CN115515536A - Method for manufacturing personalized naturally designed mitral valve prosthesis - Google Patents

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

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

Background technique

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

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

Biological and mechanical mitral valve prostheses are commercially available. Both bioprostheses and mechanical prostheses have rigid circular shapes compared to the soft tissue and asymmetric shape of the human mitral valve. Another disadvantage of mechanical valves is that blood tends to clot on the mechanical parts of the valve and cause the valve to malfunction. Patients with mechanical valves must take anticoagulants to prevent blood clots from forming on the valve and causing a stroke. Biological valves have a reduced risk of thrombosis compared with mechanical valves, but have more limited durability and need to be replaced more frequently. Like mechanical valves, biological valves consist of a rigid metal framework with metal rings covered with silicon or other synthetic material to allow passage of implant sutures.

Currently available mitral valve prostheses are often built in an unnaturally circular fashion and are often made of rigid materials. They also usually have three symmetrical leaflets, whereas the natural 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 heart muscle around these prostheses does not recover well after implant surgery. The average lifespan of a prosthesis is only 7 to 10 years, which results in a patient needing a second and sometimes a third surgery during their lifetime, a repetition that puts the patient at high risk for open-heart surgery.

Commercially available prostheses cannot match the hemodynamic performance of a healthy native human mitral valve. This results in a massive loss of energy in the left ventricle, with significant strain over time, eventually leading to heart failure and other adverse outcomes.

Some other available mitral valve prostheses can be formed from reinforced homografts, as described in U.S. Patent No. 6,074,417, which means doctors need to scan valves of various sizes to find the best match for each patient, while Sacrifice the animal in which the valve will be removed. As described in US Pat. No. 5,415,667, other useful mitral valve prostheses can be formed by suturing multiple layers of the pericardium to each other, which can result in coagulation in the area where multiple sutures are present.

Other forms of atrioventricular valves, including mitral valves, are disclosed in US Pat. No. 6,358,277, wherein a template of membrane material is sutured to the patient's mitral valve annulus. The valve has a tall, unnaturally shaped annulus that makes the perimeter of the prosthetic valve bulky and raised like a collar. Additionally, templates are provided in standard sizes, which must then be trimmed to fit the patient.

Contents of the invention

A method for manufacturing a personalized, naturally designed mitral valve prosthesis that precisely fits and functions in an individual patient is provided. Specifically, the method consists of a sequence of operations or procedures starting from receipt of a customized/personalized mitral valve prosthesis order, diagnostic imaging and analysis of imaging results, through the use of proven algorithms to quantify the geometry and dimensions of the valve prosthesis , according to the patient's individual geometry and size, and assemble into a personalized valve prosthesis suitable for each specific patient's anatomy and clinical condition, and further pack and sterilize the personalized valve prosthesis into the final A mitral valve prosthesis, sent to a specific patient for implantation and a personalized prosthetic mitral valve implanted in the patient to create the valve.

Provided is a method for fabricating a personalized, naturally designed mitral valve prosthesis to precisely fit the specific patient for whom the valve prosthesis is being fabricated. The method may include calculating the geometry and dimensions of the annular annulus, anterior leaflet, posterior leaflet, and umbilical cord for each specific patient based on a validated algorithm by measuring the size and shape of the patient's native mitral valve using imaging methods, and The annular ring, anterior leaflet, posterior leaflet, and umbilical cord are cut and joined to create a personalized prosthetic mitral valve.

According to some embodiments, the 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 patient's native mitral valve may include measuring mitral valve-related parameters, which may include: annular circumference (AC), annulus area (AA), anterior-posterior (A-P ) diameter, anterolateral-postomedial (AL-PM) diameter, commissural diameter (C-C), anterior leaflet length (ALL), posterior leaflet length (PLL), mitral valve shape, and chordae length (ACL and PCL).

According to some embodiments, the method may also include collecting patient-specific physical information for use in calculations to predict the geometry of the implanted heart after improved heart valve function, said physical information including: height, weight, age, race and gender.

A personalized mitral valve prosthesis comprising a flexible annular ring sized to match a specific patient's native mitral annulus, flexible anterior and posterior leaflets sized to match a specific patient's native mitral valve leaflets, As well as the leaflets and umbilical cord attached to the annular annulus sized to match the particular patient's native mitral valve leaflets, providing an umbilical cord attached to the papillary muscle of the heart. A personalized mitral valve prosthesis can be created by:

By using imaging methods to measure the size and shape of the native mitral valve in a given patient;

Calculate the geometry and dimensions of the annulus, leaflets, and umbilical cord for each specific patient based on proven algorithms; and

The annular ring, leaflets, and umbilical cord are cut and joined to create a personalized prosthetic mitral valve.

According to some embodiments, the 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 patient's mitral valve may include measuring mitral valve-related parameters, which may include: annular circumference (AC), annulus area (AA), anterior-posterior (A-P) diameter , anterolateral-postomedial (AL-PM) diameter, commissural diameter (C-C), anterior leaflet length (ALL), posterior leaflet length (PLL), mitral valve shape, and chordae length (ACL and PCL).

According to some embodiments, a personalized mitral valve prosthesis may also be created by collecting patient-specific anatomical information for use in calculations to predict the geometry of the implanted heart after heart valve function improves Include: height, weight, age, race and gender.

According to some embodiments, calculating may include calculating the annular ring circumference (AC) as the anterior leaflet annular ring circumference (AAC) as the apical edge of the anterior leaflet and the posterior leaflet as the apical edge of the posterior leaflet based on equation (iii) below. Combination of Leaflet Annular Circumference (PAC). According to some embodiments, the annular ring may be formed into a multi-layer reinforcement structure by folding or overlapping the 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 properly fits the natural geometry of a particular patient's left ventricle.

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

According to some embodiments, joining may include joining the two leaflets together to form two commissures, where the two commissures slope inwardly at a cone angle (δ ₁ ) to accommodate the personalized mitral valve prosthesis. The body is slightly 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 determined from the oblique angle (δ ₀ ) of each commissural edge of the two leaflets based on equation (x).

According to some embodiments, connecting may comprise connecting the anterior leaflet to the posterior leaflet by connecting the anterolateral to the anterolateral and the posteromedial to the posteromedial.

According to some embodiments, the anterior leaflet may be connected to the posterior leaflet by sutures.

According to some embodiments, the measurements may include measuring: the size and shape of the natural annular ring, commissure height (CH), inclination angle (δ ₀ ), anterior leaflet length (ALL) and Posterior leaflet length (PLL), and commissure 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 1 mm 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 circumference (AC) may be a function of the anterior-posterior diameter (A-P) and the anterolateral posteromedial diameter (AL-PM) based on equation (iii) below.

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

According to some embodiments, calculating the annular circumference (AC) of the prosthesis may be based on the annular 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 asymmetrical. According to some embodiments, the annular ring may be formed by a combination of an anterior and posterior annulus, whereby the anterior leaflet annular circumference (AAC) may be smaller than the posterior leaflet annular circumference (PAC), and the ratio between AAC/PAC (R ) can 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 proper opening and closing of the prosthetic valve.

According to some embodiments, calculations may include based on equations (viii) and (ix), respectively, based on: (a) the anterior-posterior diameter (A-P) as a theoretical minimum engagement distance, (b) the distance between AL and PL Ratio (r), (c) coaptation depth (Cd), (d) coaptation height (CoaptH) and (e) umbilical cord length (Lc) to calculate anterior leaflet length (ALL) and posterior leaflet length (PLL).

According to some embodiments, joining may include joining the two leaflets together to form the 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: an anterolateral umbilical cord and a posteromedial umbilical cord. According to some embodiments, each of the anterolateral and posteromedial umbilical cords may comprise three sub-umbilical cords, whereby the umbilical cords are evenly distributed along at least 3/8 of each edge from each end.

According to some embodiments, the calculation 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 joint depth.

According to some embodiments, measuring may include measuring the distance from the apex of the papillary muscles to the coaptation edge to indicate prosthetic umbilical cord length, and also including field measuring and adjusting the pledget umbilical caps where the umbilical cords are integrated and merged at the end of each set of umbilical cords.

According to some embodiments, a personalized mitral valve prosthesis can also be achieved by implementing the calculated annulus, anterior leaflet, posterior leaflet, and umbilical cord geometry as input for engineering mapping software or mapping tools for each specific patient. and size to form.

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

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

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

According to some embodiments, a personalized mitral valve prosthesis may also be created by implanting a personalized mitral valve prosthesis into a particular patient.

A prosthetic valve designed to resemble a patient's native mitral valve is provided. Two flexible leaflets and an asymmetric and flexible ring can move during the cardiac cycle following the natural deformation of the myocardium. An umbilical cord, which resembles the patient's natural chordae, is included in the prosthetic valve to mimic the natural prevention of blood backflow into the atrium and to provide support to the left ventricle during systole.

According to some embodiments, the mitral valve prosthesis to be implanted in the heart comprises:

an asymmetrical ring sized to mimic the patient's native mitral valve annulus, the asymmetrical ring is composed of a flexible material that rolls onto itself outwardly of the valve;

anterior flexible leaflets and posterior flexible leaflets suspended from the asymmetric ring and configured to substantially engage each other;

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 are connected at a first end to the anterior or posterior leaflets and at a second end to a cap configured to connect to the papillary muscle of the heart at the other end of the cap.

According to some embodiments, the mitral valve prosthesis may further include coaptation surfaces continuous with each of the anterior and posterior leaflets and attached to each set of umbilical cords, the coaptation surfaces being configured to enhance sealing of the mitral valve prosthesis.

According to some embodiments, the asymmetric loop may further comprise at least two wires configured in a coiled coil configuration.

According to some embodiments, the asymmetric ring may comprise 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 that provides strength.

