Abstract:
The subject invention is directed to devices and methods for producing devices for regulating blood flow in the venous system. In particular, the invention provides for artificial valves designed to regulate the flow of blood in human vessels, wherein such artificial valves include superior properties including fatigue resistance, biocompatibility, and ease of manufacture.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application claims priority to U.S. Provisional Patent Application No. 61/314,699, filed Mar. 17, 2010, which is incorporated by reference herein in its entirety. This application incorporates by reference herein each of the following commonly assigned U.S. patent applications in its entirety: application Ser. No. 12/713,476 filed Feb. 26, 2010, application Ser. No. 12/319,176 filed Jan. 2, 2009, application Ser. No. 11/801,691 filed May 10, 2007, and application Ser. No. 11/801,489 filed May 10, 2007. 
    
    
     BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     The subject invention is directed to devices for regulating blood flow in the venous system, and more particularly, to the design and production of artificial valve devices designed to regulate the flow of blood in human vessels. 
     2. Description of Related Art 
     Artificial venous valves offer numerous possibilities that can be very attractive to clinicians and patients. Benefits of such designs include, the possibility of improved functional stability and life while reducing size and bulk of the valve, which offers opportunities for interventional, less traumatic procedures for valve placement. In spite of the existence of a great number of artificial valve designs, very few of them have managed to pass through clinical trials and make it to the clinical arena. 
     Today&#39;s use of artificial valves is limited to relatively bulky mechanical valves or tissue based valves. The reason for this is that small and compact valves, suitable for interventional applications, require the use of thin metal frames and ultra thin polymer parts joined together, to meet the harsh requirements of a multimillion cycle application in blood flow. Herein is the main problem of percutaneously inserted valves—their mechanical designs, historically, have not proven to be as robust as that of bulkier valves, and have been prone to biocompatibility, long term stability, wear and fatigue issues. 
     Such conventional methods and systems have generally been considered satisfactory for their intended purpose. However, there is still a need in the art for artificial valves that allow for improved fatigue resistance. There also remains a need in the art for such artificial valves that are easy to make and use. The present invention provides a solution for these problems. 
     SUMMARY OF THE INVENTION 
     The subject invention is directed to new and useful artificial valves. The applications incorporated by reference above generally provide mechanical design details. This application is more particularly directed to the issues of valve material compatibility, stability and durability by material selection and manufacturing techniques used to address the specific requirements of fatigue related to the imbalance of stresses between metal parts and elastic polymer components, by:
         Selecting optimal, proven materials designed to perform in this harsh environment,   Reducing stress concentrations at the interfaces between materials having radically different stiffness and modulus of elasticity,   Reducing friction between component joints, and   Increasing tear resistance of the polymer components.       

     These and other features of the systems and methods of the subject invention will become more readily apparent to those skilled in the art from the following detailed description of the preferred embodiments taken in conjunction with the drawings. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       So that those skilled in the art to which the subject invention appertains will readily understand how to make and use the apparatus of subject invention without undue experimentation, preferred embodiments thereof will be described in detail hereinbelow with reference to certain figures, wherein: 
         FIG. 1  is a perspective view of the flow regulating device of the present invention, prior to full assembly; 
         FIG. 2  is a perspective view of the support of the flow-regulating device of  FIG. 1 ; 
         FIG. 3  is a side perspective view of the flow regulating device illustrating how the membrane is attached to the frame; 
         FIG. 4  is a front perspective view of the top (distal) portion of the flow regulating device of  FIG. 1  showing the membrane in the closed position; 
         FIG. 5A  is a side perspective view showing the membrane in the open position; 
         FIG. 5B  is a side perspective view similar to  FIG. 5A  showing the membrane in the closed position; 
         FIG. 6A  is a cross-sectional view of the identified area of  FIG. 5A  showing the membrane in the open position, resulting from antegrade blood flow; 
         FIG. 6B  is a cross-sectional view of the identified area of  FIG. 6A  showing the membrane in the closed position, resulting from retrograde blood flow; 
