AU2005203435B2 - Heart Valve Prosthesis and Method of Manufacture - Google Patents

Description

P/00/011 28/5/91 Regulation 3.2

AUSTRALIA

Patents Act 1990

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT Name of Applicant: Actual Inventors Address for service is: AorTech International PLC Bernard O'CONNOR David John WHEATLEY Gillian Maureen BERNACCA William Stafford HAWORTH WRAY ASSOCIATES Level 4, The Quadrant 1 William Street Perth, WA 6000 Attorney code: WR Invention Title: "Heart Valve Prosthesis and Method of Manufacture" The following statement is a full description of this invention, including the best method of performing it known to me:- 1/2 1 HEART VALVE PROSTHESIS AND METHOD OF MANUFACTURE 2 3 FIELD OF THE INVENTION 4 The present invention relates to medical 6 implants, particularly cardiac and vascular implants 7 and prostheses. More specifically, the invention 8 relates to a cardiac valve prosthesis comprising a 9 frame and leaflets. Such valves may also be made without rigid frames and may also be used as valves 11 in artificial hearts, whether the latter are intended 12 for permanent implantation or for temporary support 13 of a patient.

14 BACKGROUND OF THE INVENTION 16 17 In mammals the heart is the organ responsible 18 for maintaining an adequate supply of blood, and 19 hence of oxygen and nutrients, to all parts of the body. Reverse flow of blood through the heart is 1 2 3 4 r) 6 7 D 8 r 9 D 10 11 12 13 14 16 17 18 19 21 22 23 24 26 27 28 29 31 prevented by four valves which serve as the inlet and outlet of each of the two ventricles, the pumping chambers of the heart.

Dysfunction of one or more of these valves can have serious medical consequences. Such dysfunction may result from congenital defects, or from disease induced damage. Forms of dysfunction include stenosis (reduction in the orifice of the open valve) and regurgitation (reverse flow through the closing or closed valve), either of which increases the work required by the heart to maintain the appropriate blood flows to the body.

In many cases the only effective solution is to.:: replace the malfunctioning valve. A valve replacement operation is expensive and requires specialised facilities for open heart surgery. Replacement of failed artificial heart valves carries increased risk over the initial replacement, so there are practical limits on the number of times reoperation can be undertaken. Consequently, the design and materials of an artificial valve must provide for durability of the valve in the patient. The artificial valve must also operate without high pressure gradients or undue reverse flow during closing or when closed, because these are the very reasons for which a replacement of the natural valve is undertaken.

Mechanical valves, which use a ball or a disc or a pair of pivoting rigid leaflets as the opening member(s) can meet these combined requirements of haemodynamic performance and durability.

Unfortunately, a patient who has had a mechanical 1 valve implanted must be treated with anticoagulants, 2 otherwise blood will clot on the valve. Clotting on 3 the valve can either restrict the movement of the 4 valve opening member(s), impairing valve function, or can break free from the valve and obstruct blood 6 vessels downstream from the valve, or both. A patient 7 receiving a mechanical valve will be treated with 8 anticoagulants for life.

9 Valves excised from pigs and treated with glutaraldehyde to crosslink and stabilise the tissue 11 are also used for replacement of defective valves.

12 These may be mounted on a more or less rigid frame, 13 to facilitate implantation, or they may be unmounted 14 and sewn by the surgeon directly to the vessel walls at operation. A further type of valve replacement is 16 constructed from natural tissue, such as pericardium, 17 treated with glutaraldehyde and mounted on a frame.

18 Valves from pigs or made from other animal or human 19 tissue are collectively known as tissue valves. A major advantage of tissue valves over mechanical 21 valves is that they are much less likely to provoke 22 the blood to clot, and so patients receiving tissue 23 valves are not normally given anticoagulants other 24 than during the immediate post operative period.

Unfortunately, tissue valves deteriorate over time, 26 often as a result of calcification of the crosslinked 27 natural tissue. This deterioration presents a 28 problem, particularly in young patients. Thus, 29 although the recipient of a tissue valve is not required to take anticoagulants, the durability of 31 tissue valves is less than that of mechanical valves.

1 In third world countries, where rheumatic fever 2 is still common, the problems of valve replacement in 3 young patients are considerable. Anticoagulants, 4 required for mechanical valves, are impractical and accelerated calcification of tissue valves precludes 6 their use.

7 In the Western world, life expectancy continues 8 to increase, and this results in a corresponding rise 9 both in patients requiring cardiac valve replacement, and in those patients needing replacement of 11 deteriorating artificial valves implanted in the 12 past. There is, therefore, a need for a replacement 13 heart valve with good haemodynamics, extended 14 durability and having sufficiently low risk of inducing clotting so that anticoagulants are not 16 necessary.

17 The natural heart valves use thin flexible 18 tissue leaflets as the closing members. The leaflets 19 move readily out of the orifice as blood begins to flow through the valve so that flow through the open 21 valve is unrestricted by the leaflets. Tissue valves 22 function similarly, providing a relatively 23 unrestricted orifice when the valve is open. For 24 mechanical valves, on the other hand, the closing member rotates in the orifice, but is not removed 26 from the orifice when the valve opens. This provides 27 some restriction to flow, but, more importantly, 28 disturbs the blood flow patterns. This disturbance to 29 the flow is widely held to initiate, or at least to contribute significantly to, the observed tendency of 31 mechanical valves to produce clotting.

1 A number of trileaflet polyurethane valve 2 designs have been described.

3 A valve design, comprising a leaflet geometry 4 which was elliptical in the radial direction and hyperbolic in the circumferential direction in the 6 closed valve position, with leaflets dip-coated from 7 non-biostable polyurethane solutions onto injection- 8 moulded polyurethane frames has attained durabilities 9 in excess of 800 million cycles during in vitro fatigue testing (Mackay TG, Wheatley DJ, Bernacca GM, 11 Hindle CS, Fisher AC. New polyurethane heart valve 12 prosthesis: design, manufacture and evaluation.

13 Biomaterials 1996; 17:1857-1-863; Mackay. TG, Bernacca 14 GM, Wheatley DJ, Fisher AC, Hindle CS. In vitro function and durability assessment of a polyurethane 16 heart valve prosthesis. Artificial Organs 1996; 17 20:1017-1025; Bernacca GM, Mackay TG, Wheatley DJ. In 18 vitro function and durability of a polyurethane heart 19 valve: material considerations. J Heart Valve Dis 1996; 5:538-542; Bernacca GM, Mackay TG, Wilkinson

R,

21 Wheatley DJ. Polyurethane heart valves: fatigue 22 failure, calcification and polyurethane structure.

J

23 Biomed Mater Res 1997; 34:371-379; Bernacca

GM,

24 Mackay TG, Gulbransen MJ, Donn AW, Wheatley

DJ.

Polyurethane heart valve durability: effects of 26 leaflet thickness. Int J Artif Organs 1997; 20:327- 27 331.). However, this valve design became 28 unacceptably stenotic in small sizes. Thus, a 29 redesign was effected, changing the hyperbolic angle from the free edge to the leaflet base, and replacing 31 the injection-moulded frame with a rigid, high 1 modulus polymer frame. This redesign permitted the 2 use of a thinner frame, thus increasing valve orifice 3 area. This valve design, with a non-biostable C 4 polyurethane leaflet material, was implanted in a growing sheep model. Valve performance was good over 6 the six month implant period, but the region close to 7 the frame posts on the inflow side of the valve, at 8 which full leaflet opening was not achieved, suffered l~ 9 a local accumulation of thrombus (Bernacca GM, Raco L, Mackay TG, Wheatley DJ. Durability and function of 11 a polyurethane heart valve after six months in vivo.

12 Presented at the XII World Congress of International 13 Society for Artificial Organs and XXVI Congress of 14 the European Society for Artificial Organs, Edinburgh, August 1999. Wheatley DJ, Raco L, 16 Bernacca GM, Sim I, Belcher PR, Boyd JS.

17 Polyurethane: material for the next generation of 18 heart valve prostheses? Eur. J. Cardio-Thorac. Surg.

19 2000; 17; 440-448). This valve design used nonbiostable polyurethane, which had tolerable 21 mechanical durability, but which showed signs of 22 polymer degradation after six months in vivo.

