• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    METHOD FOR PREPARING BIOPROTECTIC TISSUE MEMBRANE MATERIAL, METHOD FOR PREPARING AND MANUFACTURING A HEART VALVE LEAFLET The present invention relates to methods for conditioning bioprosthetic material using bovine pericardium membrane. A laser directed at the fibrous surface of the membrane and moved with respect to it reduces the thickness of the membrane to a uniform thickness it reduces the thickness of the membrane to a specific uniform thickness and smooths the surface. The wavelength, energy and pulse rate of the laser are selected which will smooth the fibrous surface as well as ablate the surface to the appropriate thickness. Alternatively, a dermatome is used to remove a layer of material from the fibrous surface of the membrane. Thinning can also employ compression. Stepwise compression with crosslinking to stabilize the membrane is used to prevent damage to the membrane through inelastic compression. More precisely, the membrane is bonded in the compressed elastic state by the addition of crosslinking. In the above, several thinning techniques can be used together to obtain strong thin membranes. The finally fine-tuned membrane can then be treated by leveling the nucleation sites of (...).
    公开号:BR112012023769B1
    申请号:R112012023769-1
    申请日:2011-03-23
    公开日:2020-11-10
    发明作者:Jeffrey S. Dove；Bin Tian；Ralph Schneider；Jeffrey S. Cohen；Ivan Jankovic；John F. Migliazza；Gregory A. Wright；James M. Young；Louis A. Campbell
    申请人:Edwards Lifesciences Corporation；
    IPC主号:
    专利说明:

    RELATED REQUESTS
    [001] The present application claims priority under 35 USC §119 (e) for US Provisional Application No. Series 61 / 316,801 filed on March 23, 2010, and US Provisional Application No. Series 61 / 381,858 filed on September 10, 2010 . FIELD OF THE INVENTION
    [002] The field of the present invention is the conditioning of bioprosthetic tissues for use in implants and, more particularly, for methods to soften and fine-tune sheet of bioprosthetic tissue for use in prophetic heart valves. BACKGROUND OF THE INVENTION
    [003] Medical technology has long been able to replace damaged or diseased heart valves through open heart surgery. These valves included mechanical devices as well as those that use biological material from humans (homograft tissue) and animals (xenographic tissue). The first two types of prophetic heart valves known in the art are mechanical valves and bioprosthetic valves. Bioprosthetic valves can be formed from an intact multi-leaf swine (pig) heart valve, or by forming a plurality of individual leaflets outside of bovine pericardial tissue or other materials, and combining the leaflets to form the valve. An advantage of bioprosthetic valves, unlike mechanical valves, is that the patient receiving the valve typically does not require long-term treatment with anticoagulants.
    [004] Pericardium is a sac around the heart of vertebrate animals that contains lubricating fluid, and bovine (cow) pericardium is commonly used to make individual leaflets for prosthetic heart valves. The bovine pericardium is first collected from the animal and then chemically fixed to cross-link the collagen and elastin molecules in the tissue and increase the durability of the tissue, before being cut into leaflets.
    [005] A good discussion of the various physical properties of fixed bovine pericardium is given in Simionescu, et al. Mapping of Glutaraldehyde-Treated Bovine Pericardium and Tissue Selection For Bio-prosthetic Heart Valves, Journal of Bio-Medical Materials Research, Vol. 27, 697-704, John Wiley & Sons, Inc., 1993. Simionescu, et al. sometimes recognized marked variations in the physical properties of the pericardial tissue, even in the same pericardial sac.
    [006] The pericardial sac consists of two distinct tissue elements. The visceral and serous layer is very thin translucent tissue adjacent to the heart that is not used to construct the artificial heart valve leaflets. This inner layer of the pericardium is conical and surrounds the heart and the roots of large blood vessels. The parietal pericardial membrane is a thicker membrane of the multilayer connective tissue covered with adipose tissue. The external / adipose fat tissue is removed (for example, peeled) when collected. The remaining multi-layer fibrous tissue primarily contains fibers with a generally fibrous outer surface and a smooth inner surface. The remaining membrane is used to produce the leaflets for artificial heart valves.
    [007] A number of steps in a typical commercial process for preparing pericardial tissue for heart valve leaflets are illustrated in figure 1. First, a new pericardial bag 20 is obtained from a slaughterhouse. The bag 20 is then cut open along the predetermined anatomical landmarks, as indicated at 22. The bag is then flattened at 24 and typically cleaned of excess fat and other impurities. After obviously trimming the useless areas, a window 26 of the tissue is fixed, typically immersing in an aldehyde to crosslink the tissue, and then quarantined for a period of about two weeks. Typically, two 10 to 15 cm (4 to 6 inch) windows on one side can be obtained from a bovine pericardial sac. The rough edges of the fabric window 26 are removed and the fabric bioclassified to result in a section of fabric 28. The bioclassification process involves visually inspecting window 26 for useless areas, and trimming section 28 from there. Subsequently, section 28 is still cleared as indicated at 30.
    [008] Section 28 is then placed flat on a platform 32 for thickness measurement using a contact indicator 34. The thickness is measured by moving section 28 randomly around platform 32 while a spindle 36 of indicator 34 moves to up and down at various points. The thickness of each stitch is displayed at 38 and recorded by the operator. After sorting sections 28 measured by thickness, as indicated in 40, leaflets 42 are cut into the matrix from the sections, with thinner leaflets 42 being generally used for smaller valves, and thicker leaflets being used for valves bigger. Of course, this process is relatively time consuming and the quality of the final brochures depends on several steps in the technician's skill. Furthermore, the number of leaflets obtained from each bag is inconsistent, and subject to some inefficiency from the manual selection process. A solution to this time-consuming manual process is provided in US Patent No. 6,378,221 to Ekholm etal., In which a programmable three-axis controller manipulates a pericardial sheet with respect to a thickness measurement head to topographically map the sheet within zones of similar thickness for later use. However, even with advanced methods, the variability of the bovine pericardium results in an extremely low leaf yield useful for heart valve leaflets; on average less than 2 sheets per bag.
    [009] Typically the collected bovine pericardial tissue is in the 250 micron to 700 micron thickness range, although most of the material is between 300-700 microns in thickness.
    [0010] The valves that use the flexible leaflets, such as those made of bovine pericardial tissue, acquired a late increased meaning because these valves can be implanted except in open heart surgery. The valves are constructed using radially expandable stents with fixed flexible leaflets (for example, pericardium). Implantation methods include compressing the valve radially by a significant amount to reduce its diameter or release profile, inserting the valve into a release tool, such as a catheter or cannula, and advancing the release tool to the correct anatomical position in the heart. Once properly positioned, the valve is implanted by radial expansion into the annular space of the native valve, both through the stent structure and an expansion balloon. The valve collapsed in the catheter can be introduced through the vasculature, such as through the femoral artery, or more directly through the intercostal incision in the chest. The procedure can be performed without open heart surgery and possibly without stopping the heart during the procedure.
    [0011] An example of percutaneous heart valve release is US Patent No. 6,908,481 to Cribiere Edwards Lifesciences of Irvine, CA, which shows a valve prosthesis with an expandable frame on which a foldable valve structure is mounted. Another foldable / expandable heart valve is shown in US Patent Publication No. 2010/0036484, also by Edwards Lifesciences. Other examples of such methods and devices are disclosed in US Patent No. 27,621,948 and US Patent Publication No. 2006/0259136, and the number of other configurations of these valves is exploding as the promise of technology develops. Disclosures for each of these references are incorporated herein by reference.
    [0012] These new devices require thinner components that allow the valve to ripple to a size that can pass through the release tool. A limiting component is the thickness of the bioprosthetic tissue. As mentioned, the pericardial layers are in the 250-700 micron range, but only a small percentage of the collected pericardium falls close to the lower end, which is most useful for compressible / expandable valves.
    [0013] US Patent No. 7,141,064 proposes to compress the bovine pericardium to reduce the thickness by about 50 percent for use in heart valve leaflets. Compression can also smooth the fabric surface to reduce non-uniform thickness.
    [0014] Despite much research on various bioprosthetic tissues, in particular for heart valve leaflets, there remains a need for thinner and more consistent thickness tissues for use in the manufacture of smaller release profile bioprostheses. SUMMARY OF THE INVENTION
    [0015] The present invention is directed to the preparation of bioprosthetic material for cardio implant. Bovine pericardial membranes having a fibrous surface and a smooth surface are selected. This preparation can increase to give cardio valve leaflets from the pericardial membrane and can eliminate thrombogenic agents such as dangling fibers.
    [0016] According to one aspect, a method for preparing bioprosthetic tissue membrane material includes first selecting a tissue membrane (e.g., bovine pericardium membrane) having a fibrous side and a smooth side. The material is then removed from the fibrous side of the selected membrane to reduce the thickness of the membrane and smooth the fibrous side. The material can be removed by shearing with a mechanical device, such as a dermatome or vibratom. Alternatively, the material can be removed by ablation with a laser.
    [0017] In the exactly described method, the selected membrane can be conditioned by compressing the selected tissue membrane and cross-linking the material of the membrane while under compression. Furthermore, the method may involve treating the reduced membrane in thickness by leveling the calcification nucleation sites and / or by reducing the borohydride. According to one aspect, the method further comprises at least partially fixing the selected membrane before the removal step.
    [0018] According to another method disclosed in this document, the bioprosthetic tissue membrane material is prepared first by selecting a tissue membrane that has a fibrous side and a smooth side, conditioning the selected tissue membrane by compression and cross-linking the membrane while under compression, and then removing the conditioned material from the fibrous side of the selected tissue membrane to reduce the thickness of the membrane and smooth the fibrous side. The tissue membrane can be the pericardial membrane, such as bovine or equine. The method may involve treating the membrane reduced in thickness by leveling and / or reducing borohydride. According to one aspect, the removal step is carried out by shearing with a mechanical device, such as a dermatome or vibrato. Or, the removal step is performed by ablating the conditioned material with a laser.
    [0019] According to yet another aspect, a method for preparing bioprosthetic tissue membrane material comprises first selecting a tissue membrane that has a fibrous side and a smooth side. The membrane material is the minimum partially crosslinked and then infused with a second crosslinking material of a chain length to allow the expenditure of large interfibrillary domains. Subsequently, the tissue membrane is the least partially compressed. The tissue membrane can be a bovine pericardium membrane. The method may also involve lightly compressing the selected membrane before at least partially cross-linking the membrane. The method may include treating the reduced membrane in thickness by leveling and / or reducing borohydride. According to one aspect, the material is removed from the fibrous side of the lightly compressed fabric membrane.
    [0020] Another aspect of the present application is a heart valve comprising a plurality of leaflets, each made of a tissue sheet having a first region with a first uniform thickness and a second region with a second uniform thickness greater than the first thickness. The leaflets each preferably have a cusp edge in front of a free edge, and the second region extends in a strip of generally uniform width along the cusp edge. The second region can also extend on a strip of generally uniform width along the free edge of each leaflet. In addition, the second region may extend in strips of generally uniform width from the center of the free edge to the cusp edge. Desirably, the transitions between the thickness of the first and second regions are gradual. In one embodiment, the heart valve includes a support frame in which the peripheral edges of the leaflets are fixed with sutures, and the second region extends along the edges of the leaflets through which the sutures are passed.
    [0021] In a first separate aspect of the invention, a dermatome is employed with the fibrous surface of the membrane and moved with respect to it to smooth the surface and / or reduce the thickness of the membrane to a specific uniform thickness, for example, no more than 250 microns. The dermatome is restricted by spacers to control the thickness of the membrane while remaining with the trimmed material removed.
    [0022] In a second separate aspect of the invention, the fibrous surface of the membrane is removed to smooth the surface and / or reduce the thickness of the membrane to a specific uniform thickness. The membrane is first subjected to light compression and crosslinking to smooth the fibrous surface and improve the material for ablation.
    [0023] In a third aspect of the invention, a laser is directed at the fibrous surface of the membrane and moved with respect to it by ablating the surface to smooth the surface and / or to reduce the thickness of the membrane to a specific uniform thickness. The wavelength, energy and pulse rate of the laser are selected, which will smooth the fibrous surface as well as ablate the surface to the appropriate thickness. The membrane can first be subjected to light compression and crosslinking to smooth the fibrous surface and improve the material by ablation.
    [0024] In a fourth separate aspect of the present invention, the bovine pericardium membrane is first at least partially crosslinked, then infused with a second crosslinking material of a chain length to allow the transposition of large fibril domains. The membrane is then compressed and can then be treated with leveling and reduction of borohydride.
    [0025] In a separate fifth aspect of the present invention, any of the above processes can be used in combination for greater advantage.
