Claims:WE CLAIM
1. A process of anti-calcification of leaflets comprising:
• treating a tissue with a fixative agent in an environment having a low-oxygen concentration;
• heat treating the fixed tissue at a predefined temperature for a predefined time duration in an environment having the low-oxygen concentration;
• treating the heat-treated tissue with a solution of one or more blocking agents in predefined concentrations;
• rinsing the treated tissue with a solution of aldehyde, alcohol and surfactant (AAS solution); and
• washing the rinsed tissue with an alcohol solution to yield an anti-calcified tissue.
2. The process for anti-calcification of the leaflets as claimed in claim 1 wherein the environment having the low-oxygen concentration includes 5%- 10% of oxygen.
3. The process for anti-calcification of the leaflets as claimed in claim 1 wherein the fixative agent includes an aldehyde compound.
4. The process for anti-calcification of the leaflets as claimed in claim 1 wherein the aldehyde compound includes glutaric dialdehyde, formaldehyde, glutaraldehyde acetals, epoxy compound, carbodiimides or combinations thereof.
5. The process for anti-calcification of the leaflets as claimed in claim 1 wherein the predefined temperature is in a range of 30-60 °C.
6. The process for anti-calcification of the leaflets as claimed in claim 1 wherein the predefined duration is in a range of 06-08 days.
7. The process for anti-calcification of the leaflets as claimed in claim 1 wherein the blocking agent solution is a mixture of one or more of sodium borohydride, ethanolamine, di-potassium phosphate, monopotassium phosphate, sodium chloride, and potassium chloride.
8. The process for anti-calcification of the leaflets as claimed in claim 1 wherein the AAS solution includes a mixture of one or more of aldehyde, alcohol and surfactant.
9. The process for anti-calcification of the tissue as claimed in claim 1 wherein the alcohol solution is a mixture of 99.9% pure ethanol and 20% saline. , Description:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(Section 10 and Rule 13)

1. TITLE OF THE INVENTION:
PROCESS OF ANTI-CALCIFICATION OF LEAFLETS
2. APPLICANTS:
Meril Life Sciences Pvt Ltd, an Indian company, of the address Survey No. 135/139 Bilakhia House Muktanand Marg, Chala, Vapi-Gujarat 396191

3. The following specification particularly describes the invention and the manner in which it is to be performed:

The following complete specification is filed as a divisional application of the pending Indian patent application no. 201921029558 filed on 22nd July, 2019.
FIELD OF INVENTION
[001] The present invention relates to a prosthetic heart valve, more specifically, the present invention relates to the prosthetic heart valve having a low crimp profile, highly anti-calcified leaflets and longer life span inside body lumen.
BACKGROUND
[002] The valves of a human heart can suffer from various diseases which result in malfunctioning of the heart causing serious cardiovascular compromise or death. The diseased heart valve may be stenotic and/or incompetent. A stenotic valve is one that is not able to open sufficiently to allow adequate blood flow through it while an incompetent valve is one that is not able to close completely causing blood to flow backwards in quantities more than that in a normally functioning valve. In such medical condition, prosthetic valve has been used for many years to replace the diseased valve. The prosthetic valve may incorporate a stent or a support frame which may be a tubular scaffold structure including a plurality of struts. Further, leaflets may be provided inside the tubular structure and a skirt around the inner/outer surface of the tubular structure. The prosthetic valve inside a body lumen has to mimic the function of a natural valve by performing rhythmic opening and closing of the leaflets. The skirt may function to prevent paravalvular leakage during aforesaid operation of the leaflets. Therefore, the aforesaid components play a significant role in determining performance of the prosthetic valve in a patient.
[003] However, the conventional prosthetic valve may pose several limitations such as high crimp profile and breakdown of struts of the support frame due to unequal stress distribution during crimping and/or expansion. The high crimp profile of the prosthetic valve may hinder optimal placement and/or maneuverability of the prosthetic valve.
[004] Further, the conventional prosthetic valve may have lesser life span after deployment in the body lumen due to wear and tear of the points of attachment of the leaflets and/or the skirt. Additionally, calcification of the leaflets and/or the skirt may lead to lesser life span. The calcification may further lead to obstruction and blockage of arterial region in a patient. Therefore, in order to solve the problem of calcification, various anti-calcification agents and/or methods have been adopted. Conventional anti-calcification methods may include blocking of aldehyde groups, calcium binding sites on the tissue, etc. using anti-calcification agents. However, all the conventional anti-calcification methods available involve treatment of tissue under an oxygen rich environment. Such treatment poses several problems such as deterioration of elasticity and strength of the tissue, early degradation of the tissue, oxidation of aldehyde groups to acid which forms a potential binding site for calcium, etc. to name a few.
[005] Therefore, there exists a need for an improved prosthetic valve that overcomes drawbacks of the conventional prosthetic valves.
SUMMARY
[006] The present invention discloses a prosthetic heart valve. The prosthetic heart valve includes a support frame having a proximal end, a distal end and three adjacently placed rows of cells between the proximal end and the distal end. The three rows include a primary row, a secondary row and a base row. The heart valve further includes a plurality of commissure posts which is provided in the primary row of the support frame. An inner skirt is attached to an inner side of the proximal end of the support frame. An outer skirt is provided in the prosthetic heart valve. The outer skirt includes a first cuff having an upper end, a second cuff having a lower end and an intermediate region. The upper end, the lower end and the intermediate region are sutured to their respective predefined locations.
[007] A leaflet structure including three leaflets is provided. Each leaflet includes a first tab and a second tab oppositely placed with respect to the first tab. The first tab of a first leaflet and a second tab of a second leaflet are attached to the respective commissure post to firmly hold the leaflet to the support frame. The first tab of the first leaflet and the second tab of the second leaflet are projected from the respective commissure post to the outer side of the support frame. The first tab of the first leaflet and the second tab of a second leaflet are thereafter folded to form an L-shaped structure at the inner side of the support frame.
[008] The leaflets of the present invention are anti-calcified using a process of anti-calcification in a condition of low concentration of oxygen.
BRIEF DESCRIPTION OF DRAWINGS
[009] The summary above, as well as the following detailed description of illustrative embodiments, is better understood when read in conjunction with the appended drawings. For the purpose of illustrating the present disclosure, exemplary constructions of the disclosure are shown in the drawings. However, the disclosure is not limited to specific methods and instrumentalities disclosed herein. Moreover, those in the art will understand that the drawings are not to scale.
