPM stands for interpapillary muscle distance; ZH represents the Z height from the papillary muscle to the orbicularis annulus; BPTH represents bovine pericardial thickness, and BPYM represents bovine pericardial Young's modulus.

[0218] According to certain embodiments, an empirical formula can be proposed that can calculate the anterior lobule length (ALL) and posterior lobule length (PLL) for other patients based on the above CC36.0mm FEM related data. The final anterior lobule length and posterior lobule length should be confirmed by FEM method. According to certain embodiments, ALL and PLL are calculated by equations (xiv) and (xv) in order. (xiv) ALL=(CC*DBPM*ZH*BPTH / BPYM)*α (xv) PLL=(CC*DBPM*ZH*BPTH / BPYM)*β It can be calculated as follows: α is the anterior lobule length amplification factor, e.g., 0.1033; β is the posterior lobule length amplification factor, e.g., 0.1033.

[0219] Mitral valve prosthesis tendon: In a normal mitral valve, the tendons are fan-shaped, originating from the papillary muscles and penetrating into the leaflets. Depending on where they are attached, they are classified as primary, secondary, and tertiary tendons.

[0220] Some mitral valve prostheses disclosed herein have only a primary tendon attached to the free edge of the anterior or posterior leaflet, and some have two sets of tendons (FIG. 24A) and three tendons within each set (FIG. 24B) evenly distributed along 3 / 8 of the free edge from each end, referred to as the anterior lateral tendons and the posteromedial tendons.

[0221] The tendons play an important role in ensuring the proper opening and closing of the valve prosthesis. Compared to other geometrical properties of the mitral valve, the geometrical properties of the tendons, specifically the tendon length, are currently less considered in the clinical pre-diagnosis, especially for valve replacement. Tendon measurements can be defined as the distance from the papillary muscle apex to the annular plane, the distance from the papillary muscle apex to the junctional margin, or the distance from the papillary muscle apex to the annulus.

[0222] To personalize the prosthetic tendon length, the lobule length (ALL or PLL), lobule junction height (CoaptH), lobule junction depth (Cd), and the distance from the papillary muscle apex to the lobule junction edge (Lc) must be related to ensure the function of the complex structured prosthesis. That is, the anterolateral tendon length (ACL) and the posteromedial tendon length (PCL) are calculated using the following equations (xvi) and (xvii): (xvi) ACL=f(ALL,CoaptH,Cd,Lc(anterolateral)) (xvii) PCL=f(ALL,CoaptH,Cd,Lc(posterior medial)) It can be expressed as a function of multiple parameters according to

[0223] A simplified method is also introduced in the present disclosure by using the measured distance from the papillary muscle apex to the junction edge as the prosthesis tendon length, i.e., ACL=Lc (anterolateral) and PCL=Lc (posteromedial), and at the design level, the three tendons of each set are gathered at their free ends and gathered in a pledget-like tendon cap 2240 (FIGS. 22A and 22B). The clinical surgeon can complete the final part of the personalization or customization of this mitral valve prosthesis by performing on-site measurements and adjustments. FIG. 25 is an echocardiogram of a sheep heart implanted with a natural design personalized mitral valve prosthesis manufactured according to the method of the present disclosure.

[0224] Reference is now made to Figures 26A and 26B, which are schematic depictions of the posterior and anterior leaflets, respectively, illustrating the tendon width and tendon distance, according to certain embodiments of the present disclosure. According to certain embodiments, the tendon width (CW), tendon distance to the posterior leaflet (DCPL), and tendon distance to the anterior leaflet (DCAL) can be determined using FEM techniques. For an example where the CC is 36.0mm, the CW is 3mm for both the anterior and posterior leaflets. According to certain embodiments, the tendon width (CW) can be calculated using equation (xviii) given a CC of 36.0mm. (xviii) CW=(CC*DBPM*ZH*BPTH / BPYM)*γ It can be calculated as follows: γ represents the tendon width amplification factor, e.g., 0.0124.