    [0026] Further understanding of the nature and advantages of the present invention are described in the following description and claims, particularly when considered in conjunction with the accompanying drawings in which equal parts have equal reference numbers. BRIEF DESCRIPTION OF THE DRAWINGS
    [0027] The invention will now be explained and other advantages and features will appear with reference to the attached schematic drawings, in which:
    [0028] figure 1 illustrates a sequence of steps in the prior art to prepare and measure the thickness of bovine pericardial tissue before forming the leaflets from the tissue;
    [0029] figure 2 is a perspective view of a representative embodiment of a prosthetic heart valve that can be made with conditioned tissue according to the present application;
    [0030] figure 3 is a perspective view of a support frame that can be used on the prosthetic valve in figure 2;
    [0031] figure 4 is a flat view of a valve leaflet shown in figure 2;
    [0032] figure 5 is a bottom perspective view of a valve leaflet structure connected to a reinforcement skirt to form a leaflet assembly;
    [0033] figure 6A depicts a side view of an exemplary prosthetic heart valve waved in a balloon-release catheter;
    [0034] figure 6B shows the prosthetic valve of figure 6A mounted on the balloon release catheter and in its expanded state;
    [0035] figure 7 is a schematic view of a tissue conditioning sequence of the pericardial membrane with laser ablation;
    [0036] figure 8 is a flattened plan view of a valve leaflet showing a reinforcement region formed by uniformly thick tissue adjacent to the bottom edge of the leaflet;
    [0037] figure 9 is an edge view of a valve leaflet showing a reinforcement region;
    [0038] figure 10 is a plan view of a prosthetic heart valve leaflet having a thickened peripheral edge in areas where the sutures penetrate for fixation to a structural stent;
    [0039] figures 10A and 10B are sectional views through a radial median line of the leaflet of figure 10 shown two profiles of different thickness;
    [0040] figure 11 is a plan view of a prosthetic heart valve leaflet having a thickened peripheral edge in areas where the sutures penetrate for fixation to a structural stent as well as a thickened free edge to reduce the risk of stretching in that location;
    [0041] figures 11A and 11B are sectional views through a radial median line of the leaflet of figure 11 showing two profiles of different thickness;
    [0042] figure 12 is a plan view of a prosthetic heart valve leaflet having a thickened peripheral edge in areas where the sutures penetrate for fixation to a structural stent as well as a thickened triple stitch area on the free edge simulating Arantius nodules;
    [0043] figures 12A and 12B are sectional views through a radial median line of the leaflet of figure 12 showing two profiles of different thickness;
    [0044] figure 13 illustrates in plan view an alternative leaflet having a thickened peripheral edge region, a thickened strip along the free edge, and a plurality of thickened radial strips extending from the free edge to the cusp edge ;
    [0045] Figures 14A and 14B are schematic views of processes for scraping exemplary leaflets using contoured forming molds;
    [0046] figure 15A is a schematic view of a dermatome cut tissue, while figure 15B illustrates the result in a generic section of pericardial tissue;
    [0047] figure 16 is a schematic side view of a press with a spacer nearby removed for clarity. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
    [0048] In the first embodiment, the preparation of leaflets for prosthetic heart valves, in particular expandable heart valves, is described. The leaflets are desirably incorporated into expandable prosthetic heart valves that are initially waved (or even laminated) in a small release profile or diameter to be passed through a catheter or other delivery system and then expanded at the implantation site, typically a space annul the valve. The heart valves comprise structural stent bodies with a plurality of flexible leaflets incorporated therein. Various materials are suitable for the stent body, although certain nickel-titanium alloys (ie, Nitinol) are preferred for their super elasticity and biocompatibility. It should also be noted that configurations of specific stent bodies should not be considered limiting, and various construction details can be modified.
    [0049] Although forming the prosthetic heart valve leaflets to be thinner helps to reduce the size of expandable valve releases, it believes that forming thinner leaflets as well as conditioning the leaflets as described in this document is advantageous for conventional heart valves as well. For example, it is believed that smoothing the rough surface of the pericardial tissue improves the durability of the leaflets by reducing loose fibers and concomitant thrombogenicity.
    [0050] Heart valves with durability in excess of 10 years had the thickness of the bovine pericardium leaflet in the range of 0.014-0.023 inch (-35-459 microns), with smaller valves using thinner leaflets and larger valves having thicker leaflets. Current percutaneous valves can employ swine pericardial tissue with thicknesses below 0.004-0.005 inches (-100-130 microns). Although naturally occurring pig tissue is slightly thinner than naturally occurring pericardial tissue, there are certain advantages to using pericardial leaflets.
    [0051] Various tissues can be used for the leaflets, although a preferred fabric for use in the primary application of heart valve leaflets is the bovine parietal pericardial membrane. Although the thickness and strength of the bovine pericardium tissue is considered desirable for longer lasting valves, other bioprosthetic tissue such as porcine, equine and other mammalian pericardium, including human, can be used. In addition, tissue from other anatomical sources can be used, such as dura mater, peritoneum, diaphragm, or others. Any tissue membrane that has a suitable durability and elasticity as a pericardium is a candidate, although those skilled in the art will appreciate that certain materials may be better suited for any specific application. In general, tissues containing fibrous collagen, in particular type I or type III collagen, and elastic fibers or elastin, may be suitable for use in the manufacture of cardiac valve leaflets. Other potential types of collagens that can be used are hybrid natural collagen solution or electrorotation collagen elastin tissue. Also, certain fabrics called engineered can be used, which are synthesized by developing the collagen tissue over a frame typically made of mesh or scaffolding. These sources are collectively referred to as "tissue membranes" and can all benefit from the principles described in this document, although some similar bovine pericardium is especially well suited for conditioning heart valve leaflets according to the present application.
    [0052] As mentioned above, the pericardial sac consists of two or more distinct layers, one side being relatively smooth while the opposite surface comprises connective tissue covered with adipose tissue, some of which is peeled off when collected, and is thus fibrous. The methods described in this document are particularly useful for smoothing fibrous tissue to form a consistently thick and smooth membrane. In some cases, the thickness of the fibrous adipose tissue side can also be reduced to produce a uniformly thin membrane, preferably below 300 microns for use in foldable / expandable valves.
    [0053] With reference to figure 2, a prosthetic heart valve of an exemplary part 50 is shown that can use a bovine membrane of uniform thickness. Valve 50 will be described in some detail to illustrate some of the benefits of the leaflet making methods described in this document, but, more specific in the valve structure, can be found in Patent Publication No. 2010/0036484, filed on June 8, 2009, entitled "LOW PROFILE TRANSCATETER HEART VALVE" and assigned to Edwards Lifesciences, the description of which is incorporated herein by reference. Alternatively, another minimally invasive valve that can use thin pericardial membrane is found in US Patent No. 6,733,525, issued on May 11, 2004, entitled "MINIMALLY INVASIVE LAMINATED HEART VALVES AND METHODS OF USE", whose disclosure is expressly incorporated in the present document by reference.
    [0054] The valve 50 in the illustrated embodiment generally comprises a structural frame, or stent52, a flexible leaflet structure 54 supported by the frame, and a flexible skirt 56 secured to the external surface of the leaflet structure. The illustrated valve 50 can be implanted in the annular space of the native aortic valve, but it can also be adapted to be implanted in other native heart valves or in several other body ducts or orifices. The valve 50 has a "lower" or inflow end 60 and a "upper" or flow end 62. Blood flows freely up through the valve 50, but the flexible leaflet structure 54 closes to prevent reverse downward flow. The flexible booklet structure 54 thus provides flexible fluid occlusion surfaces to enable unidirectional blood flow.
    [0055] Valve 50 and frame 52 are configured to be radially foldable in a contracted or wavy state for introduction into the body over a release catheter and radially expandable in an expanded state to implant the valve in a desired location on the body (for example, example, the native aortic valve). The frame 52 can be made of a plastically expandable material that allows to ripple the valve to a smaller profile for release and expansion of the valve using an expansion device such as the balloon of a balloon catheter. Exemplary plastically expandable materials include, without limitation, stainless steel, a nickel-based alloy (e.g., a nickel-cobalt-chromium alloy), polymers or combinations thereof. Alternatively, valve 50 may be a so-called self-expanding valve in which the frame is made of a self-expanding material such as Nitinol. A self-expanding valve can be corrugated and retained in the contracted state with a restraining device such as a sheath covering the valve. When the valve is positioned at or near the target site, the restriction device is removed to let the valve self-expand to its expanded, functional size.
    [0056] Referring also to figure 3 (which shows the frame alone for purposes of illustration), frame 52 is a stent-like structure, usually tubular, having a plurality of vertically extending, angularly spaced struts, or posts. commissure fixing 64. The reader will notice that the posts 64 in figure 3 are slightly modified from those shown in figure 2, the differences being minimal. The posts 64 are interconnected through several rows of struts 66 extending circumferentially. The thinnest vertical (axial) struts 68 of the commissure fixing posts 64 connect to and extend between the adjacent horizontal rows of struts 66. The struts in each row are desirably arranged in a zigzag or generally tooth pattern saw blade extending towards the circumference of the frame as shown. The adjacent struts in the same row can be interconnected to each other as shown, to form an angle when expanded, desirably between about 90 and 110 degrees. This optimizes the radial resistance of the frame 52 when expanded, yet allows the frame 52 to be equally corrugated and then expanded in the manner described below.
    [0057] The structure of the leaflets 54 desirably comprises three separate connected leaflets 70 as shown in figure 4, which can be arranged to contract in a tricuspid arrangement, as best shown in figures 2 and 5. Each leaflet 70 has a cusp edge curved bottom 72 in front of a generally straight top free edge 74, and two commissure flaps 76 extending between the free edge 74 and the bottom edge 72. The curved cusp edge 72 forms a scallop in the booklet structure 54. When secured to two other leaflets 70 to form the leaflet structure 54, the curved cusp edges 71 of the leaflets collectively form a scalloped bottom edge of the leaflet structure (as best shown in figure 5). As still shown in figure 4, two reinforcement bars 78 can be secured in each leaflet 70 adjacent to flaps 76 (for example, using sutures). The flaps can then be folded over the bars 78 and secured in the folded position using sutures. If desired, each bar 78 can be placed on a protective sleeve (for example, a PET sleeve) before being secured in a leaflet.
    [0058] Leaflets 70 are attached to each other on their adjacent sides to form commissures 80 of the leaflet structure (see figure 2 on the edges where the leaflets arrive together). The booklet structure 54 can be secured to frame 52 using various techniques and mechanisms. For example, as best seen in figure 2, the commissures 80 of the booklet structure are desirably aligned with the support posts 64 and secured in them using sutures through the holes 82 (figure 3). The point of attachment of the leaflets to the posts 64 can be reinforced with the bars 78 (figure 4), which desirably are made of a relatively rigid material (compared to the leaflets), such as stainless steel.
    [0059] As mentioned, the bottom edge of the booklet structure 54 desirably has a wavy, curved scallop shape. A suture line 84 visible on the outside of the skirt 56 in figure 2 tracks the scallop shape of the leaflet structure 54. By forming the leaflet with this scallop-shaped geometry, the stresses on the leaflet are reduced, which in turn improves the valve durability. Furthermore, due to the scallop shape, folds and small undulations in the center of each leaflet (the central region of each leaflet), which can cause premature calcification in these areas, can be eliminated or at least minimized. The scallop-shaped geometry also reduces the amount of fabric material used to form the leaflet structure, thereby allowing an even more wavy, smaller profile at the inflow end of the valve.
    [0060] With reference again to figures 2 and 5, the skirt 56 can be formed, for example, from polyethylene terephthalate (PET) tape. The leaflet structure 54 is attached to the skirt by means of a thin PET reinforcement strip 88 (or sleeve), figure 5, which allows for a secure suture and protects the pericardial tissue of the leaflet structure from tears. The leaflet structure 54 is interspersed between the skirt 56 and the reinforcement strip 88. The suture 84, which holds the reinforcement strip and the leaflet structure 54 in the skirt 56 can be any appropriate suture and desirably tracks the curvature of the edge of bottom of the leaflet structure 54, as seen from the outside of the skirt 56 in figure 2. The assembly of the skirt 56 and the leaflet structure 54 resides inside the frame 52 and is held in the horizontal struts 66 through a series of standard sutures in zigzag 86, as shown in figure 2.
    [0061] To assemble, the heart valve leaflets 70 are cut from a membrane such as bovine pericardium and tuned, conditioned or otherwise conformed according to the principles described in this document. In the expandable valve 50 described above, the leaflets 70 are fixed within the frame of tubular stent52 and the three adjacent pairs of free edges 74 meet in the center of the valve in combination lines oriented equiangularly with respect to each other. The free edges 74 grow inward to come together along the pieces combination lines. The assembled valve is then stored in a sterile fluid, typically glutaraldehyde, for a period before implantation.
    [0062] Figure 6A shows a prosthetic heart valve 50 waved over the balloon 92 of a balloon release catheter 90. As explained in this document, the thinning of the bioprosthetic tissue applied to the material for the leaflets helps to enable the outer diameter D of the assembled valve and the balloon catheter to be as small as 6 mm. The sizes of expanded prosthetic heart valves are typically anywhere between 20 mm to about 30 mm.
    [0063] Figure 6B shows an alternative embodiment of a prosthetic valve 100 comprising a frame 102 and a leaflet structure 104 mounted within the frame (for example, using sutures as shown and described above). The valve 100 is shown in an expanded state after the expansion balloon 92 has been inflated. The size of the expanded valve 100 varies depending on the patient, typically between 22 to 40 mm.
    [0064] Implantation methods include compressing valve 50 radially in a significant amount to reduce its diameter or release profile, inserting the valve into a release tool such as a catheter or cannula, and advancing the release tool into the correct anatomical position in the heart. Once properly positioned, valve 50 is implanted by radial expansion into the annular space of the native valve with expansion balloon 92. The contracted valve 50 in the catheter can be introduced through the vasculature, such as through the femoral artery, or more directly through an intercostal incision in the chest. It is important for the valve to be as small as possible. A large valve requires a large diameter catheter, which is difficult to push through the femoral artery, for example, to enable smaller constricting heart valves, the manufacturer tunes the tissue used to make the 70 leaflets. Preferably, conditioning includes reducing the thickness of the fabric, but it can also involve softening the fabric to result in a thin, constantly thick membrane from which to cut the leaflets. Or, brochures can be formed first and then refined. There are a number of ways to thin the tissue including using laser ablation, as explained below.