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

According to some embodiments, the asymmetric ring, the anterior flexible leaflet and the posterior flexible leaflet, at least two umbilical cords, a cap, or any combination thereof may be made from bovine pericardium.

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

According to some embodiments, the leaflets may be shaped in a semicircular manner along half the length of the anterior and posterior flexible leaflets such that the two leaflets form an "S" shaped seal when joined.

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

According to some embodiments, at least two sets of umbilical cords may be attached to an opening of the cap 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 the medial portion of the anterior or posterior leaflets, thereby simulating a naturally occurring mitral valve.

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

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

According to some embodiments, the mitral valve prosthesis to be implanted in the heart may include:

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

two leaflets suspended from an asymmetrical ring constructed on opposite sides of an incision made along a similar material to that making up the asymmetrical ring, wherein the incision forms an orifice along which blood flow through the orifice in one direction;

at least two sets of umbilical cords, each set of umbilical cords connected at a first end to one of the two leaflets and connected at a second end in a bundle; and

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

According to some embodiments, each set of umbilical cords 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 include:

Imaging methods to measure the size and shape of the patient's mitral valve;

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

An incision is made along the single piece of material, creating an orifice for blood flow and two leaflets, one on each side of the orifice;

Measure the length of the required umbilical cord by imaging methods;

attach the umbilical cord to one of the two caps; and

A flexible ring is attached to the leaflets to create a complete mitral valve prosthesis that mimics the patient-specific natural mitral valve.

According to some embodiments, the desired length of the umbilical cord may be measured at the same time as 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.

Provided is a method for fabricating a personalized, naturally designed mitral valve prosthesis to precisely fit the specific patient for whom the valve prosthesis is being fabricated. The method can include:

By using an imaging device to measure the size and shape of a patient's native mitral valve, providing data on the materials from which a personalized mitral valve prosthesis is made,

Based on the size and shape of the natural mitral valve and material data of a specific patient, a personalized 3D model of the mitral valve prosthesis is constructed,

Optimizing 3D models using FEM methods, and

A personalized mitral valve prosthesis was fabricated 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 comprise: 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 native mitral valve comprises measuring mitral valve related parameters including: annular circumference (AC), annulus area (AA), anterior-posterior (A-P) diameter, anterior Lateral-posteromedial (AL-PM) diameter, commissural diameter (C-C), anterior leaflet length (ALL), posterior leaflet length (PLL), mitral valve shape, and chordae length (ACL and PCL).

According to some embodiments, the method further includes collecting patient-specific physical information to predict heart geometry following implantation of the personalized mitral valve prosthesis, the physical information including: height, weight, age, race, and gender.

In some embodiments, a personalized mitral valve prosthesis is provided. A personalized mitral valve prosthesis may include a flexible annular ring sized to match a particular patient's native mitral annulus, flexible anterior and posterior leaflets sized to match a particular patient's native mitral valve leaflets, attached to a The leaflets of the annular ring, and an umbilical cord sized to match the particular patient's native mitral valve leaflet, the umbilical cord is connected to the flexible anterior leaflet and the flexible posterior leaflet, and the umbilical cord is also configured to attach the flexible anterior leaflet to the flexible posterior leaflet. The lobules are attached to the papillary muscles of the heart. In some embodiments, a personalized mitral valve prosthesis can be created by:

Measuring the size and shape of the natural mitral valve in a given patient by using an imaging device;

Provide data on the materials used to manufacture personalized mitral valve prostheses;

Construct a personalized 3D model of the mitral valve prosthesis based on the size and shape of the natural mitral valve and material data for the specific patient;

Optimizing 3D models using FEM methods;

as well as

Based on the optimized FEM model by cutting the material into annular rings, flexible anterior and flexible posterior leaflets, and umbilical cords and attaching the flexible anterior and flexible posterior leaflets to the annular rings and the Create a personalized mitral valve prosthesis. In some embodiments, the personalized prosthetic mitral valve can optionally be further formed by including visualization of the personalized mitral valve prosthetic model prior to the manufacturing operation.

According to some embodiments, the 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 comprises measuring mitral valve related parameters including: annular circumference (AC), annulus area (AA), anterior-posterior (A-P) diameter, anterolateral- Posteromedial (AL-PM) diameter, commissural diameter (C-C), anterior leaflet length (ALL), posterior leaflet length (PLL), mitral valve shape, and chordae length (ACL and PCL).

According to some embodiments, a personalized prosthetic mitral valve can also be formed by collecting patient-specific physical information to predict the geometry of the heart after implantation of a personalized mitral valve prosthesis, including: height, Weight, age, race and gender.

According to some embodiments, measuring comprises measuring the annular ring circumference (AC) as the anterior leaflet annular ring circumference (AAC) as the top edge of the anterior leaflet and the posterior leaflet annulus as the top edge of the posterior leaflet based on equation (iii). Combination of Ring Circumference (PAC).

According to some embodiments, the annular ring forms a multi-layer reinforcement structure by folding or overlapping the 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 a particular patient's left ventricle.

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

According to some embodiments, joining includes joining the flexible anterior and posterior leaflets together, thereby forming two commissures, wherein the two commissures slope inwardly at a cone angle (δ ₁ ) to form a tapered individualized dichotomy. Cube prosthesis to fit the native left ventricle in specific patients.

According to some embodiments, the cone angle (δ ₁ ) is determined from the oblique angle (δ ₀ ) of each commissural edge of the flexible anterior and posterior leaflets based on equation (x).

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

According to some embodiments, connecting the anterior leaflet to the posterior leaflet comprises suturing.

According to some embodiments, the measurement comprises, based on equation (xi), measuring: the size and shape of the natural annular ring, commissure height (CH), inclination angle (δ ₀ ), anterior leaflet length (ALL) and posterior leaflet length (ALL) for a particular patient. 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 1 mm 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 circumference (AC) is a function of the anterior-posterior diameter (A-P) and the anterolateral posteromedial diameter (AL-PM) based on equation (iii).

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

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 asymmetrical, and wherein the annular ring is further formed by a combination of an anterior leaflet annulus and a posterior leaflet annulus, wherein the anterior leaflet annular circumference (AAC) is smaller than the posterior leaflet annular circumference (PAC), The ratio (R) between AAC/PAC was 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 includes calculating an anterior leaflet annular circumference (AAC) and a posterior leaflet annular circumference (PAC) based on the suture positions A and B.

According to some embodiments, constructing a 3D model of a personalized mitral valve prosthesis includes, based on equations (viii) and (ix), based on: (a) an anterior-posterior diameter (A-P) as a theoretical minimum coaptation distance; (b) ratio between ALL and PLL (r); (c) coaptation depth (Cd); (d) coaptation height (CoaptH); and (e) umbilical cord length (Lc) to calculate anterior leaflet length (ALL) and Posterior leaflet length (PLL).

According to some embodiments, joining includes joining the anterior and posterior leaflets together to form the body of the personalized mitral valve prosthesis.

According to some embodiments, each anterior leaflet and each posterior leaflet includes two sets of umbilical cords: an anterolateral umbilical cord and a posteromedial umbilical cord, wherein each anterolateral umbilical cord and posteromedial umbilical cord includes three sub-umbilical cords, wherein the umbilical cords are drawn from each side along each At least 3/8 of the strip sides are evenly spaced.

According to some embodiments, constructing the 3D model includes calculating the 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.

According to some embodiments, measuring includes measuring the distance from the apex of the papillary muscle to the coaptation edge to represent the prosthetic cord length, and also includes measuring in situ and adjusting the pledget umbilical caps where the umbilical cords are integrated and merged at the end of each set of umbilical cords.

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

According to some embodiments, the engineering drawing software or drawing tool outputs a template for manually cutting the 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 include 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 support prior to packaging.

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

Description of drawings

1A and 1B are schematic illustrations of embodiments of the present invention. Figure 1A depicts a prosthetic mitral valve in an open position and shows the chordae prior to attachment to the leaflets, according to some embodiments of the present disclosure. FIG. 1B depicts the prosthetic mitral valve in a closed position and shows the chordae after attachment to the leaflets, according to some embodiments of the present disclosure;

Figure 2 is a schematic illustration of an embodiment of the present invention implanted in a heart according to some embodiments of the present disclosure;

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

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

Figure 5 is a photograph of a prosthetic valve in in vitro testing according to some embodiments of the present disclosure;

6A-6B are schematic illustrations, respectively, of side views of the anterior and posterior leaflets of a prosthetic mitral valve, and a top view of the leaflets as they engage each other, according to some embodiments of the present disclosure;

6C is a schematic illustration of a superior view of a mitral valve prosthesis looking down from the left atrium to the left ventricle (during diastole, when the valve is open to allow blood into the left ventricle) according to an embodiment of the disclosure;

Figure 6D is a schematic illustration of a single piece of material comprising an anterior leaflet and a posterior leaflet, according to an embodiment of the disclosure;

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

8A-8B are schematic diagrams of possible positions of the umbilical cord relative to the leaflets, and a cross-section of the umbilical cord when attached to the leaflets, respectively, according to some embodiments of the present disclosure;

9A-9B are each a schematic illustration of a prosthetic mitral valve with two leaflets attached using an alternative with a curved (ellipsoid/droplet) configuration, according to some embodiments of the present disclosure. design to enlarge the joint surface, and possible joint surface configurations;

10 is a schematic illustration of a measured replica of a patient's mitral valve derived from a 2D or 3D echocardiographic image, according to some embodiments of the present disclosure;

Figure 11 is a schematic illustration of forming a bilobed prosthesis according to some embodiments of the present disclosure;

Figure 12 is a schematic illustration of an opening formed along a leaflet portion according to some embodiments of the present disclosure;

13 is a schematic illustration of an echocardiographic or MRI scan of a patient's left heart chamber or ventricle, according to some embodiments of the present disclosure;

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

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

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

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

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

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

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

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

21A is a schematic illustration of the annular valve margin preserved when the native mitral valve is removed in clinical practice, according to some embodiments of the present disclosure;

21B is a schematic illustration of an elliptical ring model used to calculate the annular ring circumference (AC) of a valve prosthesis, with the AL-PM diameter as the major axis and the A-P diameter as the minor axis, according to some embodiments of the present disclosure;

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

Figure 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 illustrations of customized anterior and posterior leaflet models according to some embodiments of the present disclosure;

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;

Figure 23C is a schematic diagram of the relationship of multiple parameters influencing each other when the leaflets of the prosthesis coapt, according to some embodiments of the present disclosure;

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

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

25 is a photograph of an echocardiogram of a sheep heart implanted with a personalized natural engineered mitral valve prosthesis fabricated according to the methods of the present disclosure; and

26A-26B are schematic illustrations of the posterior and anterior leaflets, respectively, according to some embodiments of the present disclosure;

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

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 illustrations of a prosthetic mitral valve in a hydrodynamic chamber in open and closed configurations, respectively, according to some embodiments of the present disclosure;

Figure 30 is an echocardiogram of a custom-made prosthetic mitral valve during its closed configuration after implantation in a porcine heart; and

Figure 31 is the blood pressure gradient of a porcine heart following implantation of a custom prosthetic mitral valve.