         FIG. 6C  is a top view of the upper region of the membrane of  FIG. 5B  showing the membrane in the closed position; 
         FIG. 6D  is a top view of the upper region of the membrane of  FIG. 5A  showing the membrane in the open position; 
         FIG. 6E  is a top view of the upper region of another exemplary embodiment of the membrane shown in the open position; 
         FIG. 7  is a view similar to  FIG. 4  showing another exemplary embodiment of the membrane with flaps forming larger openings for increased antegrade blood flow; 
         FIG. 7A  is a cross-sectional view similar to  FIG. 6B  except showing the membrane of  FIG. 7  in the closed position; 
         FIG. 8  is a drawing of the anatomy of the patient showing two examples of locations of placement of the flow regulating device; 
         FIG. 9  is a front elevation view of the frame of a flow-regulating device constructed in accordance with another embodiment of the subject invention with the membrane or sail removed for clarity; 
         FIG. 10  is a side elevation view of the frame of  FIG. 9 , showing one of the symmetrical x-shaped linking members connecting the two axially spaced apart ring portions; 
         FIG. 11  is a perspective view of the frame of  FIG. 9 , showing both of the symmetrical x-shaped linking members; 
         FIG. 12  is a front elevation view of the flow-regulating device of  FIG. 9 , showing the membrane or sail in place; 
         FIG. 13  is a side elevation view of the flow-regulating device of  FIG. 12 , showing one of the symmetrical x-shaped linking members connecting the two axially spaced apart ring portions with the membrane or sail attached to a portion of the cross members of the x-shaped linking member; and 
         FIG. 14  is a perspective view of the flow-regulating device of  FIG. 12 , showing both of the x-shaped linking members with the membrane or sail in place in the flow restricting position. 
     
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     Reference will now be made to the drawings wherein like reference numerals identify similar structural features or aspects of the subject invention. For purposes of explanation and illustration, and not limitation, a partial view of an exemplary embodiment of an artificial valve in accordance with the invention is shown in  FIG. 1  and is designated generally by reference character  10 . Other embodiments of valves in accordance with the invention, or aspects thereof, are provided in  FIGS. 2-14 , as will be described. The system of the invention can be used to improve performance and manufacturing of artificial valves. 
     Regulating device  10  includes an elongated support  12  that has upper and lower substantially annular ring portions  14  and  24 , each having a series of rounded V-shaped apices  15   a  facing in an upward direction and a series  15   b  facing in a downward direction. That is, the upper or distal (with respect to the direction of blood flow) ring portion  14  has a first series of angled struts  13   a  forming a V and a second series of angled struts  13   b  forming an inverted V which together form a group of closed substantially diamond shaped cells  19  connected at region  17 . Similarly, the lower or proximal (with respect to the direction of blood flow) ring portion  24  has a first series of angled struts  29   a  and a second series of angled struts  29   b , facing in opposite directions and forming closed substantially diamond shaped cells  28  connected at region  27 . The cells  28  have upper apices  25  and lower apices  26 . For clarity, not all of the identical parts in the drawings are labelled. Note that in the preferred embodiment, the rings and linking member (described below) are preferably integral so that terms “joined”, “connected”, etc. are used for ease of description. 
     Support  12  has two curved linking or connecting members  21   a ,  21   b , best shown in  FIG. 2  in which the membrane is removed for clarity. The top of each connecting member  21   a ,  21   b  extends from a common lower apex  15   b  of one of the pairs of angled struts  13   b  of upper ring  14  (see also  FIGS. 3 and 4 ) The lower end of connecting members  21   a ,  21   b  extend from separate upper apices  25   a ,  25   b , respectively, of cells  28  of lower ring  24 . In the illustrated embodiment, the apices  25   a ,  25   b , are about 36 degrees apart as ten cells are formed. However, a different number of cells can be provided with different spacing between apices. Also, it should be appreciated that the connecting members can extend from other apices of lower ring  24  or upper ring  14 . The connecting members  21   a ,  21   b  have a curve or twist extending close to about 180 degrees (and extending substantially across the vessel when implanted) so that an upper end is connected to one end (viewed radially/transversely) of the device  10  and the lower end is connected to an opposite end (viewed radially/transversely) of the device  10 . That is, with ten closed cells in the illustrated embodiment, apex  15   b  is approximately 162 degrees out of phase from apex  25   a  and from apex  25   b . Other spacing and alternate number of cells is also contemplated. 