23 International Patent Application WO 98/32400 24 entitled "Heart Valve Prosthesis" discloses a similar design, i.e. closed leaflet geometry, comprising 26 essentially a trileaflet valve with leaflets moulded 27 in a geometry derived from a sphere towards the free 28 edge and a cone towards the base of the leaflets. The 29 spherical surface, defined by its radius, is intended to provide a tight seal when the leaflets are under 31 back pressure, with ready opening provided by the 1 conical segment, defined by its half-angle, at the 2 base of the leaflets. Were the spherical portion 3 located at the leaflet base it is stated that this 4 would provide an advantage in terms of the stress distribution when the valve is closed and under back 6 pressure.

7 U.S. Patent No. 5,376,113 entitled "Closing 8 Member Having Flexible Closing Elements, Especially a 9 Heart Valve" issued December 27, 1994 to Jansen et al. discloses a method of producing flexible heart 11 valve leaflets using leaflets attached to a base ring 12 with posts extending from this upon which the 13 leaflets are mounted. The leaflets are formed with 14 the base ring in an expanded position, being effectively of planar sheets of polymer, which become 16 flaccid on contraction of the ring. The resulting 17 valve is able to maintain both a stable open and a 18 stable closed position in the absence of any 19 pulsatile pressure, though in the neutral unloaded position the valve leaflets contain bending stresses.

21 As a consequence of manufacturing the valve from 22 substantially planar sheets, the included angle 23 between the leaflets at the free edge where they 24 attach to the frame is 60 for a three leaflet valve.

U.S. Patent No. 5,500,016 entitled "Artificial 26 Heart Valve" discloses a valve having a leaflet shape 27 defined by the mathematical equation z 2 y 2 2RL 28 2 where g is the offset of the leaflet 29 from the frame, RL is the radius of curvature of the leaflet at and c is the shape parameter and 31 is >0 and <1.

1 A valve design having a partially open 2 configuration when the valve is not subject to a 3 pressure gradient, but assuming a fully-open position 4 during forward flow is disclosed in International Patent Application WO 97/41808 entitled "Method for 6 Producing Heart Valves". The valve may be a 7 polyurethane trileaflet valve and is contained within 8 a cylindrical outer sleeve.

9 U.S. Patent Nos. 4,222,126 and 4,265,694 disclose a trileaflet polyurethane valve with 11 integral polyurethane elastomeric leaflets having 12 their leading edges reinforced with an integral band 13 polymer and the leaflets reinforced radially with 14 thicker lines of polyurethane.

The problem of chronic thrombus formation and 16 tissue overgrowth arising from the suture ring of 17 valves has been addressed by extension of the valve 18 body on either side of the suture ring as disclosed 19 in U.S. Patent No. 4,888,009 entitled "Prosthetic Heart Valve".

21 Current polyurethane valve designs have a number 22 of potential drawbacks. Close coaptation of leaflets, 23 while ensuring good valve closure, limits the wash- 24 out of blood during haemodynamic function, particularly in the regions close to the stent posts 26 at the commissures. This region of stagnation is 27 likely to encourage local thrombogenesis, with 28 further restriction of the valve orifice in the 29 longer term as well as increasing the risk of material embolising into the circulation. Associated 31 with the thrombosis may be material degradation (in 1 non-biostable polyurethanes) and calcification 2 resulting in localised stiffening the leaflets, 3 stress concentrations and leaflet failure. As 4 previously discussed, animal implants of a trileaflet polyurethane valve design have indicated that 6 thrombus does tend to collect in this region, 7 restricting the valve orifice and damaging the 8 structure of the valve.

9 Present valve designs are limited by the availability of suitable polyurethanes which possess 11 good mechanical properties as well as sufficient 12 durability to anticipate clinical functionality of up 13 to twenty years or more. Many low modulus materials, 14 which provide good hydrodynamic function, fail during fatigue testing at unacceptably low durations, due to 16 their greater susceptibility to the effects of 17 accumulated strain. Higher modulus polyurethanes may 18 be better able to withstand repeated stress without 19 accumulating significant damage, but are too stiff to provide good hydrodynamic function in conventional 21 almost-closed geometry valve designs. Current design 22 strategies have not been directed towards enabling 23 the incorporation of potentially more durable, higher 24 modulus leaflet materials, nor the creation of a valve design that is able to maintain good 26 hydrodynamic function with low modulus polyurethanes 27 manufactured as thick leaflets.

28" The nature of the valve leaflet attachment to 29 the frame is such that, in many valve designs, there is a region of leaflet close to the frame, which is 31 restrained by the frame. This region may extend some 1 distance into the leaflet before it interfaces with 2 the free-moving part of the leaflet, or may be 3 directly at the interface between frame and leaflet.

4 There thus exists a stress concentration between the area of leaflet that is relatively mobile, undergoing 6 transition between fully open and fully closed, and 7 the relatively stationary commissural region. The 8 magnitude of this flexural stress concentration is 9 maximised when the design parameters predicate high bending strains in order for the leaflet to achieve 11 its fully open position.

12 U.S. Patent Nos. 4,222,126 and 4,265,694 3 disclose a valve which uses thickened leaflet areas 14 to strengthen vulnerable area of the leaflets.

However this approach is likely to increase the 16 flexure stress and be disadvantageous in terms of 17 leaflet hydrodynamic function.

18 The major difficulties which arise in designing 19 synthetic leaflet heart valves can be explained as follows. The materials from which the natural 21 trileaflet heart valves (aortic and pulmonary) are 22 formed have deformation characteristics particularly 23 suited to the function of such a valve. Specifically, 24 they have a very low initial modulus, and so they are very flexible in bending, which occurs at low strain.

26 This low modulus also allows the leaflet to deform 27 when the valve is closed and loaded in such a way 28 that the stresses generated at the attachment of the 29 leaflets, the commissures, are reduced. The leaflet material then stiffens substantially, and this allows 31 the valve to sustain the closed loads without 1 prolapse. Synthetic materials with these mechanical 2 properties are not available.

3 Polyurethanes can be synthesised with good blood 4 handling and good durability. They are available with a wide range of mechanical properties, although none 6 has as low a modulus as the natural heart valve 7 material. Although they show an increase in modulus 8 at higher strains, this does not occur until strains 9 much higher than those encountered in leaflet heart valves.

11 Polyurethanes have been the materials of choice 12 for synthetic leaflet heart valves in the last decade 13 or more. More--recently, polyurethanes have become 14 available which are resistant to degradation when implanted. They are clearly more suitable for making 16 synthetic leaflet heart valves than non-stable 17 polyurethanes, but their use suffers from the same 18 limitations resulting from their mechanical 19 properties. Therefore, design changes must be sought which enable synthetic trileaflet heart valves to 21 function with the best available materials.

22 Key performance parameters which must be 23 considered when designing a synthetic leaflet heart 24 valve include pressure gradient, regurgitation, blood handling, and durability.

26 To minimise the gradient across the open valve, 27 the leaflets must open wide to the maximum orifice 28 possible, which is defined by the inside diameter of 29 the stent. This means that there must be adequate material in the leaflets so they can be flexed into a 31 tube of diameter equal to the stent internal 1 diameter. In addition, there has to be a low energy 2 path for this bending because the pressure forces 3 available to open the valve are small, and the lower 4 the gradient, the smaller the pressure becomes. All the leaflets must open for the lowest cardiac output 6 likely to be encountered by that valve in clinical 7 service.

8 To minimise closing regurgitation (reverse flow 9 lost through the closing valve the valve leaflets must be produced at or close to the closed position 11 of the valve. To minimise closed valve regurgitation 12 (reverse flow through the valve once it has closed), .13 the apposition of the leaflets ip.the commissural 14 region is found to be key, and from this perspective the commissures should be formed in the closed 16 position.

17 Proper blood handling means minimising the 18 activation both of the coagulation system and of 19 platelets. The material of construction of the valve is clearly a very important factor, but flow through 21 the valve must also avoid exposing blood either to 22 regions of high shear (velocity gradient) or to 23 regions of relative stasis. Avoiding regions of high 24 shear is achieved if the valve opens fully, and relative stasis is avoided if the leaflet/frame 26 attachment and the commissural region in particular 27 opens wide. This is not achieved with typical 28 synthetic materials when the commissures are molded 29 almost closed, because the stiffness of synthetics is too high.

1 Durability depends to a large extent on the 2 material of construction of the valve leaflets, but 3 for any given material, lifetime will be maximised if 4 regions of high stress are avoided. The loads on the closed valve are significantly greater than loads 6 generated during valve opening. Therefore, the focus 7 should be on the closed position. Stresses are 8 highest in the region of the commissures where loads 9 are transmitted to the stent, but they are reduced when the belly of the leaflet is as low as 11 practicable in the closed valve. This means that 12 there must be sufficient material in the leaflet to 13 allow the desired low closing. 14 SUMMARY OF THE INVENTION 16 17 The present invention provides a cardiac valve 18 prosthesis comprising a frame and two or more 19 leaflets (preferably three) attached to the frame.

