CN115515536A

CN115515536A - Method for manufacturing personalized naturally designed mitral valve prosthesis

Info

Publication number: CN115515536A
Application number: CN202180034248.8A
Authority: CN
Inventors: T·科菲德斯
Original assignee: National University of Singapore; National University Hospital Singapore Pte Ltd
Current assignee: National University of Singapore; National University Hospital Singapore Pte Ltd
Priority date: 2020-04-15
Filing date: 2021-04-15
Publication date: 2022-12-23
Also published as: JP2023522046A; WO2021211062A1; KR20230007372A; EP4135628A4; EP4135628A1; AU2021257389A1

Abstract

A personalized naturally designed mitral valve prosthesis and a method for manufacturing the same are provided to precisely fit a particular patient for whom the valve prosthesis is being manufactured. The method includes constructing a 3D model of a personalized mitral valve prosthesis by measuring a size and shape of a mitral valve of a particular patient using an imaging device, optimizing the 3D model using a FEM method, and manufacturing the personalized mitral valve prosthesis by cutting and joining annular rings, leaflets, and umbilical cord to form the personalized prosthetic mitral valve.

Description

Method for manufacturing personalized naturally designed mitral valve prosthesis

Background

The mitral or left atrioventricular valve is the mitral valve (i.e., a valve consisting of two leaflets), which is the valve in the heart that separates the left atrium and the left ventricle. The mitral valve allows blood to flow from the left atrium to the left ventricle during ventricular diastole, while preventing retrograde flow during systole. The naturally occurring mitral valve is composed of an annulus, two leaflets, atrial myocardium, chordae tendineae, pupillary muscle, and ventricular myocardium.

Mitral valve replacement is a procedure intended to replace a diseased or non-functional valve. During mitral valve replacement surgery, the patient's mitral valve is removed and replaced with a prosthesis. The unique configuration of the mitral valve presents challenges to manufacturing a durable and properly functioning mitral valve prosthesis.

Biological and mechanical mitral valve prostheses are commercially available. Both bioprostheses and mechanical prostheses have rigid, circular shapes, as compared to the soft tissue and asymmetric shapes of the human mitral valve. Another disadvantage of mechanical valves is the tendency of blood to clot on the mechanical parts of the valve and cause the valve to function abnormally. Patients using mechanical valves must take anticoagulants to prevent thrombus from forming on the valve, resulting in a stroke. Biological valves have a reduced risk of thrombosis compared to mechanical valves, but are more limited in durability and require more frequent replacement. Like mechanical valves, biological valves comprise a rigid metal skeleton and have a metal ring covered with silicon or other synthetic material to allow passage of implant sutures.

Currently available mitral valve prostheses are typically constructed in an unnatural circular manner and are typically made from rigid materials. They also typically have three symmetric leaflets, whereas the native human mitral valve includes only two leaflets, a larger anterior leaflet and a smaller posterior leaflet. Due to its rigid and unnatural structure, this mitral valve prosthesis distorts the natural anatomy of the heart. The myocardium surrounding these prostheses does not recover well after implantation surgery. The average life span of the prosthesis is only 7 to 10 years, which results in the patient having to undergo a second, sometimes even a third, surgery during their life cycle, which repetition exposes the patient to high risk of open heart surgery.

Commercially available prostheses do not achieve the hemodynamic performance of a healthy, native human mitral valve. This results in a large energy loss in the left ventricle, significant strain over time, and ultimately heart failure and other undesirable phenomena.

Some other mitral valve prostheses that are available can be formed by reinforcing the allograft, as described in U.S. patent No. 6,074,417, which means that the physician needs to scan valves of various sizes in order to find the best fit for each patient, while sacrificing the animal from which the valve is to be removed. Other useful mitral valve prostheses may be formed by suturing multiple pericardial layers to one another, as described in U.S. patent No. 5,415,667, which may result in clotting in areas where multiple sutures are present.

Other forms of atrioventricular valves, including the mitral valve, are disclosed in U.S. patent No. 6,358,277, wherein a template of membrane material is sutured to the mitral annulus of the patient. Such valves have a tall and unnatural-shaped annulus, making the periphery of the prosthetic valve bulky and convex like a collar. In addition, the template is provided in a standard size and then must be trimmed to fit the patient.

Disclosure of Invention

A method is provided for manufacturing a personalized, naturally designed mitral valve prosthesis that precisely fits and functions with an individual patient. Specifically, the method includes a series of operations or procedures that begin with receiving a customized/personalized mitral valve prosthesis order, diagnostically imaging and analyzing the imaging results, quantifying the geometry and dimensions of the valve prosthesis by using a validated algorithm, assembling a personalized valve prosthesis that fits each specific patient's anatomy and clinical condition according to the personalized geometry and dimensions of the recipient patient, and further packaging and sterilizing the personalized valve prosthesis into a final mitral valve prosthesis, which is sent to the specific patient for implantation and implanting the personalized prosthetic mitral valve in the patient to create the valve.

A method for manufacturing a mitral valve prosthesis that is personalized to a natural design is provided to precisely fit a particular patient for whom the valve prosthesis is manufactured. The method can comprise the following steps: the personalized prosthetic mitral valve is formed by measuring the size and shape of a native mitral valve of a particular patient using an imaging method, calculating the geometry and dimensions of the annular ring, anterior leaflet, posterior leaflet, and umbilical cord of each particular patient based on a validated algorithm, and cutting and joining the annular ring, anterior leaflet, posterior leaflet, and umbilical cord.

According to some embodiments, an imaging method may include: 2D or 3D echocardiography, computed Tomography (CT), cardiac Magnetic Resonance (CMR), or any combination thereof.

According to some embodiments, measuring the size and shape of the native mitral valve of the patient may include measuring mitral-valve related parameters, which may include: annular ring circumference (AC), annulus Area (AA), anterior-posterior (A-P) diameter, anterolateral-posteromedial (AL-PM) diameter, commissure diameter (C-C), anterior Leaflet Length (ALL), posterior Leaflet Length (PLL), mitral valve shape, and chordae tendineae length (ACL and PCL).

According to some embodiments, the method may further comprise collecting patient-specific physical information for use in a computational process to predict the geometry of the implanted heart after improved heart valve function, the physical information comprising: height, weight, age, race and gender.

A personalized mitral valve prosthesis comprising a flexible annular ring sized to match a native mitral annulus of a particular patient, flexible anterior and posterior leaflets sized to match native mitral leaflets of the particular patient, and leaflets and an umbilical cord connected to the annular ring sized to match native mitral leaflets of the particular patient, providing an umbilical cord that connects with papillary muscles of the heart. The personalized mitral valve prosthesis may be formed by:

measuring the size and shape of the native mitral valve of a particular patient by using an imaging method;

calculating the geometry and dimensions of the annular ring, leaflets and umbilical cord for each particular patient according to a validated algorithm; and

the annular ring, leaflets and umbilical cord are cut and connected to form a personalized prosthetic mitral valve.

According to some embodiments, measuring the size and shape of the patient's mitral valve may include measuring mitral valve-related parameters, which may include: annular ring circumference (AC), annulus Area (AA), anterior-posterior (A-P) diameter, anterolateral-posteromedial (AL-PM) diameter, commissure diameter (C-C), anterior Leaflet Length (ALL), posterior Leaflet Length (PLL), mitral valve shape, and chordae tendineae length (ACL and PCL).

According to some embodiments, the personalized mitral valve prosthesis may also be formed by collecting physical information of a particular patient for use in a computational process to predict the geometry of the implanted heart after improved heart valve function, the physical information including: height, weight, age, race, and sex.

According to some embodiments, the calculating may include calculating the annular ring perimeter (AC) as a combination of an anterior leaflet annular ring perimeter (AAC) as the top edge of the anterior leaflet and a posterior leaflet annular ring Perimeter (PAC) as the top edge of the posterior leaflet based on equation (iii) below. According to some embodiments, the annular ring may be formed into a multi-layered reinforcement structure by folding or overlapping a top edge of each of the anterior and posterior leaflets.

According to some embodiments, the top edge of each of the anterior and posterior leaflets may be straight or curved so that the personalized mitral valve prosthesis fits properly to the natural geometry of the left ventricle of a particular patient.

According to some embodiments, connecting may include connecting an edge of the anterior leaflet with an edge of the posterior leaflet to form a commissure between the anterior and posterior leaflets. According to some embodiments, coaptation may control the function and performance of the personalized mitral valve prosthesis by controlling the size of the valve orifice, thereby affecting the transcuspid pressure gradient.

According to some embodiments, connecting may include connecting two leaflets together to form two commissures, wherein the two commissures are at a taper angle (δ) ₁ ) Inwardly inclined to form a body of the personalized mitral valve prosthesisSlightly tapered to properly fit the natural left ventricle of each shape and contour of a particular patient.

According to some embodiments, the cone angle (δ) ₁ ) May be derived from the angle of inclination (δ) of each commissure edge of the two leaflets based on equation (x) ₀ ) And (4) determining.

According to some embodiments, attaching may include attaching the anterior leaflet to the posterior leaflet by attaching the anterolateral side to the anterolateral side and the posteromedial side to the posteromedial side.

According to some embodiments, the anterior leaflet can be attached to the posterior leaflet by suturing.

According to some embodiments, the measuring may comprise measuring: the size and shape of the natural annular ring, commissure Height (CH), angle of inclination (δ) of a particular patient based on the following equation (xi) ₀ ) Anterior Leaflet Length (ALL) and Posterior Leaflet Length (PLL), and coaptation height (CoaptH) used to calculate the length of each leaflet edge.

According to some embodiments, the height of the reinforcing annular ring may be between 1mm and 4 mm.

According to some embodiments, the height of the reinforcing annular ring may be between 2mm and 3mm.

According to some embodiments, the annular ring perimeter (AC) may be a function of the anterior-posterior diameter (a-P) and the anterolateral-posterior-medial diameter (AL-PM) based on equation (iii) below.

According to some embodiments, the anterior-posterior diameter (a-P) and the anterolateral-posterior-medial diameter (AL-PM) may be measured when the mitral valve is closed during left ventricular contraction.

According to some embodiments, calculating the annular ring circumference (AC) of the prosthesis may be based on the annular ring width (d) of the native leaflets preserved during the clinical procedure.

According to some embodiments, calculating the annular ring circumference (AC) of the prosthesis may be based on the ratio (λ) in equation (iii).

According to some embodiments, the annular ring may be asymmetric. According to some embodiments, the annular ring may be formed by a combination of the anterior and posterior valve rings, whereby the anterior leaflet annular perimeter (AAC) may be smaller than the posterior leaflet annular Perimeter (PAC), and the ratio (R) between AAC/PAC may be between 49/51 and 30/70.

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

According to some embodiments, the ratio (R) between AAC/PAC may be 40/60.

According to some embodiments, the ratio (R) between AAC/PAC may be between the Anterior Leaflet Length (ALL) and the Posterior Leaflet Length (PLL), and may be critical to ensure that the prosthetic valve is properly opened and closed.

According to some embodiments, the calculating may comprise calculating based on equations (viii) and (ix), respectively, based on: the Anterior Leaflet Length (ALL) and Posterior Leaflet Length (PLL) are calculated as (a) the anterior-posterior diameter (a-P), (b) the ratio (r) between AL and PL, (c) the coaptation depth (Cd), (d) the coaptation height (CoaptH), and (e) the umbilical cord length (Lc) of the theoretical minimum coaptation distance.

According to some embodiments, connecting may include connecting two leaflets together to form a body of the personalized mitral valve prosthesis.

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

According to some embodiments, calculating may include calculating the length of each umbilical cord to ensure proper opening and closing of the personalized mitral valve prosthesis, whereby calculating the length of each umbilical cord is based on several parameters, including: leaflet length, coaptation height, and coaptation depth.

According to some embodiments, the measuring may include measuring the distance from the papillary muscle apex to the junction edge to represent the prosthetic umbilical cord length, further including on-site measuring and adjusting the cotton-wool umbilical cap to where the umbilical cords are integrated and merged at the end of each set of umbilical cords.

According to some embodiments, the personalized mitral valve prosthesis may also be formed by performing calculated geometries and dimensions of the annular ring, anterior leaflet, posterior leaflet, and umbilical cord for each particular patient as input for engineering mapping software or mapping tools.

According to some embodiments, the engineering mapping software or mapping tool may output a template for manually cutting leaflets of the valve prosthesis.

According to some embodiments, the engineering drawing software or drawing tool may output a template for machine cutting the leaflets.

According to some embodiments, the personalized mitral valve prosthesis may also be formed by packaging, labeling, and sterilizing the personalized mitral valve prosthesis prior to release for use.

According to some embodiments, the personalized mitral valve prosthesis may also be formed by assembling the personalized mitral valve prosthesis onto a valve stent prior to packaging.

According to some embodiments, the personalized mitral valve prosthesis may also be formed by implanting the personalized mitral valve prosthesis in a particular patient.

A prosthetic valve designed to resemble a patient's native mitral valve is provided. Two flexible leaflets and one asymmetric and flexible ring can move with the natural deformation of the myocardium in the cardiac cycle. An umbilical cord similar to the patient's natural chordae tendineae is included in the prosthetic valve to simulate natural prevention of blood backflow into the atria and to provide support to the left ventricle during systole.

According to some embodiments, a mitral valve prosthesis to be implanted into a heart comprises:

an asymmetric ring sized to mimic the patient's native mitral annulus, the asymmetric ring being constructed of a flexible material that rolls onto itself outside the valve;

an anterior flexible leaflet and a posterior flexible leaflet suspended over the asymmetric annulus and configured to substantially coapt with one another;

each of the anterior and posterior leaflet shapes is configured to mimic the shape of a native mitral valve, whereby the anterior and posterior leaflets form an orifice through which blood flows in one direction; and

at least two sets of umbilical cords, each set of umbilical cords connected at a first end to either the anterior or posterior leaflet and connected at a second end to a cap, the cap configured to connect at the other end of the cap to papillary muscles of the heart.

According to some embodiments, the mitral valve prosthesis may further comprise an engagement surface that is continuous with each of the anterior and posterior leaflets and attached to each set of umbilicals, the engagement surface configured to enhance sealing of the mitral valve prosthesis.

According to some embodiments, the asymmetric ring may further comprise at least two strands configured in a coil-on-coil configuration.

According to some embodiments, the asymmetric ring may include two layers of material folded together to provide elasticity and a third layer to provide structural stability.

According to some embodiments, the asymmetric ring may comprise two layers of bovine pericardium; and a third layer of glycine or proline to provide strength.

According to some embodiments, the layers may be attached together by staples, glue, or any combination thereof.

