WO 2009/156471
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`PCT/EP2009/057970
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`Prosthetic heart valve and method for making such a valve
`
`1
`
`The present invention relates to a prosthetic heart valve from
`5 biological tissue and to a method of making such a valve.
`
`The human heart has a right side and a left side. The function of the
`right side of the heart is to collect de-oxygenated blood from the body, in the
`right atrium, and pump it, via the right ventricle, into the lungs so that carbon
`1 o dioxide can be dropped off and oxygen picked up. The left side collects
`oxygenated blood from the lungs into the left atrium. From the left atrium the
`blood moves to the left ventricle which pumps it out to the body.
`Starting in the right atrium, the blood flows through the tricuspid
`valve to the right ventricle. Here it is pumped out through the pulmonary valve
`15 and travels through the pulmonary artery to the lungs. From there, blood flows
`back through the pulmonary vein to the left atrium. It then travels through the
`mitral valve to the left ventricle, from where it is pumped through the aortic
`valve to the aorta. From the aorta, the blood is divided between major arteries
`which supply the upper and lower body.
`The tricuspid valve, pulmonary valve and aortic valve each comprise
`three leaflets (or cusps). The mitral valve has two leaflets. All heart valves are
`non-return valves, i.e. they ensure blood flow in only one direction and open
`under the influence of pressure differences. The mitral valve and tricuspid
`valve ensure that blood can flow from the atria to the ventricles and not the
`2 5 other way. The pulmonary valve and aortic valve ensure blood flow from the
`ventricles to the pulmonary vein and aorta respectively.
`A malfunctioning heart valve may result in either backward flow
`(regurgitation) or impeded
`forward
`flow (stenosis). Certain heart valve
`pathologies may necessitate the complete surgical replacement of the natural
`3 o heart valves with heart valve prostheses.
`US 4,441,216 discloses a method for making a replacement heart
`valve. In this document, the replacement heart valve is made by taking a piece
`of pericardia! tissue, tanning the tissue and cutting three leaflets. The leaflets
`are then connected to each other and to a stent via stitching.
`US 2003/0130729 describes a percutaneously
`
`implantable
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`replacement heart valve device
`replacement heart valve device. The
`comprises a stent member and a biological tissue artificial valve means
`disposed within the inner space of the stent member. The method of making
`the replacement heart valve device involves taking a rectangular fragment of
`5 animal pericardium, treating, drying, folding and rehydrating it in such a way
`that it forms a two- or three-leaflet valve. At its cylindrical base, two borders are
`stitched together.
`
`It is an object of the present invention to provide an improved
`1 o prosthetic heart valve and an improved method of making a prosthetic heart
`valve. This object is achieved by a method of making a prosthetic valve
`according to claim 1 and a prosthetic heart valve according to claim 8.
`According to one aspect of the invention, the method of making a
`prosthetic heart valve comprises the steps of placing a piece of biological
`15 tissue in or over a mould, and simultaneously tanning said tissue and forming it
`to an appropriate shape.
`Traditionally, biological tissue is tanned in a first step. After tanning,
`the tissue is cut into several pieces of appropriate shape. These pieces are
`then sutured back together to form the prosthetic heart valve. Inventors
`2 o however have found that the biological tissue can be tanned and given the
`appropriate shape simultaneously by placing it in or over a mould and applying
`appropriate tension. There is thus no need for cutting tissue into several pieces
`and then suturing them back together. The result is a heart valve that
`resembles a human heart valve much better. Since the heart valve is from a
`2 5 single biological tissue (thus also from a single animal), the tissue of the heart
`valve is more homogeneous. Additionally, no sutures are required. Sutures in
`a prosthetic heart valve device are problematic for a number of reasons. They
`cause local stress concentrations and limit the life time of a prosthetic heart
`valve and are the main cause for leakage occurring in prosthetic heart valves.
`3 o Also, a prosthetic heart valve aims at being anatomically correct in comparison
`to a normal heart valve, and sutures are not anatomically correct.