[0010] In the figures and the description to follow, the terms “frame” or “stent” or “frame structure” or “scaffold structure” or “support frame” or “scaffold” refer to the metallic frame of this invention. These terms are used interchangeably but carry the same meaning. The term “valve” or “prosthetic valve” or “prosthetic heart valve” refer to the prosthetic valve of this invention assembled using the frame structure and other components like leaflets of animal tissue, skirt, etc. These terms are also used interchangeably. The term “native valve” is used for the natural valve in human heart
[0011] FIGs. 1A-1B represent perspective views of a prosthetic heart valve in accordance with different embodiments of the present invention.
[0012] FIGs. 2A-2D represent perspective views of a support frame in accordance with different embodiments of the present invention.
[0013] FIG. 3 represents a flow chart depicting a process involved in anti-calcification of a tissue in accordance with an embodiment of the present invention.
[0014] FIG. 3A represents a graph of pH of glutaric dialdehyde solution with time duration of heat treatment under an environment of low oxygen concentration in accordance with an embodiment of the present invention.
[0015] FIG. 3B represents a graph of pH of glutaric dialdehyde solution with time duration of heat treatment under an environment of normal oxygen concentration in accordance with an embodiment of the present invention.
[0016] FIG.4 represents a front view of a leaflet in accordance with an embodiment of the present invention.
[0017] FIGs. 4A-4G represents stitching of the leaflet to the support frame in accordance with an embodiment of the present invention.
[0018] FIG. 5 represents a front view of a skirt in accordance with an embodiment of the present invention.
[0019] FIG.5A-5C represent different embodiments of the skirt in accordance with an embodiment of the present invention.
[0020] FIG.5D represents stitching of the skirt to the frame in accordance with an embodiment of the present invention.
[0021] FIG.5E represents interweaving of PET fibers in accordance with an embodiment of the present invention.
DETAILED DESCRIPTION OF DRAWINGS
[0022] Prior to describing the invention in detail, definitions of certain words or phrases used throughout this patent document will be defined: the terms "include" and "comprise", as well as derivatives thereof, mean inclusion without limitation; the term "or" is inclusive, meaning and/or; the phrases "coupled with" and "associated therewith", as well as derivatives thereof, may mean to include, be included within, interconnect with, contain, be contained within, connect to or with, couple to or with, be communicable with, cooperate with, interleave, juxtapose, be proximate to, be bound to or with, have a property of, or the like; Definitions of certain words and phrases are provided throughout this patent document, and those of ordinary skill in the art will understand that such definitions apply in many, if not most, instances to prior as well as future uses of such defined words and phrases.
[0023] Particular embodiments of the present disclosure are described herein below with reference to the accompanying drawings; however, it is to be understood that the disclosed embodiments are merely examples of the disclosure, which may be embodied in various forms. Well-known functions or constructions are not described in detail to avoid obscuring the present disclosure in unnecessary detail.
[0024] Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting, but merely as a basis for the claims and as a representative basis for teaching one skilled in the art to variously employ the present disclosure in virtually any appropriately detailed structure.
[0025] Although the operations of exemplary embodiments of the disclosed method may be described in a particular, sequential order for convenient presentation, it should be understood that the disclosed embodiments can encompass an order of operations other than the particular, sequential order disclosed. For example, operations described sequentially may in some cases be rearranged or performed concurrently. Further, descriptions and disclosures provided in association with one particular embodiment are not limited to that embodiment, and may be applied to any embodiment disclosed herein. Moreover, for the sake of simplicity, the attached figures may not show the various ways in which the disclosed system, method, and apparatus can be used in combination with other systems, methods, and apparatuses.
[0026] Furthermore, the described features, advantages, and characteristics of the embodiments may be combined in any suitable manner. One skilled in the relevant art will recognize that the embodiments may be practiced without one or more of the specific features or advantages of a particular embodiment. In other instances, additional features and advantages may be recognized in certain embodiments that may not be present in all embodiments. These features and advantages of the embodiments will become more fully apparent from the following description and appended claims, or may be learned by the practice of embodiments as set forth hereinafter.
[0027] Disclosed embodiments of an improved radially expandable and compressible support frame having a plurality of leaflets made of animal tissue can be used with any prosthetic valve, such as a prosthetic aortic heart valve. The prosthetic valve with the embodiments of the support frame offers many advantages as described further.
[0028] The terms “upper”, “middle”, “lower”, “vertical” and “horizontal” refer to a specific way an item or a component is shown in a diagram and do not refer to absolute direction or location.
[0029] The present invention discloses a balloon expandable prosthetic valve implanted by catheterization technique in a human stenosed aortic orifice.
[0030] The description interchangeably mentions “tissue”, “biological tissue” and “bioprosthetic tissue”. It must be noted that all such aforesaid stated phrases relate to the same interpretation.
[0031] In accordance with the present disclosure, a prosthetic heart valve having highly anti-calcified leaflets, low crimp profile and longer life span is disclosed. In various embodiments, the frame of the valve includes without limitation bracket shaped cells, honeycomb shaped cells and chevron shaped cells. The arrangement of the aforesaid shaped cells provides lower crimp profile leading to easy maneuverability and/or delivery of the valve at a treatment site. The frame holds a plurality of leaflets made of a biological tissue which are highly anti-calcified. The biological tissue may be an animal tissue which is anti-calcified via a series of steps in a low oxygen environment. The process of anti-calcification of the tissue under low oxygen environment prevents oxidative reaction of aldehyde groups, thereby preventing conversion of the aldehyde groups into acidic groups. Further, processing of the tissue under low oxygen environment prevents putrefactive changes in cells of the tissue, thereby preventing early degeneration and/or enzymatic degradation of the tissue. Moreover, maintaining low oxygen concentration during processing of the tissue improves physical properties of the tissue such as elasticity, strength etc. and/or chemical properties such as tissue shrinkage temperature.
[0032] In addition, a method of attachment of the leaflets and skirt over the frame of the prosthetic heart valve is disclosed. The novel method of the instant invention enhances deployment life of the prosthetic valve as wear and tear of the leaflets at the point of attachment is reduced.
[0033] Now referring specifically to the drawings, FIG. 1A represents a perspective view of a prosthetic heart valve 200. The prosthetic heart valve 200 may be a balloon expandable prosthetic valve implanted by catheterization technique in a human stenosed aortic annulus. A representative embodiment of the present disclosure provides a prosthetic valve having a flexible support frame which can expand and collapse, a plurality of leaflets (preferentially three leaflets) formed from an animal tissue and an annular skirt made from a fabric attached to the frame.
[0034] It is important that the prosthetic valve 200 is implanted precisely at an optimal location to ensure optimal performance. Ideally, the location of the leaflet structure 104 of the prosthetic valve 200 should be located where the cusps of the native valve are located i.e. at orthotopic location. This is generally achieved by the operator’s judgment during implantation under fluoroscopic imaging. The prosthetic valve 200 of the present invention guides the operator to position the prosthetic valve 200 precisely at the orthotopic position during implantation.