According to some embodiments, the asymmetric ring, the anterior and posterior flexible leaflets, the at least two umbilicals, the cap, or any combination thereof may be made of bovine pericardium.

According to some embodiments, the leaflet shape may be 1-5mm longer for better coaptation and umbilical cord connection.

According to some embodiments, the leaflet shape can be designed in a semi-circular fashion along half of the length of the anterior and posterior flexible leaflets, such that the two leaflets form an "S" shaped seal when engaged.

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

According to some embodiments, at least two sets of umbilicals may be attached to an opening of the cap, the opening being located in the middle of the cap.

According to some embodiments, each of the at least two sets of umbilical cords may be attached to a middle portion of the anterior or posterior leaflet, thereby simulating a naturally occurring mitral valve.

According to some embodiments, the anterior and posterior leaflets can be made of a single unit, connected to the asymmetric ring and attached to at least two sets of umbilical cords.

According to some embodiments, the mitral valve can further comprise an extension connected at one end to the anterior flexible leaflet and at the other end to the at least two sets of umbilicals, and configured to allow coaptation between the anterior flexible leaflet and the posterior flexible leaflet.

According to some embodiments, a mitral valve prosthesis to be implanted into a heart may comprise:

an asymmetric ring sized to mimic a patient's native mitral annulus; the asymmetric ring is made of a flexible material that rolls onto itself towards the outside of the valve;

two leaflets suspended from the asymmetrical loop, the leaflets configured on opposite sides of an incision made in a material similar to the material comprising the asymmetrical loop, wherein the incision forms an orifice through which blood flows in one direction;

at least two groups of umbilicals, each group of umbilicals connected at a first end to one of the two leaflets and connected at a second end in a bundle; and

a cap to be connected to at least two sets of umbilical cords at one end of the cap and configured to be sutured to papillary muscles of the heart at the other end of the cap.

According to some embodiments, each set of umbilicals is attached to one of the two leaflets by an extension configured to allow coaptation between the two leaflets.

According to some embodiments, a method of manufacturing a mitral valve prosthesis may comprise:

measuring the size and shape of the patient's mitral valve by an imaging method;

cutting a replica of a subject's mitral valve from a single sheet of material;

making an incision along a single sheet of material, thereby forming an orifice for blood flow and two leaflets, one on each side of the orifice;

measuring the length of the required umbilical cord by an imaging method;

connecting an umbilical cord to one of the two caps; and

a flexible ring is attached to the leaflets to form a complete mitral valve prosthesis that mimics the native mitral valve of a particular patient.

According to some embodiments, the length of umbilical cord required may be measured while measuring the size and shape of the subject's mitral valve.

According to some embodiments, the method may further comprise attaching an extension to each of the two leaflets to carry the umbilical cord prior to attaching the umbilical cord to one of the two caps.

A method is provided for manufacturing a mitral valve prosthesis that is personalized to a natural design to precisely fit a particular patient for whom the valve prosthesis is being manufactured. The method can comprise the following steps:

by measuring the size and shape of the native mitral valve of a particular patient using an imaging device, data is provided for the material from which the personalized mitral valve prosthesis is manufactured,

constructing a 3D model of the personalized mitral valve prosthesis based on data of the size and shape and material of the native mitral valve of the particular patient,

optimizing the 3D model using the FEM method, and

and manufacturing a personalized mitral valve prosthesis based on the optimized FEM model.

According to some embodiments, the method may further comprise visualizing the personalized mitral valve prosthesis model after the optimization operation.

According to some embodiments, the imaging device may include: 2D or 3D echocardiography, computed Tomography (CT), cardiac Magnetic Resonance (CMR), or any combination thereof.

According to some embodiments, measuring the size and shape of the native mitral valve of the patient comprises measuring mitral valve-related parameters, including: annular ring circumference (AC), annulus Area (AA), anterior-posterior (A-P) diameter, anterolateral-posteromedial (AL-PM) diameter, commissure diameter (C-C), anterior Leaflet Length (ALL), posterior Leaflet Length (PLL), mitral valve shape, and chordae tendineae length (ACL and PCL).

According to some embodiments, the method further comprises collecting patient-specific body information to predict the geometry of the heart after implantation of the personalized mitral valve prosthesis, the body information comprising: height, weight, age, race and gender.

In some embodiments, a personalized mitral valve prosthesis is provided. A personalized mitral valve prosthesis can include a flexible annular ring sized to match a native mitral annulus of a particular patient, flexible anterior and posterior leaflets sized to match a native mitral valve leaflet of the particular patient, the leaflets connected to the annular ring, and an umbilical cord sized to match a native mitral valve leaflet of the particular patient, the umbilical cord connected to the flexible anterior and posterior leaflets, the umbilical cord further configured to connect the flexible anterior and posterior leaflets with papillary muscles of the heart. In some embodiments, the personalized mitral valve prosthesis can be formed by:

measuring the size and shape of the native mitral valve of a particular patient by using an imaging device;

providing data on materials from which to manufacture a personalized mitral valve prosthesis;

constructing a 3D model of a personalized mitral valve prosthesis based on data of the size and shape and material of a native mitral valve of a particular patient;

optimizing the 3D model using a FEM method;

and

a personalized mitral valve prosthesis is fabricated based on the optimized FEM model by cutting material into an annular ring, flexible anterior and posterior leaflets, and an umbilical cord and attaching the flexible anterior and posterior leaflets to the annular ring, and the umbilical cord to the flexible anterior and posterior leaflets. In some embodiments, the personalized prosthetic mitral valve can optionally be formed further by including visualizing a personalized mitral valve prosthesis model prior to the manufacturing operation.

According to some embodiments, an imaging device comprises: 2D or 3D echocardiography, computed Tomography (CT), cardiac Magnetic Resonance (CMR), or any combination thereof.

According to some embodiments, measuring the size and shape of the patient's mitral valve includes measuring mitral-valve related parameters including: annular ring circumference (AC), annulus Area (AA), anterior-posterior (A-P) diameter, anterolateral-posteromedial (AL-PM) diameter, commissure diameter (C-C), anterior Leaflet Length (ALL), posterior Leaflet Length (PLL), mitral valve shape, and chordae tendineae length (ACL and PCL).

According to some embodiments, the personalized prosthetic mitral valve may also be formed by collecting physical information of a particular patient to predict the geometry of the heart after implantation of the personalized mitral valve prosthesis, the physical information including: height, weight, age, race, and sex.

According to some embodiments, measuring comprises measuring the annular ring perimeter (AC) as a combination of the anterior leaflet annular ring perimeter (AAC) as the top edge of the anterior leaflet and the posterior leaflet annular ring Perimeter (PAC) as the top edge of the posterior leaflet based on equation (iii).

According to some embodiments, the annular ring forms a multi-layered reinforcing structure by folding or overlapping a top edge of each of the anterior and posterior leaflets.

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

According to some embodiments, the joining comprises coapting an edge of the anterior leaflet with an edge of the posterior leaflet to form a commissure between the anterior and posterior leaflets.

According to some embodiments, the connecting comprises connecting the flexible anterior leaflet and the flexible posterior leaflet together, thereby forming two commissures, wherein the two commissures are at a taper angle (δ) ₁ ) Angled inward to form a tapered personalized mitral valve prosthesis to fit the native left ventricle of a particular patient.

According to some embodiments, the cone angle (δ) ₁ ) From the angle of inclination (δ) of each commissure edge of the flexible anterior leaflet and the flexible posterior leaflet based on equation (x) ₀ ) And (5) determining.

According to some embodiments, the connecting comprises connecting the anterior leaflet to the posterior leaflet by connecting the anterolateral side to the anterolateral side and the posteromedial side to the posteromedial side.

According to some embodiments, attaching the anterior leaflet to the posterior leaflet includes suturing.

According to some embodiments, measuring comprises measuring, based on equation (xi): size and shape of the natural annular ring, commissure Height (CH), angle of inclination (δ) of a particular patient ₀ ) Anterior Leaflet Length (ALL) and Posterior Leaflet Length (PLL), and coaptation height (CoaptH) used to calculate the length of each leaflet edge.

According to some embodiments, the height of the reinforcing annular ring is between 1mm and 4 mm.

According to some embodiments, the height of the reinforcing annular ring is between 2mm and 3mm.

According to some embodiments, the annular ring perimeter (AC) is a function of the anterior-posterior diameter (a-P) and the anterolateral-posterior-medial diameter (AL-PM) based on equation (iii).

According to some embodiments, measuring comprises measuring an anterior-posterior diameter (a-P) and an antero-lateral posteromedial diameter (AL-PM) when the mitral valve is closed during left ventricular contraction.

According to some embodiments, calculating the annular ring circumference (AC) of the prosthesis is based on the ratio (λ) in equation (iii).

According to some embodiments, the annular ring is asymmetric, and wherein the annular ring is further formed by a combination of an anterior leaflet ring and a posterior leaflet ring, wherein the anterior leaflet annular perimeter (AAC) is less than the posterior leaflet annular Perimeter (PAC), and the ratio (R) between AAC/PAC is between 49/51 and 30/70.

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

According to some embodiments, the ratio (R) between AAC/PAC is 40/60.

According to some embodiments, the ratio (R) between AAC/PAC is between the Anterior Leaflet Length (ALL) and the Posterior Leaflet Length (PLL).

According to some embodiments, constructing the 3D model of the personalized mitral valve prosthesis comprises calculating an anterior leaflet annular perimeter (AAC) and a posterior leaflet annular Perimeter (PAC) based on the suture positions a and B.

According to some embodiments, constructing the 3D model of the personalized mitral valve prosthesis comprises constructing the personalized mitral valve prosthesis based on equations (viii) and (ix) based on: (a) An anterior-posterior diameter (a-P) as a theoretical minimum engagement distance; (b) the ratio (r) between ALL and PLL; (c) a bonding depth (Cd); (d) a bond height (CoaptH); and (e) umbilical cord length (Lc) to calculate Anterior Leaflet Length (ALL) and Posterior Leaflet Length (PLL).

According to some embodiments, the connecting comprises connecting the anterior leaflet and the posterior leaflet together to form a body of the personalized mitral valve prosthesis.

According to some embodiments, each anterior leaflet and each posterior leaflet includes two sets of umbilicals: anterolateral and posteromedial umbilical cords, wherein each anterolateral and posteromedial umbilical cord comprises three sub-umbilical cords, wherein the umbilical cords are uniformly distributed along at least 3/8 of each side from each side.

According to some embodiments, constructing the 3D model includes calculating a length of each umbilical cord, wherein calculating the length of each umbilical cord is based on parameters including: leaflet length, coaptation height, and coaptation depth.

According to some embodiments, measuring comprises measuring the distance from the papillary muscle apex to the junction edge to represent the prosthetic umbilical cord length, further comprising measuring in situ and adjusting the cotton wool umbilical cap to where the umbilical cords are integrated and merged at the end of each group of umbilical cords.

According to some embodiments, constructing the 3D model includes providing each particular patient with calculated geometries and dimensions of the annular ring, anterior leaflet, posterior leaflet, and umbilical cord as inputs for engineering mapping software or mapping tools.

According to some embodiments, the engineering mapping software or mapping tool outputs a template for manually cutting leaflets of the valve prosthesis.

According to some embodiments, the engineering drawing software or drawing tool outputs a template for machine cutting the leaflets.

According to some embodiments, the method may further comprise packaging, labeling and sterilizing the personalized mitral valve prosthesis prior to release for use.

According to some embodiments, the method may further comprise assembling the personalized mitral valve prosthesis onto the valve stent prior to packaging.

According to some embodiments, the method may further comprise implanting the personalized mitral valve prosthesis in a particular patient.

Drawings

FIGS. 1A and 1B are schematic diagrams of embodiments of the present invention. Fig. 1A depicts a prosthetic mitral valve in an open position and shows chordae tendineae prior to attachment to leaflets according to some embodiments of the present disclosure. Fig. 1B depicts a prosthetic mitral valve in a closed position and shows chordae tendineae after attachment to leaflets, in accordance with some embodiments of the present disclosure;

FIG. 2 is a schematic view of an embodiment of the present invention implanted in a heart, according to some embodiments of the present disclosure;

fig. 3 is an image of a 3D reconstruction of a mitral valve region in 3D CT image analysis software according to some embodiments of the present disclosure;

fig. 4 is a photograph of a 3D printed valve mold and porcine pericardium mitral valve leaflets according to some embodiments of the present disclosure;

fig. 5 is a photograph of a prosthetic valve in an in vitro test according to some embodiments of the present disclosure;

fig. 6A-6B are schematic diagrams of a side view of an anterior leaflet and a posterior leaflet, respectively, of a prosthetic mitral valve according to some embodiments of the present disclosure, and a top view of the leaflets when engaged with one another;

fig. 6C is a schematic diagram of a top view of a mitral valve prosthesis looking down from the left atrium into the left ventricle (at diastole, when the valve is open to allow blood to enter the left ventricle), in accordance with an embodiment of the present disclosure;

fig. 6D is a schematic view of a single sheet of material comprising an anterior leaflet and a posterior leaflet, according to an embodiment of the present disclosure;

figures 7A-7B are schematic illustrations of a cap for connecting an umbilical cord to papillary cardiac muscles and a mitral valve prosthesis having two caps attached to the umbilical cord, in accordance with an embodiment of the present disclosure;

fig. 8A-8B are schematic diagrams of possible locations of an umbilical cord relative to a leaflet, and cross-sections of the umbilical cord when attached to a leaflet, respectively, according to some embodiments of the present disclosure;

fig. 9A-9B are schematic views of a prosthetic mitral valve with two leaflets attached, employing alternative designs with curved (ellipsoid/droplet) configurations to enlarge the coaptation surface, and possible coaptation surface configurations, according to some embodiments of the present disclosure, respectively;

figure 10 is a schematic diagram of a measured copy of a patient's mitral valve derived from 2D or 3D echocardiographic images, according to some embodiments of the present disclosure;

FIG. 11 is a schematic view of forming a bileaflet prosthesis according to some embodiments of the present disclosure;

fig. 12 is a schematic view of an opening formed along a leaflet portion according to some embodiments of the present disclosure;

fig. 13 is a schematic illustration of an echocardiogram or MRI scan of a left cardiac chamber or ventricle of a patient according to some embodiments of the present disclosure;

14A-14B are schematic illustrations of a patient's left ventricle in diastole and systole, respectively, according to some embodiments of the present disclosure;

15A-15B are schematic diagrams of extensions attached to the anterior and posterior leaflets, respectively, according to some embodiments of the present disclosure;

figures 16A-16B are schematic illustrations of side views of a mitral valve prosthesis having an extension and attached umbilical cord in diastole and systole, respectively, according to some embodiments of the present disclosure;

fig. 17 is a schematic illustration of attaching an asymmetric flexible ring to the periphery of a valve prosthesis to mimic the native valve annulus, according to some embodiments of the present disclosure;