The leaflets are attached to the frame between posts, 21 with a free edge which can seal the leaflets together 22 when the valve is closed under back pressure. The 23 leaflets are created in a mathematically defined 24 shape allowing good wash-out of the whole leaflet orifice, including the area close to the frame posts, 26 thereby relieving the problem of thrombus deposition 27 under clinical implant conditions.

28 The leaflet shape has a second design feature, 29 by which the pressure required to open the valve and the pressure gradient across the valve in the open 31 position is reduced by creating a valve which is 14 1 partially open in its stable unstressed position.

2 Moulding the leaflets in a partially open position 3 permits them to open easily to a wider angle 4 resulting in an increased effective orifice area, for any given polyurethane/elastomeric material. This .6 permits the use of materials from a wider range of 7 mechanical properties to fabricate the leaflets, 8 including those of a relatively stiff nature, and 9 also permits lower modulus materials to be incorporated as thicker and hence more durable 11 leaflets, while retaining acceptable leaflet 12 hydrodynamic function.

13 A third design feature is ,the reduction of a 14 stress concentration in the vicinity of the commissural region of the leaflets. In many valve 16 designs, there exists a region of localised high 17 bending where the opening part of the flexible 18 leaflet merges into the stationary region of the 19 leaflet adjacent to the valve frame. The current design reduces the bending, and hence the local 21 stress concentration, in this region. This feature is 22 designed to enhance the valve durability.

23 The wide opening of the leaflet coaptation close 24 to the stent posts improves blood washout, reduces thrombogenesis and minimises embolic risks to the 26 recipient, by allowing a clear channel for blood flow 27 throughout the whole valve orifice.

28 The partially open design acts to reduce the 29 fluid pressure required to open the valve. This in turn results in lower pressure gradients across the 31 valve, allowing the use of durable, stiffer 1 polyurethanes to fabricate the valve which may be 2 better equipped to deal with a cyclic stress 3 application or thicker leaflets of lower modulus 4 polyurethanes, hence achieving good durability with good hydrodynamic function. The position of the 6 leaflet in its stable unstressed state acts to reduce 7 the stress concentration resulting from leaflet 8 bending, hence increasing valve durability.

9 In one aspect the invention is a cardiac valve prosthesis comprising a frame defining a blood flow 11 axis and at least two leaflets attached to the frame.

12 The at least two leaflets are configured to be 13 movable,from an open to a closed position. The 14 leaflets have a blood inlet side and a blood outlet side and are in the closed position when fluid 16 pressure is applied to the outlet side, and in the 17 open position when fluid pressure is applied to the 18 inlet side. The leaflets are in a neutral position 19 intermediate the open and closed position in the absence of fluid pressure being applied to the 21 leaflets. The at least two leaflets include a first 22 leaflet. The first leaflet has a surface contour 23 such that an intersection of the first leaflet with 24 at least one plane perpendicular to the blood flow axis forms a first composite wave. The first 26 composite wave is substantially defined by a first 27 wave combined with at least a second wave 28 superimposed over the first wave. The first wave has 29 a first frequency and the second wave has a second frequency, different from the first frequency.

31 Alternatively, the first composite wave may be o 1 defined by a first wave combined with second and 2 third waves superimposed over the first wave. The 3 third wave has a third frequency which is different 4 from the first frequency.

Both the first wave and the second wave may be 6 symmetric or asymmetric about a plane parallel to and 7 intersecting the blood flow axis and bisecting the 8 first leaflet. The first composite wave may be S 9 symmetric or asymmetric about a plane parallel to and intersecting the blood flow axis and bisecting the 11 first leaflet. The at least two leaflets may include 12 second and third leaflets. An intersection of the 13 second and third leaflets'with a'plane perpendicular 14 to the blood flow axis forms second and third composite waves. The second and third composite 16 waves are substantially the same as the first 17 composite wave. The first and second waves may be 18 defined by an equation which is trigonometric, 19 elliptical, hyperbolic, parabolic, circular, a smooth analytic function or a table of values. The at least 21 two leaflets may be configured such that they are 22 substantially free of bending stresses when in the 23 neutral position. The frame may be substantially 24 cylindrical having first and second ends, one of the ends defining at least two scalloped edge portions 26 separated by at least two posts, each post having a 27 tip, and wherein each leaflet has a fixed edge joined 28 to a respective scalloped edge portion of the frame 29 and a free edge extending substantially between the tips of two posts. The first and second waves may be 31 symmetric about a plane parallel to and intersecting 1 the blood flow axis and bisecting the first leaflet 2 or at least one of the first and second waves may be 3 symmetric about such plane. The first leaflet may 4 have a surface contour such that when the first leaflet is in the neutral position an intersection of 6 the first leaflet with a plane parallel to and 7 intersecting the blood flow axis and bisecting the 8 first leaflet forms a fourth wave.

9 In another aspect the invention is a method of making a cardiac valve prosthesis. The valve 11 prosthesis includes a frame defining a blood flow 12 axis substantially parallel to the flow of blood S13 through the valve prosthesis and at least two..- 14 flexible leaflets attached to the frame. The method includes providing a forming element having at least 16 two leaflet forming surfaces. The forming element is 17 engaged with the frame. A coating is applied over 18 the frame and engaged forming element. The coating 19 binds to the frame. The coating over the leaflet forming surfaces forms the at least two leaflets.

21 The at least two leaflets are configured to be 22 movable from an open to a closed position. The 23 leaflets have a blood inlet side and a blood outlet 24 side and are in the closed position when fluid pressure is applied to the outlet side, and in the 26 open position when fluid pressure is applied to the 27 inlet side. The leaflets are in a neutral position 28 intermediate the open and closed position in the 29 absence of fluid pressure being applied to the leaflets. The at least two leaflets include a first 31 leaflet. The first leaflet has a surface contour 1 such that the intersection of the first leaflet with 2 at least one plane perpendicular to the blood flow 3 axis forms a first composite wave. The first 4 composite wave is substantially defined by a first wave combined with a second superimposed wave. The 6 first wave has a first frequency and the second wave 7 has a second frequency different from the first 8 frequency. After the coating is applied the forming 9 element is disengaged from the frame. The first composite wave formed in the coating step may be 11 defined by a first wave combined with second and 12 third waves superimposed over the first wave. The 13 third wave has a third frequency which is different 14 from the first frequency.

The first and second waves formed in the coating 16 step may be either symmetric or asymmetric about a 17 plane parallel to and intersecting the blood flow 18 axis and bisecting the first leaflet. The first 19 composite wave formed in the coating step may be symmetric or asymmetric about a plane parallel to and 21 intersecting the blood flow axis and bisecting the 22 first leaflet. The at least two leaflets formed in 23 the coating step may include second and third 24 leaflets. An intersection of the second and third leaflets with a plane perpendicular to the blood flow 26 axis forms second and third composite waves, 27 respectively. The second and third composite waves 28 are substantially the same as the first composite 29 wave. The first and second waves formed in the coating step may be defined by an equation which is 31 trigonometric, elliptical, hyperbolic, parabolic, 1 circular, a smooth analytic function or a table of 2 values.

3 The first and second waves in the coating step 4 may be symmetric about a plane parallel to and intersecting the blood flow axis and bisecting the 6 first leaflet or at least one of the first and second 7 waves may be asymmetric about such plane. The at 8 least two leaflets in the coating step are configured 9 such that they are substantially free of bending stresses when in the neutral position.

11 In a further aspect the invention is a cardiac 12 valve prosthesis comprising a frame defining a blood 13 :'flow axis and at least two leaflets attached to the 14 frame including a first leaflet. The first leaflet has an internal surface facing the blood flow axis 16 and an external surface facing away from the blood 17 flow axis. The first leaflet is configured such that 18 a mean thickness of a first half of the first leaflet 19 is different than a mean thickness of a second half of the first leaflet. The first and second halves 21 are defined by a plane parallel to and intersecting 22 the blood flow axis and bisecting the first leaflet.

23 The first leaflet may be further configured such that 24 a thickness of the first leaflet between the internal and external surfaces along a cross section defined 26 by the intersection of a plane perpendicular to the 27 blood flow axis and the first leaflet changes 28 gradually and substantially continuously from a first 29 end of the cross section to a second end of the cross section.