[0035] In an embodiment, the prosthetic heart valve 200 includes an inflow end 101, an outflow end 103, a support frame 100 which can expand and collapse, a leaflet structure 104, an inner skirt 50 and an outer skirt 40. In an embodiment, the outer skirt 40 includes two fabrics, a first fabric 40b and a second fabric 40c attached to the support frame 100. The presence of two fabrics 40b and 40c helps in effective sealing of an upper and a lower part of the native annulus and/or prevents paravalvular leakage more efficiently. In another embodiment, the prosthetic valve 200 includes a single outer skirt 40 (as depicted in FIG.1B). The outer skirt 40 may provide bulginess in the expanded state of the prosthetic valve 200, thereby preventing paravalvular leakage.
[0036] The support frame 100 of the prosthetic valve 200 is designed such that the frame 100 experiences equal stress distribution throughout its surface during crimping/ expansion and/or imparts lower crimp profile resulting in enhanced performance of the prosthetic valve 100. The design of the support frame 100 may assist an operator in positioning and deploying the prosthetic valve 200 in precise orthotopic position by viewing under fluoroscopy during the process of implantation. The support frame 100 is a cylindrical structure having a predefined length and diameter. The length of the support frame 100 is such that the protrusion of the support frame 100 in LVOT after implantation at orthotopic position is limited to maximum 8.5mm, preferably around 6.5mm to 7.5 mm. This eliminates any possibility of disturbance of the cardiac muscles which carry electrical signals and/or interfere with normal functioning of the anterior leaflet of the aortic valve. The design of the support frame 100 makes the prosthetic valve 200 mechanically stronger and/or makes it possible to reduce the strut thickness of the frame 100 without compromising mechanical strength (radial strength and fatigue resistance) of the support frame 100.
[0037] The blood enters from the inflow end 101 of the prosthetic valve 200 and is discharged through the outflow end 103. Hence, after implantation of the prosthetic valve 200, the inflow end 101 is towards the left ventricle and the outflow end 103 is towards the ascending aorta.
[0038] FIGs 2A-2D represents different embodiments of the support frame 100 of an exemplary embodiment of the prosthetic heart valve 200. FIG. 2A depicts an elemental view of the support frame 100 of FIG.1A, when cylindrical portion of the support frame 100 is cut vertically along its length and flattened.
[0039] The support frame 100 includes a proximal end 106, a distal end 108 and three adjacently placed rows of cells extending between the proximal end 106 and the distal end 108. The support frame 100 includes a plurality of repetitive strut members a, b, b’, b’’, c and d interconnected to each other to form a scaffold of cells (as elaborated below). The cells may be interconnected to each other in order to yield a predefined geometry of the frame 100.
[0040] In an embodiment, the support frame 100 has three rows of cells. The three rows of cells include a primary row 105, a secondary row 107 and a base row 109. Each of the rows includes a plurality of cells. In an embodiment, the cells located in a single row have same cross-sectional area, e.g. cross-sectional area of the cells located in the primary row 105 is same. However, the cross-sectional area of the cells located in different rows may be same or different, e.g. cross-sectional area of cells in the primary row 105 may be same and/or different than the cells located in the secondary row 107 or the base row 109. In embodiment, the area of the cells of the primary row 105 is different than the area of the cells of one or more of the remaining rows.
[0041] The prosthetic valve 200 is structured and implanted in such a manner that the blood flows in at the proximal end 106 and flows out from the distal end 108. Thus, the end 106 of the support frame 100 may be considered as the “inflow end” (corresponding to the inflow end 101 in FIG. 1A) and the end 108 may be considered as the “outflow end” (corresponding to the outflow end 103 in FIG.1A). After the valve 200 is implanted across the native aortic annulus, the blood would enter the prosthetic valve 100 from the end 106 and would leave the valve 200 from the end 108. Hence, the end 106 of the frame 100 is placed towards the left ventricle and end 108 of the frame 100 is placed towards the ascending aorta.
[0042] The support frame 100 may include a plurality of commissure posts 102 which function to attach the leaflet structure 104 to the support frame 100. As shown in FIG. 2A, three commissure posts 102 are located on the primary row 105 of the support frame 100. In an embodiment, the commissure posts 102 are disposed at 120° with respect to each other.
[0043] The cells 201, 202 and 203 as depicted in FIG.2A may have same or different number of struts leading to same or different shapes of the cells. The sides of the cells 201, 202, 203 are commonly shared with sides of adjacent cells 201, 202, 203. The cells of each row may be designed in any shape. The shape of the cells 201 of the primary row 105 may be same and/or different to the secondary and the base row (107, 109). In various embodiments, the shape of the cells includes bracket shape, honeycomb shape, chevron shape. The combination of the different shapes of the cells of the three rows (105, 107, 109) provides a mechanically symmetric design and/or imparts equal stress distribution throughout the frame 100 resulting in adequate crimping and/or expansion of the prosthetic heart valve 200.
[0044] In the first embodiment of the present invention as depicted in FIG.2A, the cells 201 of the primary row 105 are designed in chevron shape and the cells 202 and 203 of the secondary row 107 and the base row 109 respectively are designed in the honeycomb shape. For instance, the cells 201 of the primary row 105 have strut members a, a’ and b and b’’. The cells 201 have a pair of chevron shaped strut members ‘a’ and v shaped strut members a’. The angle between the two struts forming the chevron shape and the V shape may be in a range of 90° to 105° and 120° to 135° respectively. Each straight strut that acts as the commissure post 102 is composed of a pair of commissure strut members b’ which form a window.
[0045] The cells 202 and 203 of the secondary row 107 and the base row 109 are hexagonal. As depicted in FIG.2A, each of the cells (202, 203) have strut members a’, c and d. Each of the cells (202, 203) has two pairs of v-shaped strut members a’ and two straight strut members c and d.
[0046] In the second embodiment as depicted in FIG. 2B, the cells of the primary row 105 are designed in the chevron shape and the cells of the secondary row 107 and the base row 109 are designed in pear shape. For instance, the cells 201 of the primary row 105 have strut members a, a’ and b. The cells 201 have two pairs of chevron shaped strut members ‘a’ and a’. Two adjacently placed cells 201 share a common strut member b. Each straight strut that acts as the commissure post 102 is composed of a pair of commissure strut members b’ which form a window.
[0047] The cells 202 and 203 of the secondary row 107 and the base row 109 are tetragonal. As depicted in FIG.2B, each of the cells (202, 203) have strut members a’.