The foregoing will be readily understood from the following more particular description of exemplary embodiments of the invention, as shown in the accompanying drawings, wherein like reference numerals refer to like parts throughout the different views. The drawings are not necessarily to scale; emphasis instead is placed upon illustrating embodiments of the invention.

detailed description

A mitral valve prosthesis of the present invention is shown in FIGS. 1A and 1B . The mitral valve prosthesis 100 has a physiological shape similar to a natural human mitral valve. The mitral valve prosthesis comprises a flexible, asymmetrical ring 1 and two flexible, membranous leaflets 2 suspended from the asymmetrical ring 1 . The mitral valve prosthesis also includes two sets of umbilical cords 3 that simulate the cardiac chordae. Each set of umbilical cords 3 is configured to be attached to the rim and/or body of the leaflet 2 at one end and to converge into a fixed cap 8 at the other end. The fixation cap 8 is configured to be sutured to the papillary muscle of the left ventricle.

The mitral valve 100 is shown without the umbilical cord 3 attached to the leaflet 2 in FIG. 1A and with the leaflet 2 attached in FIG. 1B . The umbilical cords 3 may be attached to the leaflets 2 prior to 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 integral design. The mitral valve 100 is shown in an open state in FIG. 1A and in a closed state in FIG. 1B . In the closed state, leaflet 2 is shown coapted.

Figure 2 shows a mitral valve 100 implanted in a heart. The mitral valve 100 is shown implanted in place of the native mitral valve annulus 12 , on one side close to the aortic valve 6 where the aortic root 7 connects with the left ventricle, and on the other side against the opposing ventricular wall 5 . The umbilical cord 3 is shown attached to the papillary muscle 4 .

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

The flexible ring 1 may be formed, for example, by an elastic annuloplasty ring. Leaflets 2 may be formed from a natural material or a biocompatible composite material that resists coagulation 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 the papillary muscles, which function like the patient's natural chordae. The umbilical cord 3 tethers the leaflet 2 to the patient's papillary muscle, provides support to the left ventricular wall throughout the cardiac cycle, and prevents opening of the leaflet into the atrial cavity.

The mitral valve prosthesis 100 comprising the flexible ring 1, leaflets 2 and umbilical cord 3 looks and behaves like a healthy natural mitral valve. Furthermore, the mitral valve prosthesis of the present invention can be produced from natural materials and can avoid the inclusion of foreign bodies, such as absorbent cotton. Allograft materials and/or composite materials, including various combinations of allograft, xenograft, and/or autograft materials, can be used to make flexible rings, leaflets, umbilical cords, and caps. Materials forming the annulus and leaflets may include, but are not limited to, human, bovine or porcine pericardium, decellularized bioprosthetic materials, braided biodegradable polymers associated with cells, and extracellular materials. Biodegradable natural polymers may include, but are not limited to, fibrin, collagen, chitosan, gelatin, hyaluronic acid, and similar materials. Biodegradable synthetic polymer scaffolds that can be wetted with cells and extracellular matrix materials can include, but are not limited to, poly(L-lactide), polyglycolide, poly(lactic-co-glycolic acid), poly(hexyl-lactide), lactones), polyorthoesters, poly(dioxanones), poly(anhydrides), poly(trimethylene carbonate), polyphosphazenes, and similar materials. The flexible ring can be further customized to provide individual flexibility or rigidity for the patient. In addition, some components of the mitral valve prosthesis, including the umbilical cord3, can be formed intraoperatively from the patient's native pericardium.

For example, a mitral valve prosthesis can be made from the patient's own pericardium. Alternatively, a mitral valve prosthesis could be made from a xenogeneic material (for example, animal tissue, such as an existing valve), onto which a layer of the patient's own cultured cells is applied through tissue engineering.

Prosthetic valves are often secured 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 photofixation. The mitral valve of the present invention can also be modified by using optional cross-linking agents such as epoxy compounds, carbodiimides, diglycidol, reuterin, genipin, diphenyl Phosphoryl azides, acyl azides, and cyanamides, or immobilization by physical methods such as UV light and dehydration.

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

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

Three-dimensional echocardiographic studies can be performed using, for example, a transesophageal echocardiographic (TEE) probe or a transthoracic echocardiographic (TTE) probe. The various parts of the mitral valve can be modeled and measured in three and four dimensions using software such as eSieValves.TM. (Siemens Medical Solutions USA, Inc., Malvern, Pa.). Relevant measurements may include outer and inner diameters of the annulus, annular area, intertrigonal and intercommunicative distances, and lengths along various axes of the anterior and posterior leaflets.

Additionally, or alternatively, three-dimensional studies of the mitral valve can be performed by computed tomography (CT) or magnetic resonance imaging (MRI). For example, as shown in Figure 3, a 3D reconstruction of a porcine heart was obtained using CT imaging (SOMATOM.RTM.Definition Flash, Siemens Healthcare, Erlangen, Germany), and the mitral valve region of the heart is visible on the right side of the image. The mitral valve region can be segmented and associated measurements obtained using image analysis software.

Mitral valve prostheses can be fully customized for the patient, with each component (eg, ring, leaflets, umbilical cord, cap) manufactured to have dimensions that match the patient's native valve. For example, as shown in Figure 4, a 3D printed mold of the mitral valve is created based on the 3D reconstruction of the imaged valve. The 3D printed valve shown in Figure 4 is modeled during the diastolic or open phase of the cardiac cycle. The 3D mold-based prosthetic valve is also shown in Figure 4. The mold guides the incision of the porcine pericardium into the lobules and chordal attachment sites. Alternatively, a prefabricated mitral valve or prefabricated components of a mitral valve may be selected for implantation that is closest in shape and size to the patient's native valve or native valve components.

Figure 5 shows an image of a prosthetic valve prototype sutured in an in vitro testing system. The valve prototype shown was sutured to an explanted whole heart. A saline bolus is injected through a tube into the left ventricle of the heart, and the aorta is clamped to hold the saline in the left ventricle and create pressure. For example, injection pressure can be monitored on a pressure gauge connected to the injection line. The ability of the valve prototype (eg, absence of 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.

6A-6B are schematic illustrations, respectively, of the anterior and posterior mitral leaflets of a prosthetic mitral valve and when the leaflets coapt with each other, according to some embodiments of the present disclosure. According to FIGS. 6A and 6B , the prosthetic mitral valve may be a prosthetic mitral valve 600 . According to some embodiments, valve 600 may include two leaflets, eg, anterior mitral leaflet 602A and posterior mitral leaflet 602P. Each of the mitral valve posterior leaflet 602P and anterior leaflet 602A can be designed and created separately preoperatively as a monocoque (single piece) to suit the patient's specific physiology and anatomy based on cross-sectional images 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, eg 602A, 602P, such that each leaflet is substantially the same as the patient's native leaflet. Each leaflet can be shaped to include a chordae (eg, chordae 604, 606, 608, 610) and additional material to form loop portions (eg, anterior loop portion 601A and posterior loop portion 601P). As described further below, the surgeon can determine the length of the chordae to suit the patient. The leaflets can be cut from a single piece of material using a knife or scissors, and can be sutured by a surgeon during mitral valve replacement surgery to form a mitral valve that resembles the patient's natural mitral valve.

For example, the anterior leaflet (AL) height may be about 30 mm, the AL length may be about 45 mm, the posterior leaflet (PL) height may be about 15 mm, and the posterior leaflet length may be about 60 mm. As shown in Figure 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 the portion of the leaflet perimeter, for example, 632A refers to the anterior leaflet 602A and 632P refers to the length of the posterior leaflet 602P.

According to some embodiments, cutting each of the leaflets 602A and 602P separately, and each of the ring portions 601A and 601P separately, from the same or a different piece of material can ease the burden of a prosthetic mitral valve being prepared for implantation. burden on people (e.g., surgeons). The leaflets are cut into two separate parts and the ring part is cut into two separate parts, and the leaflets are attached to the ring and the umbilicus is further attached to each leaflet, together with the leaflet and umbilical cord from the Compared to cutting from a single piece of material, the preparation time and the time required to perform the surgical procedure for implanting a prosthetic valve are shortened. Cutting the leaflets and umbilical cord as a single unit and implanting a single-piece prosthesis is more complex than the method disclosed herein due to the high precision required when cutting the leaflets and each umbilical cord while maintaining the connection between the leaflet sections and the umbilical section intact And more time consuming.