1 In another aspect the invention is a method of 2 making a cardiac valve prosthesis which includes a 3 frame defining a blood flow axis substantially 4 parallel to the flow of blood through the valve prosthesis and at least two flexible leaflets 6 attached to the frame. The method includes providing 7 a mould having a cavity sized to accommodate the 8 frame, inserting the frame into the mould, inserting 9 the mould into an injection moulding machine, and injecting molten polymer into the cavity of the mould 11 to form the at least two leaflets. The injection of 12 the molten polymer causes the at least two leaflets 13 to bond to the frame. The cavity is shaped to form 14 the at least two leaflets in a desired configuration.

The at least two leaflets are configured to be 16 movable from an open to a closed position. The 17 leaflets have a blood inlet side and a blood outlet 18 side and are in the closed position when fluid 19 pressure is applied to the outlet side, and in the open position when fluid pressure is applied to the 21 inlet side. The leaflets are in a neutral position 22 intermediate the open and closed position in the 23 absence of fluid pressure being applied to the 24 leaflets. The at least two leaflets include a first leaflet having a surface contour such that when the 26 first leaflet is in the neutral position an 27 intersection of the first leaflet with at least one 28 plane perpendicular to the blood flow axis forms a 29 first composite wave. The first composite wave is substantially defined by a first wave combined with 31 at least a second superimposed wave. The first wave 1 may have a first frequency, the second wave may have 2 a second frequency, the first frequency being 3 different from the second frequency.

4 In a still further aspect the invention is a method of designing a cardiac valve prosthesis which 6 includes a frame and at least two flexible leaflets 7 attached to the frame. The method includes defining 8 a first desired shape of the leaflets in a first 9 position, defining a second desired shape of the leaflets in a second position different from the 11 first position, and conducting a draping analysis to 12 identify values of adjustable parameters defining at 1.3 least one of the first and second shapes. The 14 draping analysis ensures that the leaflets are comprised of a sufficient amount and distribution of 16 material for the leaflets to assume both the first 17 and second desired shapes. Either of the first and 18 second positions in the defining steps may be a 19 closed position and the other of the first and second positions may be a partially open position.

21 22 DESCRIPTION OF DRAWINGS 23 24 FIG. 1 is a diagrammatic view comparing the shape of symmetric (solid line) and asymmetric 26 (dashed line) leaflets.

27 FIG. 2 is a perspective view of the valve 28 prosthesis in the neutral or partially open position.

29 FIG. 3 is a sectional view similar to the sectional view along line 3-3 of Fig. 2 except that 31 Fig. 3 illustrates that view when the leaflets are in 1 the closed position and illustrates the function 2 which is used to define the shape of the closed 3 leaflet belly Xc,,e(Z).

4 FIG. 4A is a front view of the valve leaflet shown in Fig. 2. Fig. 4B is in the same view as Fig.

6 4A and is a partial schematic view of the same closed 7 valve leaflet shown in Fig. 3 and illustrates that 8 S(X, Y)n and S(X, are contours enclosing the 9 leaflet between the function Xcosed(Z) and the scallop geometry.

11 FIG. 5 is a plot of an underlying function used 12 in defining the valve leaflet in the moulded leaflet 13 partially open position P.

14 FIG. 6 is a plot of a symmetrical superimposed function used in defining the shape of the valve 16 leaflet in the moulded leaflet position P.

17 FIG. 7 is a plot of the composite function used 18 in construction of the moulded leaflet position P 19 resulting from combining an underlying function (Fig.

5) and a symmetric superimposed function (Fig. 6).

21 FIG. 8 is a plot of an asymmetric superimposed 22 function used in the construction of the moulded 23 leaflet position P.

24 FIG. 9 is a plot of the composite function resulting from combining an underlying function 26 .(Fig.5) and an asymmetric function (Fig. 8).

27 FIG. 10 is a sectional view of the valve 28 leaflets in the neutral position along line 3-3 in 29 Fig. 2 and illustrates the function which is used to define the shape of the moulded leaflet belly 31 Xcoen Z) 1 FIG. 11A is a front view of the valve. Fig. 11iB 2 is a partial schematic view of the valve leaflets of 3 Fig. 11A and illustrates that P(X, and P(X, 4 are contours enclosing the leaflet between the function and the scallop geometry.

6 FIG. 12 is a perspective view of a valve of the 7 present invention having symmetric leaflets.

8 FIG. 13 is a perspective view of a valve of the 9 present invention having asymmetric leaflets.

FIG. 14 is a side view of a former used in the 11 manufacture of the valve of the present invention.

12 13 DESCRIPTION OF THE INVENTION 14 a. Design Considerations 16 Consideration of the factors discussed above 17 results in the identification of certain design goals 18 which are achieved by the prosthetic heart valve of 19 the present invention. First, the prosthetic heart valve must have enough material in the leaflet for 21 wide opening and low closing, but more than this 22 amount increases the energy barrier to opening. To 23 ensure that there is sufficient, but not an excess of 24 material, a draping analysis discussed in more detail below is used. Second, to ensure sufficient material 26 for wide opening and low closing, the valve can only 27 be manufactured in a partially open position: by 28 deforming the stent posts outwards during 29 manufacture; by introducing multiple curves in the leaflet free edge (but see below); by making 31 the closed position asymmetric; and combinations 24 1 of the above. Third, if there is enough material for 2 low closing and wide opening, the energy barrier to 3 opening may be high enough to prevent opening of all 4 leaflets at low flow. The energy barrier can be minimised by: introducing multiple curves in the 6 leaflet; making the leaflet asymmetric; and 7 combinations of the above. Fourth, open commissures 8 are needed for blood handling and closed commissures 9 are needed for regurgitation, so the valve should have partially open commissures. In particular the 11 included angle between adjacent leaflet free edges at 12 the valve commissures (for example see angle a of the 13 symmetric leaflets shown in Fig. 1) should be in the 14 range of 10-55°, preferably in the range 25-55° and more preferably in the range of 40-55°.

16 As discussed above, the use of multiple curves 17 in the leaflet helps assure wide opening and more 18 complete closure of the valve and to minimise the 19 energy barrier to opening of the valve. However, the introduction of multiple curves of more than 21 wavelengths to the leaflet can be a disadvantage.

22 While there may be sufficient material in the leaflet 23 to allow full opening, in order for this to happen, 24 the bends in the leaflet must straighten out completely. The energy available to do this arises 26 only from the pressure gradient across the open 27 valve, which decreases as the leaflets becomes more 28 open, i.e. as the valve orifice area increases. This 29 energy is relatively small (the more successful the valve design the smaller it becomes), and does not 31 provide enough energy to remove leaflet curves of 1 more than 1.5 wavelengths given the stiffness of the 2 materials available for valve manufacture. The result 3 is they do not straighten out and the valve does not 4 open fully.

A draping analysis is used as a first 6 approximation to full finite element analysis to 7 determine if the starting shape of a membrane is such 8 that it will take on a desired final shape when 9 placed in its final position. From a durability standpoint the focus is on the closed position, and 11 the desired shape of the leaflet in its closed 12 position is defined. Draping analysis allows the 13 leaflet to be reformed in a partially open position.

14 Draping analysis assumes that very low energy deformation is possible (in reality any form of 16 deformation requires energy). In order for this to 17 occur the bending stiffness of the leaflet/membrane 18 must be small, each element of the membrane should be 19 free to deform relative to its neighbour, and each element should be free to change shape, i.e. the 21 shear modulus of the material is assumed to be very 22 low. In applying the draping analysis, it is assumed 23 that the leaflet can be moved readily from an 24 original defined closed position to a new position in which it is manufactured. When the valve is actually 26 cycled, it is assumed that the leaflet when closing 27 will move from the manufactured position to the 28 originally defined closed position. This allows the 29 closed position to be optimized from a stress distribution aspect, and the manufactured position to 1 be optimized from the point of view of reducing the 2 energy barrier to opening.

3 Both symmetric and asymmetric shapes of the 4 leaflet can allow incorporation of sufficient material in the leaflet free edge to allow full 6 opening. FIG. 1 is a diagramatic view comparing the 7 shape of symmetric (solid line) and asymmetric 8 (dashed line) leaflets and also showing the 9 commissure area 12 where the leaflets connect to the frame. An advantage of the asymmetric shape is that 11 a region of higher radius of curvature 14 is produced 12 than is achieved with a symmetric curve having a 13 lower radius of curvature 16. This region can buckle 14 more readily and thereby the energy barrier to opening is reduced.

16 An asymmetric leaflet also reduces the energy 17 barrier through producing unstable buckling in the 18 leaflet. During opening symmetric leaflets buckle 19 symmetrically i.e. the leaflet buckles are generally mirrored about the centerline of the leaflet thus 21 balancing the bending energies about this centerline.