[0048] In the third embodiment as depicted in FIG. 2C, the cells of the primary row 105 of the frame 100 are designed in chevron shape cells of the secondary row 107 and the base row 109 are designed in honeycomb shape. The cells 201 have two pairs of v shaped strut members a’. The cells 202 and 203 of the secondary row 107 and the base row 109 respectively are hexagonal. As depicted in FIG.2C, each of the cells (202, 203) have strut member a’, c and d. Each of the cells (202, 203) has two pairs of v shaped strut members a’ and two straight strut members c and d.
[0049] In the fourth embodiment as depicted in FIG.2D, each of the rows includes a bracket shaped hexagonal cells.
[0050] The aforesaid embodiments depict a frame 100 which is mechanically strong and has reduced strut thickness without compromising the mechanical strength of the support frame 100 viz. its radial strength and fatigue resistance. The thickness of the strut members in either of the above embodiments may be in a range of 0.35mm to 0.45mm. In an embodiment, the thickness of the struts is in a range of 0.385 mm to 0.415mm. Owing to low strut thickness, during radial compression of the prosthetic heart valve 200 over a balloon (not shown), the struts of the frame 100 do not overlap with each other. Moreover, during crimping, a low crimp profile of the prosthetic heart valve 200 is achieved while maintaining radial strength of the valve 200. The crimp profile of the valve 200 may be in range of 6.8mm to 8.0 mm and preferably 7.0 mm to 7.6 mm. In an embodiment, the crimp profile of the valve 200 is 7.3mm. The radial strength of the valve 200 may be in a range of 125 N to 190N preferably in the range of 140 N to 175 N. In an embodiment, the radial strength of the valve 200 is 161N.
[0051] During expansion of the valve 200, the stress in the struts is distributed equally thereby resulting in adequate expansion of the cells and zero breakage of the struts of the frame 100.
[0052] The frame 100 may be made of any biocompatible alloy. The alloy may include without limitation any biocompatible metallic alloys such as cobalt- nickel- aluminum alloy or cobalt - chromium alloy. In an embodiment, the frame 100 is made of cobalt-nickel-chromium alloy. The said alloy is chosen due to its excellent wear-resistance properties, biocompatibility, high melting point, and higher strength at a high temperature. The frame 100 may be manufactured by a process including steps but not limited to laser cutting, de-scaling, annealing and electro-polishing.
[0053] The cells 202 and 203 are located in the lower half of the support frame 100 structure i.e. towards the inflow end 101 of the prosthetic valve 200 (upstream of the blood flow) and are placed towards the left ventricle. The inflow end 101 of the prosthetic valve 200 experiences higher mechanical forces than the outflow end 103 of the prosthetic valve 200. In an embodiment, the cells 202 and 203 have lower cross- sectional area than cells 201. This results in more dense structure of cells 202 and 203 than cells 201 which imparts higher radial strength to the lower portion of the prosthetic valve 200 to withstand higher mechanical forces at this end.
[0054] In an embodiment, the primary row 105 made of cells 201 occupies around 50%-55%, preferably 53% of the total height of the support frame 100. The secondary row 107 and the base row 109 made of cells 202 and 203 together occupy the rest of the height of the support frame 100. In an embodiment, the secondary row 107 and the base row 109 occupy 47% of the total height of the frame 100. Hence, the cross-sectional area of cells 201 is larger than that of the cells 202 and/or 203.
[0055] The coronary arteries exit the ascending aorta above the native aortic valve in coronary sinus of Valsalva or above sino-tubular junction. These exit ports are termed as coronary ostia. The cusps of the native aortic valve are located in such a way that the blood supply to the coronary arteries through these ostia is not obstructed. It is, hence, necessary that a prosthetic valve also does not occlude or jail the coronary ostia and thereby does not obstruct the blood flow into the coronary arteries. On implantation of the prosthetic valve at the orthotopic position, the cells 201 are positioned generally above the native valve i.e. where the coronary ostia are located. As stated above, the length of the support frame 100 is low which ensures that the prosthetic valve 200 does not jail the coronary ostia. In addition, the cells 201 have higher cross -sectional area which further ensures that there is no obstruction to the blood flow to the coronary ostia.
[0056] Referring FIG. 1A again, the leaflet structure 104 of the prosthetic valve 200 may be attached to the frame 100. The leaflet structure 104 may be attached at the commissures 102 of the frame 100. To each commissure post 102, an attachment node of the leaflet structure 104 is attached. The attachment node of the leaflet structure 104 is sutured to each commissure post 102 of the support frame 100 as discussed below in description of FIGs. 4A-4F. The commissure posts 102 of the frame 100 include a pair of commissure strut members b’. The length of the commissure strut member b’ constituting the commissure post 102 may be less than the length of the opposite strut member b. The length of the commissure post 102 may vary depending upon the length of the attachment node of the leaflet structure 104. In an embodiment, the length of the commissure strut members b’ (constituting the commissure post 102) is almost half of the length of the strut member b as depicted in FIG.1A. The shorter commissure strut members b’ result in shorter commissure posts 102. The shorter commissure posts 102 of the present invention do not obstruct other strut members of the frame during the process of crimping of the valve 200.
[0057] The leaflet structure 104 of the prosthetic valve 200 may include a plurality of leaflets, preferably three leaflets. The three leaflets may collectively form the leaflet structure 104 which can be arranged to collapse in tricuspid arrangement. The leaflets may be made from an animal tissue, preferably bovine pericardium tissue. However, utilization of other tissues such as of bovine, porcine, ovine, canine origin to form the leaflets is also within the scope of the present invention. In an embodiment, the aforesaid animal tissue used to make the leaflets is anti-calcified prior to attachment with the support frame 100.
[0058] In an embodiment of the present invention, FIG.3 represents a flow chart depicting a process involved in anti-calcification of the tissue used to make a leaflet 10. The tissue sheets are obtained from an FDA approved abattoir in Australia, New Zealand or the USA. The tissue sheets may be washed with deionized water, salt solution, saline and/or other suitable washing solutions. In an embodiment of the present invention, the anti-calcification of the bioprosthetic tissue may involve without limitation, the following steps: fixation, heat treatment, blocking, AAS (aldehyde, alcohol, and surfactant) treatment, alcohol treatment, dehydration and storage of the tissue.