In some embodiments, each of loop portions 601A and 601P is formed by rolling each leaflet posterior side such that each leaflet posterior side is folded or rolled onto itself (e.g., rolled anterior portion 605A and rolled posterior portion 605A). portion 605P), towards the outside of the valve 600. Depending on the embodiment, the size of the posterior end of each leaflet can be increased by 5-10 mm of additional material that can be used when rolling the posterior end of the leaflet onto itself to form the ring portion (e.g., the anterior leaflet of the mitral valve Ring portion 601A in and ring portion 601P in the posterior leaflet of the mitral valve). Rolling or folding the ring (or each ring portion 601A and 601P) towards the outside of the valve 600 onto itself can help avoid clots forming on the inside of the valve 600, and if clots were to form, they would only occur in the The folding or rolling area of the ring or ring portion is on the outside of the valve 600, 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 strips of additional material (not shown), such as suitable biomedical fibers or polymers. Such a strip may be made from a sheet of material from which the valve 600 is made and sized to fit within each ring portion 601A, 601P. Preferably, such strips have a width of 1-3 mm and a length of 10-20 mm. Such a strip of material may be added to the valve 600 as each ring portion 601A, 601P is rolled, the strip being placed within each ring portion 601A, 601P. These strips of material can be elastic and can be made of various compositions such as biocompatible rubber, recoil wire or synthetic materials.

According to FIG. 6B , leaflet 602A may have a semi-elliptical or plano-convex shape, while leaflet 602P may have a plano-concave shape. In some embodiments, valve 600 can include at least two sets of umbilical cords. In some embodiments, each of the at least two sets of umbilical cords is attached to the medial portion of the corresponding leaflet, thereby simulating a native mitral valve. For example, in some embodiments, the leaflet 602A can include at least one set of umbilical cords 603A, which can be connected to the middle portion of the leaflet 602A at one end of the leaflet 602A, which is generally connected to the end where the ring portion 601A is connected to the leaflet 602A. relatively. In some embodiments, at least one set of umbilical cords 603A can include at least two subsets of umbilical cords, eg, subset of umbilical cords 604 and subset of umbilical cords 606 . According to some embodiments, these subsets of umbilical cords 604 and 606 are spaced apart such that a gap of about 3-5 millimeters is maintained between the two subsets of cords for more efficient coaptation. The gap between the umbilical subsets 604 and 606 also serves to create a more even distribution of tension on the leaflets and potentially reduce wear. These subsets of umbilical cords 604 and 606 may be connected to different and separate caps for connecting the subset of umbilical cords to the papillary muscles of the heart, as will be explained in detail with reference to FIGS. 7A-7B .

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

In some embodiments, at least one set of umbilical cords 603P may include at least two subsets of umbilical cords, eg, subset of umbilical cords 608 and subset of umbilical cords 610 . These subsets of umbilical cords 608 and 610 are spaced apart such that a gap of about 5-8 millimeters is maintained between the two subsets of cords for more efficient coaptation. These subsets of umbilical cords 608 and 610 may be connected to different and separate caps for connecting the subset of umbilical cords to the papillary muscles of the heart, as will be explained in detail with reference to FIGS. 7A-7B .

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

According to some embodiments, the intersegmental distance in the anterior mitral valve leaflet 634A may be between 8-10 mm. In some embodiments, the intersegmental distance in the posterior mitral leaflet 634A may be between 10-15 mm. In some embodiments, the internode distance between the anterior and posterior leaflets in the commissural region, noted as distance 636 and/or 638, may be between 5-7 mm.

According to some embodiments, and as shown in FIG. 6B , the anterior leaflet 602A can be connected to the posterior leaflet 602P, and the ring portion 601A can be connected to the ring portion 601P to construct the prosthetic mitral valve 600 . Once leaflet 602A is connected to leaflet 602P, an orifice 620 created between leaflet 602A and leaflet 602P allows blood to flow in one direction, ie, from the left atrium to the left ventricle. Accordingly, the orifice 620 created between the leaflet 602A and the leaflet 602P can be configured to prevent backflow, ie, from the left ventricle to the left atrium. Leaflet 602A, leaflet 602P and the manner in which the leaflets are connected to each other in some joint, and ring portion 601A and ring portion 601P may be configured to mimic the shape, size and thus function of a native human mitral valve. In particular, ring portion 601A may be configured to simulate the anterior annulus, while ring portion 601P may be configured to simulate the posterior annulus of a native mitral valve. In some embodiments, each leaflet may include a shape extending approximately 1-5 mm between the ring 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, anterior leaflet 602A can include at least two cord subsets, eg, cord subset 604 and cord subset 606, which can be connected to leaflet 602A at different ends of leaflet 602A. In some embodiments, the posterior leaflet 602P can include at least two cord subsets, such as cord subset 608 and cord subset 610, which can be attached at different ends of the leaflet 602P. Like the natural mitral valve, the umbilical cord should connect to the papillary muscle of the heart. More specifically, in the native human mitral valve, each subset of cords attaches to a different region of the papillary muscle. Accordingly, prosthetic valve 600 may include at least two cord subsets per leaflet, whereby each 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 Figures 6C and 7A-7B, each cord subset may be connected to the papillary muscle by a cap to ensure an easy but sufficiently stable and durable attachment between any cord subset and papillary muscle. The number of umbilical cords in each subset of umbilical cords (eg, 604, 606, 608, and 610) may be different or the same. In some embodiments, each subset of umbilical cords may include at least two umbilical cords.

6C is a schematic illustration of a superior view of a mitral valve prosthesis looking down from the left atrium to the left ventricle, according to an embodiment of the disclosure. According to FIG. 6C, the posterior leaflet 602P may be connected to the anterior leaflet 602A by a connecting thread (eg, suture 609). In some embodiments, ring portion 601A can be connected to ring portion 601P, such as along line 609 , and can be rolled onto itself towards the outside of valve 600 . In some embodiments, the anterior leaflet 602A can include two subsets of umbilical cords, such as subsets 604 and 606 , whereby each of these subsets of umbilical cords can be connected to a different papillary muscle 720 by a separate cap element 700 . Accordingly, 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 can be connected to the first papillary muscle 720 by the first cap 700 and the posterior umbilical cord 608 can also be connected to the same first papillary muscle by the same first cap 700 . Similarly, the anterior umbilical cord 606 can be connected to the second papillary muscle 720 by the second cap 700 and the posterior umbilical cord 610 can also be connected to the same second papillary muscle by the same second cap 700 .

Referring to Figure 6D, in some embodiments, leaflets 602P and 602A can be cut from a single monocoque and can be joined along suture 609, eg, sutured, to form a complete valve. According to some embodiments, the umbilical cord may be adjusted to the recipient/patient's individual optimal cord length based on the patient's pre-operative scan.

7A-7B are schematic illustrations of a cap for connecting the umbilical cord to the cardiac papillary muscle and a mitral valve prosthesis, respectively, with two caps attached to the umbilical cord, according to an embodiment of the disclosure. In some embodiments, the shape of the cap 700 in the layout configuration can be arcuate. In some embodiments, the shape of the cap 700 in the closed configuration can be similar to the shape of a cone 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 can be surgically The sutures 706 are stitched to each other or one over the other to form a closed configuration. Suture 706 may be performed prior to placing cap 700 on top of pupillary muscle 720 . In some embodiments, cap 700 may have a diameter between 5mm and 10mm and a height between 5-10mm. According to some embodiments, the cap 700 may be made from a single piece of material having the shape of a cap, while according to other embodiments, the cap 700 may be made from two open leaflets or pieces of the same material to be sewn together and immediately reach the nipple muscle. For example, suture thread can start from one side of the two pieces of material of cap 700, and exit through a part of cap 700, so that cap 700 is attached on the papillary muscle, etc., until the two parts of cap 700 are fully connected to each other , and is fully connected with the papillary muscles of the heart.

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

Once the cap 700 is placed over the pupillary muscle 720, the umbilical cords, such as the cord subsets 604, 608, may be connected to the cap 700 using sutures 710, which may connect the umbilical cord, cap 700, and pupillary muscle 720 together. According to some embodiments, the cap opening 730 allows for a good fit between the cap 700 and the papillary muscle 720 because the cap opening 730 makes it possible to adjust the shape of the cap to the shape of the papillary muscle 720 . In some embodiments, cap 700 can be attached to the umbilical cord subsets 604 and 608 at one end thereof, such as by suture 710, and cap 700 can be attached to the papillary muscle of the heart from the other end, such as by suture 706, typically cap 700 The opposite end is near the bottom end 704. The cap 700 can be connected to the papillary muscle 720 through the entire circumference of the bottom end 704 of the cap 700 , but in some embodiments, the cap 700 can be connected to the papillary muscle 720 through a specific portion along the circumference of the bottom end 704 of the cap 700 .

According to some embodiments, the umbilical cords may be connected to each other to form an umbilical cord bundle. The umbilical cord may be attached as a bundle at the end of the umbilical cord to be attached to the cap 700 (eg, the ends of the umbilical cord subsets 604 and 608, attached to the leaflet 602). According to some embodiments, connecting the umbilical cords (eg, subsets of umbilical cords 604 and 608 ) to the papillary muscles 720 through the cap 700 is easier than connecting the umbilical cords directly to the papillary muscles 720 because it requires a more extensive attachment procedure. For example, if the method of attachment is suturing, then suturing each umbilical cord to the papillary muscle 720 is more complicated than suturing the umbilical cord to the unfolded cap 700 and suturing the cap 700 (which is a single bulk) to the papillary muscle 720 And time consuming. Since 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 performed conveniently.

Although FIG. 7A shows only two subsets of umbilical cords 604 and two subsets of umbilical cords 608 attached to cap 700 , it should be understood that additional umbilical cords may be connected to cap 700 . The subset of umbilical cords 604, 608 may include one or more umbilical cords. In some embodiments, four umbilical cords 604 from the right sector of the anterior mitral leaflet 602A and four umbilical cords 608 from the left sector of the posterior mitral leaflet 602P are attached to the cap 700 as shown in FIG. 6C .