`Preferably, in some methods according to the invention, the step of
`placing the biological tissue in or over a mould comprises using two moulds, a
`positive mould with substantially the desired shape of the valve and a negative
`35 mould with a negative shape of said positive mould. Using two moulds with a
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`positive and a negative shape is advantageous in the process of shaping the
`heart valve.
`Optionally, said step of placing the biological tissue in or over a
`mould comprises the steps of placing the tissue over said positive mould and
`5 then placing said negative mould over the biological tissue. Another option is
`that said step of placing the biological tissue in or over a mould comprises the
`steps of placing the biological tissue in said negative mould and then placing
`the positive mould within the negative mould.
`Optionally, the mould that the tissue is placed over has a bottom
`1 o ring and said step of placing said biological tissue over a mould includes
`folding the tissue around said bottom ring. The result of folding the tissue
`around such a bottom ring is to have a heart valve with a ring which can be
`fixed to a support structure. When the prosthetic heart valve device (prosthetic
`heart valve and support structure) is positioned appropriately in a patient's
`15 body (e.g. for an aortic heart valve, at the connection of the heart to the aorta),
`leaks around the outside of the valve may, in certain cases, be avoided.
`Optionally, said bottom ring may be a conical bottom ring. This shape may be
`given to further reduce leaks around the valve. Yet another option is that the
`bottom ring is ridged or undulated, which may also be beneficial in reducing
`2 o leaks around the valve.
`However, the appropriate mould and also whether a plurality of
`moulds should be used, depends to a large extent on the desired shape of the
`valve. In this sense, two kinds of valves should be distinguished: "open" valves
`and "closed" valves. "Open" valves have a substantially open cylindrical shape
`in a relaxed state. Their leaflets are merely defined by parts of the cylinder that
`can move
`inwardly when appropriate pressure conditions are created.
`"Closed" valves have a partly cylindrical shape which however is closed by
`three (or two) leaflets at one side. In use, under suitable pressure, these
`leaflets may move outward to open and let blood pass. Open and closed
`30 valves work in the same way, but their default state is different (respectively
`open and closed). Clearly, the mould to be used for shaping the valve depends
`on the desired end shape of the valve.
`Preferably, the tanning step occurs by subjecting the biological
`tissue to a glutaraldehyde solution. The tanning step occurs simultaneously
`35 with the shaping of the heart valve, with the biological tissue placed in or over
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`a mould. The goal of the tanning step is to make the tissue biocompatible.
`Other aldehydes are known in the art and may be used. The best results have
`been obtained with glutaraldehyde solutions with concentrations between 0.1
`and 1 %, preferably around 0.65%.
`Optionally, in the method according to the invention, said step of
`forming the tissue to an appropriate shape includes applying tension to the
`tissue. By applying tension (e.g. by pulling, by using two moulds or by creating
`a vacuum) in appropriate points at appropriate moments, the tissue takes the
`desired form of the heart valve.
`In some embodiments, the method of making a prosthetic heart
`valve includes an additional step of cutting the biological tissue to form the
`leaflets of the valve. The whole process was started with a single piece of
`biological tissue. After the tissue has been given the appropriate shape to
`function as a heart valve and has been tanned, in some embodiments, the
`15 leaflets are formed by making cuts in the single piece of biological tissue and
`as such "opening" the tissue. This way no form of suturing is required to form
`the leaflets. As mentioned before, sutures are a source of inconvenience in
`prosthetic heart valves. These cuts may be made when the tissue is placed
`over the mould, using the shape of the mould as a guide in the cutting process.
`2 o The cuts may also be made after it has been released from the mould and
`fixed on a support structure, together forming a heart valve device, hereinafter
`further described. This may be a bit more complicated, but it has the
`advantage of having the valve in its mounted position when cutting. This
`avoids possible cutting errors due to the valve being mounted in a support
`2 5 structure slightly differently. It is however also possible to use an additional
`mould or guide for the cutting process or to cut without any additional guide or
`tool.