18A-18B are schematic illustrations of an elastic material inserted into a rolling valve annulus before and after the annulus is rolled thereon, respectively, according to some embodiments of the present disclosure;

fig. 19 is a schematic flow diagram illustrating a method for manufacturing a mitral valve prosthesis, according to some embodiments of the present disclosure;

fig. 20A is a schematic diagram illustrating a method for manufacturing a personalized mitral valve prosthesis according to some embodiments of the present disclosure;

fig. 20B is a schematic flow diagram illustrating a method for manufacturing a personalized mitral valve prosthesis according to some embodiments of the present disclosure;

fig. 21A is a schematic view of an annular valve edge remaining upon removal of a native mitral valve in clinical practice according to some embodiments of the present disclosure;

FIG. 21B is a schematic diagram of an elliptical ring model for calculating the annular ring circumference (AC) of a valvular prosthesis with AL-PM diameter as the major axis and A-P diameter as the minor axis, according to some embodiments of the present disclosure;

fig. 22A-22C are schematic diagrams of an example design of an anterior leaflet, an example design of a posterior leaflet, and an example design mitral valve prosthesis assembly, respectively, according to some embodiments of the present disclosure;

fig. 22D is a schematic diagram of a ring model indicating two papillary muscles, according to some embodiments of the present disclosure;

22E-22F are schematic diagrams of customized anterior and posterior leaflet models, according to some embodiments of the present disclosure;

fig. 23A-23B are schematic diagrams of two examples of leaflets (anterior or posterior) showing the theoretical length of the leaflet free edge, according to some embodiments of the present disclosure;

FIG. 23C is a schematic illustration of the relationship of multiple parameters that interact when leaflets of a prosthesis engage, according to some embodiments of the present disclosure;

FIG. 23D is a schematic flow diagram illustrating a method of customizing a mitral valve design using FEMs, according to some embodiments of the present disclosure;

figures 24A-24B are schematic illustrations of a side view and a perspective view, respectively, of a mitral valve leaflet splice, according to some embodiments of the present disclosure;

FIG. 25 is a photograph of an echocardiogram of a sheep heart implanted with a personalized, naturally designed mitral valve prosthesis manufactured according to a method of the present disclosure; and

fig. 26A-26B are schematic diagrams of a posterior leaflet and an anterior leaflet, respectively, according to some embodiments of the present disclosure;

FIG. 27 is a schematic view of a final customized 3D model of a prosthetic mitral valve according to some embodiments of the present disclosure;

FIG. 28 is a schematic illustration of FEM simulation optimization results of a customized prosthetic mitral valve model according to some embodiments of the present disclosure;

29A-29B are schematic views of a prosthetic mitral valve in a hydrodynamic test chamber in open and closed configurations, respectively, according to some embodiments of the present disclosure;

FIG. 30 is an echocardiogram of a customized prosthetic mitral valve during its closed configuration after implantation in a porcine heart; and

fig. 31 is the blood pressure gradient of a porcine heart after implantation of a customized prosthetic mitral valve.

The foregoing will be readily understood from the following more particular description of exemplary embodiments of the invention, as illustrated in the accompanying drawings in which like reference characters refer to the same parts throughout the different views. The figures are not necessarily to scale; on the contrary, emphasis is placed upon illustrating embodiments of the invention.

Detailed Description

The mitral valve prosthesis of the present invention is shown in fig. 1A and 1B. Mitral valve prosthesis 100 has a physiological shape similar to a native human mitral valve. The mitral valve prosthesis comprises a flexible, asymmetric ring 1 and two flexible, membranous leaflets 2, which are suspended from the asymmetric ring 1. The mitral valve prosthesis also comprises two sets of umbilical cords 3 simulating the chordae tendineae of the heart. Each set of umbilicals 3 is configured to be attached at one end to the edge and/or main body of the leaflet 2 and to converge at the other end into a retaining cap 8. The securing cap 8 is configured to be sutured to the papillary muscle of the left ventricle.

Mitral valve 100 is shown unattached to leaflet 2 in fig. 1A and umbilical cord 3 attached to leaflet 2 in fig. 1B. The umbilical cords 3 may be attached to the leaflets 2 before surgery, or they may be attached during surgery. For example, the attachments 9 between the umbilical cord 3 and the leaflets 2 may be sutures or they may be of unitary design. Mitral valve 100 is shown in an open state in fig. 1A and in a closed state in fig. 1B. In the closed state, the leaflets 2 appear to coapt.

Fig. 2 shows a mitral valve 100 implanted in a heart. The mitral valve 100 is shown implanted in the native mitral annulus 12, on one side near the aortic valve 6, where the aortic root 7 is connected to the left ventricle, and on the other side against the opposite ventricular wall 5. The umbilical cord 3 is shown attached to the papillary muscle 4.

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

The flexible ring 1 may be formed, for example, from a resilient annuloplasty ring. The leaflets 2 can be formed of a natural material or a biocompatible composite material that is resistant to clotting and functions similarly to the patient's natural anterior and posterior leaflets. At least two sets of umbilical cords are provided, attached at a first end to one of the two leaflets and at a second end to papillary muscles, which function similarly to the natural chordae tendineae of the patient. The umbilical cord 3 ties the leaflets 2 to the patient's papillary muscles, provides support for the left ventricular wall throughout the cardiac cycle, and prevents the leaflets from opening into the atrial chambers.

Mitral valve prosthesis 100, including flexible ring 1, leaflets 2, and umbilical cord 3, resembles a healthy, native mitral valve in appearance and behavior. Furthermore, the mitral valve prosthesis of the present invention can be produced from natural materials and can avoid inclusion of foreign matter, such as cotton wool. Allograft materials and/or composite materials, including various combinations of allograft, xenograft and/or autograft materials, can be used to make flexible rings, leaflets, umbilicals and caps. The materials forming the valve annulus and leaflets may include, but are not limited to, human, bovine or porcine pericardium, acellular bioprosthetic materials, woven biodegradable polymers in combination with cells, and extracellular materials. Biodegradable natural polymers may include, but are not limited to, fibrin, collagen, chitosan, gelatin, hyaluronic acid, and the like. Biodegradable synthetic polymer scaffolds that can be infiltrated with cells and extracellular matrix materials can include, but are not limited to, poly (L-lactide), polyglycolide, poly (lactic-co-glycolic acid), poly (caprolactone), polyorthoesters, poly (dioxanone), poly (anhydride), poly (trimethylene carbonate), polyphosphazene, and similar materials. The flexible ring may be further customized to provide personalized flexibility or rigidity to the patient. In addition, some components of the mitral valve prosthesis, including the umbilical cord 3, may be intraoperatively formed from the patient's autologous pericardium.

For example, the mitral valve prosthesis may be made from the patient's own pericardium. Alternatively, the mitral valve prosthesis may be made of a xenogenic material (e.g., animal tissue, such as an existing valve) onto which a layer of patient-cultured cells is applied by tissue engineering.

Prosthetic valves are often fixed with glutaraldehyde, a known toxin that promotes regeneration. The mitral valve prosthesis of the present invention can be fixed by non-glutaraldehyde based methods, such as dye-mediated light fixation. The mitral valve of the present invention can also be fixed by using alternative cross-linking agents such as epoxy compounds, carbodiimides, diglycidylesters, reuterin (reuterin), genipin (genipin), diphenylphosphoryl azide, acyl azide, and cyanamide, or by physical methods such as ultraviolet light and dehydration.

The mitral valve prosthesis or some components of the prosthesis can be directly produced by biological three-dimensional (3D) printing using biological materials. Alternatively, the mitral valve prosthesis or some components of the prosthesis may be produced based on detailed dimensions obtained from three-dimensional imaging performed preoperatively using a template or mold constructed from three-dimensional printing.

A method of implanting a mitral valve prosthesis is also provided. Prior to implantation, an echocardiographic study (or other imaging study) of the patient is obtained. Cardiac chamber size and motion were measured by imaging studies. The detailed dimensions of the patient's mitral valve annulus, leaflets, and umbilical cord are also measured from the acquired images. Further, a three-dimensional depiction of the valve to be replaced may be presented. From 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 corrected for the existing pathology.

Three-dimensional echocardiography studies can be performed using, for example, a transesophageal echocardiography (TEE) probe or a transthoracic echocardiography (TTE) probe. Software such as esie valves. Tm may be used to model and measure portions of the mitral valve in three and four dimensions. (Siemens Medical Solutions USA, inc., malvern, pa.). Relevant measurements may include the outer and inner diameters of the annulus, the annulus area, the inter-trigonal and inter-communicative distances, and the length along each axis of the anterior and posterior leaflets.

Additionally, or alternatively, the three-dimensional study 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 porcine heart is obtained using CT imaging (somat. Rtm. Definition Flash, siemens Healthcare, erlangen, germany), with the mitral valve region of the heart visible on the right side of the image. Image analysis software may be used to segment the mitral valve region and obtain the associated measurements.

The mitral valve prosthesis can be completely customized for the patient, with each component (e.g., ring, leaflet, umbilical cord, cap) manufactured to have dimensions that match the patient's native valve. For example, as shown in fig. 4, a 3D printed mold of the mitral valve is created based on a 3D reconstruction of the imaged valve. The 3D printed valve shown in fig. 4 is modeled during the diastolic or open phase of the cardiac cycle. A 3D mold based prosthetic valve is also shown in fig. 4. The mold may guide the porcine pericardium into the leaflet and chordae attachment site. Alternatively, a preformed mitral valve or a preformed component of a mitral valve may be selected for implantation proximate in shape and size to the native valve or native valve component of the patient.

Fig. 5 shows an image of a prototype of a prosthetic valve sutured in an in vitro testing system. The valve prototypes shown were sutured to explanted whole hearts. A bolus of saline is injected through the tube into the left ventricle of the heart and the aorta is clamped to contain the saline in the left ventricle and create pressure. For example, the injection pressure may be monitored on a pressure gauge connected to the injection line. The ability of the valve prototype (e.g., without regurgitation and valve leaflet prolapse) under physiological pressure can then be monitored. The ability of the valve can be measured or monitored at the systolic pressure at which the left ventricle contracts and the native valve closes.

Fig. 6A-6B are schematic views of the anterior and posterior mitral leaflets, respectively, of a prosthetic mitral valve and when these leaflets engage one another, according to some embodiments of the present disclosure. According to fig. 6A and 6B, the prosthetic mitral valve may be prosthetic mitral valve 600. According to some embodiments, valve 600 can include two leaflets, e.g., anterior mitral leaflet 602A and posterior mitral leaflet 602P. Each of the posterior mitral leaflet 602P and the anterior leaflet 602A, respectively, can be pre-operatively designed and created as a single shell (unitary piece) to fit a particular physiology and anatomy of a patient based on a cross-sectional image of the patient's heart. Measurements taken from the patient's own heart can 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 native leaflet. Each leaflet may be shaped to include chordae (e.g.,

chordae

604, 606, 608, 610) and additional material to form loop portions (e.g., anterior loop portion 601A and posterior loop portion 601P). As described further below, the surgeon may determine the length of the chordae to fit the patient. The leaflets may be cut from a single sheet of material using a knife or scissors and may be sutured by the surgeon during the mitral valve replacement procedure to form a mitral valve similar to the patient's native mitral valve.

For example, the Anterior Leaflet (AL) may be about 30mm in height, the AL may be about 45mm in length, the Posterior Leaflet (PL) may be about 15mm in height, and the posterior leaflet may be about 60mm in length. As shown in fig. 6A, the medical community refers to 630A as the height of the

anterior leaflet

602A, 630P as the height of the posterior leaflet 602P, and the length of each leaflet as a fraction of the leaflet's perimeter, e.g., 632A refers to the length of the anterior leaflet 602A and 632P refers to the length of the posterior leaflet 602P.

According to some embodiments, cutting each of

leaflets

602A and 602P, respectively, and

ring portions

601A and 601P, respectively, from the same or different pieces of material may reduce the burden on a person (e.g., a surgeon) preparing a prosthetic mitral valve for implantation. Cutting the leaflets into two separate portions and cutting the annulus portion into two separate portions and attaching the leaflets to the annulus and further attaching the umbilical cord to each leaflet reduces the preparation time and time required to perform a surgical procedure to implant the prosthetic valve as compared to cutting the leaflets and umbilical cord from a single piece of material as a single unit. Because of the high precision required in cutting the leaflets and each umbilical cord while maintaining the connection between the leaflet sections and the umbilical cord section intact, cutting and implanting the leaflets and umbilical cord as a single unit is more complicated and time consuming than the methods disclosed herein.

In some embodiments, each of the

loop portions

601A and 601P is formed by rolling each leaflet's posterior side such that each leaflet's posterior side folds or rolls onto itself (e.g., a rolled anterior portion 605A and a rolled posterior portion 605P) toward the outside of the valve 600. According to this embodiment, the size of the posterior end of each leaflet may be increased by 5-10mm of additional material that may be used to form loop portions (e.g., loop portion 601A in the anterior leaflet of the mitral valve and loop portion 601P in the posterior leaflet of the mitral valve) when rolling the posterior end of the leaflet onto itself. Rolling or folding the ring (or each

ring portion

601A and 601P) onto itself towards the outside of the valve 600 can help to avoid the formation of clots on the inside of the valve 600, and if clots are to be formed, they will only appear on the outside of the valve 600 at the folded or rolled region of the ring or ring portion, which poses less risk of damage to the effective operation of the valve 600. According to some additional embodiments, the loop (or each

loop portion

601A and 601P) may be further reinforced by additional strips of material (not shown), such as suitable biomedical fibers or polymers. Such a strip may be made from the sheet of material from which the valve 600 is made and sized to fit within each

ring portion

601A, 601P. Preferably, such a strip has a width of 1-3mm and a length of 10-20 mm. Such a strip of material may be added to valve 600 as each

ring portion

601A, 601P is rolled up, the strip being placed within each

ring portion

601A, 601P. These strips of material may be elastic and may be made of various compositions, such as biocompatible rubber, recoil wire, or synthetic material.