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

In some embodiments, each of the subsets of umbilical cords 604 , 606 , 608 , and 610 may first be connected to each other to form a bundle, which may then be connected to cap 700 .

As shown in Figure 7B, a prosthetic mitral valve 600 may include a flexible asymmetric ring 601 attached to two leaflets (eg, leaflets 602A and 602P). In some embodiments, each of the two leaflets can have a set of umbilical cords attached, eg, subsets of umbilical cords 604 (not shown), 606 (not shown), 608 and 610 . In some embodiments, each set of umbilical cords can be attached to a single cap 700 according to each of the two leaflets, and each cap 700 can combine the two by connecting each subset of umbilical cords 610 to their respective cap 700. The cusp prosthesis 600 is connected to the papillary muscle 720 of the heart.

As noted 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. become. Such umbilical cords, each of which may be considered an extension of leaflets 602A and 602P, may be referred to as primary umbilical cords. According to some embodiments, additional umbilical cords may be attached to both the anterior leaflet 602A and the posterior leaflet 602P. Each of these secondary umbilical cords may be made of a different and separate material than the material used to construct the leaflets and primary umbilical cord. The secondary umbilical may be configured to connect the underside of each of the leaflets 602A and 602P to a point along the primary umbilical. The point of attachment of 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 attachment points for better coaptation of the leaflets. The secondary umbilical cord can typically be sutured at one end thereof to the anterior leaflet 602A or posterior leaflet 602P, and at its other end the secondary umbilical cord can be sutured to the primary umbilical cord. When attaching the secondary umbilical cord to the anterior leaflet 602A or the posterior leaflet 602P, respectively, for example, 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 the ) condenses. For example, there is less chance of damaging leaflets 602A and 602P when microscopic sutures are used. The purpose of the secondary umbilical cord is to provide additional support to the prosthetic valve against the pressure exerted on the ventricular side of the prosthetic valve during systole.

8A-8B are schematic illustrations, respectively, 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, according to some embodiments of the present disclosure. Posterior leaflet 602P may be rolled on its posterior end to form loop 601 as shown in FIG. 8A . In some embodiments, the posterior mitral valve leaflet 602P can be divided into several regions. Regions 812 and 814 may be regions to which a secondary umbilical (eg, umbilical 603 ) may be connected. However, there may be a region 816 along the posterior leaflet 602P that should be cordless, ie, a secondary umbilical cord should not be connected to the region 816 . This is due to the region 816 being the region where high pressure is applied after the posterior leaflet 602P attaches to the heart as part of the prosthetic valve during ventricular systole. In some embodiments, the region 816 can include approximately 2-5 mm to the right of the midline 810 of the posterior leaflet 602P, and approximately 2-5 mm to the left of the midline 810 of the posterior leaflet 602P. In some embodiments, the region 816 can be 3 mm to the right and 3 mm to the left of the midline 810 of the posterior leaflet 602P. The secondary umbilical cord can be designed to help provide additional support to the posterior leaflet 602P as the pressure gradient increases during ventricular systole.

In some embodiments, the secondary umbilical cord 603 should not reach the ends of regions 812 and 814 of the posterior leaflet 602P when in the deployed configuration. 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 may be positioned at an angle of approximately 20 degrees to 70 degrees relative to the midline 810 of the posterior leaflet 602P along either of regions 812 and 814 along the entire posterior leaflet 602P layout. In addition, the region of the posterior leaflet 602P between and about 15-20 degrees either side of the midline 810 may remain free of the secondary umbilical cord.

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

According to some embodiments, primary umbilical cord 608 may be connected to secondary umbilical cord 603, whereby each of secondary umbilical cords 603 may be connected at one end (e.g., end 823) to posterior leaflet 602P, and along the primary umbilical cord at each The opposite end (eg, end 825 ) of the secondary umbilical 603 is connected to the point of contact. According to some embodiments, the secondary umbilical cord 603 should be about 30-40% thicker and about 30-40% wider than the primary umbilical cord 608 . Depending on the desired prosthesis, one to four secondary umbilical cords can be used per scallop of the posterior leaflet of the mitral valve (602P).

9A-9B are each a schematic illustration of a prosthetic mitral valve with two leaflets attached using an alternative with a curved (ellipsoid/droplet) configuration, according to some embodiments of the present disclosure. Designed to enlarge the joint surface, and possible joint surface configurations. According to FIG. 9A, the prosthetic mitral valve 1100 may include two leaflets, such as an anterior leaflet 1602A and a posterior leaflet 1602P, whereby each of the leaflets 1602A and 1602P may have a semicircular and Yang" shape. In some embodiments, the leaflets may be shaped in a semi-circular manner along half the length of each leaflet such that the two leaflets form an "S" shaped seal when joined.

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

According to FIG. 9B, two coaptation configurations are possible between the anterior leaflet 1602A and the posterior leaflet 1602P in the immediate vicinity of the coaptation region. In some embodiments, as with prosthetic valve 600, prosthetic valve 1100 may include two types of umbilical cords; a primary umbilical cord and a secondary umbilical cord. According to some embodiments, the primary umbilical cord may be configured as an extension to the anterior leaflet 1602A and the posterior leaflet 1602P, respectively. That is, primary umbilical cords, eg, primary umbilical cords 1102A and 1102P, may be constructed from the same piece of material as the corresponding leaflets, anterior leaflet 1602A, and posterior leaflet 1602P. Primary umbilical cords 1102A and/or 1102P may extend at one end from the medial portion of the respective leaflet and may be connected to the cap at the other end. According to some embodiments, a secondary umbilical cord, such as umbilical cord 1104P, may only be attached to the posterior leaflet 1602P. A secondary umbilical cord, eg, umbilical cord 1104P, may be connected at one end to the medial portion of the posterior leaflet 1602P and at the other end to the medial portion of the primary umbilical cord 1102P. According to some embodiments, a secondary umbilical cord 1104P may be added to better mimic the native mitral valve, which includes an additional shorter umbilical cord connected between the posterior leaflet and the posterior primary umbilical cord. The addition of a secondary umbilical cord allows the posterior leaflet to withstand the pressure exerted on it during systole and produces proper leaflet coaptation (or closure) during systole of the cardiac cycle and further allows 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 an intermediate portion of the primary umbilical 1102P.

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

10 is a schematic illustration of a measured replica 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 portion may be obtained by echocardiography, although other imaging methods may be used, such as cardiac CT or cardiac MRI, among others. Accordingly, the size and shape of the prosthetic mitral valve 1200 may be substantially an exact replica of the patient's native or native mitral valve.

Figure 11 schematically illustrates the formation of a bi-leaflet prosthesis according to some embodiments of the present disclosure. In some embodiments, as shown in Figure 12, the base of the valve, the leaflet portion, can be cut from a single piece of material 1210 based on a cross-sectional image of the intended recipient's heart. The leaflet portion can be sized to replicate the image of the prosthesis at a 1:1 ratio and an incision 1220 can be made in the middle of the leaflet portion in the form of a crescent or a semicircle to provide an opening 1230 and two Definitions of leaflets, such as anterior leaflet 1202A and posterior leaflet 1202P, are shown in FIG. 12 .

Figure 12 schematically illustrates openings formed along leaflet portions according to some embodiments of the present disclosure. In some embodiments, an opening or orifice 1230 can be formed (eg, cut) in a single piece of material 1210 , and two leaflets 1202A and 1202P can be formed on opposite sides of the opening 1230 . Once the orifice 1230 is formed by cutting a single piece of material 1210, the two leaflets, such as the anterior leaflet 1202A and the posterior leaflet 1202P, may exist in the form of a flap folded into the orifice 1230, thereby further creating unidirectional blood flow through the orifice 1230 , that is, from the left atrium to the left ventricle of the heart.

Figure 13 schematically illustrates an echocardiographic or MRI scan of a patient's left heart chamber or ventricle, according to some embodiments of the present disclosure. In some embodiments, the patient's left ventricle 1500 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 the 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 fabrication of custom-made prosthetic mitral valves according to the patient's anatomical and physiological requirements.

14A-14B are schematic diagrams of a patient's left ventricle during 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., the left ventricle 1610, may comprise a smaller annulus diameter 1650 than the annulus diameter 1650 of the left ventricle 1612 in diastole as shown in FIG. 14A. 1640 in diameter. As blood flows into the left ventricle during diastole, the left ventricle 1612 may become filled with blood, so the annulus diameter 1650 becomes larger. After blood has flowed from the left ventricle to the patient's bodily blood system to reach the organs, 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 annulus and leaflets 1502A and 1502P need to achieve flexibility as they repeatedly change their diameter and size during recurring phases of cardiac function (i.e., systole and diastole), it should be clear that the annulus and leaflets are expected to be controlled by elasticity. material, just like the tissue from which the natural mitral valve is made. Thus, a prosthesis is disclosed with no stent, no metal ring, and no rigid material, and the materials chosen to make the leaflets 1502A and 1502P and the ring require a certain amount of compliance and elasticity.

15A-15B are schematic illustrations 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 dimensions of extension 1703 are approximately 1-5 mm in length and approximately the width of the incision forming the anterior leaflet (eg, incision 1220 of FIG. 11 ). In some embodiments, the extension 1703 is sutured at one end to the edge of the anterior leaflet 1202A (see incision 1220 of FIG. 11 ), and at the other end will include an umbilical cord 1704 which can be similar to the umbilical cords 604, 606 of FIG. 6A.

As shown in Figure 15B, the posterior leaflet 1202P may include an extension 1709 that includes additional material to enlarge the size of the anterior leaflet 1202P. The dimensions of extension 1709 are approximately 1-5 mm in length and approximately the width of the incision forming the anterior leaflet (eg, incision 1220 of FIG. 11 ). In some embodiments, the extension 1709 is sutured at one end to the edge of the anterior leaflet 1202P (see incision 1220 of FIG. 11 ), and at the other end will include an umbilical cord 1708 which can be similar to the umbilical cords 608, 610 of FIG. 6A.