[0059] In accordance with an embodiment of the present invention, the process of anti-calcification of the tissue commences at step 301. Prior to fixation of the tissue at step 301, the tissue is rinsed with a saline solution in a concentration of 0.9% w/v and subsequently, placed on a fixative tray. At step 301, the tissue undergoes fixation using a fixative agent. In an embodiment, the fixation of the tissue is performed under an environment having low concentration of oxygen. The fixation of the tissue is performed for fixing fats and proteins over the tissue so that the tissue becomes non-reactive. The fixation process under low oxygen concentration prevents putrefactive changes in cells of the tissue, thereby preventing degradation of the tissue. Further, the aforesaid fixation process may provide a durable, chemically stable tissue and prevents enzymatic degradation and/or tissue degeneration. Moreover, the fixation of the tissue may change the collagen properties of the tissue and render the tissue acceptable to a human host.
[0060] The fixative agent may be any aldehyde compound known in the art. The aldehyde compound may include without limitation glutaric dialdehyde, formaldehyde, glutaraldehyde acetals, epoxy compound and carbodiimides. Due to the treatment of the tissue with the aldehyde compound(s), the fixed tissue retains some content of aldehyde during fixation to form an aldehyde containing tissue. In an embodiment, fixation enhances the strength and stability of the tissue.
[0061] In an embodiment, the fixation of the tissue is performed with glutaric dialdehyde. The concentration of the glutaric dialdehyde may be in a range of 0.05% to 1.80%. In an embodiment, the concentration of the glutaric dialdehyde is 0.625%. The process of fixation may be performed at a temperature of 8-10°C in low concentration of oxygen for time duration of 06-08 days. The concentration of the oxygen may be maintained in a range of 5%- 10% of fixation bath atmosphere. In an embodiment, the concentration of the oxygen is maintained around 8%-10%.
[0062] Due to fixation of the tissue with glutaric dialdehyde, the tissue retains the glutaric aldehyde to form an aldehyde containing tissue. The tissue containing the glutaric aldehyde is prone to calcification, as the glutaric dialdehyde gets oxidized to glutaric acid, which forms a potential binding site for calcium. However, fixation of the tissue under low oxygen environment reduces the content of glutaric dialdehyde being fixed on the tissue, therefore decreasing the plausibility of calcification of the tissue. Fixed tissue is further used for the improved anti-calcification and tissue dehydration process to make it calcification free.
[0063] At step 303, the fixed tissue is subjected to a process of heat treatment. In an embodiment, heat treatment is carried out in low oxygen concentration. The low-oxygen concentration decreases oxidation of aldehyde groups and/or increases crosslinking of aldehyde groups with amine groups of the tissue present in collagen. The crosslinking of the aldehyde groups with amine groups prevents the formation of negatively charged acids, which act as potential binding sites for calcium. Further, the tissue also retains its physical properties such as elasticity, strength, color etc. in the low oxygen environment.
[0064] The chemical compounds used in the heat treatment of the tissue may include without limitation glutaric dialdehyde, formaldehyde and carbodiimides. In an embodiment, the process of heat treatment is performed with glutaric dialdehyde solution. The concentration of the chemical compounds may be in the range of 0.1% to 0.625%. In an embodiment, the concentration of the glutaric dialdehyde solution is 0.5%. The pH of the solution may be approximately 7.42.
[0065] In an embodiment, for heat treatment, the fixed tissue is rinsed with a 0.9% w/v solution of saline for time duration of around 3 minutes. The rinsed tissue is placed in a glass borosilicate vessel equipped with an inlet and a vent line for heat treatment. The vessel is fed with a medical grade nitrogen gas having a pressure in the range of 1.0-3.0 psi for time duration of 5-20 minutes, preferably 10 minutes to maintain the environment of low concentration of oxygen inside the vessel. The low concentration may include 5% -10% concentration of oxygen inside the vessel. In an embodiment, the low concentration includes 8% to 10% concentration of oxygen inside the vessel. The oxygen content and temperature is maintained at a predefined oxygen content and temperature in a range of 8-10 % and 30-60 °C respectively, preferably 45-55 °C or more preferably 50 °C inside the vessel for predefined time duration of time duration of 06-08 days.
[0066] In an embodiment, after completion of the heat treatment of the tissue, the color of the solution turns pale yellow, and pH of the solution is found to be 7.29 representing the absence of acid in the solution. The solution may be extracted with toluene and/or ethylene dichloride to further examine for the presence of glutaric acid. A testing technique such as gas chromatography may be used to examine the presence of glutaric acid in the solution. During testing, formation of glutaric acid was found to be negligible in both the toluene or ethylene dichloride (EDC) extract.
[0067] Following heat treatment at the previous step, the tissue is subjected to a treatment with a blocking agent solution at step 305. The blocking agent blocks the free/unreacted aldehyde groups which have not been cross-linked with the amine group of the tissue at the previous step, thereby preventing in-vivo calcification of the tissue. The blocking agent may include an amine group without limitation alkyl amine, 2 aminoethanol, aminoalcohol etc. In an embodiment, the blocking agent is a mixture of sodium borohydride in a concentration of 0.03% to 0.499%, ethanolamine in a concentration of 0.004% to 0.06%, di-potassium phosphate in a concentration of 4.24% to 8.72%, monopotassium phosphate in a concentration of 0.76% to 2.90%, sodium chloride in a concentration of 3.0% to 7.1%, and potassium chloride in a concentration of 0.02% to 0.20%.
[0068] In an embodiment, for treatment of the tissue obtained in previous step with the blocking agent solution, the tissue is placed in a vessel containing 500 ml to 5000 ml of the blocking agent solution at a temperature in a range of 25 °C to 37 °C. The vessel is placed in an orbital shaker for gentle fluid movement. The tissue may be immersed in the blocking agent solution for time duration of 01 hour to 04 hours. In an embodiment, the tissue is immersed in the blocking agent solution for approximately 4 hours. The container may be covered with a perforated aluminum foil to allow discharge of hydrogen gas evolved during the blocking process. The concentration of various constituents of the blocking agent solution is provided in a table 1 given below. The resulting tissue is further rinsed with an AAS solution to remove traces of blocking agents.
Chemical (Solute) Total Volume (1 L)
Sodium Borohydride 0.30 gm (37.83 g/mol)
Ethanolamine 0.04 ml (61.08 g/mol)
K2HPO4 42.40 gm
KH2PO4 7.60 gm
NaCl 30.00 gm
KCL 0.20 gm
Table 1
[0069] At step 307, the aldehyde free tissue is subjected to a process of bioburden reduction by rinsing with an AAS solution. The AAS solution includes an aldehyde, an alcohol, and a surfactant.
[0070] The aldehyde present in the AAS solution may act as a sterilant, the alcohol may remove residual phospholipid content which is a binding substrate for calcium and surfactant has a tendency to adsorb at surface thereby blocking calcium binding sites in the tissue. The AAS solution may include aldehyde compound such as without limitation formaldehyde, glutaraldehyde, alcohol such as ethanol, isopropyl alcohol, surfactant such as polysorbate 80, polysorbate 60, polysorbate 20 etc. In an embodiment, formaldehyde, ethanol, and polysorbate 80 are used in a predefined concentration.