    [0065] Again it should be noted that the tuned pericardial membrane described in this document can be used in various types of heart valves, including conventional surgical valves. The method can also be used to simply smooth or "cure" the fabric's surface to eliminate chromogenic agents such as dangling fibers, without any appreciable thinning. This softened tissue that remains relatively thick can be used in conventional surgical heart valves. A specific example of conventional heart valves that can use tissue according to the present invention is the Carpentier-Edwards® PERIMOUNT® line from Pericardial Bioprotheses, available from Edward Lifesciences. The basic construction of the PERIMOUNT® valve is observed in US Patent No. 5,928,281, the disclosure of which is expressly incorporated herein by reference.
    [0066] Desirably, the pericardial layers used for transcatheter heart valve leaflets are in the 250-500 micron range, and preferably closer to 250 microns. Unfortunately, only a small percentage is close to the 250 micron thickness. Most of the material is 300-700 microns. As a result, each pericardial sac gives only about 1-2 THV-appropriate leaflets. However, the pericardial tissue used to build the heart valves consists of multiple layers of tissue with similar components, and most collagen fibers are parallel between the layers. This unique structure makes it possible to use various means, for example, lasers, razors, to remove some of the tissue. The removed tissue desirably arrives from the fibrous side from which the adipose tissue was previously removed. This creates a thinner, more defined pericardial membrane with a more appropriate low profile.
    [0067] With the advent of laser technology, corneal tissue ablation has become common. Excimer lasers are used for such procedures. Reference is made to US Patent No. 4,840,175. Recent work with the mode of blocking lasers with very short pulse lengths in the ranges of picoseconds and fentoseconds has also been considered to reduce heat. Lasers are also used to cut tissue, for ablation of the heart muscle to treat arrhythmia and for dental applications. Two other disclosures for using lasers to remove tissue in humans are in US Patent No. 7,022,119 to Holha and US Patent No. 7,367,969 to Stoltz et al. These laser references are incorporated by reference into this document. Laser ablation using the laser-assisted keratomileuse process in situ is also suggested to reduce the thickness of the bovine pericardium to create membrane tissue for a wide variety of uses including heart valves in US Patent Publication No. 2007/0254005, whose disclosure is incorporated in this document by reference.
    [0068] Figure 7 schematically shows a sequence of events in the ablation bioprosthetic tissue in preparation to manufacture implant components, such as heart valve leaflets. To prepare the pericardial material for cardio implantation, a membrane 110 of the bovine pericardial membrane with the mass of the external fat / adipose tissue removed is selected having a thickness of 250 microns or more typically in the range of 300-700 microns). The collagenous layer 112 shown on the underside that makes up the internal surface of the pericardial sac in vivo still has some of the external fat / adipose tissue 114 attached to it.
    [0069] The tissue ablation can be performed with the membrane 110 exposed, for example, in planar form, as indicated by the flowchart of figure 7. In one configuration, the membrane 110 is fixed or retained in an appropriate plane. A laser 116 is directed at the upper fibrous surface 114 of membrane 110 with a focal point adjusted for ablation at or near the top of collagenous layer 112. Alternatively, although not shown, membrane 110 can be positioned on a rotating mandrel so that a Adjacent laser can remove tissue. Other physical configurations for creating relative tissue / laser movement are contemplated. The relative movement between the laser 116 and the surface 114 is then effected to ablate the material from the membrane 110. Depending on the degree of transparency of the tissue from the membrane to the laser beam, more than one passage may be required to obtain the desired uniform thickness.
    [0070] The specification for a laser that has been found to be useful in ablation of the pericardium to create heart valve leaflets includes: a dual-axis scanning lens; 2x beam expansion; wavelength of 1550 nm; pulse energy of 31.5 pl at the target; 1.6 W average power; repetition rate of 50 Hz; pulse width of 650 fs (ref.); laser dot size 30 pm; elliptical polarization; focal length of 112 mm; gross milling speed of 400 mm / s (20-inch cross hatch pattern filling space); and fine grinding speed of 800 mm / s (20 pm cross hatch pattern filling space).
    [0071] A substantial amount of technology has been developed to target lasers and remove tissue with greater precision with ablation. Corneal ablation has been widely practiced for almost two decades. This technology using excimer lasers has become common. Reference is again made to US Patent No. 4,840,175, the disclosure of which is incorporated herein by reference. Recent work with mode of blocking lasers in the ranges of picoseconds and fentosseconds with reduced heating has also been studied.
    [0072] Milling machines for this precise job not on a patient are also available. Milling machines employing a laser having the above specifications as the verified operating tool are useful for conveniently processing the pericardial membranes have a 2-axis scanning laser head, the fabric retainers to facilitate loading the work into the machine, a table XY to increase the laser working area and an automatic tissue retainer loading mechanism. The mechanisms as described can be employed to selectively remove a pericardial membrane assembled to generate patterns of different thickness as discussed below.
    [0073] The operation of the grinding machine is automatic according to the input data defining the pattern and the roughness of the cut. Typically, such machines are arranged to control depth of cut based on the specific height of the surface being cut. With this arrangement, the resulting surface will reflect the pre-cut outline. To prevent this result, a fixed reference can be used instead of the height of the surface that is cut. In this way, the total pattern at work will be on a plane with each cut completed. Multiple cuts are then used to achieve the desired membrane thickness.
    [0074] To retain the appropriate longevity of the pericardial membrane leaflets and obtain a package compact enough to be inserted into position through the femoral artery, a specific tissue thickness of the leaflets is required. For example, a uniform thickness of 250 microns is found to be particularly useful, although uniform thicknesses between 250-500 microns may be appropriate. The wavelength, energy and pulse rate of the laser 116, 120 are selected that will smooth the fibrous surface to eliminate thrombogenic agents as well as ablate the surface to the appropriate thickness. Various wavelengths can be appropriate for this process without generating excess heat while also being effective. If ultrashort pulse lasers are used, it is believed that the wavelength of the laser does not significantly change the result. Brochure samples are made using a wavelength of 1550 nm.
    [0075] This preparation can increase the yield of cardio valve leaflets from the pericardial membrane. Naturally, it is expected that at least 5 heart valve leaflets can be obtained per pericardial sac using the methods disclosed in this document.
    [0076] It is understood that laser ablation of the pericardium is advantageous if performed on dry tissue. This can be accomplished by first fixing the sample 110 with a glycerin-based treatment using glutaraldehyde or equivalent or drying the tissue before laser ablation. Such drying process based on glycerin is disclosed in Patent Publication No. 2008 / 0102,439 published on May 1, 2008, for Tian et al., Whose disclosure is incorporated by reference in this document.
    [0077] In addition to producing a single uniform thickness, the methods described in this document can also be used to selectively tune the fabric to obtain regions of uniform, but different thickness. A particularly useful example is shown in Figure 8, which shows a heart valve leaflet 130 having a peripheral region 132 that is thicker than the rest of leaflet 134. In particular, the lower curved or cusp edge of the leaflet can be thickened for subsequent fixing to skirt 56 described above. The thickened region 132 desirably includes a strip of generally uniform width. This is similar to the strap for holding a reinforcement strip 88 as described above, and both techniques can be used for even greater reinforcement. Three of these leaflets 130 can be prepared in the same way and then connected to each other at their commissure edges in a tricuspid arrangement to form a leaflet structure, as shown in 54 in figures 2 and 5. The reinforcement regions 132 on the leaflets collectively define a ribbon or sleeve that extends along the lower edge portion of the inner surface of the booklet structure 54.
    [0078] Figure 9 illustrates an edge view of leaflet 130 with a strain relief profile, with the reinforcement transition regions 132 slowly in thickness as seen on ramps 136 for the thinner main portion 134 of leaflet 130. The reinforcement regions 132 are illustrated a little roughly to simulate microscopic tissue irregularities, although the same surface can be made smoother using certain techniques described in this document. Reinforcement regions 132 can define the maximum Tmassa leaflet thickness of between about 300-700 microns, while the thinner main portion 134 desirably has a minimum Tmin leaflet thickness of between about 200-500 microns, and potentially thinner . More particularly, for cardiac valves smaller than 17 or 19 mm, leaflet tissue having a minimum thickness Tmin of between 150-250 microns is contemplated, although larger valves such as 26 mm valves may have tissue up to 350 microns. One contemplated modality is an ultrafine tissue in the order of only 100 microns. The maximum leaflet thickness Tmax is desirably up to twice the thickness of the thinnest portion of the leaflet. In the particular example, a valve smaller than 19 mm can have leaflets with Tmin between 150-250 microns, although the maximum leaflet thickness Tmax in the reinforcement areas is up to 300-500 microns.
    [0079] Figures 10 to 12 illustrate alternative thickness profiles in pericardial tissue prosthetic heart valve leaflets from the selective thinning processes described in this document. Each of the leaflets is shown in plan view and has an arched cusp edge 140, a relatively straight free edge 142 opposite the cusp edge, and a pair of handles 144 at either end of the free edge. Each of the handles 144 includes a tapered side 146 that transacts to the free edge 142. A central portion 148 in each of the leaflets forms the fluid occlusion surface that swings in and out of the flow stream to alternately open and close the valve . This form is only exemplary, and other forms of leaflets are known. Each of the leaflets shown in figures 10 to 12 has the same shape, and thus, equal element numbers for the shape characteristics will be used.
    [0080] Figure 10 illustrates a leaflet 150 having a thickened peripheral edge region 152 in the areas where the sutures penetrate for attachment to a structural stent (not shown). More particularly, the thickened peripheral edge region 152 extends around the entire cusp edge 140 and even within at least a portion of the loops 144. As mentioned, these are the areas where the sutures are used to lie. leaflet to a support stent. The thickness of the peripheral edge region 152 can be up to 700 microns, preferably between 300-700 microns. At the same time, the central portion 148 is formed to be relatively small in thickness, thus facilitating a smaller release profile for valves that are compressed. For example, it is believed that a uniform thickness of 250 microns for the central portion 148 is particularly useful for reducing the wavy profile of contracted / expandable valves, although uniform thicknesses between 250-500 microns may be appropriate.
    [0081] Figures 10A and 10B are sectional views through a radial (vertical) median line in the leaflet of figure 10 showing two different thickness profiles. In figure 10A, the thickest peripheral edge region 152 transacts to the thinnest central portion 148 in a relatively abrupt step 154. In contrast, Figure 10B illustrates a gradual ramp 156 between the thick rim region 152 and the thinnest central portion 148. Ramp 156 is shown to be linear, although other contours such as curved or gradually scaled may be used. The more gradual ramp 156 is believed to provide a more desirable stress distribution and flow over the leaflet. It may be possible to provide gradual transitions by adjusting the laser power application. Another way to perform gradual ramps is to use a scraping technology in combination with a forming mold, as described below with reference to figures 14A and 14B.
    [0082] Figure 11 is a plan view of a prosthetic valve leaflet 158 having a thickened peripheral edge region 152 as seen in figure 10, as well as a thickened strip 160 along the free edge 142. Prosthetic heart valves sometimes fail to elongate the free edge of the leaflet where the leaflets arrive together, or combine the parts, which ultimately can cause the valve to prolapse. The provision of the thickened strip 160 along the entire free edge 142 reduces the risk of elongation, as the stresses experienced by the free edge are proportional to its thickness. Figures 11A and 11B again show two different thickness profiles for the leaflets of figure 11, in which the thickened peripheral edge region 152 and the thickened strip 160 can transact to the thinnest central portion 148 in steps 162 (figure 1 A) or on gradual ramps 164 (figure 11B).
    [0083] Finally, figure 12 illustrates a cardiac valve leaflet 166 again having the thickened peripheral edge 152 in the areas used for attachment to a structural heart valve stent. In addition, leaflet 166 has a thickened triple point area 168 in the center of the free edge 142 simulating an Arantius nodule. To clarify, the so-called triple point in a cardiac valve leaflet is the point where the leaflet comes together (combines the pieces) with the other leaflets in the center of the flow orifice. Due to the three curved leaflets in the center, a gap between them at the triple point may be sufficient to cause regurgitation. In native leaflets, the center of the free border sometimes has a thick area known as the Arantius nodules that tends to fill the gap at the triple point. When pericardial tissue of uniform thickness is used for leaflets, leakage can only be prevented by having a long combination of parts that requires extra leaflet material. However, this adversely impacts the ability to compress a valve to a low profile, and sometimes results in distortion of the leaflet when it closes which can result in premature calcification. By producing a thickened 168-point area in each of the leaflets, an Arantius nodule can be simulated. The exemplary triple point area 168 is shown as a small triangle in the center of the free edge 142, although the shape can be curved such as a semicircle, or other shapes. In addition, the triple stitch area 168 can be combined with the thick strip 162 along the free edge 142 as seen in figure 11. Certainly, any of the various thickened regions described in this document can be combined with other regions for a desired effect.
    [0084] Figures 12A and 12B show two different thickness profiles for leaflet 166. Figure 12A shows abrupt steps between the thinnest central portion 148 and both the thickened peripheral edge 152 and the thickened triple stitch area 168, although the figure 12B shows gradual transitions in the same locations.