[0225] In some embodiments, the final tendon width needs to be verified using FEM techniques.

[0226] According to certain embodiments, the tendon distance in the posterior leaflet (DCPL) and the tendon distance in the anterior leaflet (DCAL) can be made dependent on the distance between the two papillary muscles (DBPM).

[0227] 27 is a schematic depiction of a final customized 3D model of a prosthetic mitral valve with a D-shaped annular ring that can be constructed based on patient mitral valve data provided in operation 2320 of method 2300 and also based on incoming bovine pericardium data provided in operation 2330.

[0228] 28 is a schematic depiction of the results of a FEM simulation optimization of a customized prosthetic mitral valve model, according to operation 2340 of method 2300. In FIG. 28, the FEM model of the prosthetic mitral valve is depicted in a closed configuration. As can be seen, the annular ring of this valve model is D-shaped, resembling the annular shape of the native mitral valve.

[0229] After visualization of the customized mitral valve prosthetic in operation 2350, and subsequent to creation of the customized mitral valve in operation 2360, performance validation testing of the customized mitral valve can be performed in operation 2370. Figures 29A and 29B are schematic depictions of a prosthetic mitral valve in a fluid dynamic test chamber in open and closed configurations, respectively.

[0230] Figures 30 and 31 show echocardiographic images of a custom mitral valve prosthesis implanted in a pig heart in the closed configuration and the blood pressure gradient of the pig heart after implantation, respectively. This custom mitral valve prosthesis can open and close in a very efficient and effective manner and does not exhibit any leakage. Its maximum pressure gradient can be 3.87 mmHg and the average pressure gradient can be 1.61 mmHg, which is similar to the pressure exhibited by the human natural mitral valve.

[0231] The personalized geometries and dimensions discussed above can be taken as input for a variety of engineering drafting software or tools.

[0232] The drawing can be printed out as a template and the leaflets of the valve prosthesis can be manually cut out, for example hand cut under a microscope, according to the template.

[0233] The drawing can be programmed into a machining tool, such as a laser cutting machine, which can cut out the leaflets with greater precision and efficiency than manual cutting.

[0234] The drawing can also be programmed into a machining tool to create a personalized mold cutter or die cutter that can be used to cut the leaflets at a lower temperature than the temperature at which the laser cutting occurs, thereby minimizing the thermal effects on the material that is cut to become the valve prosthesis.

[0235] The mitral valve prosthesis can be created by joining together the annulus and the suture edges of the anterior and posterior leaflets according to the orientation of anterolateral to anterolateral and posteromedial to posteromedial (FIG. 22C). According to one method, the joining together of the two leaflets can be by suturing with a surgical suture, for example suture 2314 in FIG. 22C.

[0236] The valve prosthesis described above can be further packaged, labeled, sterilized and released for use, i.e., for implantation into the patient for whom the valve prosthesis was personalized.

[0237] For ease of operation, the valve prosthesis described above can be assembled onto the valve holder prior to packaging.

[0238] The valve prostheses of the present disclosure can be delivered, eg, shipped, as a finished product for personalized implantation into a particular patient.

[0239] According to certain embodiments, any of the disclosed anterior and posterior leaflets, any of the annulus, any of the tendons (and any of the tendon subsets), any of the caps, and / or any combination thereof can be produced from natural materials, thereby avoiding the introduction of foreign bodies, such as pledgets. Allograft and / or composite materials, including various combinations of allograft, xenograft, and / or autograft materials, can also be used to create the flexible rings, leaflets, tendons, and caps. Materials from which the annulus and leaflets are formed can include, but are not limited to, human, bovine, or porcine pericardium, decellularized bioprosthetic materials, biodegradable woven polymers with cells embedded therein, 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 cells and extracellular matrix materials can include, but are not limited to, poly(L-lactide), polyglycolic acid, poly(lactic-co-glycolic acid), polycaprolactone, polyorthoesters, polydioxanone, polyanhydrides, polytrimethylene carbonate, polyphosphazenes, and similar materials. The flexible rings can also be customized to provide personalized flexibility or stiffness for the patient. Additionally, some components of the mitral valve prosthesis, such as tendons, can be shaped intraoperatively from the patient's own pericardium.