`
`According to a second aspect of the invention, a method of making
`a prosthetic heart valve device is provided, said method comprising the steps
`3 o of making a prosthetic heart valve according to the invention and the additional
`step of attaching the prosthetic heart valve to a support structure. The support
`structure, in use, has the function of supporting the heart valve, and mostly
`supporting the leaflets of the heart valve to keep them in their desired shape.
`According to another aspect of the invention, a prosthetic heart
`35 valve of a single piece of biological tissue is provided, said valve comprising a
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`substantially cylindrical base and leaflets, characterised in that said cylindrical
`base and leaflets have a continuous peripheral wall. The single piece of
`biological tissue ensures a homogeneous heart valve, and the continuous
`peripheral wall avoids the need of any sutures (which are known to cause
`5 problems during the life-time of the heart valve).
`Preferably, the heart valve is formed using a method according to
`the invention. The method of making a prosthetic heart valve described here
`within
`is
`the most advantageous way of providing a heart valve of
`homogeneous tissue without any sutures.
`In an aspect of the invention, the invention provides a prosthetic
`heart valve of a single piece of biological tissue, said valve being an open
`valve and having a continuous peripheral wall.
`In another aspect according to the invention, a prosthetic heart
`valve device is provided comprising a prosthetic heart valve of a single piece
`15 of biological tissue and a support structure for supporting said valve, said valve
`comprising a cylindrical base and leaflets, said cylindrical base and leaflets
`having a continuous peripheral wall. The support structure is provided such
`that the leaflets in use can maintain their original shape and function properly.
`Any suitable support structure may be used.
`In some embodiments, the support structure of the heart valve
`device comprises three legs for fixing three leaflets of the valve. The present
`invention is especially aimed at prosthetic aortic heart valves. Aortic heart
`valves comprise three leaflets. However, within the scope of the present
`invention, any suitable support structure may be used such as e.g. balloon
`2 5 expandable or self-expandable stents.
`A preferred way of connecting the leaflets to the support structure is
`through suturing. It is to be noted that these sutures are not sutures for closing
`or forming the heart valve (the peripheral wall of the heart valve is continuous);
`the heart valve itself is completely free from sutures and thus has a continuous
`3 o peripheral wall. The sutures serve merely to attach the valve to the support
`structure. Another preferred way of fixing the leaflets of the valve to the
`support structure is by using bendable piercing members (like staples) along
`the support structure. It is possible to provide the support structure with these
`piercing members already during its manufacturing. It is also possible to
`35 provide them separately. These piercing members can be bent around the
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`support perforating the tissue of the heart valve, and as such securing the
`valve in place. Other mechanical means, such as clamps or clips could also be
`used for fixing the leaflets along the support structure.
`In some embodiments, the support structure comprises two annular
`s discs for positioning the prosthetic heart valve in place, said two annular discs
`interconnected by a cylinder. By using two annular discs interconnected by a
`cylinder, the support structure can be positioned at the junction of e.g. the left
`heart ventricle and the aorta, in the place of the original malfunctioning heart
`valve (if the prosthetic heart valve is an aortic heart valve). Additionally, in
`1 o combination with the heart valve comprising a bottom ring (if a mould with a
`bottom ring has been used) it avoids leaks around the prosthetic heart valve
`device.
`
`Preferably, the support structure of the heart valve device is
`collapsible. Optionally, the support structure is made from nitinol. Heart valve
`15 replacement can occur in open heart surgery, but preferably it occurs
`percutaneously by using a catheter or in minimally invasive surgery, such as
`thoracotomy or sternotomy (or similar). To enable this, the support structure
`needs to be collapsible. One way of giving the support this collapsibility is to
`manufacture it (or its parts) with nitinol. Nitinol is a shape memory alloy and
`2 o additionally has the necessary characteristic of biocompatibility. Alternatively, it
`is possible to use other shape memory alloys. A valve device with a nitinol
`support structure as such is self-expandable. It can expand to its proper size
`and shape once delivered in the appropriate position. Alternatively, the valve
`device may be made with a different support structure which may expand to its
`2 s desired form using other known conventional means, such as by mechanical
`means or by a balloon. One known alternative way is e.g. the use of a balloon
`expandable stent as the support structure. Materials which may be used for
`the support structure in this case are e.g. stainless steel and cobalt chromium
`alloys.