    [0085] Figure 13 illustrates an alternative leaflet 170 of the present application that can help to reduce flaccidity in the leaflets, which has been found to be a cause of failure in some prosthetic heart valves. The resistance to stretching of the leaflets is directly proportional to the thickness of the leaflet along the lines of radial tension. Therefore, in addition to a thickened peripheral edge region 152 and a thickened strip 160 along the free edge 142, booklet 170 includes a plurality of thickened radial strips 172,174 extending from approximately the center of the free edge 142 to the edge arcuate cusp 140. The "radial lines" in this sense are extracted as if cusp edge 140 were the edge of a circle centered in the center of free edge 142, although it should be understood that cusp edge 140 cannot be defined by a single arch, and cannot be centered on the free edge 142. Typically, prosthetic leaflets are symmetrical around a radial midline, however, and thus a preferred arrangement includes a thickened radial strip 172 along the midline (vertical) and the symmetrical thickened radial strips 174 on either side of the vertical strip 172. In the illustrated embodiment, there are three strips: one midline strip 172 and two radial strips 174 at angles of approx approximately 30 ° from the midline strip. It should also be noted that, as illustrated, the various thickened strips around the leaflet are approximately the same width, although this does not have to be the case. For example, the cusp edge strip 160 and radial strips 172, 174 can be substantially thinner than the edge region 152 through which the sutures must pass.
    [0086] As mentioned above, contoured forming molds can be used to create gradual thickness changes in the brochures described in this document. Figures 14A and 14B are schematic views of exemplary leaflet scraping processes using these molds. In figure 14A, a forming mold 176 includes a leaflet support surface having one side 178 lower than the other side 180. A milling tool such as a laser 182 passes over an upper surface of a leaflet 184 and can be controlled to remove material on a predetermined reference plane. In this way, the left edge of the leaflet remains thicker while more material is removed from the right side to result in a thinner leaflet area at that location. In figure 14B, a second forming mold 186 includes a leaflet support surface having peripheral sides 188 lower than a central portion 189. Again, when a laser 182 passes over the top surface of leaflet 184, and is controlled to remove material below a reference plane, more material will be removed from the central region of the leaflet. Naturally, very different ways of forming molds are contemplated, those illustrated in figures 14A and 14B being only exemplary.
    [0087] The resulting uniform membrane is preferably treated to make it generally inert and safe for human implantation. Treatment typically includes submerging the membrane in a chemical solution such as glutaraldehyde for a predefined period of time to rid the tissue of microbial entities, or "bugs". An exemplary quarantine period is about 14 days. Alternatively or, in addition, the contemplated membrane can be treated using leveling of calcification nucleation sites and reduction of borohydride to mitigate subsequent in vivo calcification.
    [0088] For example, a sequence contemplated for tissue conditioning includes first cross-linking the tissue (for example, bovine pericardium) with a buffered solution with glutaraldehyde. Then, the fabric can be heat treated using a process as disclosed in US Patent No. 5,931,969 to Carpentier, issued August 3, 1999, the disclosure of which is expressly incorporated herein by reference. Subsequently, the thickness of the fabric can be reduced using any of the methods disclosed in the present application. Finally, the thinner tissue can be treated with a leveling and / or reducing agent to mitigate subsequent in vivo calcification, this can also include treatment with a glycerol / ethanol solution. For prosthetic heart valve leaflets, the tissue is then formed in the leaflets, attached to a surrounding heart valve support frame or other such components, and sterilized as with ethylene oxide. After the tissue has been ground, stamped, sliced, removed by laser ablation, spread or extruded to reduce its thickness, calcification nucleation sites (eg, aldehydes and Schiff's bases) can be exposed, which creates a propensity for calcification. Treatment with a leveling agent (eg, ethanolamine), a reducing agent (eg, sodium borohydride) and a collagen preserving agent (eg, glycerol) levels the nucleation sites and preserves the integrity of the collagen. This allows the fabric to be as durable as it was before it was reduced in thickness. In addition, this process will also allow the tissue to be stored in a non-liquid environment (ie, glutaraldehyde). In other words, the process is especially suitable for dry storage of the fabric.
    [0089] As noted above, the membrane can be at least partially cross-linked or "fixed". The crosslinking of the collagenous matrix provides stability before implantation to delay degeneration. In addition, the fixation process generally operates by blocking the reactive molecules on the surface of and within the donor tissue, thereby rendering them substantially non-antigenic and suitable for implantation. Fixing bioprosthetic tissue typically involves contacting the tissue with a crosslinking agent, usually a solution. Exemplary fixation solutions for bioprosthetic tissue such as bovine pericardium include glutaraldehyde, formaldehyde, other aldehydes, EDC, polyethylene glycol, etc. There are other ways of fixing the tissue, including heating, irradiation, etc. The fixation step can help to maintain the pericardium in a particular three-dimensional shape if performed after the membrane is otherwise prepared.
    [0090] It should be understood that although the reticulation of the fabric results in a little easier to manipulate the workpiece, the thinning can occur before the reticulation as well. Likewise, the sheet of dough fabric can be thinned first before or after fixing, or the leaflets can first be cut from the dough membrane which are then thinned before or after fixing.
    [0091] In addition to the laser tissue removal described above, various mechanical devices for shearing the tissue such as razor or planing device can be used to remove some of the tissue. For example, a device that has a flat press cylinder on which a planing razor or translated blade can be replaced by the linear laser configuration of figure 7. Other physical configurations for creating relative tissue / razor movement are contemplated, such as , for example, using a vise similar to a vise to smooth the outer surface of the fabric. Each of these devices can be controlled automatically or by computer using an optical surface measurement component to control the depth of cut. Removing abrasive tissue (for example, sanding or scraping) can also prove to be appropriate, although the grain of the tool can be relatively fine.
    [0092] An instrument that is a particularly attractive mechanical system for thinning a sheet of pericardial tissue is a dermatome. A dermatome is used surgically to collect thin slices of skin from a donor area to use skin grafts, particularly for 3rd degree burns or trauma. These devices date back to 1930 and are well-known surgical instruments. Dermatomes are operated manually, pneumatically or electrically. Uniformity of skin thickness for grafting is not important to the degree necessary for a heart valve leaflet.
    [0093] Figures 15A and 15B illustrate a dermatome 192 scraping a coarse layer from a generic section of pericardial tissue. Instead of collecting thin slices of material for use as heart valve leaflets from the membrane, the material 190 removed by dermatome 192 is discarded in the remaining pericardial membrane factor 194. To obtain a reliable sheet thickness, spacers 196 are employed over which the dermatome 192 travels through. The scraped surface material 190 of the membrane 194 is the fibrous side of the pericardium. The membrane is placed on a black rubber plate 198 and secured. The black plate has a spacer 196 on either side of the membrane to act as rails to support dermatome 192 as it passes through membrane 194. Dermatome 192 can also be controlled to limit the cut to a desired pattern so that regions of heights different can be produced. The use of a mechanical means to produce a uniform thickness advantageously does not generate heat or chemical effects on the pericardial membrane. It should be understood that as used herein, the term, "dermatome" refers to a dermatome, vibratome, or any other mechanical cut or abrasion device that functions similar to a conventional tissue shear dermatome.
    [0094] To overcome the resulting surface removed by laser ablation reflecting a pre-cut outline otherwise, a first compression of the pericardial membrane can be employed. Sufficient compression to smooth out the surface irregularities and obtain a more uniform thickness can be performed before laser ablation. Flattening the surface irregularities in this way helps to ensure that the laser ablation step results in a more uniform removal of the surface. Conversely, without compression, the laser operation can follow the contour of an uneven surface and remove the same amount of material across its surface, resulting in an uneven final product. Another method for ensuring that a regular starting surface is removed by ablation in a way that results in a smooth surface is to control the laser grinding machine using a reference program that tells the laser to remove material relative to a surface level. uniform, fixed, as opposite to follow the contours of the surface being ground.
    [0095] The typical pericardial tissue is in balance at around 78% water, and water can be squeezed from the tissue. Excessive compression to obtain the flattening of the fibrous surface and a more uniform thickness can stretch and break the polymeric collagen dorsal structure, eliminate the collagen "ripple" structure and destroy the intrinsic bio-elasticity of the tissue. Not exceeding the flow point, however, allows intrinsic bioelasticity to go back in time. A partial or complete fixation of the pericardial membrane while under elastic compression can retain the advantageous effect of pending compression laser ablation. Even with reasonably less compression, some bonds are broken, resulting in some aldehyde, amine and acid groups. By fixing the pericardial membrane in this gently compressed state, connections are created to retain this state. Alternatively, the pericardial membrane tends not to recede completely immediately. Laser ablation immediately after compression can mitigate elastic re-expansion.
    [0096] Alternatively, a sequence of the first irregularities of the conditioning surface and then the compression of the tissue membrane can be employed. For example, major surface irregularities on the fibrous side of the pericardial tissue can be smoothed using a laser, a mill, or a dermatome, after which the tissue is compressed using various methods as described in this document. Preferably, the fabric is compressed while at least partially fixing the fabric to help prevent elastic recovery. This sequence can yield a more mechanical uniform fabric construction.
    [0097] As noted above, gentle compression with fixation of the pericardial membrane in the compressed state can smooth the fibrous surface of the pericardium and make the thickness more uniform. This compression and fixation can be used before or after the fabric is thinned. After thinning, a stabilization step using leveling and reduction of borohydride can mitigate subsequent in vivo calcification.
    [0098] Even greater compression is possible, with or without the ablation or machining process. If laser ablation or a machining process is used, the degree to which the tissue is fixed after compression is somewhat immaterial as a physical trimming of the tissue instead of another compression is used. If fully attached to a first soft compression, another compression tends to be fully elastic unless the fabric is damaged. A partial fixation process with soft compression and then another fixation with larger compression can be used to obtain a thinner final membrane with significant tensile strength.
    [0099] A soft initial compression and fixation step are considered above. The process can also proceed without the initial soft compression, but at least partially fixing the tissue. Again, glutaraldehyde or another fixing agent or method can be used. This first stabilization sequence stabilizes the biomechanics of the tissue and preserves the natural "ripple" structure of collagen. Infusion with a second fixation material of sufficient chain length to allow transposition of large interfibrillary domains can then result in a stable membrane. Substantial chain length di- or polyamine material can be employed. Other crosslinking materials for transposing large interfibrillary domains include polyethyleneimine, polyvinyl alcohol and various Jeffamine polymers both linear and branched. Alternatively, the tissue can be oxidized with, for example, sodium chloride to convert newly formed aldehydes into carboxylic acids. These can then be coupled with the above amines using EDC chemistry. Compression can occur either at the beginning of the process, after infusion with a second fixation material, or both. Laser ablation or machining can be injected with smoothing or further thinning either after the compression step, and / or after the first fixation step. The fabric can be leveled and reduced after the first fixing step, or alternatively, the compressed and cross-linked fabric sheet can be stabilized with leveling and reduction of borohydride after the forming process. Another treatment may include drying and sterilization. Such processing is described in US Patent Publication No. 2009/0164005, published on June 25, 2009 to Dove et al., The disclosure of which is expressly incorporated herein by reference.
    [00100] The apparatus used in any or all of the compression stages is illustrated in figure 16. The porous ceramic pressure plates 200, 202 are used to provide rigid compression to the fabric 204. Dialysis membranes 206, 208 are placed between plates 200, 202 and fabric 204. Ceramic pressure plates 200, 202 allow the free calculation of various chemical treatments within fabric 204. Disposable dialysis membranes 206,208 are used to prevent clogging of pressure plates from ceramic 200, 202, preventing the flow of solution during production. The spacers 210 between the ceramic pressure plates 200, 202 to either side of the fabric 204 limit compression.
    [00101] Another application for the thinning and conditioning processes described in this document is in the field of pericardial patches, made from either bovine or equine pericardium. The pericardial patch product can be used as a building material for tissue repair, such as aortic conduit, pericardium, vessels, etc., which is very common in pediatric patients with congenital cardiovascular diseases. Such a commercial bovine pericardial patch available from Edwards Lifesciences comes in 10 x 15 cm (4x6 inches) sizes, although equine patches may be smaller than 7.62 cm x 10 cm (3x4 inches). The pericardial patch product is usually treated with a similar process with heart valve leaflets (they may be slightly different for equine patches). One problem is that the pericardial patch can be very thick for some of these applications, so making the patch even thinner can significantly improve its applicability. Also, there is often substantial variability in thickness between patches and at different locations in any given patch. A desirable uniform thickness for the final product can be in the range of 150 to 500 microns depending on the size of the patch product. The selective thinning described above can also benefit patches with an edge or the entire periphery being formed thicker to help retain the anchoring sutures.
    [00102] Thus, improved methods for preparing pericardial material for cardio implantation have been disclosed. Although the modalities and applications of this invention have been shown and described, it should be apparent to those skilled in the art that many more modifications are possible from the concepts of the invention in this document, and it should be understood that the words that were used are words of description and not of limitation. Therefore, changes can be made within the attached claims without departing from the true spirit of the invention.
    权利要求:
    Claims (6)
    [0001]
    1. Method for preparing bioprosthetic tissue membrane material, characterized by comprising the steps of: selecting a tissue membrane that has a fibrous side and a smooth side, conditioning the membrane by compressing the selected tissue and at least partially reticulating the membrane during compression, where the step of conditioning the membrane is carried out before the removal step, remove material from the fibrous side of the selected membrane to reduce the thickness of the membrane and to smooth the fibrous side, and treat the reduced membrane in thickness by leveling nucleation sites of calcification and / or reduction of borohydride.
    [0002]
    2. Method, according to claim 1, characterized by the fact that the removal step is performed by ablation with a laser (116,182).
    [0003]
    Method according to claim 1 or 2, characterized in that the treatment step comprises the treatment step with a glycerol / ethanol solution.
    [0004]
    4. Method, according to claim 1, characterized by the fact that the removal step is performed by a mechanical device.
    [0005]
    Method according to claim 4, characterized in that the step in which the mechanical device is a dermatome or a vibratome.
    [0006]
    6. Method according to claim 1, characterized by the fact that it still comprises the step of forming a heart valve leaflet from the membrane after the treatment step, the heart valve leaflet having an arcuate cusp edge (140) and a free edge (142) opposite the cusp edge (140), both of which surround a central portion (148), and a pair of handles (144) at either end of the free edge.