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

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

16A-16B are schematic illustrations of side views of a mitral valve prosthesis with extensions and an attached umbilical cord during 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 showing the profile 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. Anterior leaflet 1202A and posterior leaflet 1202P are spaced apart from each other to allow blood to flow into the left ventricle through the orifice between leaflets 1202A and 1202P. Extensions 1703, 1709 impart an enhanced coaptation profile to the valve prosthesis. Each of the leaflets 1202A and 1202P may have attached extensions 1703, 1709 that provide additional material to the anterior and posterior leaflets, providing the necessary coaptation during systole to prevent backflow of blood into the atrium and to the left during systole. The ventricles provide support.

In some embodiments, extension 1703 and extension 1709 are made to have different dimensions (eg, length, width, and shape). In some embodiments, the umbilical cords 1704, 1708 may be tied and secured together by sutures prior to attachment to the cap 1870.

Extensions 1703 and 1709 are respectively configured to carry respective umbilical cords (1704, 1708), which are similar to those of a natural heart valve and which should be inserted into a heart chamber and attached to the heart wall muscles or papillary muscles. For example, extension 1703 may carry umbilical cord or set of umbilical cords 1704 and extension 1709 may carry umbilical cord or set of umbilical cords 1708 . Each of the at least two umbilical cords may be connected at the other 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 Figure 16A, leaflets 1202A and 1202P and respective extensions 1703 and 1709 are spaced apart from each other to allow blood to flow in one direction from the left atrium to the left ventricle.

In some embodiments, during systole, as shown in FIG. 16B , leaflets 1202A and 1202P and their respective extensions 1703 and 1709 are in close proximity to each other to prevent flow of blood in the opposite direction (i.e., from the left ventricle to the left atrium). Backflow or leakage. According to some embodiments, extensions (eg, extensions 1703 and 1709 ) provide the necessary coaptation or closure of the valve to prevent leakage of blood backflow from the left ventricle to the left atrium.

According to some embodiments, extensions may be cut to fit leaflet edges and measure different widths not less than 5mm to ensure adequate coaptation. The extension will be attached to the leaflet by suturing, gluing, stapling or otherwise attaching to the edge of the leaflet.

According to some embodiments, the umbilical cords (e.g., umbilical cords 1704 and 1708) may be attached individually, e.g., sutured to the ventricular wall or to the papillary muscles, or may be bundled together, e.g., in pairs, tetrads, and so on, It depends on the design determined to be optimal for a particular patient.

According to some embodiments, the umbilical cord may be asymmetrical. That is, the size of the umbilical cord can vary because the left ventricle has two papillary muscles, and the umbilical cord arising from various points of the lobulal extension can include different lengths and distances from the top edge of these muscles. Thus, each umbilical cord or cord bundle may have an individualized different length compared to the other umbilical cords or cord bundles. This will ensure perfect closure and adequate coaptation length of the prosthetic valve.

In some embodiments, the umbilical cords (eg, umbilical cords 1704 and 1708 ) arising from the leaflet extensions (eg, extensions 1703 and 1709 ), respectively, can be distributed along the edges of the anterior and posterior leaflet extensions so that when the valve As it moves through the body, tension is evenly distributed along the edges of these leaflets, reducing wear and tear on the prosthetic valve.

17 is a schematic illustration of attaching an asymmetric flexible ring to the periphery of a valve prosthesis to mimic a 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 ring, or by rolling a piece of material with a hole in the middle onto itself, towards the outside of the material. In some embodiments, the coiled ring 1901 can be attached to the periphery of the mitral valve prosthesis 1200 to allow for surgical attachment, such as suturing to the patient's annulus, to allow for better stiffness of the annulus, and to allow for better stiffness in the annulus when using elastic materials. The case provides better elasticity in the cardiac cycle that varies between systole and diastole. The crimp ring 1901 can fit around the perimeter of the initial severed valve 1200 (FIG. 10).

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

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

17, prosthetic valve 1200 can include umbilical cords 1704 and 1706, which can be attached to anterior leaflet 1202A (with or without extensions), and umbilical cords 1708 and 1710, which can be attached to Posterior leaflet 1202P (with or without extension). As shown in FIGS. 16A-16B , the umbilical cord can be attached to at least two caps configured to attach the valve 1200 to the papillary muscles of the heart so that the mitral prosthetic valve 1200 can be properly attached to A patient's left ventricle, according to the specific anatomical and physiological requirements of a particular patient.

18A-18B are schematic illustrations, respectively, of elastomeric material inserted into a rolled valve annulus before and after the ring is rolled thereon, according to some embodiments of the present disclosure. According to some embodiments, as shown in FIGS. 18A-18B , the valve ring 2201 can include an added elastic material 2205 that can be inserted into the ring 2201 such that the ring 2201 rolls on the elastic material 2205 and the elastic material 2205 "clamps". In" ring 2201. The addition of elastic material 2205 within ring 2201 serves to provide additional elasticity to ring 2201, which may help to better mimic the elastic properties of the native mitral valve. In some embodiments, elastic material 2205 can 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 as to enable easy insertion of the elastic material 2205 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 extension of an alternative material attached to the outer edge of the leaflets) may be on the elastic material 2205 towards the inside of the synthetic valve. Roll, for example, towards incision 2220, which can be made along the middle of the leaflet portion, in a crescent or semicircular shape, to provide an opening between the two leaflets defined by incision 2220, for example, anterior leaflet 2202A and Posterior leaflet 2202P. The incision 2220 is actually the actual mitral prosthetic orifice through which blood flows from the left atrium to the left ventricle. Thus, the outer edge of the mitral valve prosthesis can include ring 2201, then connected to ring 2201 are the major surfaces of the leaflets, such as leaflets 2201A and 2202P, which are then connected to the papillary muscle via cap 2270 via the umbilical cord (e.g., umbilical cord 2204) .

Figure 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 fabricating a mitral valve prosthesis customized for each patient may include operation 2002, which may include measuring the size and shape of a patient's mitral valve by imaging methods. The imaging modality to measure the shape and size of the mitral valve in a particular patient can be echocardiography, cardiac CT, cardiac MRI and any other imaging modality. Method 2000 may also include an operation 2004 of cutting a replica of the patient's mitral valve from the single piece of material at a 1:1 ratio. In some embodiments, method 2000 may include an operation 2006 of cutting an incision along the single piece of material, thereby creating an orifice for blood flow and creating two leaflets, one on each side of the orifice. Method 2000 can include an operation 2008 of measuring a desired umbilical cord length by an imaging method, which can be similar to the imaging method used to measure mitral valve shape and size in operation 2002 .

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

In some embodiments, method 2000 can include operation 2012, which can include attaching a flexible ring to the leaflets, thereby creating an entire mitral valve prosthesis that mimics the native mitral valve for each particular patient.

In some embodiments, method 2000 may also 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 can help provide proper coaptation and closure during systole of the cardiac cycle.

According to an embodiment of the present disclosure, the motivation for implementing the method for fabricating a personalized, naturally designed mitral valve prosthesis is the expectation that the valve will last longer than current valve prostheses because the personalized valve is fabricated to Fits the exact anatomical dimensions and limitations of each patient. A personalized prosthesis will serve better than any best quality prosthesis because it fits the patient, allows superior hemodynamic performance and faster or better cardiac recovery after prosthesis implementation.

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 an off-the-shelf product in current practice. Conversely, after ordering a personalized mitral valve prosthesis at operation 2022, the remote diagnostic imaging scan performed at operation 2024 may be used as the basis for personalized mitral valve prosthesis dimensions at operation 2026, thereby providing a basis for personalizing mitral valve prosthesis dimensions at operation 2028. Create more accurate personalized valve prostheses for individual patients. In some embodiments, method 2020 may include packaging and shipping the individualized nature-designed mitral valve prosthesis for implantation in a particular patient at operation 2030 . In some embodiments, scanning is performed in a very short time prior to manufacture 2028 in order to enable a personalized mitral valve prosthesis to be fully compatible with the patient.

Reference is now made to FIG. 20B , which is a schematic flowchart illustrating a method 2040 for fabricating a personalized mitral valve prosthesis, according to some embodiments of the present disclosure. Method 2040 is similar to method 2020, but may include different operations. In some embodiments, method 2040 may include operation 2042, which may include measuring the size and shape of the patient's native mitral valve by imaging methods. Diagnostic imaging techniques can be, but are 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 also include operation 2044, which may include calculating the geometry and dimensions of the annular ring, leaflets, and umbilical cord of each patient-specific mitral valve prosthesis based on a validated algorithm. Proven algorithms such as the calculations that help define the appropriate mitral valve prosthesis size for each specific patient are detailed below.

In some embodiments, method 2040 can include operation 2046, which can include cutting and joining all parts of a personalized prosthetic mitral valve, i.e., annular ring, leaflets, and umbilical cord, based on calculations, which can be tailored to each patient. Patient-specific anatomy and individual physiology are performed to create a personalized mitral valve prosthesis.

In some embodiments, method 2040 may include operation 2048, which may include implanting a personalized prosthetic mitral valve into a heart of a patient for whom a personalized mitral valve prosthesis has been fabricated.

Reference is now made to FIGS. 21A-21B , which illustrate schematic diagrams of the annular valve margins preserved when the native mitral valve is removed in clinical practice, and schematic diagrams of oval valve annulus models, respectively, according to some embodiments of the present disclosure, wherein AL- The PM diameter as the major axis and the A-P diameter as the minor axis were used to calculate the annular circumference (AC) of the valve prosthesis.

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

mitral annulus (MA);

Circumference of the annular ring (AC);

Anterior-posterior diameter (A-P);

Anterolateral posteromedial diameter (AL-PM);

commissural diameter (C-C); and

Annular Area (AA).