[0240] According to certain embodiments, any of the disclosed asymmetric flexible rings, whether with an anterior and posterior annular portion or fabricated as a single unit, can be formed by winding or folding the edge of the or their leaflets on itself. According to other embodiments, the flexible ring can further comprise at least two strands or layers of material, such as human, bovine or porcine pericardium or any of the materials listed above, and the at least two strands or layers can be wound, twisted, braided or looped around each other. The ring structure in the form of a coiled coil can provide increased strength compared to a ring formed by simply winding the edge of a leaflet on itself, but the coiled ring itself should remain elastic.

[0241] In some embodiments, the ring may have two strands or layers of material folded together to provide elasticity, with a third layer added to provide structural stability. In some embodiments, the ring may have two layers made of bovine pericardium, while the third strand or layer is made of glycine or proline to provide strength to the ring.

[0242] According to certain embodiments, the at least two layers or strands can be attached, e.g., sewn, to one another. According to certain embodiments, the third layer can be attached, e.g., sewn, to the at least two layers of the ring.

[0243] According to certain embodiments, the components of the mitral valve prosthesis may be attached or connected to one another by a number of connection methods. For example, the components of the mitral valve prosthesis may be interconnected by sutures, staples, glue, or some other attachment means.

[0244] According to certain embodiments, the suture or stitching may be made of a non-biodegradable synthetic material, such as nylon (Ethilon®), Prolene® (polypropylene), Novafil®, polyester, etc. According to certain embodiments, the suture or stitching may be made of a non-biodegradable synthetic material, such as surgical silk or surgical cotton.

[0245] According to certain embodiments, the stapler needles can be made of a biocompatible material, such as stainless steel or titanium.

[0246] According to certain embodiments, the glue can be made of a biocompatible material, such as an aldehyde-based glue, a fibrin sealant, a collagen-based adhesive, a polyethylene glycol polymer (hydrogel), or a cyanoacrylate.

[0247] According to certain embodiments, every leaflet, every annulus, every tendon (and every tendon subset), and / or every combination thereof can be customized for each patient based on ultrasound imaging of the patient's native mitral valve and surrounding anatomy. Customized mitral valves can also be produced based on data obtained by other imaging modalities that provide three-dimensional information, such as echocardiography, cardiac CT, and cardiac MRI. Thus, the mitral valve prosthesis of the present disclosure can be selected or designed to match the patient's individual anatomy, thereby improving the likelihood of improved prosthesis acceptance in the patient's surrounding tissue, such as the myocardium surrounding the prosthesis.

[0248] To prepare the patient for implantation, the patient's heart is arrested, as is customary for mitral valve surgery. During implantation, the flexible ring of the prosthesis is secured to the native annulus with sutures, and the papillary cap is sewn to the native papillary muscle. For example, two sutures can be applied to the tip of each native papillary muscle to secure the cap to the muscle. The clinician ensures that the valve is fully open and closed by filling the ventricular cavity with saline under appropriate pressure, and checking the behavior and suitability of the replacement valve as it closes under the applied pressure. After implantation, the valve is examined by transesophageal echocardiography (TEE) after cardiac closure and return of cardiac flow.

[0249] If necessary, the subject can be placed on anticoagulant therapy after implantation. Given the natural shapes and materials used to construct the mitral valve prosthesis of the present invention, it is anticipated that most patients will require low doses or no anticoagulant therapy.

[0250] Currently available biological and mechanical prostheses have several shortcomings, including the inclusion of large foreign bodies, the need for heavy anticoagulation therapy, a short life span that requires the patient to undergo a second surgery when replacement is required, and the lack of assistance to the heart in terms of efficient recovery from implantation. The present invention has several advantages over the biological and mechanical prostheses described above. Designed to more closely match the patient's native mitral valve and constructed from natural materials, the mitral valve prosthesis described herein is expected to reduce patient recovery time, increase life span, and reduce or eliminate the need for anticoagulation therapy.