22 In the asymmetric valve the region of higher radius 23 buckles readily, and because these bending energies 24 are not balanced about the center line, this buckle proceeds to roll through the leaflet producing a 26 sail-like motion producing a low energy path to open.

27 An additional feature of the asymmetric valve is 28 that the open position is also slightly asymmetric, 29 as a result of which it offers a somewhat helical flow path, and this can be matched to the natural 31 helical sense of the aorta. Suggested benefits of 1 this helical flow path include reduction of shear 2 stress non-uniformity at the wall, and consequent 3 reduction of platelet activation.

4 b. The Valve Prosthesis 6 The valve prosthesis will be described with 7 reference to the accompanying drawings. Fig. 2 is a 8 perspective view of one embodiment of the heart valve 9 prosthesis of the present invention. The valve comprises a stent or frame 1 and attached leaflets 11 2a, 2b, and 2c. The leaflets are joined to the frame 12 at scallops 5a, 5b, and 5c. Between each scallop is 13 post 8, the most down-streampart of which is known 14 as a stent tip 6. Leaflets 2a, 2b, and 2c have free edges 3a, 3b, and 3c, respectively. The areas 16 between the leaflets at the stent tips 6 form 17 commissures 4.

18 The following describes a particular way of 19 designing a valve of the present invention. Other different design methodology could be utilized to 21 design a valve having the structural features of the 22 valve disclosed herein. Five computational steps are 23 involved in this particular method: 24 Define the scallop geometry (the scallop, is the intersection of the leaflet, 2, with 26 the frame, 1); 27 Geometrically define a valve leaflet in the 28 closed position C; 29 Map and compute the distribution of area across the leaflet 'in the closed position; 1 Rebuild the leaflet in a partially open 2 position P; and 3 Match the computed leaflet area distribution 4 in the partially open or moulded position P to the defined leaflet in the closed position 6 C. This ensures that when an increasing 7 closing pressure is applied to the leaflets, 8 they eventually assume a shape which is 9 equivalent to that defined in closed position

C.

11 This approach allows the closed shape of the 12 leaflets in position C to be optimised for durability 13 ':While the leaflets shaped in the .moulded partially 14 open shape P can be optimised for haemodynamics. This allows the use of stiffer leaflet materials for 16 valves which have good haemodynamics. An XYZ co- 17 ordinate system is defined as shown in Fig. 2, with 18 the Z axis in the flow direction of blood flowing 19 through the valve.

The leaflets are mounted on the frame, the shape 21 of which results from the intersection of the 22 aforementioned leaflet shape and a 3-dimensional 23 geometry that can be cylindrical, conical or 24 spherical in nature. A scallop shape is defined through intersecting the surface enclosed by the 26 following equations with a cylinder of radius R 27 (where R is the internal radius of the valve): Hj E, zEJ 1 where f(Z) is a function changing with Z.

X H( H, 2 The shape of the scallop can be varied using the 3 constants Eso, Esj, Hso, The definition of 4 parameters used in these and the other equations herein are contained-in Table 4.

6 The shape of the leaflet under back pressure 7 in the closed position C) can be approximated 8 mathematically using elliptical or hyperbolic co- 9 ordinates, or a combination of the above in an XYZ co-ordinate system where XY is the plane of the valve 11 perpendicular to the blood flow and Z is the 12 direction parallel to the blood flow. The parameters 13 are chosen to define approximately the shape of the 14 leaflet under back pressure so as to allow convenient leaflet re-opening and minimise the effect of the 16 stress component which acts in the direction parallel 17 to the blood flow, whilst also producing an effective 18 seal under back pressure.

19 The closed leaflet geometry in closed position C is chosen to minimise stress concentrations in the 21 leaflet particularly prone to occur at the valve 22 commissures. The specifications for this shape 23 include: 1 inclusion of sufficient material to allow a 2 large open-leaflet orifice; 3 arrangement of this material to minimise 4 redundancy (excess material in the free edge, 3) and twisting in the centre of the free 6 edge, 3; and 7 arrangement of this material to ensure the 8 free edge, 3, is under low stress i.e.

9 compelling the frame and leaflet belly to sustain the back-pressure.

11 Fig. 3 is a partial sectional view (using the 12 section 3-3 shown in Fig. 2) showing only the I3" intended position of the leaflet in the,-closed 14 position. The shape of this intended position is represented by the function XCloSd(Z). This function 16 can be used to arrange the shape of the leaflet in 17 the closed position C to meet the aforementioned 18 specification. The curve is defined using the 19 following equation and manipulated using the constants Eca, Eco, Zo and the functions EcN(Z) and 21 XT(Z).

XCled(z)=-[ Ecj l- Z- Eo XT (Z) Ecv (Z) 22 where EcN is a function changing linearly with Z and 23 XT(Z) is a function changing nonlinearly with Z.

24 Thus the scallop shape and the function XCoIbd(Z) are used to form the prominent boundaries for the 26 closed leaflet in the closed position C. The 1 remaining part of the leaflet is formed using 2 contours S(X, Y)n sweeping from the scallop to the 3 closed leaflet belly function Xclosed(Z), where n is an 4 infinite number of contours, two of which are shown in Fig. 4B.

6 The length of the leaflet (or contours S(X, 7 in the circumferential direction (XY) is calculated 8 and repeated in the radial direction yielding a 9 function L(Z) which is used later in the definition of the geometry in the partially open position P. The 11 area contained between respective contours is also 12 computed yielding a function K(Z) which is also used 13 in the definition of the geometry in position P. The 14 area contained between contours is approximated using the process of triangulation as shown in Fig. 4B.

16 This entire process can be shortened by reducing the 17 number of contours used to represent the surface 18 (100< n <200) 19 The aforementioned processes essentially define the leaflet shape and can be manipulated to optimise 21 for durability. In order to optimise for 22 haemodynamics, the same leaflet is moulded in a 23 position P which is intermediate in terms of valve 24 opening. This entails moulding large radius curves into the leaflet which then serve to reduce the 26 energy required to buckle the leaflet from the closed 27 to the open position. The large radius curves can be 28 arranged in many different ways. Some of these are 29 outlined herein.

The leaflet may be moulded on a dipping former 31 as shown in Fig. 14. Preferably the former is tapered o 1 with an included angle e so that the end 29 has a 2 diameter which is greater than the end 22. (This 3 ensures apposition of the frame and former during 4 manufacture.). In this case, the scallop shape, defined earlier, is redefined to lie on a tapered V) 6 geometry (as opposed to the cylindrical geometry used 7 in the definition of the closed leaflet shape). This 8 is achieved by moving each point on the scallop S 9 radially, and in the same movement, rotation of each point about an X-Y plane coincident with the bottom 11 of the scallop, until each point lies on the tapered 12 geometry.

13 The geometry of the leaflet shape can be defined 14 as a trigonometric arrangement (or other mathematical function) preferably sinusoidal in nature in the XY 16 plane, comprising one or more waves, and having 17 anchoring points on the frame. Thus the valve 18 leaflets are defined by combining at least two 19 mathematical functions to produce composite waves, and by using these waves to enclose the leaflet 21 surface with the aforementioned scallop.

22 One such possible manifestation is a composite 23 curve consisting of an underlying low frequency 24 sinusoidal wave upon which a second higher frequency sinusoidal wave is superimposed. A third wave having 26 a frequency different from the first and second waves 27 could also be superimposed over the resulting 28 composite wave. This ensures a wider angle between 29 adjacent leaflets in the region of the commissures when the valve is fully open thus ensuring good wash- 31 out of this region.

o1 The composite curve, and the resulting leaflet, 2 can be either symmetric or asymmetric about a plane 3 parallel to the blood flow direction and bisecting a 4 line drawn between two stent tips such as, for leaflet 2a, the section along line 3-3 of Fig. 2.

6 The asymmetry can be effected either by combining a 7 symmetric underlying curve with an asymmetric 8 superimposed curve or vice versa.

S9 The following describes the use of a symmetric underlying function with an asymmetric superimposed 11 function, but the use of an asymmetric underlying 12 function will be obvious to one skilled in the art.

13 The underlying function is defined in the XY plane 14 and connects the leaflet attachment points to the scallop at a given height from the base of the valve.

16 This underlying function shown in Fig. 5, can be 17 trigonometric, elliptical, hyperbolic, parabolic, 18 circular, or other smooth analytic function or could 19 be a table of values.