`
`30
`
`The present invention is especially aimed at providing prosthetic
`heart valves and heart valve devices for replacing aortic and pulmonary heart
`valves. However, the invention may explicitly also be used to provide a
`prosthetic tricuspid or mitral valve.
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`These and further possible embodiments of the invention and their
`
`advantages will be explained, only by way of non-limiting example, with
`
`reference to the appended figures, in which:
`
`Figure 1 (a) is a perspective view of a preferred mould used in the
`5 method according to the present invention;
`Figure 1 (b) is a perspective view of another preferred mould used in
`the method according to the present invention;
`Figure 1 (c) is a top view of the mould shown in figure 1 (a);
`Figure 1 (d) is a perspective view of yet another preferred mould
`1 o used in the method according to the present invention;
`Figures 2(a)-2(d) show perspective views of different steps in a
`preferred method of making a "closed" valve according to the present
`invention;
`
`Figures 2(e)-2(h) show perspective views of different steps in a
`15 preferred method of making an "open" valve according to the present
`invention;
`
`Figures 3(a)-3(c) show perspective, schematic views of three
`possible heart valves according to the invention.
`Figures 4(a)-4(c) show perspective views of support structures that
`2 o may be used in heart valve devices according to the present invention;
`Figures 5(a) and 5(b) shows in perspective view two steps in a
`preferred method of making a "closed" heart valve device according to the
`present invention;
`Figure 5(c) shows the top view of the heart valve device shown in
`
`2 5 5(a);
`
`Figure 5(d) shows a perspective view of an "open" heart valve
`device according to an embodiment of the present invention.
`
`Before the heart valve is actually made, suitable tissue needs to be
`30 harvested. Preferably, biological tissue is tissue from bovine, equine or porcine
`pericardium.
`In principle, other biological
`tissue may be used as well.
`Preferably, the whole pericardia! sac is harvested and is inspected for defects,
`such as blood in the tissue, or anatomical defects. Then the fat tissue is
`removed. Once a clean pericardium has been selected, it is normally put in a
`35 clean container
`in sterile distilled water or similar
`for cleansing and
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`transportation. During the cleansing, the distilled water may be refreshed a
`number of times. The tissue is then transported to the laboratory where the
`heart valve is going to be made.
`From the selected pericardium, the most suitable tissue must now
`5 be selected. Positive criteria used for this selection may include: homogeneous
`colour and texture of tissue, well hydrated, absence of blood, absence of
`grooves and homogeneous thickness (depending on the application, the
`desired thickness may be different, e.g. of at least a 100 microns. The
`invention is not limited in this sense.). A piece of tissue is then cut from the
`1 o pericardium. This piece of tissue should of course be big enough to be placed
`over the mould used in the manufacturing process, and the exact dimensions
`of the selected piece may vary with the desired size of the heart valve and the
`mould chosen.
`With reference to figures 1(a) and (b), two possible moulds (10)
`15 which may be used in the method according to the invention are shown. In
`figure 1 (a), the mould includes a bottom ring (11 ), a cylindrical base (19) for
`forming a continuous cylindrical base in the resulting heart valve, and a three
`winged structure at the top for forming three leaflets. In figure 1 (b), the mould
`does not have such a bottom ring, but has the same cylindrical base and the
`2 o same three winged structure. In another mould that may be used, the bottom
`ring may be conical in shape (not disclosed in any figure). Yet another option is
`that the bottom ring (11) of the mould may be ridged or undulated (not
`disclosed in any figure) such that the resulting heart valve also comprises an
`undulated or ridged bottom ring. Both figures 1 (a) and 1 (b) refer to moulds that
`2 5 are suitable for making a "closed" heart valve. "Closed" valves have a partly
`cylindrical shape which is closed by three (or two) leaflets at one side. In use,
`under suitable pressure, these leaflets may move outward to open and let
`blood pass. The moulds shown in figures 1 (a) and 1 (b) have an appropriate
`shape with (in this case) three wings (17) for forming the leaflets of the heart
`30 valve.