     Although two connecting members are shown, one connecting member or more connecting members could be provided. Also, the connecting members could be spaced further or closer apart and have different curves than shown. 
     The rings  14 ,  24  are collapsed to a reduced diameter (profile) position for delivery. The rings  14 ,  24 , when implanted, are substantially perpendicular to the direction of blood flow. Preferably, the rings  14 ,  16  in their expanded (deployed) configuration are larger in diameter than the internal diameter of the target vessel to apply a sufficient radial force against the vessel to ensure that the device remains in a desired position and orientation after implantation. For example, for use in an 8 mm vessel, the rings could have an expanded outer diameter of about 10 mm and preferably could be collapsed sufficiently to be delivered through a 12 Fr (4 mm) delivery catheter. Others ring diameters are also contemplated. 
     The support  12  is preferably composed of shape memory material, such as Nitinol or Elgitoy, with a shape memorized larger diameter configuration as shown in the drawings. In the illustrated embodiment, the support is laser cut from a tube so that the connecting members and rings are integral. However, it is also contemplated that alternatively the support can be formed from wire(s). Also, it should be appreciated that instead of being integral, separate members could be provided, with separate rings joined by separate linking (connecting) members. 
     Device  10  includes a valve member or membrane  50  that is operatively associated with support  12  for regulating the flow of blood through a vessel by moving between open and closed positions. Membrane  50  is preferably formed from a sheet of ultra thin membrane material such as a ePTFE material or the like. It is envisioned that the membranes disclosed herein could be bonded or otherwise coated with an anti-clotting or anti-coagulant/anti-thrombogenic agent such as Heparin and/or an anti-proliferative coating, to retard the body&#39;s desire to reject the implant. In a preferred embodiment, the membrane is coated with an anti-thrombogenic agent and the frame is coated with an anti-proliferative agent, such as Dexamethasone by way of example. 
     As shown, valve membrane  50  has an upper portion  52 , an intermediate portion  62 , and a lower portion  72 . With reference to  FIG. 3  which illustrates how the membrane  50  is attached to support  12  in manufacture, the top portion  52  has first and second flaps  54 ,  56  which are folded down over respective connecting members  21   a ,  21   b  and attached to the membrane to secure the upper portion  52  of membrane  50  about the support  12 .  FIG. 3  illustrates flap  56  already folded in the direction of arrow F 4  from its unfolded position shown in phantom.  FIG. 3  also illustrates flap  54  in its unfolded position before movement in the direction of arrow F 3  in manufacture to its folded position depicted in phantom. Flaps  57  and  59  at the uppermost region of membrane  50  are wrapped around struts  13   b  in the direction of arrows F 1 , F 2 , respectively. 
     With continued reference to  FIG. 3 , the intermediate portion  62  of membrane  50  has flaps  64 ,  66  for connection to linking (connecting) members  21   a ,  21   b , respectively. Flap  64  is shown in a mostly unfolded position to be folded in the direction of arrows F 6  to its folded position shown in phantom where it is attached to the membrane  50 . Flap  66  is shown in its unfolded position to be folded in the direction of arrows F 5  to its folded position depicted in phantom. 
     Lower portion  72  of membrane  50  has flaps  74  and  76  which are each folded around a separate strut  29   a . Arrows F 8 , F 7 , respectively, illustrate the direction of the fold. 
     Cuts in the membrane  50  create an unattached flap  84  between upper attached flap  54  and intermediate attached flap  64  and an unattached flap  86  between upper attached flap  56  and intermediate attached flap  66 . These unattached flaps  84 ,  86  are positioned adjacent the respective connecting member  21   a ,  21   b  as shown, but create a respective opening  90 ,  91  for blood flow between the membrane  50  and connecting members  21   a ,  21   b  as described below. Note, alternatively, the flaps  84 ,  86  can extend over the connecting member, as long as it remains unattached and creates a sufficient space from the linking member to create a sufficiently sized opening to allow blood flow therethrough. 