    类似技术:
    公开号 | 公开日 | 专利标题
    BR112012023769B1|2020-11-10|method for preparing bioprosthetic tissue membrane material
    US6129758A|2000-10-10|Products and methods for circulatory system valve repair
    US20210212818A1|2021-07-15|Method for directing cellular migration patterns on a biological tissue
    CN106510901A|2017-03-22|Integral forming ring design of novel folding patch
    AU2014233651B2|2016-05-19|Methods of conditioning sheet bioprosthetic tissue
    AU2020258258A1|2021-11-11|A naturally designed mitral prosthesis
    同族专利:
    公开号 | 公开日
    US9498288B2|2016-11-22|
    BR122014006876A2|2019-08-13|
    US20130116676A1|2013-05-09|
    US20110238167A1|2011-09-29|
    BR122014006918B1|2020-09-29|
    EP2656863A2|2013-10-30|
    WO2011119754A3|2012-02-16|
    NZ602706A|2014-02-28|
    CA2794121A1|2011-09-29|
    CA2794121C|2016-10-11|
    US8846390B2|2014-09-30|
    BR122014006918A2|2019-08-13|
    US20190038403A1|2019-02-07|
    EP2656863A3|2014-01-08|
    EP3636293A1|2020-04-15|
    US9492230B2|2016-11-15|
    US20130110097A1|2013-05-02|
    US11213385B2|2022-01-04|
    NZ602066A|2013-09-27|
    US20130310929A1|2013-11-21|
    CN102811681A|2012-12-05|
    AU2011232510A1|2012-09-20|
    EP2674174B1|2019-10-16|
    NZ602707A|2014-05-30|
    US9498287B2|2016-11-22|
    EP2549957A4|2014-01-08|
    WO2011119754A2|2011-09-29|
    CN102811681B|2016-10-12|
    US10092399B2|2018-10-09|
    EP2656863B1|2019-09-18|
    US20170071731A1|2017-03-16|
    EP2674174A3|2014-01-01|
    EP2674174A2|2013-12-18|
    BR112012023769A2|2017-09-19|
    EP2549957A2|2013-01-30|
    EP2549957B1|2019-01-30|
    BR122014006876B1|2020-09-29|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US2567929A|1951-09-18|Process for preserving plant tissues |
    US2393580A|1942-03-31|1946-01-22|Edwin C Weiskopf|Method of preparing tissue|
    US2484813A|1945-06-06|1949-10-18|John O Bower|Spun suture|
    US3002895A|1957-02-11|1961-10-03|Freedman David|Incubator-shaker apparatus|
    US3093439A|1961-07-05|1963-06-11|Johnson & Johnson|Process for preparing tanned collagenous material with dialdehyde starch|
    US3961097A|1971-10-28|1976-06-01|Gravlee Jr Joseph F|Method of preparing tissue for microscopic examination|
    US3870789A|1972-12-01|1975-03-11|Kurt W Mikat|Enhancement of morphologic detail in tissue|
    US3927422A|1973-12-12|1975-12-23|Philip Nicholas Sawyer|Prosthesis and method for making same|
    US3966401A|1974-07-01|1976-06-29|Hancock Laboratories Incorporated|Preparing natural tissue for implantation so as to provide improved flexibility|
    US4050893A|1974-07-22|1977-09-27|Hancock Laboratories, Inc.|Arrangement for preparing natural tissue for implantation|
    IL47062A|1975-04-10|1979-07-25|Yeda Res & Dev|Process for diminishing antigenicity of tissues to be usedas transplants by treatment with glutaraldehyde|
    US4082507A|1976-05-10|1978-04-04|Sawyer Philip Nicholas|Prosthesis and method for making the same|
    US4067091A|1976-11-15|1978-01-10|Backman Philip E|Method of preparing human remains for storage|
    US4120991A|1976-12-10|1978-10-17|Technicon Instruments Corporation|Process for mounting tissue sections with an U.V. light curable mounting medium|
    CA1087101A|1977-08-05|1980-10-07|Cesar Romero-Sierra|Freeze dried biological specimens|
    US4197658A|1978-05-12|1980-04-15|Fts Systems, Inc.|Tissue freeze dryer|
    US4328256A|1978-08-18|1982-05-04|Queen's University At Kingston|Preservation of green plant tissues|
    DE2914181C2|1979-04-07|1982-06-16|Kernforschungsanlage Jülich GmbH, 5170 Jülich|Method and device for drying temperature-sensitive goods in the pharmaceutical and food industries|
    US4294753A|1980-08-04|1981-10-13|The Regents Of The University Of California|Bone morphogenetic protein process|
    US4320157A|1980-08-08|1982-03-16|Hagens Gunther Von|Method for preserving large sections of biological tissue with polymers|
    SE444640B|1980-08-28|1986-04-28|Bergentz Sven Erik|IN ANIMAL OR HUMAN IMPLANTABLE KERLPROTES AND SET FOR ITS MANUFACTURING|
    US4378224A|1980-09-19|1983-03-29|Nimni Marcel E|Coating for bioprosthetic device and method of making same|
    US4323358A|1981-04-30|1982-04-06|Vascor, Inc.|Method for inhibiting mineralization of natural tissue during implantation|
    US4372743A|1981-06-22|1983-02-08|American Hospital Supply Corp.|Low-pressure fixation of valvular tissue intended for implantation|
    US4350492A|1981-08-24|1982-09-21|Vascor, Inc.|Method for preparing tissue heart valve|
    FR2523810B1|1982-03-23|1988-11-25|Carpentier Alain|ORGANIC GRAFT FABRIC AND PROCESS FOR ITS PREPARATION|
    US4481009A|1982-05-13|1984-11-06|American Hospital Supply Corporation|Polymer incorporation into implantable biological tissue to inhibit calcification|
    US4405327A|1982-08-25|1983-09-20|Extracorporeal Medical Specialties, Inc.|Method for inhibiting mineralization of natural tissue during implantation|
    US4402697A|1982-08-25|1983-09-06|Extracorporeal Medical Specialties, Inc.|Method for inhibiting mineralization of natural tissue during implantation|
    US4477930A|1982-09-28|1984-10-23|Mitral Medical International, Inc.|Natural tissue heat valve and method of making same|
    JPS60500014A|1982-11-12|1985-01-10|
    US4885005A|1982-11-12|1989-12-05|Baxter International Inc.|Surfactant treatment of implantable biological tissue to inhibit calcification|
    US5215541A|1982-11-12|1993-06-01|Baxter International Inc.|Surfactant treatment of implantable biological tissue to inhibit calcification|
    US4599084A|1983-05-24|1986-07-08|American Hospital Supply Corp.|Method of using biological tissue to promote even bone growth|
    CA1220001A|1983-07-12|1987-04-07|Robert P. Totten|Tissue valve|
    IT1159433B|1983-07-25|1987-02-25|Sorin Biomedica Spa|PROCEDURE AND EQUIPMENT FOR THE MANUFACTURE OF VALVE FLAPS FOR CARDIAC VALVE PROSTHESIS AND CARDIAC VALVE PROSTHESIS PROVIDED WITH SUCH FLAPS|
    US5024830A|1983-08-23|1991-06-18|The Board Of Regents, The University Of Texas|Method for cryopreparing biological tissue for ultrastructural analysis|
    US4865871A|1983-08-23|1989-09-12|Board Of Regents The University Of Texas System|Method for cryopreparing biological tissue|
    US4676070A|1984-11-30|1987-06-30|The Board Of Regents, The University Of Texas|Apparatus and method for cryopreparing biological tissue|
    US4753652A|1984-05-04|1988-06-28|Children's Medical Center Corporation|Biomaterial implants which resist calcification|
    GB8413319D0|1984-05-24|1984-06-27|Oliver Roy Frederick|Biological material|
    DE169259T1|1984-07-25|1986-04-30|Surgical Patent Products Inc. Ltd., Panama|VESSEL PROSTHESES FOR DRY STORAGE, METHOD FOR TREATMENT AND THEIR USE IN SURGERY.|
    US4553974A|1984-08-14|1985-11-19|Mayo Foundation|Treatment of collagenous tissue with glutaraldehyde and aminodiphosphonate calcification inhibitor|
    IT1180531B|1984-09-21|1987-09-23|Ge Sv In Srl|BICUSPID CARDIAC VALVE PROSTHESIS|
    US4759758A|1984-12-07|1988-07-26|Shlomo Gabbay|Prosthetic heart valve|
    US5011913A|1985-06-28|1991-04-30|The Procter & Gamble Company|Diphosphonate-derivatized macromolecules|
    DE229810T1|1985-07-09|1987-11-05|Quadrant Bioresources Ltd., Soulbury, Leighton Buzzard, Bedfordshire, Gb|PROTECTION OF PROTEINS AND SIMILAR.|
    US4729139A|1985-11-05|1988-03-08|Baxter Travenol|Selective incorporation of a polymer into implantable biological tissue to inhibit calcification|
    US4770665A|1985-11-05|1988-09-13|American Hospital Supply Corporation|Elastomeric polymer incorporation into implantable biological tissue to inhibit calcification|
    DE3541478A1|1985-11-23|1987-05-27|Beiersdorf Ag|HEART VALVE PROSTHESIS AND METHOD FOR THE PRODUCTION THEREOF|
    US4911713A|1986-03-26|1990-03-27|Sauvage Lester R|Method of making vascular prosthesis by perfusion|
    US5904718A|1986-03-27|1999-05-18|Biocoll Laboratories, Inc.|Delayed drug delivery system|
    US5108923A|1986-04-25|1992-04-28|Collaborative Research, Inc.|Bioadhesives for cell and tissue adhesion|
    GB8618374D0|1986-07-28|1986-09-03|Hsc Res Dev Corp|Biological vascular prostheses|
    US4786287A|1986-10-10|1988-11-22|Baxter Travenol Laboratories|Process for decreasing residual aldehyde levels in implantable bioprosthetic tissue|
    US4813964A|1986-10-14|1989-03-21|Hancock Jaffe Laboratories|Crosslinked anisotropic xenogeneic diaphragm tissue in flexor tendon pulley reconstruction|
    CA1340581C|1986-11-20|1999-06-08|Joseph P. Vacanti|Chimeric neomorphogenesis of organs by controlled cellular implantation using artificial matrices|
    US5044165A|1986-12-03|1991-09-03|Board Of Regents, The University Of Texas|Cryo-slammer|
    US4840175A|1986-12-24|1989-06-20|Peyman Gholam A|Method for modifying corneal curvature|
    US4800603A|1987-01-30|1989-01-31|Jaffe Norman R|Tissue fixation with vapor|
    US4838888A|1987-04-17|1989-06-13|Baxter Travenol Laboratories, Inc.|Calcification mitigation of implantable bioprostheses|
    FR2617855B1|1987-07-08|1992-02-21|Bioetica Sa|PROCESS FOR CROSSLINKING COLLAGEN BY INTRODUCING AZID GROUPS AS WELL AS TISSUES AND BIOMATERIALS OBTAINED BY IMPLEMENTING THE PROCESS|
    US5147514A|1987-08-02|1992-09-15|University Of North Carolina|Process for cross-linking collagenous material and resulting product|
    EP0411925B1|1989-08-02|1997-09-24|University Of North Carolina At Chapel Hill|Process for cross-linking collagenous materials and resulting product|
    US5149621A|1987-08-21|1992-09-22|Cryolife, Inc. & Medical Univ. Of South Carolina|Kit for cryopreserving blood vessels|
    JP2529112B2|1987-08-31|1996-08-28|株式会社高研|Biological valve|
    US4990131A|1987-09-01|1991-02-05|Herbert Dardik|Tubular prostheses for vascular reconstructive surgery and process for preparing same|
    US5131908A|1987-09-01|1992-07-21|Herbert Dardik|Tubular prosthesis for vascular reconstructive surgery and process for preparing same|
    US4994237A|1987-10-02|1991-02-19|The Beth Israel Hospital Association|Microwave preservation of bioprostheses|
    US4793344A|1987-11-02|1988-12-27|Recore, Inc.|Method for preparing corneal donor tissue for refractive eye surgery|
    GB8801338D0|1988-01-21|1988-02-17|Quadrant Bioresources Ltd|Preservation of viruses|
    US4976733A|1988-02-03|1990-12-11|Biomedical Design, Inc.|Prevention of prosthesis calcification|
    US4969912A|1988-02-18|1990-11-13|Kelman Charles D|Human collagen processing and autoimplant use|
    US5746775A|1988-04-01|1998-05-05|The Board Of Regent6S Of The University Of Michigan|Method of making calcification-resistant bioprosthetic tissue|
    US5094661A|1988-04-01|1992-03-10|The University Of Michigan|Calcification-resistant materials and methods of making same through use of trivalent aluminum|
    US5368608A|1988-04-01|1994-11-29|University Of Michigan, The Board Of Regents|Calcification-resistant materials and methods of making same through use of multivalent cations|
    US4994030A|1988-06-28|1991-02-19|Osteotech, Inc.|Reconstitution of human bone and tissue|
    US4975526A|1989-02-23|1990-12-04|Creative Biomolecules, Inc.|Bone collagen matrix for zenogenic implants|
    US5011494A|1988-09-16|1991-04-30|Clemson University|Soft tissue implant with micron-scale surface texture to optimize anchorage|
    DE3834545C2|1988-10-11|1992-08-27|Josef Dr.-Ing. Jansen|
    US5002566A|1989-02-17|1991-03-26|Baxter International Inc.|Calcification mitigation of bioprosthetic implants|
    US5068100A|1989-03-09|1991-11-26|The Procter & Gamble Company|Anticalculus compositions|
    US5051401A|1989-04-07|1991-09-24|University Of South Alabama|Inhibition of mineral deposition by phosphorylated and related polyanionic peptides|
    AU626686B2|1989-06-09|1992-08-06|Medtronic, Inc.|Dynamic fixation of porcine aortic valves|