[0071] In an embodiment, for this step, the tissue is placed in a vessel containing 80 ml of AAS solution at a temperature of 37°C for time duration of approximately 03 hours. The vessel may be placed on a shaker having a rotational speed of approximately 50-60rpm. Due to gentle shaking, the process may be completed within a short period. The concentration of various constituents in the AAS solution is provided in table 2 given below.
Chemical Concentration %
Formaldehyde 1-5%
Ethanol 2-5%
Polysorbate 80 1-3%
Table 2
[0072] Optionally, after completion of the aforesaid process, the tissue may be washed with saline and/or stored in 0.625% glutaric dialdehyde solution in low concentration of oxygen. Storage of the tissue in low oxygen concentration increases shelf life of the tissue. Further, the storage of the tissue in low-oxygen environment helps to retain mechanical properties of the tissue.
[0073] At step 309, the AAS treated tissue is subjected to washing with alcohol. The alcohol may act as a denaturing agent for proteins and facilitate extraction of phospholipids from the tissue. Phosphorus molecule present in phospholipids acts as a potential binding site for calcium. Therefore, extraction of phospholipids mitigates the problem of in-vivo calcification after implantation. Further, treatment with alcohol may lead to alteration in collagen conformation and enhance tissue resistance to collagenases enzyme ultimately provides structural integrity to the AAS treated tissue. The alcohol may include without limitation ethanol, isopropyl alcohol.
[0074] In an embodiment, the tissue is treated with a solution having a mixture of 80% v/v (99.97% pure) of ethanol and 20% of saline. The tissue is immersed in a glass flask containing 1000 ml of the solution. The glass flask may be placed on an agitator having a rotational speed of approximately 50-60 rpm for rapid chemical reaction. The tissue may be treated for time duration of 2-8 hours, at a temperature of 37 °C. In an embodiment, the tissue is treated for approximately 4 hours.
[0075] After completion of the process, the tissue is rinsed with saline and may be examined for the presence of free reactive aldehyde groups. In an embodiment, the examination may be performed with the help of gas chromatography. The tissue was found to be free of any free aldehyde groups. Additionally and optionally, the tissue may be stored in the 0.625% of glutaric dialdehyde solution in low oxygen environment.
[0076] Lastly, at step 311, the tissue is subjected to a process of dehydration using a dehydrating agent. The dehydrating agent may include without limitation polyols, alcohols. In an embodiment, the tissue is immersed in a mixture of 75% glycerol and 25% ethanol for time duration of 1 hour at a temperature of 37°C temperature. The dehydration step may replace oxidane molecules by glycerol and may penetrate high amount of glycerol inside the tissue by applying adequate pressure. Thus, the tissue is dehydrated and can be stored in a “solid” state rather than “liquid” state. The storage of the tissue under dry conditions reduces oxidative reaction and prevents further calcification.
[0077] After completion of the process of dehydration, the dehydrated tissue is removed from the solution and may be dried in a clean hood that leads to drip off of excess glycerol solution. Additionally, the tissue may be exposed to incandescent light for elimination of excess glycerol present on the surface. The dehydrated tissue is further used to fabricate the heart valve and is subjected to EtO sterilization.
[0078] Lastly, at the step 313, the anti-calcified tissue is laser cut to form the leaflet 10 as depicted in FIG.4
[0079] The process of anti-calcification will now be explained with the help of the following examples.
[0080] Example 1- A tissue was obtained and washed with cold saline to remove debris, toxins, dead colonies, etc. from the tissue surface. The tissue was fixed with a solution of 0.625% glutaric dialdehyde for time duration of 06 to 08 days in a low oxygen environment. The fixation is performed at a concentration of 8.8 - 9.0 % of oxygen. Following fixation, the tissue was rinsed thrice for time duration of 3 minutes with 0.9% saline solution. Following rinsing of the tissue, the tissue was subjected to a process of heat treatment. The process of heat treatment was performed at a temperature of 45-50°C with 0.5% glutaric dialdehyde having pH 7.42. The heat treatment was performed for time duration of 6 days in low oxygen environment. The heat treatment was performed at a concentration of around 9.0 % of oxygen. On completion of the process after 6 days, the pH of the solution was found to be 7.29 as depicted in FIG.6A. The pH mentioned above of the solution represents the absence of acid. The residual aqueous glutaric dialdehyde solution was extracted thrice with solvent Toluene (AR Grade). These solvent extracts were further examined for Glutaric acid formation by a standard gas chromatographic method. The formation of Glutaric acid was found to be negligible.
[0081] Further, the heat treated tissue was subjected to a process of blocking to yield an aldehyde free bovine tissue. Blocking solution includes a mixture of ethanolamine and other salts as shown in Table 3 given below. Heat treated tissue was immersed in the blocking solution for a time duration of 04 hours at a temperature of 37 °C in a glass container. Additionally, the tissue was washed with an AAS solution for time duration of 3 minutes for removal of traces of blocking agents and salt from the tissue surface.
Chemical (Solute) Total Volume (1 L)
Sodium Borohydride 0.30 gm (37.83 g/mol)
Ethanolamine 0.04 ml (61.08 g/mol)
K2HPO4 42.40 gm
KH2PO4 7.60 gm
NaCl 30.00 gm
KCL 0.20gm
Table 3
[0082] Further, the tissue was subjected to a process of bioburden reduction by treatment with the AAS solution. The treatment was performed for time duration of 03 hours at a temperature of 37°C. Further, the tissue was treated with a mixture of 80% v/v (99.97% pure) of ethanol and 20% of saline for time duration of approximately 4 hours. Lastly, the tissue was subjected to the process of dehydration. The tissue was dehydrated with a mixture of 75% glycerol and 25% ethanol for time duration of 01 hour.
[0083] Further, the dehydrated tissue was tested for the presence of acid by gas chromatographic evaluation. The results of the gas chromatography show negligible presence of the acid in the solution.
[0084] Example 2- As per conventional process, the tissue was obtained and washed with cold saline to remove debris, toxins, dead colonies, etc. from the tissue surface. The tissue was fixed with a solution of 0.625% glutaric dialdehyde for time duration of 06 to 08 days in a normal oxygen environment. Fixation was performed at a concentration of 20.8-21 % of oxygen. Following fixation, the tissue was rinsed thrice for time duration of 3 minutes with 0.9% saline solution. Following rinsing of the tissue, the tissue was subjected to a process of heat treatment. The process of heat treatment was performed at a temperature of 30°C - 60°C with 0.5% glutaric dialdehyde having pH 7.4±0.2. The heat treatment was performed for a time duration of 6 days a hot air oven under normal oxygen environment. The heat treatment is performed at a concentration of around 20.8 – 21.0 % of oxygen. On completion of the process after 6 days, the pH of the solution was found to be 6.0 as depicted in FIG.6B. The aforesaid pH indicates conversion of glutaric dialdehyde to glutaric acid. The pH mentioned above of the solution represents the presence of acid.