`
`Figure 1 (c) shows a top view of the mould shown in figure 1 (a). It
`more clearly shows the three wings (17) of the structure at the top of the
`mould. The cylindrical base (19) indicated in figure 1 (a) may also be more
`pronounced, i.e. the point where the base transforms into the leaflets may be
`35 higher.
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`5
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`Figure 1 (d) shows a cylindrical mould, which is suitable for making
`an "open" valve. "Open" valves have a substantially open cylindrical shape in a
`relaxed state. Their leaflets are merely defined by parts of the cylinder that can
`move inwardly when appropriate pressure conditions are created.
`Figures 2(a) and 2(b) show the first steps according to the invention.
`The mould (10) shown in these figures has a substantially flat bottom ring. As
`has been mentioned before, this ring may also be conical or the mould may
`not have a ring. The biological tissue (12) has been made available and it is
`placed over the mould. The tissue placed over the mould is shown as hatched
`1 o in this figure. The top side of the mould should be covered as completely as
`possible, in order for the tissue to take the shape of the mould. The goal of the
`bottom ring of the mould is that by covering the ring with tissue, a ring is
`formed which may reduce, in certain cases, the leaks around the valve when in
`use. Tension is applied to the tissue to shape it more accurately.
`A negative mould (15), which has the negative shape of the positive
`mould (such as shown in figure 2(c)) may be placed over the tissue to help
`shape the tissue. At this point, the tanning process begins. The tissue
`including the mould (and optionally a second mould) is placed in a tanning
`solution. Preferably, a glutaraldehyde solution with a concentration between
`2 o 0.1 % and 1 %, most preferably around 0.65%, is used. It is important to note
`that
`the shaping of the
`tissue and
`the
`tanning of the
`tissue occur
`simultaneously. This allows the valve to be formed from a single piece of
`biological tissue without any sutures.
`The order of using the two moulds may also be reversed. The tissue
`25 may first be placed in negative mould (15) and then positive mould (10) may
`be used to help the tissue take the proper shape. In the following, the tanning
`and shaping process is described in a method using two moulds. It should
`however be noted that the tanning and shaping may also occur using a single
`mould.
`
`15
`
`3 o
`
`Steps of an alternative method according to the present invention
`are illustrated in figures 2(e) - 2(g). Figure 2(e) shows a single piece of
`biological tissue (12) and a mould (1 0'). The mould (1 0') is suitable for making
`an "open" valve. The biological tissue is placed over the mould (1 0'), similarly
`to the steps described before with respect to figures 2(a) and 2(b). Also, when
`35 forming an "open" valve, a negative mould (15') may be used. This is illustrated
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`in figure 2(g). Negative mould (15') has the negative shape of positive mould
`(1 O').
`
`The tanning (and shaping) process may pass through various
`phases. One possibility is that after some 15 minutes, the negative mould is
`5 taken away and it is ensured that the tissue takes the desired shape of the
`mould by forcing it in the appropriate shape. The tissue may extend beyond
`the borders of the mould, since some form of tension may have been applied
`to the tissue to give it the appropriate shape. In a next step, the tissue, still on
`the positive mould, is placed in a fresh glutaraldehyde solution for a few hours,
`1 o e.g. approximately two hours.
`An alternative possibility is that the positive mould is taken away
`after some 15 minutes and the tissue stays positioned in the negative mould. It
`is important to also ensure in this case that the tissue assumes the desired
`shape, i.e. the tissue is manipulated in such a way that it has no folds. Then,
`15 the tissue, still in the negative mould, is placed in a glutaraldehyde solution for
`a few hours, e.g. approximately two hours.