    US5154007A|1989-08-17|1992-10-13|Board Of Regents University Of Texas System|Method and apparatus for cryopreparing biological tissue|
    US5290558A|1989-09-21|1994-03-01|Osteotech, Inc.|Flowable demineralized bone powder composition and its use in bone repair|
    US5147391A|1990-04-11|1992-09-15|Carbomedics, Inc.|Bioprosthetic heart valve with semi-permeable commissure posts and deformable leaflets|
    WO1991017724A1|1990-05-17|1991-11-28|Harbor Medical Devices, Inc.|Medical device polymer|
    US5108425A|1990-05-30|1992-04-28|Hwang Ned H C|Low turbulence heart valve|
    US5068086A|1990-06-12|1991-11-26|Raytheon Company|Method and apparatus for batch fixating tissue specimens|
    US5336616A|1990-09-12|1994-08-09|Lifecell Corporation|Method for processing and preserving collagen-based tissues for transplantation|
    US8067149B2|1990-09-12|2011-11-29|Lifecell Corporation|Acellular dermal matrix and method of use thereof for grafting|
    US5200399A|1990-09-14|1993-04-06|Boyce Thompson Institute For Plant Research, Inc.|Method of protecting biological materials from destructive reactions in the dry state|
    IL96092D0|1990-10-23|1991-07-18|
    US5163955A|1991-01-24|1992-11-17|Autogenics|Rapid assembly, concentric mating stent, tissue heart valve with enhanced clamping and tissue alignment|
    US5104405A|1991-02-21|1992-04-14|The University Of Southern California|Process for improving the biostability of tissue implant devices and bioprosthetic implants so produced|
    US5275954A|1991-03-05|1994-01-04|Lifenet|Process for demineralization of bone using column extraction|
    IT1245750B|1991-05-24|1994-10-14|Sorin Biomedica Emodialisi S R|CARDIAC VALVE PROSTHESIS, PARTICULARLY FOR REPLACING THE AORTIC VALVE|
    US5329846A|1991-08-12|1994-07-19|Bonutti Peter M|Tissue press and system|
    US6503277B2|1991-08-12|2003-01-07|Peter M. Bonutti|Method of transplanting human body tissue|
    US5998483A|1991-09-20|1999-12-07|Camiener; Gerald W.|Glyoxal-containing preservative compositions|
    US5476516A|1992-03-13|1995-12-19|Albert Einstein College Of Medicine Of Yeshiva University|Anticalcification treatment for aldehyde-tanned biological tissue|
    US5436291A|1992-07-09|1995-07-25|University Of Michigan, The Board Of . . .|Calcification-resistant synthetic biomaterials|
    US5296583A|1992-07-09|1994-03-22|University Of Michigan|Calcification-resistant synthetic biomaterials|
    US5437287A|1992-08-17|1995-08-01|Carbomedics, Inc.|Sterilization of tissue implants using iodine|
    US5509932A|1993-04-08|1996-04-23|Keogh; James R.|Fixed tissue medical devices comprising albumin-binding dyes|
    US5507813A|1993-12-09|1996-04-16|Osteotech, Inc.|Shaped materials derived from elongate bone particles|
    US5460962A|1994-01-04|1995-10-24|Organogenesis Inc.|Peracetic acid sterilization of collagen or collagenous tissue|
    GB9400163D0|1994-01-06|1994-03-02|Geistlich Soehne Ag|Membrane|
    EP0663214B1|1994-01-18|1999-03-31|Sci-Can, A Division Of Lux And Zwingenberger Ltd.|Assembly for the steam sterilization of surgical instruments, implants and the like|
    IL108413D0|1994-01-23|1994-04-12|Turovets Igor|Method and device for deep ultraviolet laser microsurgery in biological liquid environment|
    US5447536A|1994-02-17|1995-09-05|Biomedical Design, Inc.|Method for fixation of biological tissue|
    US6203755B1|1994-03-04|2001-03-20|St. Jude Medical, Inc.|Electron beam sterilization of biological tissues|
    EP1452153A1|1994-03-14|2004-09-01|Cryolife, Inc|Treated tissue for implantation and preparation methods|
    US5595571A|1994-04-18|1997-01-21|Hancock Jaffe Laboratories|Biological material pre-fixation treatment|
    AU2399495A|1994-04-29|1995-11-29|W.L. Gore & Associates, Inc.|Improved blood contact surfaces using endothelium on a subendothelial extracellular matrix|
    EP0757564A1|1994-04-29|1997-02-12|Gore Hybrid Technologies, Inc.|Improved blood contact surfaces employing natural subendothelial matrix and method for making and using the same|
    US5558875A|1994-06-06|1996-09-24|Wang; Su|Method of preparing collagenous tissue|
    JPH09502379A|1994-06-15|1997-03-11|セントジュードメディカルインコーポレイテッド|Improved cross-linking of natural tissues|
    KR0131046B1|1994-07-13|1998-04-14|김은영|Calcification-resistant tissue heart valve|
    US5554184A|1994-07-27|1996-09-10|Machiraju; Venkat R.|Heart valve|
    DE69523074T2|1994-07-29|2002-06-06|Edwards Lifesciences Corp|METHOD FOR TREATING IMPLANTABLE BIOLOGICAL TISSUES TO REDUCE CALCIFICATION|
    US5931969A|1994-07-29|1999-08-03|Baxter International Inc.|Methods and apparatuses for treating biological tissue to mitigate calcification|
    US6586006B2|1994-08-04|2003-07-01|Elan Drug Delivery Limited|Solid delivery systems for controlled release of molecules incorporated therein and methods of making same|
    US6024735A|1996-03-20|2000-02-15|Lifenet Research Foundation|Process and composition for cleaning soft tissue grafts optionally attached to bone and soft tissue and bone grafts produced thereby|
    US5556379A|1994-08-19|1996-09-17|Lifenet Research Foundation|Process for cleaning large bone grafts and bone grafts produced thereby|
    US5549666A|1994-09-02|1996-08-27|Baxter International Inc.|Natural tissue valve prostheses having variably complaint leaflets|
    US5674298A|1994-10-21|1997-10-07|The Board Of Regents Of The University Of Michigan|Calcification-resistant bioprosthetic tissue and methods of making same|
    KR0129833B1|1994-11-09|1998-04-04|박성수|Method of orgna culture and apparatus thereof|
    US6372228B1|1994-11-15|2002-04-16|Kenton W. Gregory|Method of producing elastin, elastin-based biomaterials and tropoelastin materials|
    US6290991B1|1994-12-02|2001-09-18|Quandrant Holdings Cambridge Limited|Solid dose delivery vehicle and methods of making same|
    AU692330B2|1994-12-30|1998-06-04|National University Of Singapore, The|Method for reducing calcification of biological tissue used in implantable bioprostheses|
    EP0821573A4|1995-04-19|2000-08-09|St Jude Medical|Matrix substrate for a viable body tissue-derived prosthesis and method for making the same|
    US5792603A|1995-04-27|1998-08-11|Advanced Tissue Sciences, Inc.|Apparatus and method for sterilizing, seeding, culturing, storing, shipping and testing tissue, synthetic or native, vascular grafts|
    US5913900A|1995-06-07|1999-06-22|Corsscart, Inc.|Substantially native meniscal cartilage heterografts|
    US6231608B1|1995-06-07|2001-05-15|Crosscart, Inc.|Aldehyde and glycosidase-treated soft and bone tissue xenografts|
    US5865849A|1995-06-07|1999-02-02|Crosscart, Inc.|Meniscal heterografts|
    US6383732B1|1999-02-11|2002-05-07|Crosscart, Inc.|Method of preparing xenograft heart valves|
    US6685940B2|1995-07-27|2004-02-03|Genentech, Inc.|Protein formulation|
    US5882918A|1995-08-08|1999-03-16|Genespan Corporation|Cell culture incubator|
    US5902338A|1995-09-15|1999-05-11|Crosscart, Inc.|Anterior cruciate ligament heterograft|
    US5782915A|1995-09-15|1998-07-21|Stone; Kevin R.|Articular cartilage heterografts|
    US5716399A|1995-10-06|1998-02-10|Cardiomend Llc|Methods of heart valve repair|
    US5720894A|1996-01-11|1998-02-24|The Regents Of The University Of California|Ultrashort pulse high repetition rate laser system for biological tissue processing|
    US6193749B1|1996-02-05|2001-02-27|St. Jude Medical, Inc.|Calcification-resistant biomaterials|
    US6206873B1|1996-02-13|2001-03-27|El. En. S.P.A.|Device and method for eliminating adipose layers by means of laser energy|
    IT1285308B1|1996-03-12|1998-06-03|Sorin Biomedica Cardio Spa|PROCEDURE FOR THE PREPARATION OF BIOLOGICAL MATERIAL FOR PLANT|
    US5919472A|1996-03-19|1999-07-06|Medtronic, Inc.|Treatment of aldehyde-fixed tissue|
    US5925552A|1996-04-25|1999-07-20|Medtronic, Inc.|Method for attachment of biomolecules to medical devices surfaces|
    US5945319A|1996-04-25|1999-08-31|Medtronic, Inc.|Periodate oxidative method for attachment of biomolecules to medical device surfaces|
    US5928916A|1996-04-25|1999-07-27|Medtronic, Inc.|Ionic attachment of biomolecules with a guanidino moiety to medical device surfaces|
    IL118149D0|1996-05-05|1996-09-12|Rdc Rafael Dev Corp|Method for producing heart valves and heart valves produced by the method|
    CN1198546C|1996-05-30|2005-04-27|奇龙泰思诺拉斯眼科系统公司|excimer laser eye surgery system|
    US5645587A|1996-06-05|1997-07-08|Chanda; Jyotirmay|Prevention of calcification and degeneration of biological tissue grafts for implantation in humans|
    US5695820A|1996-06-20|1997-12-09|Hewlett-Packard Company|Method for alleviating marangoni flow-induced print defects in ink-jet printing|
    US5766520A|1996-07-15|1998-06-16|Universal Preservation Technologies, Inc.|Preservation by foam formation|
    US5782931A|1996-07-30|1998-07-21|Baxter International Inc.|Methods for mitigating calcification and improving durability in glutaraldehyde-fixed bioprostheses and articles manufactured by such methods|
    US6302909B1|1996-07-31|2001-10-16|St. Jude Medical, Inc.|Calcification-resistant biomaterials|
    US6121041A|1996-07-31|2000-09-19|St. Jude Medical, Inc.|Use of microorganisms for decellularizing bioprosthetic tissue|
    AU3950297A|1996-08-21|1998-03-06|Sulzer Vascutek Limited|Method of sterilising material for implantation|
    US6764509B2|1996-09-06|2004-07-20|Carbomedics Inc.|Prosthetic heart valve with surface modification|
    US5782914A|1996-11-29|1998-07-21|Bio-Vascular, Inc.|Method for preparing heterogeneous tissue grafts|
    FR2756741B1|1996-12-05|1999-01-08|Cird Galderma|USE OF A CHROMOPHORE IN A COMPOSITION INTENDED TO BE APPLIED TO THE SKIN BEFORE LASER TREATMENT|
    WO1998025549A1|1996-12-10|1998-06-18|Purdue Research Foundation|Artificial vascular valves|
    EP0850607A1|1996-12-31|1998-07-01|Cordis Corporation|Valve prosthesis for implantation in body channels|
    US5856172A|1997-01-03|1999-01-05|Quality Technologies, Llc|Preservation of microorganisms in a vial with a cap comprising an immobilized desiccant|
    AU735988B2|1997-02-10|2001-07-26|Biomedical Design, Inc.|Method of sterilization|
    US6506339B1|1997-02-10|2003-01-14|Biomedical Design, Inc.|Method of sterilization|
    US5856102A|1997-02-26|1999-01-05|Bierke-Nelson; Diane Lynn|Home/self-storage to improve DNA banking|
    US5928281A|1997-03-27|1999-07-27|Baxter International Inc.|Tissue heart valves|
    CA2286655C|1997-04-11|2009-02-24|Cryolife, Inc.|Tissue decellularization|
    US6206917B1|1997-05-02|2001-03-27|St. Jude Medical, Inc.|Differential treatment of prosthetic devices|
    US5993844A|1997-05-08|1999-11-30|Organogenesis, Inc.|Chemical treatment, without detergents or enzymes, of tissue to form an acellular, collagenous matrix|
    US6156030A|1997-06-04|2000-12-05|Y-Beam Technologies, Inc.|Method and apparatus for high precision variable rate material removal and modification|
    US5987720A|1997-07-08|1999-11-23|Yamamoto; William Shigeru|Portable tomb for resurrection from mummified tissue DNA|
    US6117979A|1997-08-18|2000-09-12|Medtronic, Inc.|Process for making a bioprosthetic device and implants produced therefrom|
    US6166184A|1997-08-18|2000-12-26|Medtronic Inc.|Process for making a bioprosthetic device|
    US5862806A|1997-10-30|1999-01-26|Mitroflow International, Inc.|Borohydride reduction of biological tissues|
    US6267782B1|1997-11-20|2001-07-31|St. Jude Medical, Inc.|Medical article with adhered antimicrobial metal|
    US6008292A|1997-12-02|1999-12-28|Baxter International Inc.|Method for inhibiting calcification of aldehyde-fixed bioprosthetic materials|
    US5921980A|1997-12-03|1999-07-13|University Of Kentucky Research Foundation|Laser skin graft harvesting apparatus and related method|
    DE19755738A1|1997-12-16|1999-07-15|Adiam Medizintechnik Gmbh & Co|Process for separating and / or removing processing of prefabricated plastic films|