[0085] The residual aqueous glutaric dialdehyde solution was extracted twice with Toluene (AR Grade). These solvent extracts were further examined for Glutaric acid formation by a standard gas chromatographic method. The gas chromatography reveals that 57.2% of Glutaric dialdehyde gets converted into Glutaric acid. Rests of the steps of the anti-calcification were performed as per example 1.
[0086] FIG. 4 represents leaflets of the prosthetic valve 200. The leaflet 10 includes a free end 11, a first tab 12, a second tab 14 on the opposite side of the leaflet 10, and a semicircular arc 15 on the opposite side of the free end 11. The tab 12 of the leaflet 10 may include an inner end a’ and an outer end b’. Similarly, the tab 14 may include an inner end a’’ and an outer end b’’. Further, the leaflet 10 may include a plurality of holes 13 located at each of the tab 12 and 14. In an embodiment, the leaflet 10 includes vertically placed three holes located at each of the tab 12 and 14. The holes 13 may be provided on one of the inner and outer ends of the tabs 12, 14. In an embodiment, the holes 13 are located at the inner end (a’ and a’’) of each tab 12 and 14. The holes 13 help in attachment of the leaflet 10 to the frame 100. The length of the tabs 12 and 14 may play a vital role in attachment of the leaflets to the frame 100. The length of the tabs 12 and 14 may be in a range of 7mm to 13mm. In an embodiment, the length of the tabs is in a range of 9mm to 11mm.
[0087] As stated earlier, three leaflets 10 may be attached together to form the leaflet structure 104. Each of the three leaflets 10 may be attached to an adjacently placed leaflet 10 through the tabs 12 and 14 with the help of a commissure fabric 20 and a commissure support fabric 30. The attachment of the leaflets 10 may be explained with the help of FIG. 4A-4F. It should be noted that though the said figures depict attachment of the tabs of two adjacently placed leaflets at a commissure post, a similar/identical procedure of attachment will be followed for other tabs also.
[0088] FIG. 4A depicts attachment of a first tab 12a of a first leaflet 10a with a second tab 14a of an adjacently placed second leaflet 10b. The inner end 12a’ of the first tab 12a may be stitched to the inner end 14a’of the second tab 14a to form a T-shaped structure as shown in FIG. 4A. The first tab 12a and the second tab 14a may be perpendicular to the corresponding free ends 11a, 11b of the respective first leaflet 10a and the second leaflet 10b. In an embodiment. The inner end 12a’ and the inner end 14a’ may be attached via the plurality of holes 13 by way of suturing. The suturing may be performed by using polyester or PTFE (polytetrafluoroethylene) suture. The commissure support fabric 30 may be stitched at a first side 16a, 16b of the first tab 12a and the second tab 14a respectively. The commissure fabric 20 may be provided over the commissure support fabric 30 in such a way that the commissure fabric 20 completely covers the first side 16a,16b. In an embodiment, the length of the commissure fabric 20 in greater than the length of the commissure support fabric 30. The commissure fabric 20 and the commissure support fabric 30 may prevent damage to the leaflets during crimping and/or expansion of the valve 200.
[0089] The tabs of the other leaflet may also be attached with each other in a like manner to form the leaflet structure 104 which is subsequently placed with on the frame 100 for attachment with the commissure post.
[0090] The leaflet structure 104 may include three T shaped structure. Each of the T-shaped structure may then be inserted into a window of the commissure posts 102. In order to insert the T-shaped structure into the commissure post 102, the perpendicularly disposed first and second tabs 12a, 14a are bent away from the first and second free ends 11a, 11b. As shown in FIG. 4B, the first and second tabs 12a, 14a are so bent that the angles between the first tab 12a and the first free end 11a as well as the second tab 14a and the second free end 11b are 180o respectively.
[0091] Once, the first tab 12a and the second tab 14a are passed through the commissure post 102, the portions of the first tab 12a and the second tab 14a which extend outwards with respect to the commissure post 102, are loosely folded in a direction away from each other as shown in FIG. 4C. In an embodiment, the tabs 12a, 14a are loosely folded at a predefined angle of inclination as depicted in FIG. 4C.
[0092] Further, the folds of the first tab 12a and the second tab 14a are pulled tightly and the excess portion of the first and second tabs 12a, 14a are inserted inside the frame 100 as shown in FIG.4D. In an embodiment, the folds maintain their angle of inclination with respect to the commissure post 102.
[0093] Further, as shown in FIG. 4E, the folds are pressed against the commissure post 102 in a way that the folds lie flat against the commissure post 102.
[0094] Subsequently, the excess portion of the first and second tabs 12a and 14a which are disposed inside the frame 100 are tightly folded to form an L-shaped structure as shown in FIG. 4F. The L -shaped structure includes a folded portion 17a and free portion 17b. It is evident from above attachment of the leaflets 10, that the tabs of leaflets lie inside as well as outside of the frame 100. At this stage, the free portion 17b (disposed inside the frame 100), commissure post 102 and the portion of tabs disposed outside the frame 100 are sutured together as shown in fig. 4F.
[0095] The tabs of other leaflet are attached to the commissure post 102 in a similar manner as described above to from as assembly as shown in FIG.4E.
[0096] Suturing of the leaflets in aforesaid manner may help in dissipating equal pressure to each leaflet during continuous operation (opening and closing) of the leaflet structure 104 and/or minimize wear and tear of leaflets upon implantation, thereby increasing time span of the valve 200 in the body lumen. Further, the suturing may also help in retaining the prosthetic heart valve 200 at the same position, in other words, may avoid deflection of the prosthetic heart valve 200 due to high pressure of blood flow.