According to fig. 6B, leaflet 602A can be a semi-elliptical or plano-convex shape, while leaflet 602P can have a plano-concave shape. In some embodiments, the valve 600 can include at least two groups of umbilical cords. In some embodiments, each of the at least two groups of umbilicals is attached to a middle portion of a respective leaflet, thereby simulating a native mitral valve. For example, in some embodiments, leaflet 602A can include at least one set of umbilical cords 603A that can be attached to a middle portion of leaflet 602A at one end of leaflet 602A, which is generally opposite the end where ring portion 601A is attached to leaflet 602A. In some embodiments, the at least one set of umbilicals 603A can include at least two umbilical subsets, e.g., umbilical subset 604 and umbilical subset 606. According to some embodiments, these

umbilical subsets

604 and 606 are spaced apart such that a gap of about 3-5 millimeters is maintained between the two umbilical subsets to achieve a more effective joint. The gap between the

umbilical cord subsets

604 and 606 also serves to create a more uniform tension distribution on the leaflets and potentially reduce wear. These

umbilical cord subsets

604 and 606 may be connected to different and separate caps for connecting the umbilical cord subsets to the papillary muscles of the heart, as will be explained in detail with reference to fig. 7A-7B.

In some embodiments, leaflet 602P can include at least one set of umbilical cords 603P that can be connected to a middle portion of leaflet 602P at one end of leaflet 602P, which end of leaflet 602P is generally opposite the end where ring portion 601P is connected to leaflet 602P.

In some embodiments, the at least one set of umbilicals 603P can include at least two umbilical subsets, e.g., umbilical subset 608 and umbilical subset 610. These

cord subsets

608 and 610 are spaced apart such that a gap of about 5-8 millimeters is maintained between the two cord subsets to achieve a more effective engagement. These

umbilical cord subsets

608 and 610 may be connected to different and separate caps for connecting the umbilical cord subsets to the papillary muscles of the heart, as will be explained in detail with reference to fig. 7A-7B.

In some embodiments, the width of umbilical 603A and/or umbilical 603P may be between 1mm and 2mm, although other widths may be implemented. In some embodiments, the posterior mitral leaflet 602P can be connected on one side to the loop portion 601P of the asymmetric annulus. Once the loop portion 601A is attached to the loop portion 601P, for example by sutures, fasteners, or the like, a complete asymmetric and flexible loop may be formed.

According to some embodiments, the internodal distance in anterior mitral leaflet 634A can be between 8-10 mm. In some embodiments, the internode distance in posterior leaflet 634A of the mitral valve can be between 10-15 mm. In some embodiments, the internodal distance, labeled as distance 636 and/or 638, between the anterior leaflet and the posterior leaflet in the commissure region can be between 5-7 mm.

According to some embodiments, and as shown in fig. 6B, an anterior leaflet 602A can be connected to a posterior leaflet 602P, and a ring portion 601A can be connected to the ring portion 601P to construct a prosthetic mitral valve 600. Once leaflet 602A is attached to leaflet 602P, the resulting aperture 620 between leaflet 602A and leaflet 602P can cause blood to flow in one direction, i.e., from the left atrium to the left ventricle. Thus, the orifice 620 created between the leaflet 602A and the leaflet 602P can be configured to prevent regurgitation, i.e., from the left ventricle to the left atrium. The

leaflets

602A, 602P and the manner in which these leaflets are connected to one another in some coaptation, and the ring portion 601A and ring portion 601P can be configured to mimic the shape, size and therefore function of a native human mitral valve. Specifically, ring portion 601A may be configured to mimic the anterior annulus, while ring portion 601P may be configured to mimic the posterior annulus of the native mitral valve. In some embodiments, each leaflet may include a shape extending approximately 1-5mm between the annulus portion and the umbilical cord to allow for better coaptation between the two leaflets and better attachment of the umbilical cord to each leaflet.

In some embodiments, the anterior leaflet 602A can include at least two umbilical cord subsets, e.g., an umbilical cord subset 604 and an umbilical cord subset 606, which can be connected to the leaflet 602A at different ends of the leaflet 602A. In some embodiments, the posterior leaflet 602P can include at least two umbilical cord subsets, such as an umbilical cord subset 608 and an umbilical cord subset 610, which can be attached at different ends of the leaflet 602P. Like the native mitral valve, the umbilical cord should be connected to the papillary muscles of the heart. More specifically, in the native human mitral valve, each umbilical cord subset is attached to a different region of the papillary muscles. Thus, the prosthetic valve 600 can include at least two umbilical cord subsets per leaflet, whereby each umbilical cord subset will attach to a different papillary muscle region in order to closely mimic the configuration and operation of a native mitral valve. As will be explained with respect to fig. 6C and 7A-7B, each umbilical cord subset may be connected to the papillary muscles by a cap to ensure an easy but sufficiently stable and durable attachment between any umbilical cord subset and the papillary muscles. The number of umbilicals in each umbilical subset (e.g., 604, 606, 608, and 610) may be different or the same. In some embodiments, each umbilical cord subset may include at least two umbilical cords.

Fig. 6C is a schematic diagram of a top view of a mitral valve prosthesis looking down from the left atrium to the left ventricle, according to an embodiment of the present disclosure. According to fig. 6C, the posterior leaflet 602P can be connected to the anterior leaflet 602A by a connection wire (e.g., suture 609). In some embodiments, the ring portion 601A can be connected to the ring portion 601P, e.g., along line 609, and can roll on itself toward the outside of the valve 600. In some embodiments, the anterior leaflet 602A can include two umbilical cord subsets, such as

subsets

604 and 606, whereby each of these umbilical cord band sets can be connected to a different papillary muscle 720 through a separate cap element 700. Thus, the posterior leaflet 602P may include two

umbilical cord subsets

608 and 610, whereby each umbilical cord subset may be attached to the papillary muscle 720 by a different cap element 700. For example, the anterior umbilical cord 604 may be connected to a first papillary muscle 720 through the first cap 700, and the posterior umbilical cord 608 may also be connected to the same first papillary muscle through the same first cap 700. Similarly, the anterior umbilical cord 606 may be connected to a second papillary muscle 720 through a second cap 700, and the posterior umbilical cord 610 may also be connected to the same second papillary muscle through the same second cap 700.

According to fig. 6D, in some embodiments,

leaflets

602P and 602A can be cut from a single monolithic housing and can be joined along suture lines 609, e.g., to form a complete valve. According to some embodiments, the umbilical cord may be adjusted according to the preoperative scan of the patient, according to the individual optimal umbilical cord length of the recipient/patient.

Fig. 7A-7B are schematic diagrams of a cap for connecting an umbilical cord to papillary cardiac muscles and a mitral valve prosthesis having two caps attached to the umbilical cord, respectively, in accordance with an embodiment of the present disclosure. In some embodiments, the shape of cap 700 in the deployed configuration may be an arc. In some embodiments, the shape of the cap 700 in the closed configuration may resemble a tapered shape with a small opening 730 at its top end 702 and a wider opening at its bottom end 704, whereby the ends of the arc may be sutured to each other or one over the other using surgical sutures 706, thereby forming the closed configuration. The suture 706 may be made prior to placing the cap 700 on top of the pupil muscle 720. In some embodiments, the cap 700 may be between 5mm and 10mm in diameter and between 5-10mm in height. According to some embodiments, the cap 700 may be made of a single piece of material having a cap shape, while according to other embodiments, the cap 700 may be made of two open leaflets or pieces of the same material to be sutured together and reach the papillary muscles immediately. For example, the suture may begin from one side of the two pieces of material of cap 700 and exit through a portion of cap 700 to attach cap 700 to the papillary muscles, and so on, until the two portions of cap 700 are fully connected to each other and to the papillary muscles of the heart.

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

Once the cap 700 is placed over the pupillary muscle 720, the umbilical cord, such as the

umbilical cord subsets

604, 608, may be connected to the cap 700 using sutures 710, which sutures 710 may connect the umbilical cord, cap 700, and pupillary muscle 720 together. According to some embodiments, the cap opening 730 may enable a good fit between the cap 700 and the papillary muscle 720, as the cap opening 730 makes it possible to adapt the shape of the cap to the shape of the papillary muscle 720. In some embodiments, the cap 700 may be attached at one end thereof to the

umbilical cord subsets

604 and 608, e.g., by a suture 710, while the cap 700 may be attached from the other end to the papillary muscles of the heart, e.g., by a suture 706, typically with the opposite end of the cap 700 near the bottom end 704. The cap 700 may be connected to the papillary muscles 720 through the entire circumference of the bottom end 704 of the cap 700, but in some embodiments, the cap 700 may be connected to the papillary muscles 720 through a specific portion along the circumference of the bottom end 704 of the cap 700.

According to some embodiments, the umbilicus may be connected to one another to form an umbilical cord harness. The umbilical cord may be connected as a bundle at the end of the umbilical cord that is to be connected to the cap 700 (e.g., the end of the

umbilical cord subsets

604 and 608, to the leaflets 602). According to some embodiments, it is easier to connect the umbilical cord (e.g., umbilical cord subsets 604 and 608) to papillary muscles 720 through cap 700 than to connect the umbilical cord directly to papillary muscles 720, as it requires a wider range of attachment procedures. For example, if the attachment method is suturing, suturing each umbilical cord to the papillary muscle 720 is more complicated and time consuming than suturing an umbilical cord to the deployed cap 700 and suturing the cap 700 (which is a single large piece) to the papillary muscle 720. Because the patient receiving the prosthesis of the present disclosure is connected to a cardiopulmonary bypass, also commonly referred to as a heart-lung machine, mitral valve replacement is preferably conveniently performed.

Although fig. 7A only shows two umbilical subsets 604 and two umbilical subsets 608 attached to the cap 700, it should be understood that additional umbilicals may be connected to the cap 700. The

umbilical subsets

604, 608 may include one or more umbilicals. In some embodiments, as shown in fig. 6C, four umbilicals 604 from the right sector of anterior mitral leaflet 602A and four umbilicals 608 from the left sector of posterior mitral leaflet 602P are connected to cap 700.

In some embodiments, each of the

umbilical subsets

604, 606, 608, and 610 may be connected to the cap 700 along the outside of the cap 700. In other embodiments, the umbilical cord, or the umbilical cord of at least some prosthetic valves, may be attached to the cap 700 through an opening 730, and the opening 730 may be located in the middle of the cap 700. That is, the umbilical cord may pass through the opening 730 and may be attached to the inside of the cap 700.

In some embodiments, each of the

umbilical cord subsets

604, 606, 608, and 610 may first be connected to each other to form a bundle, and then may be connected to the cap 700.

As shown in fig. 7B, prosthetic mitral valve 600 can include a flexible asymmetric ring 601 attached to two leaflets (e.g.,

leaflets

602A and 602P). In some embodiments, each of the two leaflets may have an attached set of umbilicals, e.g., umbilical subsets 604 (not shown), 606 (not shown), 608, and 610. In some embodiments, each set of umbilicals may be attached to a single cap 700, according to each of the two leaflets, and each cap 700 may connect the mitral valve prosthesis 600 to the papillary muscles 720 of the heart by connecting each subset of the umbilicals 610 to their respective caps 700.

As described above, according to some embodiments, each of the umbilical cord subsets 604 (not shown), 606 (not shown), 608, and 610 may be made from the same piece of material from which the anterior and posterior leaflets are made. Such an umbilical cord, each of which may be considered an extension of

leaflets

602A and 602P, may be referred to as a primary umbilical cord. According to some embodiments, additional umbilical cords may be attached to both anterior leaflet 602A and posterior leaflet 602P. Each of these secondary umbilicals may be made of a different and separate material from that used to construct the leaflets and the primary umbilical cord. The secondary umbilical cord may be configured to connect the bottom side of each of

leaflets

602A and 602P to a point along the primary umbilical cord. The connection point for the secondary umbilical along the primary umbilical cord may be the middle of the primary umbilical cord, although other locations along the primary umbilical cord may be implemented as connection points in order to achieve better engagement of the leaflets. The secondary umbilical cord may generally be sutured to either the anterior leaflet 602A or the posterior leaflet 602P at one end thereof, and at the other end thereof, the secondary umbilical cord may be sutured to the primary umbilical cord. When attaching the secondary umbilical cord to the anterior leaflet 602A or the posterior leaflet 602P, respectively, such as by sutures, damage to the outer surface of the anterior leaflet 602A or the outer surface of the posterior leaflet 602P should be avoided to prevent clotting along the connecting lines (e.g., sutures). For example, when using microscopic sutures, the

leaflets

602A and 602P have less chance of being damaged. The purpose of the secondary umbilical cord is to provide additional support for the prosthetic valve against pressure applied to the ventricular side of the prosthetic valve during systole.

Fig. 8A-8B are schematic illustrations of possible locations of the secondary umbilical cord relative to the posterior leaflet and cross sections of the primary and secondary umbilical cords when attached to the posterior leaflet, respectively, according to some embodiments of the present disclosure. As shown in fig. 8A, the posterior leaflet 602P may roll over its posterior end to form a loop 601. In some embodiments, the posterior mitral leaflet 602P can be divided into several regions.

Regions

812 and 814 may be regions to which a secondary umbilical (e.g., umbilical 603) may connect. However, there may be a region 816 along the posterior leaflet 602P, which region 816 should be umbilical-free, i.e., a secondary umbilical should not be connected to region 816. This is due to the fact that during ventricular systole, region 816 is the region where the posterior leaflet 602P applies high pressure after attachment to the heart as part of the prosthetic valve. In some embodiments, the region 816 can include about 2-5mm to the right of the midline 810 of the posterior leaflet 602P, and about 2-5mm to the left of the midline 810 of the posterior leaflet 602P. In some embodiments, the region 816 can be 3mm to the right and 3mm to the left of the midline 810 of the posterior leaflet 602P. The secondary umbilical cord may be designed to help provide additional support to the posterior leaflet 602P as the pressure gradient increases during ventricular systole.

In some embodiments, when in the deployed configuration, the secondary umbilical 603 should not reach the ends of the

regions

812 and 814 of the posterior leaflet 602P. In some embodiments, the umbilical should not be connected to the ends of

regions

812 and 814, which are in close proximity to ring 601. For example, the umbilical cord can be positioned along either of the

regions

812 and 814 along the entire posterior leaflet 602P at an angle of about 20 to 70 degrees relative to the midline 810 of the posterior leaflet 602P. In addition, the regions of the posterior leaflet 602P located between the centerlines 810 and approximately 15-20 degrees to either side of the midline 810 may remain free of the secondary umbilical cord.

Fig. 8B schematically illustrates a cross-section of the posterior mitral valve showing the primary and secondary umbilicals when attached to the posterior leaflet 602P. Fig. 8B shows a primary umbilical cord 608, which is made from the same piece of material as the leaflets. A primary umbilical 608 extending from the posterior leaflet 602P at one end thereof is attached to the cap 700 at the other end thereof. In some embodiments, the primary umbilicals 608 can be connected to one another to form a bundle (not shown), which can then be connected to the outside of the cap 700. Cap 700 may then be attached to papillary muscles 720.