Using sine functions, one possible underlying 21 wave is shown in Fig. 5 and is defined using the 22 following equation.

x X~n.0) A, sin 0.57r 23 The superimposed wave is defined in the XY 24 plane, and connects the attachment points of the leaflet to the scallop at a given height above the 26 base of the valve. The superimposed wave is of higher 27 frequency than the underlying wave, and can be 1 trigonometric, elliptic, hyperbolic, parabolic, 2 circular, or other smooth analytic function, or a 3 table of values.

4 Using sine functions, one possible symmetric leaflet design is formed when the underlying wave is 6 combined with a superimposed wave formed using the 7 following equation.

X, (Y)sin[ 8 As can be varied across the leaflet to produce 9 varying wave amplitude across the leaflet, for example lower amplitude at the commissures than in 11 the leaflet centre. Bs can be varied to adjust the 12 length of the wave. The superimposed wave is shown 13 in Fig. 6. The composite wave formed by combining 14 the underlying wave (Fig. 5) with the superimposed wave (Fig. 6) is shown in Fig. 7.

16 Using sine functions, one possible asymmetric 17 leaflet design is formed when the underlying wave 18 (Fig. 5) is combined with a superimposed wave formed 19 using the following equation.

S0 (Y)sin 2 r L 1 As can be varied across the leaflet to produce 2 varying wave amplitude across the leaflet, for 3 example lower amplitude at the commissures than in 4 the leaflet centre. Bs(Y) can be varied to adjust the length of the wave. The superimposed wave is shown 6 in Fig. 8. The resulting asymmetric composite wave 7 is shown in Fig. 9. The composite wave W(Xc, Yc)n is 8 created by offsetting the superimposed wave normal to 9 the surface of the underlying wave (Figs. 7, 9).

While the general shape of the leaflet in 11 position P has been determined using the composite 12 wave, at this stage it is not specified in any 13 particular position. In order .to specify the position 14 of P, the shape of the partially open leaflet position can be defined as Xopen(Z). This is shown as 16 reference numeral 7 in Fig. 17 One possible function determining this shape is 18 given as follows: Xopen(Z) I( Zfj 19 In order to manipulate the composite wave to produce the belly shape Xopen(Z) the respective 21 amplitudes of the individual sine waves can be varied 22 from the free edge to the leaflet base. For example, 23 the degree of 'openness' of the leaflet in position p 24 can be varied throughout the leaflet.

The composite wave is thus defined to produce 26 the moulded "buckle" in the leaflet, and X,,,(Z)is 27 used to define the geometry of the leaflet at 1 position P. At this stage it may bear no.

2 relation to the closed leaflet shape in position C.

3 In order to match the area distribution of both 4 leaflet positions, (thus producing essentially the same leaflet in different positions) the composite 6 wave length is iterated to match the length of the 7 relevant leaflet contour in position C. Thus the 8 amplitude and frequency of the individual waves can 9 be varied in such a manner as to balance between: (a) producing a resultant wave the length of which is 11 equal to the relevant value in the length function 12 L(Z) thus approximating the required closed shape 13 when back pressure is applied, and allowing 14 efficient orifice washout and ready leaflet opening.

Also the area contained between the contours in the 16 open leaflet is measured using the same process of 17 triangulation as in the closed position C, and is 18 iterated until it matches with the area contained 19 between relevant contours in position C (denoted (through tilting the contours in P relative to 21 each other). Thus the composite waves 22 pertaining to the contour n and length L(Z) can be 23 tilted at an angle to the XY plane about attachment 24 points Y(n,o) and X(n,o, -Yfn,o) until the correct area is contained between P(X,Y)n and P(X,Y)n-I (See 26 Figs. 10 11).

27 This process identifies the values of Bs, Au and 28 the contour tilt angle to be used in constructing the 29 mould for the valve leaflet. As long as the constants such as BE and Au, and the tilt angle of the contours 31 relative to the XY plane, are known, the surface of 1 the leaflet in its moulded position can be 2 visualised, enclosed and machined in a conventional 3 manner. As a result of this fitting process the 4 composite wave retains the same basic form but changes in detail from the top of the leaflet to the 6 bottom of the leaflet. A composite wave can be 7 defined in the leaflet surface as the intersection of 8 the leaflet surface with a plane normal to the Z 9 axis. This composite wave will have the same general form as the composite wave used in the leaflet design 11 but will differ from it in detail as a result of the 12 tilting process described above.

13 In summary therefore one-..possible method of 14 designing the leaflet according to the present invention is in the following way: 16 Define a scallop shape; 17 Define a shape approximating the shape of the 18 closed leaflet using elliptical, hyperbolic, 19 parabolic or circular functions, smooth analytical functions or table of values; 21 Compute the functions L(Z) and which 22 define the length of the leaflet in the XY 23 plane along the Z axis and the area 24 distribution of the leaflet along the Z axis; Use one or more associated sine waves to 26 generate a geometry which is partially-open, 27 which'pertains to a leaflet position which is 28 between the two extreme conditions of normal 29 valve function, i.e. leaflet open and leaflet closed; 1 Vary the frequency and amplitude of the 2 sinewaves to fit to the length function L(Z) 3 and the angle at which the contour is tilted 4 to the XY plane to fit to the area function and 6 The respective amplitudes of the individual 7 sine waves can be varied from the free edge 8 to leaflet base, for example the degree of 9 'openness' of the leaflet can be varied throughout the leaflet.

11 Herein are some examples of how this invention 12 can be put into practice. Using the scallop constants 13 in Table 1, the constants required to produce an 14 example of a symmetric leaflet valve and an example of an asymmetric leaflet valve are given in Table 2 16 and Table 3 respectively. These constants are used in 17 conjunction with the aforementioned equations to 18 define the leaflet geometry.

19 With one leaflet described using the aforementioned equations, the remaining two leaflets 21 are generated by rotating the geometry about the Z 22 axis through 1200 and then through 2400. These 23 leaflet shapes are inserted as the leaflet forming 24 surfaces of the dipping mould (otherwise known as a dipping former), which then forms a 3-dimensional 26 dipping mould. The composite wave described in the 27 aforementioned equations, therefore substantially 28 defines the former surface which produces the inner 29 leaflet surface.

As seen in Fig. 14 the dipping mould 20 is 31 slightly tapered so that the end 29 has a diameter 1 which is greater than the end 22, and has a first end 2 22 having an outside diameter slightly smaller than ;3 the inside diameter of the frame. The former 4 includes at least two and preferably three leaflet forming surfaces 24 which are defined by scalloped V)6 edges 26 and flats 28. Sharp edges in the 7 manufacturing former and on the frame are radiused to 8 help reduce stress concentrations in the finished 9 valve. During the dip moulding process the frame is inserted over end 22 of the former so that the 11 scallops 5 and stent posts 8 of the frame align with 12 the scalloped edges 26 and flats 28 of the former.

13 The leaflet forming surfaces 24 are configured to 14 form leaflets during the moulding process which have the geometry described herein. This mould can be 16 manufactured by various methods, such as, machining, 17 electrical discharge machining, injection moulding.

18 In order that blood flow is not disturbed, a high 19 surface finish on the dipping mould is essential.

For the frame there are preferably three posts 21 with leaflets hung on the frame between the posts. A 22 crown-like frame or stent, i, is manufactured with a 23 scallop geometry, which matches the dipping mould 24 scallop. The frame scallop is offset radially by 0.1mm to allow for the entire frame to be coated with 26 a thin layer of leaflet material to aid adhesion of 27 the leaflets. Leaflets may be added to the frame by a 28 dip-moulding process, using a dipping former machined 29 or moulded to create the multiple sinewave form.

The material of preference should be a semi- 31 rigid fatigue- and creep-resistant frame material 1 such as PEEK, high modulus polyurethane, titanium, 2 reinforced polyurethane, or polyacetal (Delrin) 3 produced by machining or injection-moulding etc.

4 Alternatively, a relatively low modulus polymer may be used, which may be fibre-reinforced, to more 6 closely mimic the aortic wall. The frame can be 7 machined or injection moulded, and is manufactured 8 preferably from polyetheretherketone (PEEK) or 9 polyacetal (Delrin).