[0251] The teachings of all patents, published applications and references cited throughout this application are hereby incorporated by reference in their entirety.

[0252] While the present invention has been particularly shown and described with reference to illustrative embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention as encompassed by the appended claims.

Claims

1. A method for producing a personalized mitral valve prosthesis for a particular patient, comprising: measuring the size and shape of the patient's native mitral valve using imaging means; providing data about materials from which the personalized mitral valve prosthesis is made; constructing a 3D model of the personalized mitral valve prosthesis based on the size and shape of the particular patient's native mitral valve and the material data; optimizing the 3D model by using FEM methods; fabricating the personalized mitral valve prosthesis by cutting the blank into an annular ring, an anterior leaflet, a posterior leaflet, and a tendon based on the optimized 3D model, the FEM model, and connecting the anterior leaflet and the posterior leaflet to the annular ring; connecting the tendons to the anterior and posterior leaflets; Measuring the size and shape of the particular patient's native mitral valve includes measuring mitral valve-related parameters including annular circumference (AC), annular area (AA), anterior-posterior diameter (A-P), anterior-lateral-posterior diameter (AL-PM), suture span (C-C), anterior leaflet length (ALL), posterior leaflet length (PLL), mitral valve geometry, and chordae lengths (ACL and PCL); Measuring the annular circumference (AC) is based on equation (iii): The method includes combining an anterior leaflet annular circumference (AAC) that is the upper edge of the anterior leaflet and a posterior leaflet annular circumference (PAC) that is the upper edge of the posterior leaflet based on AC(2) = [2π (diameter (A-P)-2d) / 2 + 4((diameter (AL-PM)-2d) / 2-(diameter (A-P)-2d) / 2)] x (1-λ); In the equation, d is the edge width of the annular ring, λ is the AC reduction ratio from the natural annular circumference to the personalized mitral valve prosthesis annular circumference, and The method, wherein creating the personalized mitral valve prosthesis includes forming the annular ring into a multi-layered reinforced structure by folding or overlapping the upper edge of each of the anterior and posterior leaflets.

2. 2. The method of claim 1, wherein the upper edges of each of the anterior and posterior leaflets are straightened or curved to properly fit the personalized mitral valve prosthesis to the native geometry of the left ventricle of the particular patient.

3. 2. The method of claim 1, wherein joining the anterior and posterior leaflets comprises joining an edge of the anterior leaflet with an edge of the posterior leaflet such that a junction occurs between the anterior and posterior leaflets.

4. 4. The method of claim 1, wherein connecting the anterior and posterior leaflets comprises forming two sutures joining the anterior and posterior leaflets together, the two sutures inclining inward at a cone angle (δ 1 ) to create a conical shape for the personalized mitral valve prosthesis to fit within the particular patient's native left ventricle.

5. 5. The method of claim 4, wherein the cone angle (δ １ ) in equation (x): d １ =arctan[(2・sin(d ０ )) / (π・cos(δ) ０ ))] Based on this, the inclination angle (δ ０ ) determined by the method.

6. 6. The method of claim 1, wherein connecting the anterior and posterior leaflets comprises connecting the anterior leaflet to the posterior leaflet by connecting anterior-lateral to anterolateral and posteromedial to posteromedial.

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

8. 5. The method of claim 4, wherein the measuring comprises measuring a distance in accordance with equation (xi): Free edge length={2π×(ALL (or PLL)−CH×cos(δ ０ )-CoaptH) + 4[(1 / 2) · AAC (or PAC)-CH × sin(δ ０ ) - (ALL (or PLL) - CH × cos (δ ０ )-CoaptH)]} / 2 Based on the above, the size and shape of the annulus, the suture height (CH), the inclination angle (δ) of the annulus of the specific patient are taken into account in order to calculate the length of each leaflet edge. ０ ), anterior leaflet length (ALL) and posterior leaflet length (PLL) and junctional height (CoaptH).