According to some embodiments, the primary umbilical 608 may be connected to the secondary umbilicals 603, whereby each of the secondary umbilicals 603 may be connected to the posterior leaflet 602P on one end (e.g., end 823) and to contact points at an opposite end (e.g., end 825) of each secondary umbilical 603 along the primary umbilical. According to some embodiments, the secondary umbilical 603 should be about 30-40% thicker and about 30-40% wider than the primary umbilical 608. Depending on the prosthesis desired, one to four secondary umbilicals may be used per leaflet sector (smallop) of the posterior mitral leaflet (602P).

Fig. 9A-9B are schematic views of a prosthetic mitral valve with two leaflets attached that employs an alternative design with a curved (ellipsoid/droplet) configuration to enlarge the coaptation surface, and possibly the coaptation surface configuration, respectively, according to some embodiments of the present disclosure. According to fig. 9A, prosthetic mitral valve 1100 can include two leaflets, e.g., an anterior leaflet 1602A and a posterior leaflet 1602P, whereby each of

leaflets

1602A and 1602P can have a semi-circular shape and together the two leaflets can create a "cloudy-and-sunny" shape. In some embodiments, the leaflet shape may be designed in a semi-circular manner along half the length of each leaflet such that the two leaflets form an "S" shaped seal when engaged.

This unique shape can achieve sufficient coaptation between the anterior leaflet 1602A and the posterior leaflet 1602P, particularly at region 1120. In some embodiments, there can be coaptation or overlap between the anterior leaflet 1602A and the posterior leaflet 1602P along the region 1120. Symmetrically, there can be a similar coaptation or overlap region between the posterior leaflet 1602P and the anterior leaflet 1602A (not shown). Similarly, for the valve 600 detailed above, each leaflet can include a respective ring, such as ring 601A and ring 601P, which can be formed by rolling one end of the material from which each leaflet is constructed onto itself.

According to fig. 9B, there can be two coaptation configurations between the anterior leaflet 1602A and the posterior leaflet 1602P immediately adjacent the coaptation region. In some embodiments, with respect to the prosthetic valve 600, the prosthetic valve 1100 can include two types of umbilical cords; a primary umbilical cord and a secondary umbilical cord. According to some embodiments, the primary umbilical cord can be configured to extend to the anterior leaflet 1602A and the posterior leaflet 1602P, respectively. That is, the primary umbilical cords, e.g., primary umbilical cords 1102A and 1102P, can be constructed from the same piece of material as the respective leaflets, anterior leaflet 1602A and posterior leaflet 1602P. The primary umbilicals 1102A and/or 1102P may extend from a mid-portion of the respective leaflet at one end and may be connected to a cap at the other end. According to some embodiments, a secondary umbilical cord, such as umbilical cord 1104P, can be attached to only the posterior leaflet 1602P. A secondary umbilical, for example, umbilical 1104P can be connected at one end to a middle portion of the posterior leaflet 1602P and at the other end to a middle portion of the primary umbilical 1102P. According to some embodiments, a secondary umbilical cord 1104P may be added to better mimic the native mitral valve, including an additional shorter umbilical cord connected between the posterior leaflet and the posterior primary umbilical cord. The addition of a secondary umbilical cord can subject the posterior leaflet to pressure applied to the posterior leaflet during systole and produce proper leaflet coaptation (or closure) during systole of the cardiac cycle and further allow the leaflet to open during diastole.

For example, the posterior leaflet 1602P may have attached the secondary umbilical cord 1104P to the posterior edge of the leaflet 1602P. The secondary umbilical 1104P may be further connected to a middle portion of the primary umbilical 1102P.

In some embodiments, each umbilical cord and/or each umbilical cord may be attached to a cap, such as cap 700, which may connect the umbilical cord to the papillary muscles of the heart.

Fig. 10 is a schematic view of a measured copy of a patient's mitral valve, according to some embodiments of the present disclosure. In some embodiments, measurements of the length, width, and height of the leaflet segment may be obtained by echocardiography, although other imaging methods may be used, such as cardiac CT or cardiac MRI, and the like. Thus, the size and shape of prosthetic mitral valve 1200 can be substantially an exact copy of the patient's native or native mitral valve.

Fig. 11 schematically illustrates the formation of a bileaflet prosthesis according to some embodiments of the present disclosure. In some embodiments, as shown in fig. 12, the base of the valve, i.e., the leaflet portion, may be cut out of a single piece of material 1210 based on a cross-sectional image of the heart of the intended recipient. The leaflet section can be sized to replicate a prosthetic image in a 1 ratio, and a cut 1220 can be made in a crescent or semi-circular form along the middle of the leaflet section to provide an opening 1230 and a definition of two leaflets, such as the anterior leaflet 1202A and the posterior leaflet 1202P, as shown in fig. 12.

Fig. 12 schematically illustrates an opening formed along a leaflet portion, according to some embodiments of the present disclosure. In some embodiments, an opening or aperture 1230 can be formed (e.g., cut) in the single piece of material 1210, and the two

leaflets

1202A and 1202P can be formed on opposite sides of the opening 1230. Once the aperture 1230 has been formed by cutting the single piece of material 1210, two leaflets, e.g., the anterior leaflet 1202A and the posterior leaflet 1202P, may be in the form of a flap that folds into the aperture 1230, thus creating a unidirectional flow of blood further through the aperture 1230, i.e., from the left atrium to the left ventricle of the heart.

Fig. 13 schematically illustrates an echocardiogram or MRI scan of a left cardiac chamber or ventricle of a patient according to some embodiments of the present disclosure. In some embodiments, the left ventricle 1500 of the patient may be imaged or scanned by echocardiography, CT, or MRI, or other imaging techniques. Such an image or scan of the left ventricle 1500 may provide a desired precise or substantially precise length of the patient's umbilical cord, from the tip of the papillary muscle 1520 to the

leaflets

1502A and 1502P. This enables the manufacture of a customized prosthetic mitral valve according to the anatomical and physiological requirements of the patient.

Fig. 14A-14B are schematic illustrations of a patient's left ventricle in diastole and systole, respectively, according to some embodiments of the present disclosure. In some embodiments, as shown in fig. 14B, the left ventricle in systole, i.e., left ventricle 1610, may comprise an annulus diameter 1640 that is smaller than an annulus diameter 1650 of the left ventricle 1612 in diastole as shown in fig. 14A. When blood flows into the left ventricle during diastole, the left ventricle 1612 may become filled with blood, and thus the annulus diameter 1650 becomes larger. After blood flows from the left ventricle to the patient's bodily blood system to reach the organ, the blood exits the left ventricle 1610 during systole. Thus, the volume of the left ventricle 1610 in systole is smaller than the volume of the left ventricle 1612 in diastole, which results in a smaller annulus diameter 1640 in systole compared to annulus diameter 1650 in diastole.

Since the valve annuli and

leaflets

1502A and 1502P need to achieve flexibility as they repeatedly change diameter and size in the recurring phases of heart function (i.e., systole and diastole), it should be clear that the valve annuli and leaflets are desirably made of a resilient material, just like the tissue from which the native mitral valve is made. Thus, a prosthesis is disclosed that is devoid of a stent, devoid of a metal ring, and devoid of a rigid material, and a certain amount of compliance and resilience is required to select the materials used to fabricate the

leaflets

1502A and 1502P and the ring.

Fig. 15A-15B are schematic views of extensions attached to the anterior and posterior leaflets, respectively, according to some embodiments of the present disclosure. In some embodiments, as shown in fig. 15A, the anterior leaflet 1202A can include an extension 1703 that includes additional material to enlarge the size of the anterior leaflet 1202A. The extension 1703 has dimensions of a length of about 1-5mm and a width that is approximately the width of the cut that forms the anterior leaflet (e.g., cut 1220 of fig. 11). In some embodiments, the extension 1703 is sutured to the edge of the anterior leaflet 1202A at one end (see the incision 1220 of fig. 11), and will include an umbilical 1704 at the other end, which may be similar to the

umbilicals

604, 606 of fig. 6A.

As shown in fig. 15B, the posterior leaflet 1202P can include an extension 1709 that includes additional material to enlarge the size of the anterior leaflet 1202P. The extension 1709 has dimensions of a length of about 1-5mm and a width that is approximately the width of the cut that forms the anterior leaflet (e.g., cut 1220 of fig. 11). In some embodiments, the extension 1709 is sutured to the edge of the anterior leaflet 1202P at one end (see incision 1220 of fig. 11), and will include an umbilical 1708 at the other end that may be similar to the

umbilicals

608, 610 of fig. 6A.

As shown in fig. 15B, the posterior leaflet 1202P has an extension 1709 attached at one end (leaflet end) and an umbilical 1708 attached at the other end. Umbilical 1708 is connected to extension 109 at one end and to cap 1870 at the other end, which may be similar in structure to the cap described in connection with fig. 7A. The anterior leaflet 1202A has an extension 1703 attached at one end (leaflet end) and an umbilical 1704 attached at the other end. Umbilical 1704 is connected at one end to extension 1703 and at the other end to cap 1870, which may be similar in structure to the cap described in connection with fig. 7A.

Each of the

umbilicals

1704 and 1708 may include several umbilicals, also described herein as primary umbilicals, e.g., four primary umbilicals, although any other number of umbilicals may be implemented according to the specific requirements of each patient. In some embodiments, the umbilical may also include a secondary umbilical (not shown) as described above.

Figures 16A-16B are schematic illustrations of side views of a mitral valve prosthesis having an extension and attached umbilical cord in diastole and systole, respectively, according to some embodiments of the present disclosure. Referring now to fig. 16A, a side view of the mitral valve prosthesis shows the contour of the mitral valve prosthesis when the heart is in diastole, and referring to fig. 16B, a side view of the mitral valve prosthesis when the heart is in diastole. The anterior leaflet 1202A and the posterior leaflet 1202P are spaced a distance from each other to allow blood to flow into the left ventricle through the orifice between the

leaflets

1202A and 1202P. The

extensions

1703, 1709 provide the valve prosthesis with an enhanced coaptation profile. Each of the

leaflets

1202A and 1202P can have an attached

extension

1703, 1709 that provides additional material to the anterior and posterior leaflets, providing the necessary coaptation during systole to prevent backflow of blood into the atrium and to provide support to the left ventricle during systole.

In some embodiments, the extension 1703 and the extension 1709 are prepared to have different dimensions (e.g., length, width, and shape). In some embodiments, the

umbilicals

1704, 1708 may be tied and secured together by suturing prior to attachment to the cap 1870.

Extensions

1703 and 1709 are each configured to carry a respective umbilical cord (1704, 1708) that is similar to that of a native heart valve and should be inserted into the heart cavity and attached to the heart wall muscle or papillary muscle. For example, extension 1703 may carry an umbilical cord or umbilical cord set 1704, while extension 1709 may carry an umbilical cord or umbilical cord set 1708. Each of the at least two umbilicals may be connected at another end (opposite the end connected to each extension) to a cap 1870 configured to attach the valve to the papillary muscle.

In some embodiments, during diastole, as shown in fig. 16A, the

leaflets

1202A and 1202P and

respective extensions

1703 and 1709 are at a distance from each other to enable blood to flow in one direction from the left atrium to the left ventricle.

In some embodiments, during systole, as shown in fig. 16B, the

leaflets

1202A and 1202P and their

respective extensions

1703 and 1709 are in close proximity to each other to prevent backflow or leakage of blood in the opposite direction (i.e., from the left ventricle to the left atrium). According to some embodiments, the extensions (e.g., extensions 1703 and 1709) provide the necessary coaptation or closure of the valve to prevent leakage of blood from the left ventricle back into the left atrium.

According to some embodiments, the extensions can be cut to fit the leaflet edges and measure different widths of no less than 5mm to ensure adequate coaptation. The extension will be attached to the leaflet by suturing, gluing, stapling or otherwise attaching to the leaflet edge.

According to some embodiments, the umbilicals (e.g., umbilicals 1704 and 1708) may be attached separately, e.g., sutured to the ventricular wall or to the papillary muscles, or may be bundled together, e.g., in pairs, quadrants, and so forth, depending on the design determined to be optimal for a particular patient.

According to some embodiments, the umbilical may be asymmetric. That is, the umbilical cord may vary in size because the left ventricle has two papillary muscles, and the umbilical cord resulting from various points of leaflet extension may include different lengths and distances from the top edges of these muscles. Thus, each cord or bundle may have a different length that is personalized compared to the other cords or bundles. This will ensure a perfect closure and a sufficient coaptation length of the prosthetic valve.

In some embodiments, the umbilical cords (e.g., umbilical cords 1704 and 1708) generated from leaflet extensions (e.g.,

extensions

1703 and 1709, respectively) may be distributed along the edges of the anterior and posterior leaflet extensions to evenly distribute tension along the edges of these leaflets as the valve moves in the body, thereby reducing wear of the prosthetic valve.

Fig. 17 is a schematic illustration of attaching an asymmetric flexible ring to the periphery of a valve prosthesis to mimic the native valve annulus, according to some embodiments of the present disclosure. According to some embodiments, the flexible loop 1901 may be formed by rolling a piece of elongated material onto itself and closing it into a loop, or by rolling a piece of material with a hole in the middle onto itself, toward the outside of the material. In some embodiments, the crimp ring 1901 may be attached to the periphery of the mitral valve prosthesis 1200 to allow surgical attachment, e.g., suturing, to the annulus of the patient to allow for better rigidity of the annulus and provide better elasticity in the cardiac cycle that varies between systolic and diastolic phases with the use of elastic materials. The crimp ring 1901 may fit around the periphery of the initially severed valve 1200 (fig. 10).

According to some embodiments, the outer ring reinforcement 1901 may be made of an elastic material comprising a variable elasticity to allow variable expansion and contraction of the prosthetic valve in diastole and systole, respectively, of the heart cycle. In some embodiments, the elasticity of the ring 1901 may be derived from a continuous study of the patient's native valve annulus motion based on a 3D echocardiographic study.

In some embodiments, the stiffener ring 19010 can be exposed to the blood environment within the heart, or can be rolled into a sandwich to enclose an elastic material, which can be made of the same material as the leaflets surrounding it.

As shown in fig. 17, the prosthetic valve 1200 can include

umbilicals

1704 and 1706, which can be attached to the anterior leaflet 1202A (with or without an extension), and

umbilicals

1708 and 1710, which umbilicals 1708 and 1710 can be attached to the posterior leaflet 1202P (with or without an extension). As shown in fig. 16A-16B, the umbilical cord may be attached to at least two caps configured to attach the valve 1200 to the papillary muscles of the heart, thereby enabling the mitral valve prosthetic valve 1200 to be properly attached to the left ventricle of a patient, depending on the particular anatomical and physiological requirements of the particular patient.