`Optionally, the next step may be to cut the tissue along the three
`wings of the mould to form three leaflets. This is illustrated in figure 2(d).
`Suitable scissors (13) or other cutting means may be used. The cut may be
`2 o performed on the top of the union of the leaflets, e.g. by cutting parallel to the
`vertical plane of the valve. Alternatively, the cut may be performed slightly
`below the union of the leaflets by cutting in a plane perpendicular to the
`vertical plane of the valve. Additionally, it is possible to use both cutting
`methods. In the case of the open valve of figure 2(h), cuts are also made to
`2 5 provide a valve with a cylindrical shape, which is open on both sides. Notice
`that in this case, no cuts are made to form leaflets of the valve.
`After these hours in the glutaraldehyde solution, the remaining
`mould is removed when it is ensured that the tissue has taken the appropriate
`shape. Yet another possibility is leaving the valve in or over the mould for a
`3 o longer time. The benefit of removing the mould after a while is to put the tissue
`in contact with the glutaraldehyde along its entire surface, which accelerates
`the tanning process. By keeping the valve in the mould longer, the tanning
`process may be slower, but the valve will keep its shape better. A way to
`balance both these advantages and disadvantages can be to provide the
`35 mould with a plurality of perforations along its surface or to make the mould out
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`of a meshed material, such that it is permeable to a certain extent.
`The tanning may continue until the desired tanning level has been
`obtained. At this point, tissue that sticks out beyond the desired shape of the
`valve may be cut. But this should be done carefully; the final cut is only made
`s after the heart valve has been fixed on a support structure.
`At this point, the heart valve is ready to be positioned on a support
`structure. For reasons of clarity, the tissue is no longer hatched. Figures 3(a)
`and 3(b) show two possible embodiments of the heart valve (1) according to
`the invention. Figure 3(a) shows a heart valve (1) comprising three leaflets (2),
`1 o a cylindrical base (3) and a bottom ring (4 ). If another mould is used, the
`resulting heart valve may look differently, as illustrated in figure 3(b). The
`cylindrical base (3) is much less pronounced and it does not have a bottom
`ring. Additionally in figure 3(b), the leaflets have already been separated
`through cuts (5). Both figures 3(a) and 3(b) refer to closed heart valves. Figure
`15 3(c) illustrates an open valve (1 '), which may result from the previously
`described process. In figure 3(c), the cylindrical base (3') cannot be readily be
`distinguished from the leaflets (2'). The composition of open valve (1 ')
`comprising a cylindrical base (3') and leaflets (2') can more clearly be
`recognized in figure 5(d). Also the open valve according to the present
`2 o invention has a continuous peripheral wall.
`A support structure (20) is shown in figure 4. It comprises a bottom
`annular disc (21 ), a top annular disc (23) connected with each other through a
`cylindrical structure (22). In the case of a prosthetic heart valve device used as
`a replacement aortic valve, the bottom disc (21) may be regarded as the
`2 s ventricular disc and the top disc (23) may be regarded as the aortic disc. The
`top disc (23) preferably comprises three legs (24) for supporting three leaflets
`of the heart valve. In order to be able to replace a heart valve percutaneously
`or by minimally invasive surgery (i.e. not through open heart surgery), the
`support structure has to be made collapsible. A preferred way of making the
`30 support structure collapsible is by making it from nitinol. The heart valve device
`in this case is self-expandable. Alternative collapsible support structures may
`also be used. Suitable means for expanding the valve device once it has been
`delivered in the appropriate position may then need to be provided.
`Another possible support structure is shown in figure 4(b), which
`3 s shows a schematic view of a balloon expandable stent. A self-expandable
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`stent may also be used, such as shown in figure 4(c). Such alternative
`structures are well known in the art. The invention is not limited to any
`particular support structure. Instead the heart valve according to the present
`invention may be used with any suitable support structure.