9. 4. The method of claim 1, wherein the annular circumference (AC) is a function of the anterior-posterior diameter (A-P) and the anterior-lateral-posterior-medial diameter (AL-PM) according to equation (iii).

10. 10. The method of claim 9, wherein measuring includes performing the measurements of the anterior-posterior diameter (A-P) and the anterior-lateral-posterior-medial diameter (AL-PM) during left ventricular systole and when the mitral valve is closed.

11. 4. The method of claim 1, wherein the calculation of the annular circumference (AC) of the personalized mitral valve prosthesis is based on the ratio (λ) in equation (iii).

12. 2. The method of claim 1, wherein the annular ring is asymmetric and has an annulus circumference including an anterior leaflet annular circumference (AAC) and a posterior leaflet annular circumference (PAC), the anterior leaflet annular circumference (AAC) being smaller than the posterior leaflet annular circumference (PAC), and the ratio (R) of AAC / PAC being between 49 / 51 and 30 / 70 of the annular circumference.

13. The method according to claim 12, wherein the ratio (R) of AAC / PAC is from 35 / 65 to 42 / 58.

14. 13. The method of claim 12, wherein the ratio (R) of AAC / PAC is 40 / 60.

15. 13. The method of claim 12, wherein the ratio (R) AAC / PAC is the ratio between the anterior lobule length (ALL) and the posterior lobule length (PLL).

16. 16. The method of claim 1, wherein constructing the 3D model of the personalized mitral valve prosthesis comprises calculating an anterior leaflet annular circumference (AAC) and a posterior leaflet annular circumference (PAC) based on suture positions A and B.

17. 10. The method of claim 8, wherein constructing the 3D model of the personalized mitral valve prosthesis comprises: ALL = (diameter (A-P)) / 2 + 10 (in millimeters) PLL = (Diameter (A-P)) / 2 + 5 (in millimeters) (a) the anterior-posterior diameter (A-P), which is the theoretical minimum distance for junction; (b) the ratio of ALL to PLL (r); (c) junction depth (Cd); (d) the junction height (CoaptH); and (e) the tendon length (Lc).

18. 18. The method of any one of claims 1 to 17, wherein connecting comprises connecting the anterior leaflet and the posterior leaflet together to form a body of the personalized mitral valve prosthesis.

19. 19. The method according to any one of claims 1 to 18, wherein each of the anterior leaflets and each of the posterior leaflets comprises two sets of tendons, anterior lateral tendons and posteromedial tendons, each of the anterior lateral tendons and posteromedial tendons comprising three accessory tendons, which are evenly distributed along at least 3 / 8 of each edge from each side.

20. 20. The method of claim 19, wherein constructing the 3D model includes calculating a length of each tendon, the calculation of the length of each tendon being based on parameters including leaflet length, junction height, and junction depth.

21. 21. The method of any one of claims 1 to 20, wherein measuring includes measuring the distance from the papillary muscle apex to the coaptation edge to indicate tendon length of the personalized mitral valve prosthesis, and further includes on-site measurement and adjustment of a pledget-like tendon cap into which the tendons are gathered and where the ends of each pair of tendons meet.

22. 22. The method of any one of claims 1 to 21, wherein constructing the 3D model comprises providing the calculated geometry and dimensions of the annulus, the anterior leaflet, the posterior leaflet and the tendon for the particular patient as input for engineering drafting software or tools.

23. 23. The method of claim 22, wherein the engineering drawing software or tool outputs a template for manual cutting of the leaflets of the personalized mitral valve prosthesis.

24. 23. The method of claim 22, wherein the engineering drawing software or tool outputs a template for machine cutting of the leaflets.

25. 25. The method of any one of claims 1 to 24, further comprising packaging, labelling and sterilising the personalized mitral valve prosthesis prior to release for use.

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