Fig. 18A-18B are schematic views of an elastic material inserted into a rolling valve annulus before and after the annulus is rolled thereon, respectively, according to some embodiments of the present disclosure. According to some embodiments, as shown in fig. 18A-18B, valve ring 2201 may include the addition of elastic material 2205, the elastic material 2205 being insertable into ring 2201 such that ring 2201 rolls over elastic material 2205 and elastic material 2205 "clips" into ring 2201. The addition of elastic material 2205 within ring 2201 serves to provide additional elasticity to ring 2201, which may help to better simulate the elastic properties of a native mitral valve. In some embodiments, the elastic material 2205 may be rubber or any other biocompatible synthetic material. In some embodiments, the shape of the elastic material 2205 is similar to the shape of the ring 2201 into which it is inserted, so that the elastic material 2205 can be easily inserted into the ring 2201.

According to some embodiments, as shown in fig. 18B, a ring 2201 (which may be made of the same material as the leaflets or may be made of an alternative material extension attached to the outer edges of the leaflets) may be rolled over the resilient material 2205 toward the inside of the synthetic valve, e.g., toward a cut 2220, which cut 2220 may be made along the middle of the leaflet portion, in a crescent or semi-circular shape, so as to provide an opening between the two leaflets defined by the cut 2220, e.g., an anterior leaflet 2202A and a posterior leaflet 2202P. Incision 2220 is actually the actual mitral valve prosthesis orifice through which blood flows from the left atrium to the left ventricle. Thus, the outer edge of the mitral valve prosthesis can include the ring 2201, and then attached to the ring 2201 are the major surfaces of the leaflets, e.g., leaflets 2201A and 2202P, which are then connected to papillary muscles by the cap 2270 via the umbilical cord (e.g., umbilical cord 2204).

Fig. 19 is a schematic flow diagram illustrating a method for manufacturing a mitral valve prosthesis according to some embodiments of the present disclosure. According to some embodiments, method 2000 for manufacturing a mitral valve prosthesis customized for each patient may include an operation 2002, which may include measuring a size and shape of a patient's mitral valve by an imaging method. The imaging method to measure the shape and size of the mitral valve of a particular patient can be echocardiography, cardiac CT, cardiac MRI, and any other imaging method. The method 2000 may also include an operation 2004 of cutting a replica of the patient's mitral valve from a single sheet of material at a ratio of 1. In some embodiments, the method 2000 can include an operation 2006 of cutting a cut along a single sheet of material, thereby creating an aperture for blood flow and creating two leaflets, one on each side of the aperture. Method 2000 may include an operation 2008 of measuring a desired umbilical cord length by an imaging method, which may be similar to the imaging method of measuring mitral valve shape and size in operation 2002.

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

In some embodiments, the method 2000 may include an operation 2012, which may include attaching a flexible ring to the leaflets, thereby creating an overall mitral valve prosthesis that simulates the native mitral valve of each particular patient.

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

In accordance with embodiments of the present disclosure, a motivation for implementing methods for manufacturing personalized naturally designed mitral valve prostheses is that it is expected that the valves will last longer than current valve prostheses, as the personalized valves are manufactured to fit the precise anatomical dimensions and limitations of each patient. A personalized prosthesis will provide better service than any of the best quality prostheses, as it is patient-fitted, allowing superior hemodynamic performance and faster or better cardiac recovery after prosthesis delivery.

Reference is made to fig. 20A, which is a schematic diagram illustrating a method 2020 for manufacturing a personalized mitral valve prosthesis, according to some embodiments of the present disclosure. According to method 2020, valve prostheses are not off-the-shelf products in current practice. In contrast, after ordering the personalized mitral valve prosthesis in operation 2022, the remote diagnostic imaging scan performed in operation 2024 may be used as a basis for the personalized mitral valve prosthesis dimensions in operation 2026, thereby manufacturing a more accurate personalized valve prosthesis for the individual patient in operation 2028. In some embodiments, the method 2020 may include packaging and transporting the personalized, naturally designed mitral valve prosthesis for implantation in a particular patient in operation 2030. In some embodiments, the scan is performed in a very short time before manufacture 2028 in order to enable the personalized mitral valve prosthesis to be fully compatible with the patient.

Reference is now made to fig. 20B, which is a schematic flow chart illustrating a method 2040 for manufacturing a personalized mitral valve prosthesis, according to some embodiments of the present disclosure. Method 2040 is similar to method 2020, but may include different operations. In some embodiments, the method 2040 may include an operation 2042, which may include measuring the size and shape of the native mitral valve of the patient by an imaging method. The diagnostic imaging technique may be, but is not limited to, current imaging techniques including 2D and 3D echocardiography, computed Tomography (CT), or Cardiac Magnetic Resonance (CMR).

In some embodiments, method 2040 may further include an operation 2044, which may include calculating the geometry and dimensions of the annular ring, leaflets, and umbilical cord of the mitral valve prosthesis for each particular patient based on a validated algorithm. Validated algorithms, such as calculations to help define the mitral prosthesis size appropriate for each particular patient, are described in more detail below.

In some embodiments, method 2040 may include an operation 2046, which operation 2046 may include cutting and connecting all portions of the personalized prosthetic mitral valve based on the calculations, i.e., the annular ring, leaflets, and umbilical cord, which may be done according to the patient-specific anatomy and personal physiology of each patient, thereby forming a personalized mitral valve prosthesis.

In some embodiments, method 2040 may include an operation 2048, which may include implanting the personalized prosthetic mitral valve in a heart of a patient for which a personalized mitral valve prosthesis has been manufactured.

Reference is now made to fig. 21A-21B, which illustrate schematic illustrations of an annular valve edge remaining when a native mitral valve is removed in clinical practice, and a schematic illustration of an elliptical annulus model, with AL-PM diameter as the major axis and a-P diameter as the minor axis, respectively, for calculating an annular Annulus Circumference (AC) of a valvular prosthesis, according to some embodiments of the present disclosure.

In some embodiments, the following abbreviations are used for mitral valve prosthetic annulus components:

the Mitral Annulus (MA);

annular ring perimeter (AC);

anterior-posterior diameter (A-P);

anterolateral-posteromedial diameter (AL-PM);

commissure diameter (C-C); and

an Annular Area (AA).

Mitral prosthetic annulus:

according to some embodiments, a personalized mitral valve prosthesis of the present disclosure includes a flexible annular ring sized to match a patient's native mitral annulus. In accordance with the present disclosure, mitral valve prostheses may be individualized or personalized based on the following features.

The first feature is that the annular ring of the prosthesis is manufactured without any rigid frame constraints and is therefore compatible with the mitral annulus of the patient.

The second feature is that the circumferential size of the prosthetic annular ring is personalized based on the diagnostic imaging results of a particular patient, e.g., as performed in operation 2022 of fig. 20B. In some embodiments, the size of the prosthetic annular ring is calculated as a function of the anterior-posterior diameter (A-P) shown in FIG. 21A and the anterolateral-posterior-medial diameter (AL-PM) shown in FIG. 21A at closure of the mitral valve during left ventricular systole.

The third feature is that the annular valve rim is retained when the native mitral valve is removed in clinical practice (fig. 21A), and the annular ring of the prosthesis is sutured to the native valve rim; in other words, on the necked native annulus. The toroidal ring size of the personalized prosthesis in terms of the toroidal ring circumference (AC) can be calculated according to equation (i):

(i) AC = f (A-P diameter, AL-PM diameter, d)

Thereby it is possible to provide

The A-P diameter is the anterior-posterior diameter;

AL-PM diameter is anterolateral to posteromedial diameter; and

d is the width of the annular ring edge.

Calculate AC (1) of the valve prosthesis using an approximation formula derived from an elliptical annulus with AL-PM diameter as the major axis and a-P diameter as the minor axis (fig. 21B) based on equation (ii):

(ii)

in some embodiments, further adjustment of the annular ring circumference (AC) of the mitral valve prosthesis is required as compared to the native annulus of the patient, and such adjustment is generally referred to as reducing the size of the annular ring circumference (AC). In these cases, the annular ring of the mitral valve prosthesis may serve as an annuloplasty treatment of the dilated annulus of some patients suffering from such problems. In one aspect, the proportion of AC reduction may be in the range of 0% to 20%, and the actual value may preferably be determined by existing clinical diagnostics, or simply, more practically, by mathematical models established by big data analysis or based on comparison with healthy population Body Surface Area (BSA) index values. On the other hand, when a new valve prosthesis improves leaflet engagement, the tendency of the annulus to remodel after prosthesis implantation also needs to be reduced by AC; thus, the rate of reduction (λ) also depends on the potential for cardiac recovery of the patient. In summary, AC (2) of the mitral valve prosthesis, i.e. a more accurate value of the annular circumference of the personalized mitral valve prosthesis, can be calculated according to equation (iii):

(iii)

where λ is the rate of decrease of AC (from the natural annular ring perimeter to the annular ring of the personalized prosthesis).

According to some embodiments, when AC reduction is desired, a ring folding technique may be used. The annular fold may be a uniform annular fold along the annulus, rather than a partial annular fold typically performed during annuloplasty. Annular folding according to embodiments of the present disclosure may be more focused on the posterior leaflet annulus due to the fact that the posterior leaflet occupies a larger portion of the entire mitral valve circumference. In addition, the posterior annulus of the human heart lacks a fibrous skeleton, which is susceptible to dilation, symmetry, or asymmetry, which can dilate the annulus, leading to leaflet prolapse and leakage.

The fourth feature may be based on the fact that: a mitral valve prosthesis according to the present disclosure refers to a prosthetic valve that includes two leaflets consisting of an anterior leaflet 2210 (fig. 22A) and a posterior leaflet 2220 (fig. 22B). Thus, the annular ring of the valve prosthesis may also comprise two parts: the anterior and posterior annulus. The top edges of the anterior and posterior leaflets can be joined together in an anterolateral-to-anterolateral and posteromedial-to-posteromedial direction to form an annular ring 2230 of the mitral valve prosthesis (fig. 22C). That is, the antero-lateral side of anterior leaflet 2210 is attached to the antero-lateral side of posterior leaflet 2220, and the postero-medial side of anterior leaflet 2210 is attached to the postero-medial side of posterior leaflet 2220.

Annular ring 2230 may have a reinforcing structure and be made of multiple layers of leaflet material. The height of the annular ring 2230 may be in the range of 1mm to 4mm, and more preferably may be in the range of 2mm to 3mm, which may allow a clinician to suture the annulus to the mitral annulus of a patient's heart. The number of layers may be two to four by folding or overlapping the top edges of the anterior and posterior leaflets over themselves. In some embodiments, the annular ring can include surgical sutures 2316 for reinforcing the annular ring.

The mitral valve prosthesis of the present disclosure may have an asymmetric annular ring formed by the combination of the anterior and posterior valve annuli, which are reinforced top edges of the leaflets. An example of such an asymmetric annular ring is shown in fig. 22A and 22B, where the anterior leaflet annular perimeter (AAC) 2212 is smaller than the posterior leaflet annular Perimeter (PAC) 2222, and the ratio (R) of AAC/PAC may be in the range of 49/51 to 30/70, more preferably from 35/65 to 42/58. The anterior leaflet ring circumference (AAC) 2212 and the posterior leaflet ring circumference (PAC) 2222 may be calculated according to equations (iv) and (v), respectively:

(iv)

(v)

reference is now made to fig. 22D and 22E-22F, which illustrate an annulus model indicating two papillary muscles, and customized anterior and posterior leaflet models, respectively. In some embodiments, the anterior leaflet annular perimeter (AAC) and the posterior leaflet annular Perimeter (PAC) may be defined by using the new stitch positions a and B shown in fig. 22D. The new suture positions a and B may be selected based on the position of each of the two papillary muscles PM1 and PM2, which may define an anterior leaflet, such as anterior leaflet 602A (fig. 6A) and a posterior leaflet, such as posterior leaflet 602P (fig. 6A) between which AAC and PAC are determined. In some embodiments, when the umbilical cord is sutured to the papillary muscles PM1 and PM2, the valve umbilical cord (e.g.,

umbilical cords

604, 606, 608, 610 (fig. 6A)), the anterior and posterior leaflets that can be manufactured based on the new suture locations a and B, cause less deformation after implantation than prosthetic valves based on other suture locations (e.g., along the annulus). In some embodiments, fig. 22E-22F illustrate the anterior and posterior leaflet models after the new suture locations a and B are implemented. According to the current annuloplasty model, the anterior leaflet annulus perimeter (AAC) may be slightly longer than the posterior leaflet annulus Perimeter (PAC), which may be contrary to the disclosure of fig. 22A-22B, where PAC is longer than AAC. The surface areas of the anterior and posterior leaflets in the current annulus model are similar to each other so they can provide proper leaflet closure under blood pressure.

Mitral valve prosthetic leaflet:

reference is now made to fig. 23C, which is a schematic illustration of the relationship of various parameters that interact when the leaflets of the prosthesis are engaged, according to some embodiments of the present disclosure, and to fig. 24A-24B, which are schematic illustrations of a side view and a perspective view, respectively, of mitral valve leaflet engagement, according to some embodiments of the present disclosure. According to some embodiments, a mitral valve prosthesis of the present disclosure can include two flexible membranous leaflets that hang 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, allowing blood flow through the heart in one direction without regurgitation through the valve during the systolic cycle. The size of the two leaflets is critical to ensure proper opening and closing of the prosthetic valve.

For a healthy mitral valve, the valve prosthesis can be customized with the leaflet length replicated from the diagnostic imaging results. However, for patients with mitral valve dysfunction and need replacement, measurement of anterior leaflet length (La) and posterior leaflet length (Lp) is neither feasible nor useful in new valve prostheses that are individualized or personalized. Conversely, the anterior-posterior diameter (A-P, which may be referred to as A2P 2) may be used as a reference to represent the minimum distance or length of leaflet coaptation. The ratio of the anterior leaflet length to the posterior leaflet length (r) can vary between 1/1 to 2/1 (this is the reference ratio).