    US6254635B1|1998-02-02|2001-07-03|St. Jude Medical, Inc.|Calcification-resistant medical articles|
    US6093530A|1998-02-06|2000-07-25|Sulzer Carbomedics Inc.|Non-calcific biomaterial by glutaraldehyde followed by oxidative fixation|
    US6251579B1|1998-02-13|2001-06-26|Sulzer Carbomedics Inc.|Oxidative stabilization of collagen containing materials|
    US6258320B1|1998-04-09|2001-07-10|David H. Persing|Method for preservation of nucleic acids|
    WO1999058082A2|1998-05-14|1999-11-18|The Cleveland Clinic Foundation|Processing of implantable animal tissues for dry storage|
    US6933326B1|1998-06-19|2005-08-23|Lifecell Coporation|Particulate acellular tissue matrix|
    US6630001B2|1998-06-24|2003-10-07|International Heart Institute Of Montana Foundation|Compliant dehyrated tissue for implantation and process of making the same|
    US6293970B1|1998-06-30|2001-09-25|Lifenet|Plasticized bone and soft tissue grafts and methods of making and using same|
    US7063726B2|1998-06-30|2006-06-20|Lifenet|Plasticized bone grafts and methods of making and using same|
    US6394096B1|1998-07-15|2002-05-28|Corazon Technologies, Inc.|Method and apparatus for treatment of cardiovascular tissue mineralization|
    US6156531A|1998-07-20|2000-12-05|Sulzer Carbomedics Inc.|Cross-linking tissue with a compound having a C8 to C40 aliphatic chain|
    US6448076B2|1998-09-15|2002-09-10|The Regents Of The University Of Michigan|Method for chemically acellularizing a biological tissue sample|
    US6214054B1|1998-09-21|2001-04-10|Edwards Lifesciences Corporation|Method for fixation of biological tissues having mitigated propensity for post-implantation calcification and thrombosis and bioprosthetic devices prepared thereby|
    US6334873B1|1998-09-28|2002-01-01|Autogenics|Heart valve having tissue retention with anchors and an outer sheath|
    US6509145B1|1998-09-30|2003-01-21|Medtronic, Inc.|Process for reducing mineralization of tissue used in transplantation|
    US7078163B2|2001-03-30|2006-07-18|Medtronic, Inc.|Process for reducing mineralization of tissue used in transplantation|
    US6214055B1|1998-10-30|2001-04-10|Mures Cardiovascular Research, Inc.|Method and kit for rapid preparation of autologous tissue medical devices|
    US6613278B1|1998-11-13|2003-09-02|Regeneration Technologies, Inc.|Tissue pooling process|
    US6066160A|1998-11-23|2000-05-23|Quickie Llc|Passive knotless suture terminator for use in minimally invasive surgery and to facilitate standard tissue securing|
    GB9825938D0|1998-11-27|1999-01-20|Univ Sheffield|Skin composites|
    US6676655B2|1998-11-30|2004-01-13|Light Bioscience L.L.C.|Low intensity light therapy for the manipulation of fibroblast, and fibroblast-derived mammalian cells and collagen|
    US6375680B1|1998-12-01|2002-04-23|St. Jude Medical, Inc.|Substrates for forming synthetic tissues|
    US6106555A|1998-12-15|2000-08-22|Av Healing Llc|Method for tissue fixation|
    US6364905B1|1999-01-27|2002-04-02|Sulzer Carbomedics Inc.|Tri-composite, full root, stentless valve|
    US6267786B1|1999-02-11|2001-07-31|Crosscart, Inc.|Proteoglycan-reduced soft tissue xenografts|
    DK1154796T3|1999-02-22|2007-09-24|Univ Connecticut|New albumin-free Factor VIII formulations|
    AU3147200A|1999-03-08|2000-09-28|Asah Medico A/S|An apparatus for tissue treatment and having a monitor for display of tissue features|
    US6287338B1|1999-03-10|2001-09-11|Sulzer Carbomedics Inc.|Pre-stressing devices incorporating materials subject to stress softening|
    US6177514B1|1999-04-09|2001-01-23|Sulzer Carbomedics Inc.|Blocked functional reagants for cross-linking biological tissues|
    US6322593B1|1999-04-09|2001-11-27|Sulzer Carbomedics Inc.|Method for treating cross-linked biological tissues|
    US6283994B1|1999-04-16|2001-09-04|Sulzer Carbomedics Inc.|Heart valve leaflet|
    US6132986A|1999-04-23|2000-10-17|Sulzer Carbomedics Inc.|Tissue crosslinking for bioprostheses using activated difunctional or polyfunctional acids|
    US6328762B1|1999-04-27|2001-12-11|Sulzer Biologics, Inc.|Prosthetic grafts|
    US6790229B1|1999-05-25|2004-09-14|Eric Berreklouw|Fixing device, in particular for fixing to vascular wall tissue|
    US6734018B2|1999-06-07|2004-05-11|Lifenet|Process for decellularizing soft-tissue engineered medical implants, and decellularized soft-tissue medical implants produced|
    US6174331B1|1999-07-19|2001-01-16|Sulzer Carbomedics Inc.|Heart valve leaflet with reinforced free margin|
    US6527979B2|1999-08-27|2003-03-04|Corazon Technologies, Inc.|Catheter systems and methods for their use in the treatment of calcified vascular occlusions|
    EP1210014A1|1999-09-07|2002-06-05|Microvena Corporation|Retrievable septal defect closure device|
    US6312474B1|1999-09-15|2001-11-06|Bio-Vascular, Inc.|Resorbable implant materials|
    US7201771B2|2001-12-27|2007-04-10|Arbor Surgical Technologies, Inc.|Bioprosthetic heart valve|
    US6352708B1|1999-10-14|2002-03-05|The International Heart Institute Of Montana Foundation|Solution and method for treating autologous tissue for implant operation|
    WO2001028604A1|1999-10-15|2001-04-26|The Brigham And Women's Hospital, Inc.|Fresh, cryopreserved, or minimally fixed cardiac valvular xenografts|
    WO2001028325A2|1999-10-20|2001-04-26|Grain Processing Corporation|Compositions including reduced malto-oligosaccharide preserving agents|
    US6322994B1|1999-11-04|2001-11-27|Genetix Limited|Method of freeze-drying organisms|
    US20030097175A1|1999-12-08|2003-05-22|O'connor Bernard|Heart valve prosthesis and method of manufacture|
    US6479079B1|1999-12-13|2002-11-12|Sulzer Carbomedics Inc.|Anticalcification treatments for fixed biomaterials|
    US6576265B1|1999-12-22|2003-06-10|Acell, Inc.|Tissue regenerative composition, method of making, and method of use thereof|
    US6376244B1|1999-12-29|2002-04-23|Children's Medical Center Corporation|Methods and compositions for organ decellularization|
    US6471723B1|2000-01-10|2002-10-29|St. Jude Medical, Inc.|Biocompatible prosthetic tissue|
    MXPA02007253A|2000-01-27|2003-09-22|3F Therapeutics Inc|Prosthetic heart valve.|
    US6872226B2|2001-01-29|2005-03-29|3F Therapeutics, Inc.|Method of cutting material for use in implantable medical device|
    US6391538B1|2000-02-09|2002-05-21|The Children's Hospital Of Philadelphia|Stabilization of implantable bioprosthetic tissue|
    US6378221B1|2000-02-29|2002-04-30|Edwards Lifesciences Corporation|Systems and methods for mapping and marking the thickness of bioprosthetic sheet|
    US6610088B1|2000-05-03|2003-08-26|Shlomo Gabbay|Biologically covered heart valve prosthesis|
    US6653062B1|2000-07-26|2003-11-25|Wisconsin Alumni Research Foundation|Preservation and storage medium for biological materials|
    WO2002015948A2|2000-08-24|2002-02-28|Osteotech, Inc.|Method of treating and dehydrating bone for implantation|
    US6605667B1|2000-09-08|2003-08-12|Closure Medical Corporation|Antioxidant enriched adhesive compositions and storage containers therefor|
    US6953332B1|2000-11-28|2005-10-11|St. Jude Medical, Inc.|Mandrel for use in forming valved prostheses having polymer leaflets by dip coating|
    US6696074B2|2000-12-04|2004-02-24|Tei Biosciences, Inc.|Processing fetal or neo-natal tissue to produce a scaffold for tissue engineering|
    US20020111532A1|2000-12-19|2002-08-15|Pathak Chandrashekhar P.|Trisphosphino compounds as tissue crosslinking agents|
    US6468660B2|2000-12-29|2002-10-22|St. Jude Medical, Inc.|Biocompatible adhesives|
    US20020091441A1|2001-01-05|2002-07-11|Guzik Donald S.|Focused beam cutting of materials|
    US6605079B2|2001-03-02|2003-08-12|Erchonia Patent Holdings, Llc|Method for performing lipoplasty using external laser radiation|
    US6733525B2|2001-03-23|2004-05-11|Edwards Lifesciences Corporation|Rolled minimally-invasive heart valves and methods of use|
    GB2375771A|2001-05-24|2002-11-27|Univ Leeds|Decellularisation of tissue implant material|
    US6939378B2|2001-06-01|2005-09-06|The Board Of Trustees Of The Leland Stanford Junior University|Microfabricated tissue as a substrate for pigment epithelium transplantation|
    US6589591B1|2001-07-10|2003-07-08|Baylor College Of Medicine|Method for treating medical devices using glycerol and an antimicrobial agent|
    US6562069B2|2001-09-19|2003-05-13|St. Jude Medical, Inc.|Polymer leaflet designs for medical devices|
    GB0125925D0|2001-10-29|2001-12-19|Univ Glasgow|Mitral valve prosthesis|
    US7189258B2|2002-01-02|2007-03-13|Medtronic, Inc.|Heart valve system|
    US6878168B2|2002-01-03|2005-04-12|Edwards Lifesciences Corporation|Treatment of bioprosthetic tissues to mitigate post implantation calcification|
    DE10202036A1|2002-01-18|2003-07-31|Zeiss Carl Meditec Ag|Femtosecond laser system for precise processing of material and tissue|
    US7918899B2|2002-01-25|2011-04-05|Biomedical Design, Inc.|Variably crosslinked tissue|
    US7141064B2|2002-05-08|2006-11-28|Edwards Lifesciences Corporation|Compressed tissue for heart valve leaflets|
    US20050211680A1|2003-05-23|2005-09-29|Mingwei Li|Systems and methods for laser texturing of surfaces of a substrate|
    US20030229394A1|2002-06-06|2003-12-11|Ogle Matthew F.|Processed tissue for medical device formation|
    US7578843B2|2002-07-16|2009-08-25|Medtronic, Inc.|Heart valve prosthesis|
    US6908591B2|2002-07-18|2005-06-21|Clearant, Inc.|Methods for sterilizing biological materials by irradiation over a temperature gradient|
    US20040024452A1|2002-08-02|2004-02-05|Kruse Steven D.|Valved prostheses with preformed tissue leaflets|
    US7008763B2|2002-09-23|2006-03-07|Cheung David T|Method to treat collagenous connective tissue for implant remodeled by host cells into living tissue|
    US7189259B2|2002-11-26|2007-03-13|Clemson University|Tissue material and process for bioprosthesis|
    ES2311148T3|2003-03-20|2009-02-01|Aortech International Plc|VALVE.|
    US20040193259A1|2003-03-25|2004-09-30|Shlomo Gabbay|Sizing apparatus for cardiac prostheses and method of using same|
    US7871434B2|2003-04-01|2011-01-18|Cook Incorporated|Percutaneously deployed vascular valves|
    EP1626752A2|2003-05-16|2006-02-22|Blue Membranes GmbH|Medical implants comprising biocompatible coatings|
    US9022037B2|2003-08-11|2015-05-05|Raydiance, Inc.|Laser ablation method and apparatus having a feedback loop and control unit|
    US7361171B2|2003-05-20|2008-04-22|Raydiance, Inc.|Man-portable optical ablation system|
    IL156626A|2003-06-24|2009-12-24|Yeda Res & Dev|System for selective cell destruction|
    US7621948B2|2003-07-21|2009-11-24|The Trustees Of The University Of Pennsylvania|Percutaneous heart valve|
    US7143769B2|2003-08-11|2006-12-05|Richard Stoltz|Controlling pulse energy of an optical amplifier by controlling pump diode current|
    US7367969B2|2003-08-11|2008-05-06|Raydiance, Inc.|Ablative material removal with a preset removal rate or volume or depth|
    US7053051B2|2003-10-28|2006-05-30|Medtronic, Inc.|Methods of preparing crosslinked materials and bioprosthetic devices|
    US7955788B2|2003-10-30|2011-06-07|Medtronic, Inc.|Bioprosthetic tissue preparation with synthetic hydrogels|
    US7261732B2|2003-12-22|2007-08-28|Henri Justino|Stent mounted valve|
    US7648676B2|2004-04-20|2010-01-19|Rti Biologics, Inc.|Process and apparatus for treating implants comprising soft tissue|
    US8512730B2|2004-07-12|2013-08-20|Isto Technologies, Inc.|Methods of tissue repair and compositions therefor|
    US7919112B2|2004-08-26|2011-04-05|Pathak Holdings, Llc|Implantable tissue compositions and method|
    US20060110370A1|2004-11-23|2006-05-25|Pathak Chandrashenkhar P|Treatments for reduction of cytotoxicity and viral contamination of implantable medical devices|