The first stage of valve manufacture entails 11 dipping the frame in a polyurethane solution 12 (preferably Elast-Eon T manufactured by Elastomedic, 13 Sydney Australia) in order to apply a coating of 14 approximately 0.1mm thick. Having dried the frame with applied coating in an oven overnight, it is 16 placed on the dipping former and aligned with the 17 former scallops. The combination of frame and three 18 dimensional dipping mould is then dipped into 19 polyurethane solution, which forms a coating of solution on frame and mould. This coating flows 21 slowly over the entire mould surface ensuring a 22 smooth coating. The new coating on the frame and 23 dipping mould solvates the initial frame coating thus 24 ensuring a good bond between leaflet and frame. The dipping mould with polyurethane covering is dried in 26 an oven until all the solvent has been removed. One 27 or more dips may be used to achieve a leaflet with a 28 mean thickness between 40-m and 500pm. The shape of 29 the former, and the viscosity and solvent interactive properties of the polyurethane solution, control the 31 leaflet thickness and the distribution of thickness 41 1 over the leaflet. A dipping process does not allow 2 precise control of leaflet thickness and its 3 variation across a leaflet. In particular surfaces 4 that are convex on the dipping former result in reduced leaflet thickness when compared with surfaces 6 that are concave. Additionally the region of the 7 leaflet adjacent to the frame essentially provides a 8 very small concave radius which traps further polymer 9 solution and this results in thickening of these regions.

11 The shape of the former is substantially defined 12 by the composite wave. Radiusing and polishing of 13 the former -can both!:contribute to some variation of 14 the shape. The shape of the inner surface of the leaflets will closely replicate the shape of the 16 former. The shape of the outer surface of the 17 leaflets will be similar to the shape of the inner 18 surface but variations will result from the 19 processing properties of the polymer solution and details of the dipping process used to produce the 21 valve. The leaflet may be formed from polyurethanes 22 having a Young's modulus less than 100MPa, preferably 23 in the range 5 to 50 MPa.

24 The valve is next removed from the dipping mould. The stent posts, which had been deflected by 26 the taper on the former, now recover their original 27 position. The shape of the leaflets changes slightly 28 as a result of the movement of the stent posts.

29 At this stage the dipping mould and frame is covered with an excess of polyurethane due to the 31 drain-off of the polymer onto the region of the mould 42 1 known as the drain-off area 30. Leaflet free edges 2 may be trimmed of excess material using a sharp blade 3 rotated around the opened leaflets or using laser- 4 cutting technology.

An alternate valve manufacturing method is 6 injection moulding. A mould is constructed with a 7 cavity which allows the valve frame to be inserted in 8 the mould. The cavity is also designed with the 9 leaflet geometry, as defined above, as the inner leaflet surface. A desired thickness distribution is 11 defined for the leaflet and the outer leaflet surface 12 of the mould is constructed by adding the leaflet .13 -thickness normally to the inner leafle surface. The 14 leaflet may be of uniform thickness throughout, in the range 40 to 500 microns, preferably 50 to 200 16 microns, more preferably 80 to 150 microns. The 17 leaflet may be thickened towards its attachment to 18 the frame. Alternatively the thickness of the 19 leaflet, along a cross-section defined by the intersection of a plane perpendicular to the blood 21 flow axis and the leaflet, can change gradually and 22 substantially continuously from a first end of the 23 cross-section first edge of the leaflet) to a 24 second end of the cross-section second edge of the leaflet) in such a way that the mean thickness of 26 the first half of the leaflet is different from the 27 mean thickness of the second half of the leaflet.

28 This mould is inserted in a conventional injection 29 moulding machine, the frame is inserted in the mould and the machine injects molten polymer into the 31 cavity to form the leaflets and bond them to the 1 frame. The polymer solidifies on cooling and the 2 mould is opened to allow the complete valve to be 3 removed.

4 The leaflets may also be formed using a reaction-moulding process (RIM) whereby the polymer 6 is synthesised during the leaflet forming. A mould is 7 constructed as described above. This mould is 8 inserted in a reaction-injection moulding machine, 9 the frame is inserted in the mould and the machine injects a reactive mixture into the cavity. The 11 polymer is produced by the reaction in the cavity to 12 form the leaflets and bond them to the frame. When 13 the reaction is-.complete, the mould is opened to 14 allow the complete valve to be removed.

Yet a further option is to compression mould a 16 valve initially dipped. This approach allows the 17 leaflet thickness or thickness distribution to be 18 adjusted from that initially produced. By varying 19 the thickness of the leaflets the dynamics of the valve opening and closing can be modified. For 21 example, the thickness of the leaflet along a cross- 22 section defined by the intersection of a plane 23 perpendicular to the blood flow axis and the leaflet 24 can be varied so that the thickness changes gradually and substantially continuously from a first end of 26 the cross-section first edge of the leaflet) to 27 a second end of the cross-section second edge 28 of the leaflet) in such a way that the mean thickness 29 of the first half of the leaflet is different from the mean thickness of the second half of the leaflet.

31 This will result in the thinner half of the leaflet 1 opening first and creating a sail-like opening motion 2 along the free edge of the leaflet.

3 Leaflet shape resulting from conventional 4 injection moulding, reaction injection moulding or compression moulding, is substantially defined by the 6 composite wave described above. It will differ in 7 detail for many of the same reasons identified for 8 dip moulding.

9 The valves of the present invention are manufactured in the neutral position or close to it 11 and are therefore substantially free of bending 12 stresses in this position. As a result when the S13 leaflet is moved to its closed position the total 14 bending energy at the leaflet center free edge and at the commissures is reduced compared to a valve made 16 according to U.S. Patent No. 5,376,113.

17 The valves of the present invention may be used 18 in any required position within the heart to control 19 blood flow in one direction, or to control flow within any type of cardiac assist device.

21 The following examples use the same scallop 22 geometry described using the constants set forth in 23 Table 1: While the examples described herein relate 24 to one valve size, the same method can be used to produce valves from a wide range of sizes. This can 26 be carried out by modifying the constants used in the 27 equations, by rescaling the bounding curves such as 28 Xclosed(Z) and computing and iterating in the normal 29 fashion or by rescaling the leaflet.

31 values (mm) R 11.0 Eso 21.7 ES 21.5 EsV 13.8 Hso 0.18 f(Z) (0.05.Z)+1.0 Table 1 Example 1.

The parameters described in the preceding sections are assigned the values set forth in Table 2 and are used to manufacture a symmetric valve. The included angle between adjacent leaflet free edges at the valve commissure for this valve is approximately 500.

Parameter Value (mm) Closed position ZCo 0 Zoo 0.0 EcN(Z) EcN=3. 0.Z+50.3 Eco 22.0 Ecj 20.0 XT(Z) 0.0 Partially-open position e 12.7 EoJ 50.0 ;Z 1 Zoo 4 0 Eoo 51.8 EON 27.7 Au Result from iteration procedure finds that Au varies from le-5 at the leaflet base to 5.1 at 4mm from the leaflet base to 3.8 at the free edge.

A Result from iteration procedure finds that As varies from le-3 at the leaflet base to 1.6 at 3mm from the leaflet base to 0.6 at the free edge.

Table 2 Fig. 12 shows the symmetric valve which is manufactured, using the values outlined in Table 1 and Table 2.

Example 2 The parameters described in the preceding sections are assigned the values set forth in Table 3 and are used to manufacture an asymmetric valve. The included angle between adjacent leaflet free edges at the valve commissure for this valve is approximately 480°.

;Z 1 Parameter Value (mm) Closed position Zoo 0.0 EcN(Z) EcN= 3

O.Z+

4 8 9 Eco 18.4 EcJ 20.0 XT(Z) XTrn-( 0 .97. where XT(free edge) 2 1 Partially-open position 9 7.1 Eoj 50.0 Zoo Eoo 51.5 EON 29.0 Au Result from iteration procedure finds that Au varies from le-5 at the leaflet base to 3.1 at 3mm from the leaflet base to 2.2 at 9mm from the leaflet base to 3.8 at the free edge.

A, Result from iteration procedure finds that As varies from le-3 at the leaflet base to 1.1 at 6mm from the leaflet base to 0.4 at the free edge.

where Bs=l at leaflet base and m= 5.04 and c=-15.1 at leaflet free edge.

Table 3 1 Fig. 13 shows the valve which is manufactured 2 using the values outlined in Table 1 and Table 3.

I

O

Definition of parameters ;Z R Internal radius of valve c Scallop (Fig. 2) Xejn, Hsj, H, Xjy are used to define a surface which, when intersected with a cylinder, scribe a t function which forms the scallop for one leaflet.

c This method for creating a scallop is described Cc in Mackay et al. Biomaterials 17 1996. although an added variable f(Z) is used for added 'n versatility.

SXeii Scribes an ellipse in the radial direction.

Xyp Scribes a hyperbola in the circumferential direction.