Mitral Prosthetic Annulus:

According to some embodiments, the personalized mitral valve prosthesis of the present disclosure includes a flexible annular ring sized to match the patient's native mitral valve annulus. According to the present disclosure, a mitral valve prosthesis can be individualized or individualized based on the following characteristics.

The first feature is that the annular ring of the prosthesis is fabricated without being constrained by any rigid frame and is therefore compatible with the patient's mitral annulus.

A second feature is that the perimeter size of the prosthetic annular ring is personalized based on diagnostic imaging results for a particular patient, eg, as performed in operation 2022 of FIG. 20B . In some embodiments, the size of the prosthetic annular ring is calculated as the antero-posterior diameter (A-P) shown in FIG. 21A and the anterolateral-postomedial diameter (A-P) shown in FIG. AL-PM) functions.

A third feature is the preservation of the annular valve rim 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 valve annulus . The annular ring size of the personalized prosthesis in terms of annular circumference (AC) can be calculated according to equation (i):

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

take this

A-P diameter is anterior-posterior diameter;

AL-PM diameter is the anterolateral posteromedial diameter; and

d is the width of the annular ring edge.

Based on equation (ii) the AC(1) of the valve prosthesis was calculated using an approximate formula derived from an elliptical valve annulus with the AL-PM diameter as the major axis and the A-P diameter as the minor axis (Fig. 21B):

(ii)

In some embodiments, further adjustment of the annular circumference (AC) of the mitral valve prosthesis is required compared to the patient's native valve annulus, and such adjustment usually refers to reducing the annular circumference (AC) size. In these cases, the annular ring of the mitral valve prosthesis may serve as an annuloplasty treatment for a dilated valve ring in some patients with such problems. On the one hand, the proportion of AC reduction can be in the range of 0% to 20%, and the actual value can preferably be determined by existing clinical diagnosis, or by a mathematical model established by big data analysis or based on the relationship with healthy people's body surface area (BSA) The comparison of index values is simply and more practically determined. On the other hand, when a neovalvular prosthesis improves leaflet coaptation, the tendency toward annular remodeling after prosthetic implantation also requires a reduction in AC; thus, the rate of reduction (λ) also depends on the patient's potential for cardiac recovery. 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 ratio of AC reduction (from natural annular ring circumference to personalized prosthetic annular ring).

According to some embodiments, loop folding techniques may be used when AC reduction is required. The annular fold may be a uniform annular fold along the annulus rather than the partial annular fold typically performed during annuloplasty. Due to the fact that the posterior leaflet accounts for a greater portion of the entire mitral valve circumference, the annular folds according to embodiments of the present disclosure may be more focused on the posterior leaflet annulus. In addition, the posterior annulus of the human heart lacks a fibrous skeleton and is prone to dilatation, symmetry, or asymmetry, where the posterior annulus dilates, causing leaflet separation 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 comprising two leaflets consisting of an anterior leaflet 2210 ( FIG. 22A ) and a posterior leaflet 2220 ( FIG. 22B ). Thus, the annular ring of a valve prosthesis may also comprise two parts: an anterior annulus and a posterior annulus. The top edges of the anterior and posterior leaflets can be joined together in anterolateral to anterolateral and posteromedial to posteromedial directions to form the annular ring 2230 of the mitral valve prosthesis (Fig. 22C). That is, the anterolateral side of the anterior leaflet 2210 is attached to the anterolateral side of the posterior leaflet 2220 , and the posteromedial side of the anterior leaflet 2210 is attached to the posteromedial side of the posterior leaflet 2220 .

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

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

(iv)

(v)

Reference is now made to FIGS. 22D and 22E-22F , which show a model of the annulus indicating the two papillary muscles, and customized models of the anterior and posterior leaflets, respectively. In some embodiments, the anterior leaflet annular circumference (AAC) and posterior leaflet annular circumference (PAC) can be defined by using the new suture locations A and B shown in Figure 22D. New suture locations A and B can be selected based on the location of each of the two papillary muscles PM1 and PM2, which can define an anterior leaflet, such as anterior leaflet 602A ( FIG. 6A ) and a posterior leaflet, such as The posterior leaflets 602P of the AAC and PAC are identified relative to each other (FIG. 6A). 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 could be fabricated based on the new suture positions A and B caused less deformation after implantation. In some embodiments, Figures 22E-22F illustrate the anterior and posterior leaflet models after implementation of new suture locations A and B. According to the current annulus model, the anterior leaflet annular circumference (AAC) may be slightly longer than the posterior leaflet annular circumference (PAC), which may be contrary to the disclosure of Figs. 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 leaflets:

Reference is now made to FIG. 23C , which is a schematic diagram of the relationship of various parameters that affect each other when the leaflets of the prosthesis coapt, according to some embodiments of the present disclosure, and reference is now made to FIGS. 24A-24B , which are each according to some embodiments of the present disclosure. Schematic illustration of the side view and perspective view of the mitral valve leaflet coaptation. According to some embodiments, a mitral valve prosthesis of the present disclosure may include two flexible membranous leaflets suspended from an asymmetric annular ring 2230 . The two leaflets open during the diastolic cycle to allow blood to flow from the left atrium to the left ventricle, then the two leaflets close tightly allowing blood to flow through the heart in one direction without backflow through the valve during the systolic cycle. The size of the two leaflets is critical to ensuring proper opening and closing of the prosthetic valve.

For a healthy mitral valve, the valve prosthesis can be customized with leaflet lengths replicated from diagnostic imaging findings. However, for patients with mitral valve dysfunction requiring replacement, measurements of anterior leaflet length (La) and posterior leaflet length (Lp) are neither feasible nor useful in individualizing or individualizing a new valve prosthesis. Instead, the anterior-posterior diameter (A-P, which may be referred to as A2P2) can be used as a reference representing the minimum distance or length of leaflet coaptation. The ratio (r) of the length of the anterior leaflet to the length of the posterior leaflet can vary from 1/1 to 2/1 (this is the reference ratio).

In some embodiments, leaflet length is affected by coaptation depth (Cd), coaptation height (CoaptH), and umbilical cord length (Lc), in addition to anterior-posterior diameter (AP) and ratio (r). Thus, the anterior leaflet length (ALL) and posterior leaflet length (PLL) can be a function of all 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, empirical formulas are used to calculate the anterior leaflet length (ALL) and posterior leaflet length (PLL) in animal models when the anterior-posterior diameter (A-P) is less than 28 mm. These formulas proved effective in either porcine or sheep models, showing low mean transmitral pressure gradients and acceptable leaflet coaptation (Figure 24). Formulas (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 multilayered reinforcing annular ring of the valve prosthesis, such as asymmetrical annular ring 2230 . The top edges of the leaflets can be straight or curved, i.e. semi-elliptical, so that the finished valve prosthesis more accurately fits the natural geometry of the left ventricle. Down the annular ring, two commissures are formed when the two leaflets come together, such as commissures 2310 and 2312 (Fig. 22C). The inward slope of the commissures allows the body of the valve prosthesis to be slightly tapered to better conform to the shape and contours of the left ventricle. The tilt angle (δ ₀ ) may range between 5 degrees and 20 degrees. The cone angle (δ ₁ ) is determined from the oblique angle (δ ₀ ) of the commissural border of the leaflets according to equation (x):

(x)

According to some embodiments, the tilt angles (δ ₀ ) of the two leaflets are equal, thus the cone angles (δ ₁ ) of the two leaflets are equal.

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

(xi) Length of free edge = {2π×|ALL (or PLL)-b-CH×cosδ0-Coapt H+4a-CH×sinδ0-ALL or PLL-b-CH×cosδ0-Coapt H÷2

where CH represents the length of the commissural edges 2214 and 2216, as shown in Figures 22A and 22B, respectively.

Parameters "a" and "b" are the geometrical parameters required to define and form the shape of the top edge of the anterior or posterior leaflet which is curved to have a major axis of "a" and a minor axis of "b" A semi-ellipse, as shown in Figure 23A, or a straight line, as shown in Figure 23B.

和“b＝0”，小叶的自由边缘可以根据等式(xi)计算为：Figure 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):

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

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

Reference is now made to FIG. 23D , which is a schematic flowchart illustrating a method of customizing mitral valve design using FEM. According to some embodiments, method 2300 may include operation 2320, which may include providing patient mitral valve-related data, eg, providing the size and shape of a particular patient's native mitral valve. Patient mitral valve related data may include, for example, annulus circumference, annulus diameter, papillary muscle position, and the like. Method 2300 may also include operation 2330, which may include providing incoming bovine pericardium data describing material properties of the supplied (or incoming) bovine pericardium. In some embodiments, afferent data of the material from which the prosthetic mitral valve may be made, for example, afferent bovine pericardium data may include, for example, bovine pericardium thickness, tensile test data such as Young's modulus, stress- strain curve, etc.

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

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

In some embodiments, after the custom prosthetic mitral valve is designed, visualized, and manufactured, the method 2300 can include an additional operation 2370 comprising performance verification testing of the custom prosthetic mitral valve, e.g., at In vitro hydrodynamic chamber test.

According to some embodiments, the customized valve design method may include providing the patient's mitral valve parameters and afferent bovine pericardium data according to operations 2320 and 2330, respectively. An example of such data is provided in Table 1 below. In this example, the patient's valve commissure diameter is 36 mm.