In some embodiments, the leaflet length is affected by the coaptation depth (Cd), the coaptation height (CoaptH), and the umbilical cord length (Lc) in addition to the anterior-posterior diameter (AP) and the ratio (r). Thus, the Anterior Leaflet Length (ALL) and the Posterior Leaflet Length (PLL) may be functions of ALL of the above parameters, as shown in equations (vi) and (vii):

(vi) ALL = f (A-P diameter, r, cd, ch, lc)

(vii) PLL = f (A-P diameter, r, cd, ch, lc)

According to some embodiments, when the anterior-posterior diameter (a-P) is less than 28mm, empirical formulas are used to calculate the Anterior Leaflet Length (ALL) and Posterior Leaflet Length (PLL) of the animal model. These formulas proved to be effective in either the porcine or ovine model, showing a low mean transmitral pressure gradient and acceptable leaflet coaptation (figure 24). Equations (viii) and (ix) are as follows:

(viii) ALL = (A-P diameter) ÷ 2+10 (unit: mm)

(ix) PLL = (A-P diameter) ÷ 2+5 (unit: mm)

In some embodiments, the top edges of the anterior and posterior leaflets form a multi-layer reinforced annular ring of the valve prosthesis, such as asymmetric annular ring 2230. The top edges of the leaflets may be straight or curved, i.e., semi-elliptical, so that the finished valve prosthesis more accurately conforms to the natural geometry of the left ventricle. Downward from the annular ring, two commissures, such as commissures 2310 and 2312 (fig. 22C), are formed when the two leaflets come together. The commissures are angled inwardly to slightly taper the body of the valve prosthesis to better conform to the shape and contour of the left ventricle. Angle of inclination (delta) ₀ ) May range between 5 degrees and 20 degrees. Cone angle (delta) ₁ ) From the angle of inclination (delta) of the leaflet commissure edge according to equation (x) ₀ ) Determining:

(x)

according to some embodiments, the angle of inclination (δ) of the two leaflets ₀ ) Equal, so the cone angles (δ) of the two leaflets ₁ ) Are equal.

According to some embodiments, another element of the prosthetic leaflet that should be individualized or personalized is the free edge. Edge-to-edge coaptation between the anterior and posterior leaflets controls the function and performance of the prosthetic valve. Geometrically, the free edge of the leaflet of the invention is semi-elliptical. The length of the free edge can be calculated according to equation (xi):

(xi) Length of free edge = {2 π × | ALL (or PLL) -b-CH × cos δ 0-Coopt H +4a-CH × sin δ 0-ALL or PLL-b-CH × cos δ 0-Coopt H ÷ 2

Where CH represents the length of the commissure edges 2214 and 2216, as shown in fig. 22A and 22B, respectively.

The parameters "a" and "B" are the geometric parameters needed to define and shape the top edge of the anterior or posterior leaflet, which is curved into a semi-elliptical shape with a "major axis and a" B "minor axis, as shown in fig. 23A, or a straight line as shown in fig. 23B.

Fig. 23B is an extreme example, where the top edge of the leaflet is a straight line,

and "b =0", the free edge of the leaflet can be calculated according to equation (xi) as:

length of free edge = {2 π × (ALL (or PLL) -CH × cos (δ 0) -coach H +412AAC (or PAC) -CH × sin δ 0-ALL or PLL-CH × cos δ 0-coach H ÷ 2

According to some embodiments, an improved algorithm for calculating a customized mitral valve prosthesis leaflet length may be provided. Leaflet length is a key factor that affects the effective closing and opening of the valve. In some embodiments of the present disclosure, finite Element Methods (FEMs) may be used to optimize and calculate optimal anterior and posterior leaflet lengths to increase coaptation and reduce valve leakage. In such embodiments, a change in the afferent bovine cardiac package data, or afferent data for any other material from which the prosthetic mitral valve may be made, such as thickness and material properties, is first introduced to calculate a customized valve design. The thickness and material properties, as well as other properties of bovine pericardium or other material, may also affect the manner in which the valve closes and opens.

Reference is now made to fig. 23D, which is a schematic flow chart diagram illustrating a method of custom mitral valve design using FEM. According to some embodiments, the method 2300 may include an operation 2320, which may include providing patient mitral valve-related data, e.g., providing a size and shape of a native mitral valve of a particular patient. Patient mitral valve related data may include, for example, annulus circumference, annulus diameter, papillary muscle position, and the like. The method 2300 may also include an operation 2330, which may include providing afferent bovine pericardial data that is descriptive of material characteristics of the supplied (or afferent) bovine pericardium. In some embodiments, afferent data may be of the material from which the prosthetic mitral valve is made, for example, afferent bovine pericardial data may include, for example, bovine pericardial thickness, tensile test data such as young's modulus, stress-strain curves, and the like.

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

In some embodiments, the method 2300 may optionally include an operation 2350, which may include visualizing the customized prosthetic mitral valve. In some embodiments, method 2300 does not require operation 2350. Operation 2350 may include visualizing a 3D model of the customized prosthetic mitral valve after sizing the prosthetic mitral valve (e.g., the dimensions of the anterior leaflet, the posterior leaflet, the anterior circumference, the posterior circumference, the annulus diameter, the anterior and posterior leaflet heights, the umbilical cord width, etc., performed during operation 2340). In some embodiments, the method 2300 may include an operation 2360 that includes fabricating the prosthetic mitral valve from the constructed 3D model and following the visualization of the model in operation 2350.

In some embodiments, after the customized prosthetic mitral valve design is completed, visualized, and manufactured, method 2300 can include an additional operation 2370 that includes performing a performance verification test, e.g., in vitro hydrodynamic room testing, on the customized prosthetic mitral valve.

According to some embodiments, a customized valve design method may include providing patient mitral valve parameters and incoming bovine cardiac package data according to

operations

2320 and 2330, respectively. An example of such data is provided in table 1 below. In this example, the patient valve commissure diameter is 36mm.

Table 1: patient mitral valve data and afferent bovine pericardial data

Patient mitral valve parameters	Valve [ mm ]]
		Commissure diameter (C-C) (CC)	36.0
Distance offset between PM and annulus centerline (DPM)	6.0
		Distance between two PMs (DBPM)	24.0
Z height from PM to annulus (ZH)	30.0
		Bovine Pericardium Thickness (BPTH)	0.28
Young's modulus of Bovine Pericardium (BPYM)	30.0MPa

In the present method, customized posterior and anterior leaflet parameters tailored to the patient and implemented by FEM parameter optimization according to operation 2340 are provided in table 2 below.

Table 2: customized leaflet parameters

Customized valve leaflet	Valve [ mm ]]
		Commissure diameter C-C (CC)	36.0
Rear ring Perimeter (PAC)	51.6
		Front ring perimeter (AAC)	63.2
Rear leaflet Length (PLL)	25.0
		Front leaflet Length (ALL)	25.0

In some embodiments, anterior Leaflet Length (ALL) and Posterior Leaflet Length (PLL) may be affected by patient mitral valve data (e.g., commissure diameter, papillary muscle distance, etc.) as well as afferent bovine pericardial data (e.g., bovine pericardial thickness and young's modulus). That is, ALL and PLL may be functions of the above parameters and additional parameters, respectively, according to equations (xii) and (xiii):

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

(xiii) PLL = f (CC, DBPM, ZH, BPTH, BPYM, etc.)

Thereby it is possible to provide

CC denotes commissure diameter;

DBPM denotes the distance between papillary muscles;

ZH represents the Z height from papillary muscle to annulus;

BPTH represents bovine pericardial thickness; and

BPYM stands for young's modulus in bovine pericardium.

In some embodiments, empirical formulas may be proposed to calculate Anterior Leaflet Length (ALL) and Posterior Leaflet Length (PLL) for other patients based on the CC 36.0mm FEM-related data described above. The final anterior and posterior leaflet lengths need to be verified by the FEM method. In some embodiments, ALL and PLL may be calculated by equations (xiv) and (xv), respectively:

(xiv)ALL＝(CC*DBPM*ZH*BPTH/BPYM)*α

(xv)PLL＝(CC*DBPM*ZH*BPTH/BPYM)*β

thereby it is possible to provide

α is an anterior leaflet length magnification factor, e.g., 0.1033; and

β is a posterior leaflet length magnification factor, e.g., 0.1033.

Mitral valve prosthesis umbilical cord:

in a normal mitral valve, the umbilical cord is fan-shaped, extending from the papillary muscles and inserted into the leaflets. They are classified into primary, secondary and tertiary umbilicals according to the position where they are attached.

The mitral valve prosthesis of the present disclosure includes only a primary umbilical cord attached to the free edge of the anterior or posterior leaflet. Two groups of umbilicals (FIG. 24A) and three umbilicals in each group (FIG. 24B) are evenly distributed from both ends along 3/8 of the free edge; they are the anterolateral and posteromedial umbilical cords.

The umbilical cord plays an important role in ensuring proper opening and closing of the valvular prosthesis. In contrast to other geometric features of the mitral valve, the umbilical cord, and in particular the length of the umbilical cord, is currently not well studied during clinical pre-diagnosis, especially at each valve replacement. The umbilical cord measurement may be defined as the distance from the apex of the papillary muscle to the plane of the valve annulus, the distance from the apex of the papillary muscle to the commissure edge, or the distance from the apex of the papillary muscle to the valve annulus.

For personalization of the prosthesis umbilical cord length, leaflet length (ALL or PLL), leaflet coaptation height (Coapt H), leaflet coaptation depth (Cd), and distance from the apex of the papillary muscle to the leaflet coaptation edge (Lc) need to be correlated to ensure the function of the complex structure prosthesis. Thus, the length of the Anterolateral Cord (ACL) and the length of the Posteromedial Cord (PCL) can be expressed as a function of a number of parameters according to the following equations (xvi) and (xvii):

(xvi) ACL = f (ALL, coach H, cd, lc (anterolateral))

(xvii) PCL = f (ALL, coach H, cd, lc (posteromedial))

The present disclosure also introduces a simplified method by using the measured distance of the apex of the papillary muscle to the engagement edge as the length of the prosthetic umbilical cord, i.e. ACL = Lc (anterolateral) and PCL = Lc (posteromedial); from a design point of view, the three umbilicals of each group will merge at the free ends and merge into a cotton wool like umbilical cap 2240 (fig. 22A and 22B). The clinician may complete the final portion of the mitral valve prosthesis, personalized or customized, by performing on-site measurements and adjustments. Fig. 25 is a photograph of an echocardiogram of a sheep heart implanted with a personalized, naturally designed mitral valve prosthesis made according to the methods of the present disclosure.

Reference is now made to fig. 26A-26B, which are schematic illustrations of the posterior and anterior leaflets, respectively, showing umbilical cord width and umbilical cord distance, in accordance with an embodiment of the present disclosure. In some embodiments, the umbilical Cord Width (CW) and the umbilical cord distance per posterior leaflet (DCPL) and the umbilical cord distance per anterior leaflet (DCAL) may be determined by FEM methods. For the example with CC of 36.0mm, CW is 3mm for both anterior and posterior leaflets. In some embodiments, the umbilical Cord Width (CW) may be calculated based on the CC 36.0mm valve by equation (xviii):

(xviii)CW＝(CC*DBPM*ZH*BPTH/BPYM)*γ

thereby it is possible to provide

γ represents the umbilical cord width magnification factor, e.g., 0.0124.

In some embodiments, the final cord width needs to be verified by using the FEM method.

According to some embodiments, the posterior leaflet cord Distance (DCPL) and the anterior leaflet cord Distance (DCAL) may depend on the distance between two papillary muscles (DBPM).

Fig. 27 is a schematic diagram of a final customized 3D model of a prosthetic mitral valve including D-shaped annular rings. A 3D model of the prosthetic mitral valve can be constructed based on the patient mitral valve data provided in operation 2320, and can be further based on the incoming bovine cardiac package data provided in operation 2330 of the method 2300.

Fig. 28 is a schematic illustration of FEM simulation optimization results of a customized prosthetic mitral valve model in accordance with operation 2340 of method 2300. Fig. 28 shows a FEM model of a prosthetic mitral valve in a closed configuration. It is clear that the annular ring of the valve model is D-shaped, which resembles the annular ring shape of the native mitral valve.

After visualizing the customized prosthetic mitral valve, as in operation 2350, and after manufacturing the customized prosthetic mitral valve, as in operation 2360, a performance verification test of the customized prosthetic mitral valve may be performed, as in operation 2370. Fig. 29A-29B are schematic views of a prosthetic mitral valve in a hydrodynamic test chamber in open and closed configurations, respectively.

Fig. 30 and 31 are images showing an echocardiogram of a customized prosthetic mitral valve during its closed configuration after implantation in a porcine heart and a blood pressure gradient of the porcine heart after implantation, respectively. The customized prosthetic mitral valve can be closed and opened in a very efficient and effective manner without any leakage. The maximum pressure gradient may be 3.87mmHg and the average pressure gradient may be only 1.61mmHg, similar to the pressure experienced by a natural human mitral valve.

The personalized geometries and dimensions discussed above may be used as input to various engineering drawing software or drawing tools.

The drawings may be printed as templates for manually cutting leaflets of the valve prosthesis, for example under a microscope.

The drawing may be programmed into a machining tool, such as a laser cutter, for cutting the leaflets more accurately and efficiently than manual cutting.

The drawings may also be programmed into the machining tool to make a personalized die cutter or die cutter for leaflet cutting at a lower temperature than the laser cutting temperature in order to minimize the thermal influence on the valve prosthesis cutting material.

The mitral valve prosthesis can be formed by joining the annulus and commissure edges of the anterior and posterior leaflets together in an anterolateral-to-anterolateral and posteromedial-to-posteromedial direction (fig. 22C). One way to connect the two leaflets together may be by suturing with a surgical suture, such as suture 2314 in fig. 22C.

The aforementioned valve prosthesis may be further packaged, labeled and sterilized, i.e. implanted in the patient for which the valve prosthesis is manufactured, before being released for use.

For ease of handling, the valve prosthesis described above may be assembled to the valve stent prior to packaging.

The valve prostheses of the present disclosure can be shipped or otherwise transferred as a complete product for individualized implantation of a particular patient.

According to some embodiments, any of the disclosed anterior and posterior leaflets, any annulus, any umbilical cord (and any subset of umbilical cords), any cap, and/or any combination thereof may be produced from natural materials and may avoid inclusion of foreign matter, such as cotton wool. Allograft materials and/or composite materials, including various combinations of allograft, xenograft and/or autograft materials, can further be used to make flexible rings, leaflets, umbilicals and caps. Materials forming the valve annulus and leaflets may include, but are not limited to, human, bovine or porcine pericardium, acellular bioprosthetic materials, woven biodegradable polymers that bind to cells, and extracellular materials. Biodegradable natural polymers may include, but are not limited to, fibrin, collagen, chitosan, gelatin, hyaluronic acid, and the like. Biodegradable synthetic polymer scaffolds that can be infiltrated with cells and extracellular matrix materials can include, but are not limited to, poly (L-lactide), polyglycolide, poly (lactic-co-glycolic acid), poly (caprolactone), polyorthoesters, poly (dioxanone), poly (anhydride), poly (trimethylene carbonate), polyphosphazene, and the like. The flexible ring can be further customized to provide personalized flexibility or rigidity to the patient. In addition, some components of the mitral valve prosthesis, including the umbilical cord, may be intraoperatively formed from the patient's autologous pericardium.