`In a next step, to form a heart valve device ready for implant in the
`body, the support structure is placed over the heart valve. The legs (24) of the
`support structure are connected to the three leaflets (2), preferably though
`suturing or using mechanical means such as bendable piercing members,
`clips, or clamps. This has been shown, very schematically, in figure 5(a). The
`1 o valve is also connected to the support along its bottom periphery. Non
`absorbable polyester may be used for suturing. In a next step, the leaflets (2)
`may be formed by cutting the tissue along the three dotted lines, indicated in
`figure 5(b). This way, the three leaflets (2) are formed. It is important to note
`that even though the legs may be sutured or otherwise attached to the support
`15 structure,
`the valve still has a continuous peripheral wall. As
`is also
`schematically indicated in figure 5(b), the remaining extra tissue is cut of along
`the bottom of the support. As was mentioned before, it is also possible that the
`three leaflets have already been formed by cutting in an earlier step.
`For reasons of clarity, the tissue (12) is not shown as hatched in
`2 o these figures. In figures 5(a) and 5(b), the tissue (12) that sticks out beyond its
`desired form has been left out, also for reasons of clarity. In figure 5(c), the top
`view of a heart valve device is shown and th is extra tissue is shown. Part of
`this tissue may already have been removed in a previous step.
`It is also foreseen that with an alternative design of the support
`2 s structure the valve may be placed over the support structure (instead of the
`other way around). In this case, the support structure would still have three
`legs but would not have a top disc. The way of fixing the valve to the support
`structure is further similar to what was described before.
`An open valve mounted on a similar support structure as shown in
`30 figures 5(a)-5(c) is shown in figure 5(d). The three leaflets 2' of the heart valve
`device are formed by the parts of the cylindrical valve which are not attached
`to the three legs (24) of the support structure. The material in between the legs
`will move inward and outward in use due to the prevailing pressure conditions.
`The cylindrical base (3') of the open valve is not visible, since it is covered by
`3 s the support structure.
`
`IPR2020-01454 Page 01172
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`

`WO 2009/156471
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`PCT/EP2009/057970
`
`13
`
`Once the prosthetic heart valve device has been made available, it
`should be inspected to ensure it has the appropriate dimensions and it is well
`connected to the support structure. If the inspection results are positive, the
`device should be made sterile before it can be implanted in a patient's body.
`s The sterilization may take place through a chemical process or through
`radiation. These techniques are well known in the art.
`
`IPR2020-01454 Page 01173
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`

`

`WO 2009/156471
`
`PCT/EP2009/057970
`
`14
`
`Claims
`
`1. A method of making a prosthetic heart valve (1, 1 ') comprising the
`steps of placing a piece of biological tissue (12) in or over a mould (10, 1 O'),
`5 and simultaneously tanning said tissue and forming it to an appropriate shape.
`
`2. A method of making a prosthetic heart valve according to claim 1,
`characterised in that the step of placing the biological tissue in or over a mould
`comprises using two moulds, a positive mould (1 O; 1 O') with substantially the
`1 o desired shape of the valve and a negative mould (15; 15') with a negative
`shape of said positive mould (1 O; 1 O').
`
`3. A method of making a prosthetic heart valve according to claim 2
`and the step of placing the biological tissue in or over a mould comprises the
`15 steps of placing the tissue over said positive mould (1 O; 1 O') and then placing
`said negative mould (15; 15') over the biological tissue or comprises the steps
`of placing the biological tissue in said negative mould and then placing the
`positive mould within the negative mould.
`
`20
`
`4. A method of making a prosthetic heart valve according to any
`previous claim, characterised in that the mould has a bottom ring (11) and said
`step of placing said biological tissue in or over a mould includes folding the
`tissue around said bottom ring (11 ).
`
`25
`
`5. A method of making a prosthetic heart valve according to any
`previous claim, characterise