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

Patient Mitral Valve Parameters Valve [mm] Commissural 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 (ZH) from PM to annulus 30.0 Bovine Pericardium Thickness (BPTH) 0.28 Bovine Pericardium Young's Modulus (BPYM) 30.0MPa

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

Table 2: Customized Leaflet Parameters

Custom leaflets Valve [mm] Commissural diameter C-C(CC) 36.0 Posterior Circumference (PAC) 51.6 Anterior circumference (AAC) 63.2 Posterior leaflet length (PLL) 25.0 Anterior leaflet length (ALL) 25.0

In some embodiments, the anterior leaflet length (ALL) and posterior leaflet length (PLL) may be influenced by patient mitral valve data (e.g., commissure diameter, papillary muscle distance, etc.) as well as incoming bovine pericardial data (e.g., bovine pericardial thickness). and Young's modulus). That is, according to formulas (xii) and (xiii), ALL and PLL can be functions of the above parameters and additional parameters, respectively:

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

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

take this

CC means commissural diameter;

DBPM means the distance between the papillary muscles;

ZH represents the Z height from the papillary muscle to the annulus;

BPTH denotes bovine pericardial thickness; and

BPYM denotes bovine pericardium Young's modulus.

In some embodiments, empirical formulas can be proposed to calculate the anterior leaflet length (ALL) and posterior leaflet length (PLL) of other patients based on the CC 36.0 mm FEM correlation data described above. The final anterior and posterior leaflet lengths need to be verified by FEM methods. In some embodiments, ALL and PLL can be calculated by equations (xiv) and (xv), respectively:

(xiv)ALL=(CC*DBPM*ZH*BPTH/BPYM)*α

(xv)PLL=(CC*DBPM*ZH*BPTH/BPYM)*β

take this

α is an anterior leaflet length magnification factor, eg 0.1033; and

β is the posterior leaflet length scaling factor, eg 0.1033.

Mitral prosthetic umbilical cord:

In a normal mitral valve, the umbilical cord is fan-shaped, extending from the papillary muscle and inserting into the leaflets. Depending on where they connect, they are divided into primary, secondary and tertiary umbilical cords.

The mitral valve prosthesis of the present disclosure includes only the primary umbilical cord attached to the free edges of the anterior or posterior leaflets. Two sets of umbilical cords (Fig. 24A) and three cords in each set (Fig. 24B) are evenly spaced from both ends along 3/8 of the free edge; these are the anterolateral and posteromedial umbilical cords.

The umbilical cord plays an important role in ensuring proper opening and closure of valve prostheses. Compared with other geometric features of the mitral valve, the umbilical cord, especially the length of the umbilical cord, is currently not well studied during clinical pre-diagnosis, especially per valve replacement. Cord measurements can be defined as the distance from the apex of the papillary muscle to the plane of the annulus, the distance from the apex of the papillary muscle to the coaptation margin, or the distance from the apex of the papillary muscle to the annulus.

For individualized prosthesis 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 Function of complex structural prostheses. Thus, the length of the anterolateral umbilical cord (ACL) and the length of the posteromedial umbilical cord (PCL) can be expressed as a function of several parameters according to the following equations (xvi) and (xvii):

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

(xvii) PCL = f(ALL, Coapt H, Cd, Lc (posteromedial))

The present disclosure also introduces a simplified method by using the measured distance from the apex of the papillary muscle to the coaptation edge as the length of the prosthetic umbilical cord, namely ACL=Lc (anterolateral) and PCL=Lc (posteromedial); from the design level As seen, the three umbilical cords of each set will be merged at the free ends and fused into a pledget similar to the umbilical cord cap 2240 (FIGS. 22A and 22B). The clinical surgeon can complete the final piece of personalized or custom-made mitral valve prosthesis by performing on-site measurements and adjustments. 25 is a photograph of an echocardiogram of a sheep heart implanted with a personalized natural engineered mitral valve prosthesis fabricated according to the methods of the present disclosure.

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

(xviii)CW=(CC*DBPM*ZH*BPTH/BPYM)*γ

take this

γ represents the umbilical cord width magnification factor, for example 0.0124.

In some embodiments, the final umbilical width needs to be verified using FEM methods.

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

Figure 27 is a schematic illustration of the final customized 3D model of a prosthetic mitral valve including a D-shaped annular ring. A 3D model of the prosthetic mitral valve may be constructed based on the patient's mitral valve data provided in operation 2320 and may further be based on the incoming bovine pericardium data provided in operation 2330 of method 2300 .

28 is a schematic illustration of FEM simulation optimization results of a customized prosthetic mitral valve model according to operation 2340 of method 2300 . Figure 28 shows a FEM model of the prosthetic mitral valve in a closed configuration. It is evident that the annular ring of the valve model is D-shaped, which is similar to the annular ring shape of the native mitral valve.

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

30 and 31 are images showing, respectively, an echocardiogram of a custom-made prosthetic mitral valve during its closed configuration after implantation in a porcine heart and the blood pressure gradient of a porcine heart after implantation. The custom prosthetic mitral valve closes and opens very efficiently and effectively without any leaks. The maximum pressure gradient may be 3.87mmHg, and the average pressure gradient may be only 1.61mmHg, which is similar to the pressure experienced by the natural human mitral valve.

The individual geometries and dimensions discussed above can be used as input for various engineering drawing software or drawing tools.

The drawing can be printed out as a template for manually cutting the leaflets of the valve prosthesis, for example under a microscope.

Drawings can be programmed into processing tools, such as laser cutters, for cutting leaflets more precisely and efficiently than manual cutting.

Drawings can also be programmed into the tooling to create a personalized die cutter or die cutter for leaflet cutting at a lower temperature than laser cutting, in order to minimize damage to the valve prosthesis cutting material heat impact.

A mitral valve prosthesis can be formed by joining together the annulus and commissural edges of the anterior and posterior leaflets in an anterolateral to anterolateral and posteromedial to posteromedial orientation (Fig. 22C). One way of joining the two leaflets together may be by suturing with surgical sutures, such as suture 2314 in Figure 22C.

The aforementioned valvular prosthesis may be further packaged, labeled and sterilized before being released for use, ie implanted in the patient for whom the valvular prosthesis is manufactured.

For ease of handling, the above-mentioned valve prosthesis can be assembled on the valve support before packaging.

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

According to some embodiments, any of the disclosed anterior and posterior leaflets, any ring, any umbilical cord (and any umbilical subset), any cap, and/or any combination thereof may be produced from natural materials and may avoid the inclusion of foreign matter, such as absorbent cotton . Allograft materials and/or composite materials, including various combinations of allograft, xenograft, and/or autograft materials, can further be used to fabricate flexible rings, leaflets, umbilical cords, and caps. Materials forming the valve annulus and leaflets may include, but are not limited to, human, bovine or porcine pericardium, decellularized bioprosthetic materials, braided biodegradable polymers associated with cells, and extracellular materials. Biodegradable natural polymers may include, but are not limited to, fibrin, collagen, chitosan, gelatin, hyaluronic acid, and similar materials. Biodegradable synthetic polymer scaffolds that can be wetted with cells and extracellular matrix materials can include, but are not limited to, poly(L-lactide), polyglycolide, poly(lactic-co-glycolic acid), poly(hexyl-lactide), lactones), polyorthoesters, poly(dioxanones), poly(anhydrides), poly(trimethylene carbonate), polyphosphazenes, and similar materials. The flexible ring can be further customized to provide individual flexibility or rigidity for the patient. In addition, some components of the mitral prosthesis, including the umbilical cord, can be formed intraoperatively from the patient's native pericardium.

According to some embodiments, any of the disclosed asymmetric flexible loops, which may include anterior and posterior loop portions or may be made as a single unit, may be formed by rolling or folding the edge of the leaflet onto itself. In other embodiments, the flexible loop may further comprise at least two strands or layers of material, such as human, bovine, or porcine pericardium, or any of the materials listed above, whereby the at least two strands or layers may be coiled, stranded, Braid or wrap around another. A ring constructed with a coiled coil may include greater strength than a ring formed by merely rolling the edge of the leaflet onto itself, however, the coiled ring should retain its elasticity.

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

In some embodiments, at least two layers or strands can be attached, eg, sewn to each other. In some embodiments, a third layer can be attached, eg, sewn, to at least two layers of the ring.

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

In some embodiments, sutures or sutures may be made from non-biodegradable synthetic materials such as nylon (ethilon), acrylic (polypropylene), Novalfil, polyester, and the like. In some embodiments, the suture or thread can be made from a non-biodegradable natural material, such as surgical silk or cotton.

In some embodiments, the staples can be made of biocompatible materials, such as stainless steel or titanium.

In some embodiments, the glue can be made from biocompatible materials such as aldehyde-based glues, fibrin sealants, collagen-based adhesives, polyethylene glycol polymers (hydrogels), or cyanoacrylates.

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

While preparing the patient for implantation, 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 natural annulus with sutures, and the nipple cap is sutured to the natural papillary muscle. For example, two sutures can be applied at the tip of each natural papillary muscle, securing the cap to the muscle. Clinicians ensure that the valve will fully open and close by filling the ventricular chamber with saline at the appropriate pressure and checking the movement and ability of the replacement valve to close when pressure is applied. After implantation, the valve is examined with a transesophageal echocardiogram (TEE) after the heart has closed and resumed beating.

Subjects may be placed on anticoagulant medication after implantation, if necessary. Given the natural shape and natural materials used to construct the mitral valve prosthesis of the present invention, low doses or no anticoagulant medications are expected for most patients.

Currently available biological and mechanical prostheses have several disadvantages: they contain bulky foreign bodies, require strong anticoagulant drugs, have a short lifespan, require the patient to undergo follow-up surgery when they must be replaced, and do not help the heart function effectively after implantation. recover. The present invention offers several advantages over the biological and mechanical prostheses described above. The described mitral valve prosthesis is designed to more closely match the patient's native mitral valve and is made of natural materials, which are expected to require less patient recovery time, provide a longer useful life, and reduce or omit confrontation The need for coagulation drugs.

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

While the invention has been particularly shown and described with reference to example embodiments thereof, it will be understood by those skilled in the art that various changes may be made in form and detail without departing from the scope of the invention encompassed by the appended claims. Change.

Claims (39)

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:

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 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.

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