According to some embodiments, any of the disclosed asymmetric flexible rings, which may include a forward ring portion and a rearward ring portion or may be made as a single unit, may be formed by rolling or folding the edges of the leaflets onto themselves. In other embodiments, the flexible ring may further comprise at least two strands or layers of material, such as a human, bovine, or porcine pericardium, or any of the materials listed above, whereby the at least two strands or layers may be coiled, twisted, braided, or wrapped around one another. A loop constructed in a coiled coil may include greater strength than a loop formed by merely rolling the edges of the leaflets onto itself, however, the coiled loop should retain its elasticity.

According to some embodiments, the loop may include two strands or layers of material folded together to provide elasticity, and a third layer added to provide structural stability. In some embodiments, the annulus may include two layers made of bovine pericardium, while the third strand or layer may be made of glycine or proline to provide strength to the annulus.

In some embodiments, at least two layers or strands may be attached, e.g., sewn to each other. In some embodiments, the third layer may be attached, e.g., sewn, to at least two layers of the ring.

According to some embodiments, the components of the prosthetic mitral valve may be attached or connected to each other by several connection methods. For example, components of the prosthetic mitral valve may be connected to each other by sutures, staples, glue, or any other attachment means.

In some embodiments, the suture or suture may be made of a non-biodegradable synthetic material, such as nylon (ethilon), propylene (polypropylene), novalfil, polyester, and the like. In some embodiments, the suture or suture may be made of a natural material that is not biodegradable, such as surgical silk or surgical cotton.

In some embodiments, the staple may be made of a biocompatible material, such as stainless steel or titanium.

In some embodiments, the glue may be made of a biocompatible material, such as an aldehyde-based glue, fibrin sealant, collagen-based adhesive, polyethylene glycol polymer (hydrogel), or cyanoacrylate.

According to some embodiments, any leaflet, any ring, any umbilical cord (and any subset of umbilical cords), and/or any combination thereof may be customized for each patient based on ultrasound imaging and the surrounding anatomy of the patient's native mitral valve. The customized mitral valve can also be produced based on data obtained from other imaging modalities that provide three-dimensional information, including echocardiography, cardiac CT, and cardiac MRI. Accordingly, the mitral valve prosthesis of the present disclosure may be selected or designed to match a particular anatomy of a patient, thereby increasing the chances of high acceptance of the prosthesis by the patient's surrounding tissue (e.g., the myocardium surrounding the prosthesis).

In preparation for implantation into a patient, the patient's heart is stopped, which is common in mitral valve surgery. During implantation, the flexible ring of the prosthesis is secured to the native annulus by sutures, while the papillary caps are sutured to the native papillary muscles. For example, two sutures can be applied at the tip of each native papillary muscle to secure the cap to the muscle. The clinician ensures that the valve will fully open and close by filling the ventricular chamber with saline under the appropriate pressure and checking the movement and ability of the replacement valve when closed by the application of pressure. After implantation, after the heart has closed and resumed beating, the valve is examined with transesophageal echocardiography (TEE).

If necessary, the subject may be placed on an anticoagulant drug after implantation. In view of the natural shape and natural materials used to construct the mitral valve prosthesis of the present invention, low doses of anticoagulant medication or no anticoagulant medication are contemplated for most patients.

Currently available biological and mechanical prostheses have several drawbacks: they contain bulky foreign bodies, require potent anticoagulants, have a short life span, require subsequent surgery when the patient must be replaced, and do not help with effective recovery after cardiac implantation. The present invention provides several advantages over the biological and mechanical prostheses described above. The described mitral valve prosthesis design is more closely matched to the patient's native mitral valve and is made of native materials, and is expected to require less patient recovery time, provide longer service life, and alleviate or eliminate the need for anticoagulant drugs.

The teachings of all patents, published applications and references cited herein are incorporated by reference in their entirety.

While the present invention has been particularly shown and described with reference to exemplary 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 encompassed by the appended claims.

Claims

1. A method for manufacturing a personalized naturally designed mitral valve prosthesis to precisely fit a particular patient for whom the valve prosthesis is manufactured, the method comprising:

measuring the size and shape of the native mitral valve of the particular patient by using an imaging device;

providing data on the material from which the personalized mitral valve prosthesis is manufactured;

constructing a 3D model of the personalized mitral valve prosthesis based on the size and shape of the native mitral valve of the particular patient and the data of the material;

optimizing the 3D model using a FEM method;

and

fabricating the personalized mitral valve prosthesis based on the optimized FEM model.

2. The method of claim 1, further comprising visualizing the personalized mitral valve prosthesis model after the optimization operation.

3. The method of claim 1 or 2, wherein the imaging device comprises: 2D or 3D echocardiography, computed Tomography (CT), cardiac Magnetic Resonance (CMR), or any combination thereof.

4. The method of any of claims 1-3, wherein measuring the size and shape of the native mitral valve of the patient comprises measuring mitral-valve-related parameters, comprising: annular ring circumference (AC), annulus Area (AA), anterior-posterior (A-P) diameter, anterolateral-posteromedial (AL-PM) diameter, commissure diameter (C-C), anterior leaflet length (AL), posterior leaflet length (PL), mitral valve shape, and chordae tendineae length (ACL and PCL).

5. The method of any of the preceding claims, further comprising collecting physical information of the particular patient to predict a geometry of a heart after implantation of the personalized mitral valve prosthesis, the physical information comprising: height, weight, age, race and gender.

6. A personalized mitral valve prosthesis comprising a flexible annular ring sized to match a native mitral annulus of a particular patient, a flexible anterior leaflet and a flexible posterior leaflet sized to match a native mitral leaflet of the particular patient, the leaflets being connected to the annular ring, and an umbilical cord sized to match a native mitral leaflet of the particular patient, the umbilical cord being connected to the flexible anterior leaflet and the flexible posterior leaflet, the umbilical cord being further configured to connect the flexible anterior leaflet and the flexible posterior leaflet with papillary muscles of the heart, the personalized mitral valve prosthesis being formed by:

optimizing the 3D model using a FEM method; and

fabricating the personalized mitral valve prosthesis based on the optimized FEM model by cutting the material into the annular ring, the flexible anterior and posterior leaflets, and the umbilical cord and attaching the flexible anterior and posterior leaflets to the annular ring, and the umbilical cord to the flexible anterior and posterior leaflets.

7. The personalized mitral valve prosthesis of claim 6, wherein the personalized mitral valve prosthesis is further formable by visualizing the personalized mitral valve prosthesis model after the optimization operation.

8. The personalized mitral valve prosthesis of claim 6 or 7, wherein the imaging device comprises: 2D or 3D echocardiography, computed Tomography (CT), cardiac Magnetic Resonance (CMR), or any combination thereof.

9. The personalized mitral valve prosthesis of any of claims 6-8, wherein measuring the size and shape of the patient's mitral valve comprises measuring mitral valve-related parameters, comprising: annular ring circumference (AC), annulus Area (AA), anterior-posterior (A-P) diameter, anterolateral-posteromedial (AL-PM) diameter, commissure diameter (C-C), anterior Leaflet Length (ALL), posterior Leaflet Length (PLL), mitral valve shape, and chordae tendineae length (ACL and PCL).

10. The personalized mitral valve prosthesis of any of claims 6-9, further comprising collecting physical information of the particular patient to predict a geometry of a heart after implantation of the personalized mitral valve prosthesis, the physical information comprising: height, weight, age, race and gender.

11. The personalized mitral valve prosthesis of claim 9, wherein the measuring comprises measuring the annular ring perimeter (AC) as a combination of anterior leaflet annular ring perimeter (AAC), which is a top edge of the anterior leaflet, and posterior leaflet annular ring Perimeter (PAC), which is a top edge of the posterior leaflet, based on equation (iii):

further wherein the annular ring forms a multi-layered reinforcement structure by folding or overlapping a top edge of each of the anterior and posterior leaflets.

12. The personalized mitral valve prosthesis of claim 11, wherein a top edge of each of the anterior and posterior leaflets is straight or curved to properly fit the natural geometry of the left ventricle of the particular patient.

13. The personalized mitral valve prosthesis of claim 11, wherein connecting comprises connecting an edge of the anterior leaflet with an edge of the posterior leaflet to form a commissure between the anterior leaflet and the posterior leaflet.

14. The personalized mitral valve prosthesis of any of claims 6-13, wherein connecting comprises connecting the flexible anterior leaflet and the flexible posterior leaflet together to form two commissures, wherein the two commissures are at a taper angle (δ) ₁ ) The mitral valve prosthesis is angled inward to form a cone-shaped personalized mitral valve prosthesis to fit the native left ventricle of the particular patient.

15. The personalized mitral valve prosthesis of claim 14, wherein the taper angle (δ) ₁ ) An angle of inclination (δ) by each commissure edge of the flexible anterior leaflet and the flexible posterior leaflet based on equation (x) ₀ ) Determining:

16. the personalized mitral valve prosthesis of any of claims 6-15, wherein connecting comprises connecting the anterior leaflet to the posterior leaflet by connecting an antero-lateral side to an antero-lateral side and a posterior medial side to a posterior medial side.

17. The personalized mitral valve prosthesis of claim 16, wherein connecting the anterior leaflet to the posterior leaflet comprises suturing.

18. The personalized mitral valve prosthesis of claim 13, wherein the measuring comprises measuring: based on equation (xi), the size and shape of the natural annular ring, commissure Height (CH), inclination angle (δ) of the particular patient ₀ ) Anterior Leaflet Length (ALL) and Posterior Leaflet Length (PLL), and coaptation height (CoaptH) used to calculate the length of each leaflet edge:

the length of the free edge = {2 π × (ALL (or PLL) -CH × cos (δ 0) -Cooapt H +412AAC (or PAC) -CH × sin δ 0-ALL or PLL-CH × cos δ 0-CoaptH ÷ 2.

19. The personalized mitral valve prosthesis of any of claims 11-13, wherein the height of the reinforcing annular ring is between 1mm and 4 mm.

20. The personalized mitral valve prosthesis of any of claims 11-13, wherein the height of the reinforcing annular ring is between 2mm and 3mm.

21. The personalized mitral valve prosthesis of any of claims 11-13, wherein the annular ring circumference (AC) is a function of an anterior-posterior diameter (a-P) and an anterolateral-posterior-medial diameter (AL-PM) based on equation (iii).

22. The personalized mitral valve prosthesis of claim 21, wherein measuring comprises measuring the anterior-posterior diameter (a-P) and the anterolateral-posterior-medial diameter (AL-PM) when the mitral valve is closed during contraction of the left ventricle.

23. The personalized mitral valve prosthesis of any of claims 11-13, wherein the annular ring circumference (AC) of the prosthesis is calculated according to the ratio (λ) in equation (iii).

24. The personalized mitral valve prosthesis of claim 6, wherein the annular ring is asymmetric, and further wherein the annular ring is formed by a combination of an anterior leaflet annulus and a posterior leaflet annulus, wherein an anterior leaflet annular perimeter (AAC) is less than a posterior leaflet annular Perimeter (PAC), and a ratio (R) between AAC/PAC is between 49/51 and 30/70.

25. The personalized mitral valve prosthesis of claim 24, wherein a ratio (R) between AAC/PAC is between 35/65 and 42/58.

26. The personalized mitral valve prosthesis of claim 24, wherein the ratio (R) between AAC/PAC is 40/60.

27. The personalized mitral valve prosthesis of claim 24, wherein the ratio (R) between AAC/PAC is between Anterior Leaflet Length (ALL) and Posterior Leaflet Length (PLL).

28. The personalized mitral valve prosthesis of any of claims 6-27, wherein constructing a 3D model of the personalized mitral valve prosthesis comprises calculating an anterior leaflet annular perimeter (AAC) and a posterior leaflet annular Perimeter (PAC) based on suture positions a and B.

29. The personalized mitral valve prosthesis of claim 18, wherein constructing a 3D model of the personalized mitral valve prosthesis comprises based on equations (viii) and (ix) based on: (ii) an anterior-posterior diameter (a-P) as a theoretical minimum engagement distance; (b) a ratio (r) between ALL and PLL; (c) a bonding depth (Cd); (d) a bond height (CoaptH); and (e) umbilical cord length (Lc) to calculate the Anterior Leaflet Length (ALL) and Posterior Leaflet Length (PLL):

ALL = (A-P diameter) ÷ 2+10 (unit: mm)

PLL = (A-P diameter) ÷ 2+5 (units: mm).

30. The personalized mitral valve prosthesis of any one of claims 6-29, wherein connecting comprises connecting the anterior leaflet and the posterior leaflet together to form a body of the personalized mitral valve prosthesis.

31. The personalized mitral valve prosthesis of any of claims 6-30, wherein the each anterior leaflet and the each posterior leaflet comprise two sets of umbilicals: anterolateral and posteromedial umbilical cords, wherein each of the anterolateral and posteromedial umbilical cords comprises three sub-umbilical cords, wherein the umbilical cords are evenly distributed along at least 3/8 of each edge from each side.

32. The personalized mitral valve prosthesis of claim 31, wherein constructing the 3D model comprises calculating a length of each umbilical cord, wherein calculating the length of each umbilical cord is based on parameters comprising: leaflet length, coaptation height, and coaptation depth.

33. The personalized mitral valve prosthesis of any of claims 6-32, wherein measuring comprises measuring a distance from papillary muscle apex to junction edge to represent the prosthetic umbilical cord length, further comprising measuring in situ and adjusting a cotton-wool umbilical cap to where the umbilical cords are integrated and merged at the ends of each set of umbilical cords.

34. The personalized mitral valve prosthesis of any of claims 6-33, wherein constructing the 3D model comprises providing each particular patient with calculated geometries and dimensions of the annular ring, the anterior leaflet, the posterior leaflet, and the umbilical cord as input for engineering mapping software or mapping tools.

35. The personalized mitral valve prosthesis of claim 34, wherein the engineering mapping software or mapping tool outputs a template for manually cutting leaflets of the valve prosthesis.

36. The personalized mitral valve prosthesis of claim 34, wherein the engineering mapping software or mapping tool outputs a template for machine cutting the leaflet.

37. The personalized mitral valve prosthesis of any of claims 6-36, further comprising packaging, labeling, and sterilizing the personalized mitral valve prosthesis prior to release for use.

38. The personalized mitral valve prosthesis of any of claims 6-37, further comprising assembling the personalized mitral valve prosthesis onto a valve holder prior to packaging.

39. The personalized mitral valve prosthesis of any of claims 6-38, further comprising implanting the personalized mitral valve prosthesis in the particular patient.