Eso Ellipse X-axis offset Esj Major -axis of the ellipse Minor axis of the ellipse Hsj Major axis of the hyperbola Hs, Minor axis of the hyperbola Ho Hyperbola x-axis offset f(Z) Creates a varying relationship between HsN and Hsj Closed Leaflet geometry C (Figs. 3 4) Xclosed(Z) is defined as an ellipse (with a minor axis Ecn(Z) which changes with Z) in the XZ axis in the plane defined in Fig. 2 by cutting plane 3-3. It is defined using the following constants and functions.

Zco Closed ellipse Z-axis offset Ecn(Z) Closed ellipse minor axis which changes with Z Eco Closed ellipse X-axis offset Ecj Closed ellipse major axis XT(Z) Offset function which serves to increase the amount of material in the belly Moulded position P P is enclosed by a number of contours P(X,Y)n which run from one side of the scallop to the other. The underlying function Xu is used in defining both symmetric and asymmetric leaflets.

Xu is simply an ellipse (or other such function) running in a plane from one side of the scallop to the other. The points on the scallop are designated Y(n,o) where n refers to the contour number (see Figs. 5,7,9,11B).

Y Variable in plane from Ytn,o) to Y(n,O) Au A. is the amplitude of the underlying wave A, A, is the amplitude of the superimposed wave B, is a function which biases the wave amplitude in a defined way, e.g. the amplitude of the wave can be increased near the commissure if so desired.

Composite Curve (Figs. 7 9) Xc X coordinate for defining the composite curve. This is derived using X, and X, Yc Y coordinate for defining the composite curve. This is derived using X, and X, Open Leaflet position (Fig. Xopen(Z) is defined as an ellipse in the XZ axis in the plane defined in Fig. 2 by cutting plane 3-3.

The contours defined in Composite Curve are married to the Open Leaflet position Xopen(Z) to produce the moulded leaflet P.

It is defined using the following constants.

EoJ Open ellipse major axis Zoo Open ellipse Z-axis offset Eoo Open ellipse X-axis offset Eon Open ellipse minor axis 0 Former taper angle 1 2 Table 4 Throughout the specification, unless the context requires otherwise, the word "comprise" or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

Claims (19)

1. A method of making a cardiac valve prosthesis which includes a frame defining a blood flow axis substantially parallel to the flow of blood through the valve prosthesis and N at least two flexible leaflets attached to the frame, the method comprising: providing a forming element having at least two leaflet forming surfaces; engaging the forming element to the frame; applying a coating over the frame and engaged forming element, the coating N binding to the frame, the coating over the leaflet forming surfaces forming the at least two flexible leaflets, the at least two leaflets being configured to be movable from an open to a closed position, the at least two leaflets having a blood inlet side and a blood outlet side, the at least two leaflets being in the closed position when fluid pressure is applied to the outlet side, being in the open position when fluid pressure is applied to the inlet side and being in a neutral position intermediate the open and closed position in the absence of fluid pressure being applied to the leaflets, the at least two leaflets including a first leaflet having a surface contour such that when the first leaflet is in the neutral position an intersection of the first leaflet with at least one plane perpendicular to the blood flow axis forms a first composite wave, the first composite wave being substantially defined by a first wave combined with at least a second superimposed wave, the first wave having a first frequency, the second wave having a second frequency, the first frequency being different from the second frequency; said first composite wave providing multiple curves in the leaflet free edge and disengaging the forming element from the frame, and wherein the frame is substantially cylindrical having first and second ends, one of the ends defining at least two scalloped edge portions separated by at least two posts, each post having a tip, wherein each leaflet has a fixed edge joined to a respective scalloped edge portion of the frame and a fee edge extending substantially between the tips of the at least two posts, and wherein when the at least two leaflets are in the neutral position the valve prosthesis has partially open commissures defined by an included angle between adjacent leaflet free edges that is in the range of 10 to 550 00 -52- O

2. A method of making a cardiac valve prosthesis which includes a frame defining a blood flow axis substantially parallel to the flow of blood through the valve prosthesis and at least two flexible leaflets attached to the frame, the method comprising: Nproviding a mould having a cavity sized to accommodate the frame; t 5 inserting the frame into the mould; inserting the mould into an injection moulding machine; t injecting molten polymer into the cavity of the mould to form the at least two Sleaflets and bond the at least two leaflets to the frame, the cavity being shaped to form the at least two leaflets in a neutral position in a desired configuration, the at least two leaflets being configured to be movable from an open to a closed position, the at least two leaflets having a blood inlet side and a blood outlet side, the at least two leaflets being in the closed position when fluid pressure is applied to the outlet side, being in the open position when fluid pressure is applied to the inlet side and being in a neutral position intermediate the open and closed position in the absence of fluid pressure being applied to the leaflets, the at least two leaflets including a first leaflet having a surface contour such that when the first leaflet is in the neutral position an intersection of the first leaflet with at least one plane perpendicular to the blood flow axis forms a first composite wave, the first composite wave being substantially defined by a first wave combined with at least a second superimposed wave, the first wave having a first frequency, the second wave having a second frequency, the first frequency being different from the second frequency, and wherein the frame is substantially cylindrical having first and second ends, one of the ends defining at least two scalloped edge portions separated by at least two posts, each post having a tip, wherein each leaflet has a fixed edge joined to a respective scalloped edge portion of the frame and a fee edge extending substantially between the tips of the at least two posts, and wherein when the at least two leaflets are in the neutral position the valve prosthesis has partially open commissures defined by an included angle between adjacent leaflet free edges that is in the range of 10 to 550 00 -53- O

3. The method of claim 1 or 2 wherein the first composite wave is defined by a first wave combined with second and third waves superimposed over the first wave, the third wave having a third frequency which is different from the first frequency.

4. The method of any one of claims 1 to 3 wherein the first wave is symmetric about a plane parallel to and intersecting the blood flow axis and bisecting the first leaflet. tt

5. The method of any one of claims 1 to 3 wherein the first wave is asymmetric about e¢3 Sa plane parallel to and intersecting the blood flow axis and bisecting the first leaflet.

6. The method of any one of claims 1 to 5 wherein the second wave formed is symmetric about a plane parallel to and intersecting the blood flow axis and bisecting the first leaflet.

7. The method of any one of claims 1 to 5 wherein the second wave is asymmetric about a plane parallel to and intersecting the blood flow axis and bisecting the first leaflet.

8. The method of claim 1 or 2 wherein the first composite wave is symmetric about a plane parallel to and intersecting the blood flow axis and bisecting the first leaflet.

9. The method of claim 1 or 2 wherein the first composite wave is asymmetric about a plane parallel to and intersecting the blood flow axis and bisecting the first leaflet.

The method of any one of claims 1 to 9 wherein the prosthesis comprises a first, second and third leaflet wherein an intersection of the second and third leaflets with the plane perpendicular to the blood flow axis forms second and third composite waves, respectively, the second and third composite waves being substantially the same as the first composite wave.

11. The method of any one of claims 1 to 10 wherein the first wave formed in the coating step is defined by an equation which is one of trigonometric, elliptical, hyperbolic, parabolic, circular, a smooth analytic function and a table of values.

12. The method of anyone of claims 1 to 11 wherein the second wave formned in the coating step is defined by an equation which is one of trigonometric, elliptical, hyperbolic, parabolic, circular, a smooth analytic function and a table of values.

13. The method of claim 8 wherein the first and second waves are symmetric about a plane parallel to and intersecting the blood flow axis and bisecting the first leaflet. 00 -54-

14. The method of claim 9 wherein at least one of the first and second waves is asymmetric about a plane parallel to and intersecting the blood flow axis and bisecting the first leaflet.

The method of any one of claims 1 to 14 wherein the at least two leaflets are configured such that they are substantially free of bending stresses when in the neutral Cc position.

16. The method of any one of claims 1 to 15 wherein the included angle between adjacent leaflet free edges at the partially open cormnissures is in the range of 25 to 550.

17. The method of anyone of claims 1 to 15 wherein the included angle between adjacent leaflet free edges at the partially open commissures is in the range of 40 to 550.

18. A method of any one of claims 1 to 17, the method comprising: defining a first desired shape of the leaflets in a first position; defining a second desired shape of the leaflets in a second position different from the first position; and conducting a draping analysis to identify values of adjustable parameters defining at least one of the first and second shapes to ensure that the leaflets are comprised of a sufficient amount and distribution of material for the leaflets to assume both the first and second desired shapes.

19. The method of claim 18 wherein at least one of the first and second positions formed in the defining steps is a closed position and the other of the first and second positions is a partially open position. The method according to claim 1 or 2 as herein before described with reference to the examples.