    US20060177426A1|2005-02-09|2006-08-10|Cecil Gibson|Method of preserving lyophilized microorganisms for transport, storage and recovery of viable microorganisms|
    EP1863546B1|2005-03-11|2015-10-07|Wake Forest University Health Sciences|Production of tissue engineered heart valves|
    US20060217804A1|2005-03-25|2006-09-28|Dove Jeffrey S|Treatment of bioprosthetic tissues to mitigate post implantation calcification|
    US7579381B2|2005-03-25|2009-08-25|Edwards Lifesciences Corporation|Treatment of bioprosthetic tissues to mitigate post implantation calcification|
    US7914569B2|2005-05-13|2011-03-29|Medtronics Corevalve Llc|Heart valve prosthesis and methods of manufacture and use|
    US7217265B2|2005-05-18|2007-05-15|Cooltouch Incorporated|Treatment of cellulite with mid-infrared radiation|
    US7238200B2|2005-06-03|2007-07-03|Arbor Surgical Technologies, Inc.|Apparatus and methods for making leaflets and valve prostheses including such leaflets|
    DE502005003997D1|2005-06-09|2008-06-19|Sie Ag Surgical Instr Engineer|Ophthalmic device for the dissolution of ocular tissue|
    DE102005027355A1|2005-06-13|2006-12-14|Femtotechnologies Gmbh|Method for processing an organic material|
    US20070292459A1|2005-07-18|2007-12-20|Cooper Sarah M|Halloysite microtubule processes, structures, and compositions|
    US20090112309A1|2005-07-21|2009-04-30|The Florida International University Board Of Trustees|Collapsible Heart Valve with Polymer Leaflets|
    US20100100084A1|2005-08-03|2010-04-22|Bruno Girard|Hybrid Ultrafast Laser Surgery and Growth Factor Stimulation for Ultra-Precision Surgery with Healing.|
    US20070048340A1|2005-08-31|2007-03-01|Searete Llc, A Limited Liability Corporation Of The State Of Delaware|Multi step patterning of a skin surface|
    US8470022B2|2005-08-31|2013-06-25|Cook Biotech Incorporated|Implantable valve|
    US7682304B2|2005-09-21|2010-03-23|Medtronic, Inc.|Composite heart valve apparatus manufactured using techniques involving laser machining of tissue|
    EP2004095B1|2006-03-28|2019-06-12|Medtronic, Inc.|Prosthetic cardiac valve formed from pericardium material and methods of making same|
    WO2008016919A2|2006-07-31|2008-02-07|Organogenesis Inc.|Mastopexy and breast reconstruction prostheses and method|
    US20080299408A1|2006-09-29|2008-12-04|University Of Rochester|Femtosecond Laser Pulse Surface Structuring Methods and Materials Resulting Therefrom|
    US10876193B2|2006-09-29|2020-12-29|University Of Rochester|Nanostructured materials, methods, and applications|
    CN103933612B|2006-10-27|2016-06-22|爱德华兹生命科学公司|Biological tissue for Srgery grafting|
    US9101691B2|2007-06-11|2015-08-11|Edwards Lifesciences Corporation|Methods for pre-stressing and capping bioprosthetic tissue|
    US20090105813A1|2007-10-17|2009-04-23|Sean Chambers|Implantable valve device|
    US20090118716A1|2007-11-07|2009-05-07|Intralase, Inc.|System and method for scanning a pulsed laser beam|
    US8357387B2|2007-12-21|2013-01-22|Edwards Lifesciences Corporation|Capping bioprosthetic tissue to reduce calcification|
    WO2009129483A1|2008-04-17|2009-10-22|Musculoskeletal Transplant Foundation|Ultrashort pulse laser applications|
    US8136218B2|2008-04-29|2012-03-20|Medtronic, Inc.|Prosthetic heart valve, prosthetic heart valve assembly and method for making same|
    CN202568532U|2008-06-06|2012-12-05|爱德华兹生命科学公司|Implantable artificial valve|
    US8679100B2|2009-07-29|2014-03-25|Alcon Lensx, Inc.|Optical system with multiple scanners for ophthalmic surgical laser|
    US9492322B2|2009-11-16|2016-11-15|Alcon Lensx, Inc.|Imaging surgical target tissue by nonlinear scanning|
    CN102811681B|2010-03-23|2016-10-12|爱德华兹生命科学公司|The method of regulation lamellar bioprosthetic tissue|
    JP2013526388A|2010-05-25|2013-06-24|イエナバルブテクノロジーインク|Artificial heart valve, and transcatheter delivery prosthesis comprising an artificial heart valve and a stent|
    US9095430B2|2010-08-24|2015-08-04|Southern Lights Ventures Limited|Biomaterials with enhanced properties and devices made therefrom|
    WO2014008207A1|2012-07-02|2014-01-09|Boston Scientific Scimed, Inc.|Prosthetic heart valve formation|US9101691B2|2007-06-11|2015-08-11|Edwards Lifesciences Corporation|Methods for pre-stressing and capping bioprosthetic tissue|
    US8357387B2|2007-12-21|2013-01-22|Edwards Lifesciences Corporation|Capping bioprosthetic tissue to reduce calcification|
    WO2011104269A1|2008-02-26|2011-09-01|Jenavalve Technology Inc.|Stent for the positioning and anchoring of a valvular prosthesis in an implantation site in the heart of a patient|
    CN202568532U|2008-06-06|2012-12-05|爱德华兹生命科学公司|Implantable artificial valve|
    CA2756049C|2009-04-15|2017-05-02|Impala, Inc.|Vascular implant and delivery system|
    CN102811681B|2010-03-23|2016-10-12|爱德华兹生命科学公司|The method of regulation lamellar bioprosthetic tissue|
    JP2013526388A|2010-05-25|2013-06-24|イエナバルブテクノロジーインク|Artificial heart valve, and transcatheter delivery prosthesis comprising an artificial heart valve and a stent|
    WO2013142879A1|2012-03-23|2013-09-26|Cytograft Tissue Engineering, Inc.|Tissue-engineered heart valve for transcatheter repair|
    US9345573B2|2012-05-30|2016-05-24|Neovasc Tiara Inc.|Methods and apparatus for loading a prosthesis onto a delivery system|
    US9554902B2|2012-06-28|2017-01-31|St. Jude Medical, Cardiology Division, Inc.|Leaflet in configuration for function in various shapes and sizes|
    WO2015061431A1|2013-10-22|2015-04-30|ConcieValve LLC|Methods for inhibiting stenosis, obstruction, or calcification of a stented heart valve or bioprosthesis|
    US10058630B2|2012-10-22|2018-08-28|Concievalve, Llc|Methods for inhibiting stenosis, obstruction, or calcification of a stented heart valve or bioprosthesis|
    US10238771B2|2012-11-08|2019-03-26|Edwards Lifesciences Corporation|Methods for treating bioprosthetic tissue using a nucleophile/electrophile in a catalytic system|
    EP2964277B1|2013-03-08|2018-10-24|St. Jude Medical, Cardiology Division, Inc.|Method of preparing a tissue swatch for a bioprosthetic device|
    US9681951B2|2013-03-14|2017-06-20|Edwards Lifesciences Cardiaq Llc|Prosthesis with outer skirt and anchors|
    US20140277413A1|2013-03-15|2014-09-18|Valve Medical Ltd.|System and method for sealing percutaneous valve|
    EP3038567A1|2013-08-30|2016-07-06|JenaValve Technology, Inc.|Radially collapsible frame for a prosthetic valve and method for manufacturing such a frame|
    WO2015047979A2|2013-09-24|2015-04-02|Brigham And Women's Hospital, Inc.|Systems and methods for preparing tissue flaps|
    US9615922B2|2013-09-30|2017-04-11|Edwards Lifesciences Corporation|Method and apparatus for preparing a contoured biological tissue|
    US10959839B2|2013-10-08|2021-03-30|Edwards Lifesciences Corporation|Method for directing cellular migration patterns on a biological tissue|
    CN103750922B|2013-12-31|2016-07-13|金仕生物科技（常熟）有限公司|The method preparing Cardiac valve prosthesis leaflet|
    CN103892938A|2014-04-01|2014-07-02|薛春燕|Corneal lamellar piece and production method thereof|
    CA2974120A1|2015-01-21|2016-07-28|Lifecell Corporation|Tissue matrices with controlled porosity or mechanical properties|
    US10080820B2|2015-09-03|2018-09-25|Boston Scientific Scimed, Inc.|Tissue modification devices, systems, and methods|
    US10405975B2|2015-10-07|2019-09-10|Boston Scientific Scimed, Inc.|Cultured cell leaflet material|
    DE102015117318A1|2015-10-12|2017-04-13|Biotronik Se & Co. Kg|Method for thickness control and three-dimensional shaping of biological tissue during fixation|
    DE102015118854A1|2015-11-03|2017-05-04|UroTiss Europe GmbH|Device for introducing a tissue replacement into a hollow organ|
    US10231830B2|2015-11-10|2019-03-19|Boston Scientific Scimed, Inc.|Kidney capsule leaflet material|
    US20170173214A1|2015-12-21|2017-06-22|Medtronic Vascular, Inc.|Methods for preparing dry cross-linked tissue|
    US9968447B2|2016-01-22|2018-05-15|Medtronic Vascular, Inc.|Bioprosthetic tissue for use as a prosthetic valve leaflet and method of preparing|
    EP3454795A1|2016-05-13|2019-03-20|JenaValve Technology, Inc.|Heart valve prosthesis delivery system and method for delivery of heart valve prosthesis with introducer sheath and loading system|
    WO2018138658A1|2017-01-27|2018-08-02|Jenavalve Technology, Inc.|Heart valve mimicry|
    WO2018149587A1|2017-02-20|2018-08-23|Epygon|Prosthetic heart valve leaflet with variable thickness|
    US10973628B2|2017-08-18|2021-04-13|Edwards Lifesciences Corporation|Pericardial sealing member for prosthetic heart valve|
    CN111263622A|2017-08-25|2020-06-09|内奥瓦斯克迪亚拉公司|Sequentially deployed transcatheter mitral valve prosthesis|
    WO2019173393A1|2018-03-05|2019-09-12|Edwards Lifesciences Corporation|Optical tissue measurement|
    US10595994B1|2018-09-20|2020-03-24|Vdyne, Llc|Side-delivered transcatheter heart valve replacement|
    US11071627B2|2018-10-18|2021-07-27|Vdyne, Inc.|Orthogonally delivered transcatheter heart valve frame for valve in valve prosthesis|
    US11109969B2|2018-10-22|2021-09-07|Vdyne, Inc.|Guidewire delivery of transcatheter heart valve|
    US10653522B1|2018-12-20|2020-05-19|Vdyne, Inc.|Proximal tab for side-delivered transcatheter heart valve prosthesis|
    US11253359B2|2018-12-20|2022-02-22|Vdyne, Inc.|Proximal tab for side-delivered transcatheter heart valves and methods of delivery|
    US11185409B2|2019-01-26|2021-11-30|Vdyne, Inc.|Collapsible inner flow control component for side-delivered transcatheter heart valve prosthesis|
    US11076956B2|2019-03-14|2021-08-03|Vdyne, Inc.|Proximal, distal, and anterior anchoring tabs for side-delivered transcatheter mitral valve prosthesis|
    US11173027B2|2019-03-14|2021-11-16|Vdyne, Inc.|Side-deliverable transcatheter prosthetic valves and methods for delivering and anchoring the same|
    US10758346B1|2019-03-14|2020-09-01|Vdyne, Inc.|A2 clip for side-delivered transcatheter mitral valve prosthesis|
    US10631983B1|2019-03-14|2020-04-28|Vdyne, Inc.|Distal subannular anchoring tab for side-delivered transcatheter valve prosthesis|
    AU2020267390A1|2019-05-04|2021-11-11|Vdyne, Inc.|Cinch device and method for deployment of a side-delivered prosthetic heart valve in a native annulus|
    WO2021035032A1|2019-08-20|2021-02-25|Vdyne, Inc.|Delivery and retrieval devices and methods for side-deliverable transcatheter prosthetic valves|
    US11234813B2|2020-01-17|2022-02-01|Vdyne, Inc.|Ventricular stability elements for side-deliverable prosthetic heart valves and methods of delivery|
    US11161204B1|2020-04-10|2021-11-02|Amnio Technology Llc|Allograft optimization system|
    WO2021211838A1|2020-04-16|2021-10-21|St. Jude Medical, Cardiology Division, Inc.|Designed leaflet thickness via stretching techniques for improved valve durability|
    CN111686304A|2020-06-11|2020-09-22|四川大学|Small-size transcatheter artificial heart valve and preparation method thereof|
    法律状态:
    2019-01-08| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2019-09-17| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2020-07-07| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2020-11-10| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 23/03/2011, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    US31680110P| true| 2010-03-23|2010-03-23|
    US61/316,801|2010-03-23|
    US38185810P| true| 2010-09-10|2010-09-10|
    US61/381,858|2010-09-10|
    PCT/US2011/029654|WO2011119754A2|2010-03-23|2011-03-23|Methods of conditioning sheet bioprosthetic tissue|BR122014006876-0A| BR122014006876B1|2010-03-23|2011-03-23|METHOD FOR PREPARING BIOPROTETIC TISSUE MEMBRANE MATERIAL|
    BR122014006918-9A| BR122014006918B1|2010-03-23|2011-03-23|METHOD FOR PREPARING BIOPROTETIC TISSUE MEMBRANE MATERIAL|
    [返回顶部]