[0097] The prosthetic heart valve 200 includes the inner skirt 50 for securing the inflow end 101 of the valve 200. Then inner skirt 50 may be made of biocompatible material. The biocompatible material may include without limitation, PET (polyethylene terephthalate), polyester, nylon etc. In an embodiment, the inner skirt 50 is made of PET (polyethylene terephthalate). The PET fabric may be woven and/or textured fabric. The inner skirt 50 may include a wall thickness in a range of 0.050mm to 0.060mm. In an embodiment, the thickness of the inner skirt 50 is in a range of 0.055mm to 0.065mm. The inner skirt 50 may be attached to an inner side at the proximal end 106 of the support frame 100. In an exemplary embodiment, the inner skirt 50 is attached to the struts a’ of the secondary row 107 and the struts a’ of the base row 109. The inner skirt 50 may be attached to the frame 100 in such a way that is covers the cells 202 and 203 of the secondary row 107 and the base row 109. The inner skirt 50 may be attached to the frame 100 by means of suturing using polyester or PTFE (polytetrafluoroethylene) suture.
[0098] In an embodiment, the inflow end portion (namely, semicircular arc 15) of the leaflet 10 can be secured to the frame 100 by suturing the inner skirt 50 to the secondary row 107 and the base row 109 such that the inner skirt 50 is sandwiched between the frame 100 and the semicircular arc 15 of the leaflet 10.
[0099] The outer skirt 40 may be made of any biocompatible material. The biocompatible material may include without limitations PET (polyethylene terephthalate), polyester, nylon etc. In an embodiment, the skirt 40 is made of polyethylene terephthalate (PET). The PET fibers may be woven and/or textured fibers. The skirt 40 may be manufactured by interweaving of a plurality of PET fibers.
[00100] The weaving of the PET fibers may be performed in any manner known in the art. A bunch of PET fibers (multifilament) may be interweaved with each other at a predefined angle. The outer skirt 40 may be woven by passing a PET multifilament in one direction with another PET multifilament at right angle as shown in FIG. 5E. In an embodiment, the PET fibers are weaved at an angle of 90° with permissible variation of 5°. A bunch of vertical PET fibers may intersect with a bunch of horizontal PET fibers. In another embodiment, the PET fibers are weaved at an angle of 45°. Such weaving pattern of the PET fibers may provide excellent resistance against wear and tear to the skirt 40 during crimping as well as during expansion of the prosthetic valve 200. The thickness of the PET fibers may be in a range of 15 Denier to 25 Denier. In an embodiment, the thickness of the PET fibers is in a range of 16 Denier to 20 Denier.
[00101] The weaving of the PET fibers may affect pore size of the outer skirt 40 which play an important role in preventing paravalvular leakage. The pore size may be very minute such that when blood comes in contact with the outer skirt 40, the pores are packed and play a major role in prevention of paravalvular leakage.
[00102] The size of the outer skirt 40 may be defined as per the size of the frame 100. The outer skirt 40 may be cut at a predefined angle. Due to utilization of the textured PET fibers, the outer skirt 40 imparts same flexibility and/or resistance against wear and tear irrespective of the selected predefined angle. The predefined angle may be in a range of 45° to 90°. In an embodiment, the outer skirt 40 is cut at an angle of 90 degree with respect to interweaved PET fibers as shown in FIG.5E. In an embodiment, the size of the outer skirt 40 is in a range of 20mm to 32mm. The outer skirt 40 may include a wall thickness. The wall thickness may be in a range of 40 to 70micron, preferable 50 to 60 micron.
[00103] In an embodiment as depicted in Fig. 5, the outer skirt 40 is a single fabric which is designed to include two cuffs i.e a first cuff 40b and a second cuff 40c. The first cuff 40b and the second cuff 40c may be separated by an intermediate region 40d. Alternately, the outer skirt 40 may be in the form of two separate fabrics which correspond to a first cuff and a second cuff without any intermediate region. The two fabrics may overlap at a distance of around 1mm at their respective ends. The overlapping may be provided in order to achieve adequate sealing of the two fabrics with each other.
[00104] The presence of the two cuffs/two fabrics having corresponding rows of projections and notches as elaborated above helps to effectively seal an upper and lower part of the native annulus and/or prevents paravalvular leakage more efficiently. Further, if any calcium deposition is present at the implantation which may damage the valve 200 due to calcification, the outer skirt 40 may prevent it owing to larger covered area by due to two cuffs/two fabrics.
[00105] The first cuff 40b may include an upper end 40b’ and a lower end 40b’’. The upper end 40b’ includes a plurality of projections 41 and notches 42. The projections 41 may help in attachment of the skirt 40 to the frame 100. The notches 42 may help to provide a channel for entry of blood inside the cuffs 40b and 40c for providing bulginess to the outer skirt 40 in the deployed state of the prosthetic valve 200 to prevent paravalvular leakage.
[00106] The upper end 40b’ of the first cuff 40b may be attached at a predefined location on the support frame 100. The upper end 40b’ of the first cuff 40b may be stitched to the strut member a’ of the secondary row 107. In an embodiment, the projections 41 of the first cuff 40b of the outer skirt 40 are stitched on to the strut member a’ of the secondary row 107. The lower end 40b” is in direct contact with the intermediate region 40d which is subsequently stitched to the frame 10.
[00107] Similarly, the second cuff 40c includes the upper end 40c’ and the lower end 40c’’. The upper end 40c’ may include projections 41’ and notches 42’. In an embodiment, the upper end 40c’ is in direct contact with the intermediate region 40d which is subsequently stitched to the frame 10. In an embodiment, the lower end 40c’’ of the second cuff 40c is attached with the inner skirt 50 (shown in FIG. 5D) at the proximal end 106 of the frame 100.
[00108] Alternate to the above elaborated structure of the outer skirt 40, the outer skirt 40 may include two rows of a plurality of slits 43 disposed on the first cuff 40b and the second cuff 40c respectively as shown in FIG.5A. In yet another embodiment, the outer skirt 40 may include a row of slits 43 and a row of notches 44 disposed on the first cuff 40b and the second cuff 40c respectively as shown in FIG.5B. It will be apparent to a person skilled in the art that other structures like sacs, flaps, etc. that enable the outer skirt to bulge on inflow of blood are within the scope of the present invention.
[00109] The intermediate region 40d of the present invention may be formed by folding the outer skirt 40 in the middle. The folding may be performed three times. The intermediate region may be attached at a predefined location on the frame 100. The intermediate region 40d may be stitched to the lower strut members (a’) of the secondary row 107 of the frame 100.
[00110] Alternatively, the outer skirt 40 may be structured differently. In an embodiment, the outer skirt 40 is stitched to the full frame which also creates bulginess. In such a case, the intermediate region 40d may not be present.
[00111] In yet another embodiment, the outer skirt 40 is attached from the base row 109 till the secondary row 107. In such arrangement, the outer skirt 40 includes a plurality of slits 43 (depicted in FIG.5C) which creates more bulginess to prevent paravalvular leakage.
[00112] The scope of the invention is only limited by the appended patent claims. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and/or configurations will depend upon the specific application or applications for which the teachings of the present invention is/are used.