     Note that  FIG. 1  shows the membrane  50  with the flaps open, prior to connection in manufacture, to illustrate how it is wrapped around the support  12  and connected to other portions of the membrane for securement/attachment of the membrane to the support  12 . The flaps, after wrapping over/around the region of support  12 , can be connected to the membrane body by welding, adhesive, suturing or other methods. Also, an intermediary material can be used to facilitate welding, such as polyurethane or polycarbonate/polyurethane impregnated or otherwise combined with the ePTFE material. It is also contemplated that the membrane can be attached to the support  12  itself by methods such as by adhesive or use of suture material. 
     As can be appreciated, the body portion of the membrane  50  extends substantially if not entirely across the expanse of the vessel in the open position. However, the openings  90  and  91  adjacent the unattached flaps  84 ,  86  provide a sufficient gap for the necessary amount of blood flow, it being appreciated by applicants that a normally functioning valve is only open about 35%. In some embodiments, the openings in the membrane created by the space between flaps  84 ,  86  and the support create a space gap in the range of about 5% to about 15% of the diameter of the vessel. In the alternate embodiment depicted in  FIG. 7 , larger openings  90 ′ and  91 ′ are formed to allow more antegrade blood flow. In these large opening embodiments, a space (opening) can be created preferably representing about 15% to about 45%, and more preferably from about 15% to about 30% of the diameter of the vessel. (In all other respects the regulating device of  FIG. 7  is identical to that of  FIG. 4  and the corresponding parts are labelled by numerals with a prime designation and therefore are not discussed herein). These percentages are defined in terms of the diameter of the blood vessel. For example, if a rectangular opening is formed of dimension of 2 mm×4 mm, and is placed in a 10 mm vessel, the cross section occupied by the two openings (about 16 mm) would be about 20% of the overall diameter of the vessel (about 78 mm). It should be appreciated that the foregoing ranges and percentages are provided by way of example and other size openings creating a different percentage opening are also contemplated. Also, other shape openings can be provided other than rectangular, including square, semicircular, etc.  FIG. 6E  shows by way of example substantially semicircular openings  90 ″,  91 ″ formed by flaps  84 ″.  86 ″, respectively. 
     Movement of the membrane  50  between an open (blood flow enabling) position/condition to allow antegrade blood flow and a closed (blood flow inhibiting position/condition) to essentially block flow are shown in respective  FIGS. 5A and 5B , and shown in more detail in  FIGS. 6A-6D . In the closed position, however, a minimal amount of blood flow is allowed as will be discussed below. 
     More specifically, and with reference to  FIG. 5A , blood flowing through the blood vessel V in the downstream direction (antegrade flow) indicated by arrow “D” will act against the valve membrane  50  in such a manner as to push the body portion upwardly as viewed in the drawing, creating a concave belly on the underside. The blood will travel along the concave surface and up the membrane and the blood pressure will force the flaps  84  and  86  upwardly, separating (spreading) them from the respective connecting members  21   a ,  21   b  as also shown in  FIGS. 6A and 6D  to form an opening or gap. 
     After the pulsed blood travels in the direction of arrow D 1  ( FIG. 5A ), through the openings (spaces)  90 ,  91 , the blood backs up in the direction of arrow C of  FIG. 5B . This retrograde blood flow will act against the angled body of the membrane  50 , forcing it downwardly as viewed in  FIG. 5B  to form a convexity on its underside. This downward pressure will force flaps  84 ,  86  downwardly adjacent to the connecting members  21   a ,  21   b , respectively, and against the connecting member as shown for example in  FIGS. 6B and 6C , thus essentially closing the openings  90 ,  91  to prevent blood flow therethrough. However, a small amount of blood will force its way between the membrane  50  and the vessel wall as depicted by arrow C 1  in  FIG. 5B , thereby reducing stasis or stagnation that could lead to clotting. In embodiments wherein a larger flap is utilized to create a larger opening, such as in the embodiment of  FIG. 7 , the flap  84 ′ (and  86 ′, not shown) in the closed position would lie adjacent the connecting members, and extend underneath the connecting member (e.g. connecting member  21   a ′) to lie against the vessel wall as shown in  FIG. 7A , thereby inhibiting blood flow. 
     It should be appreciated that the membrane extends at an angle across the vessel of about 50 to about 70 degrees to help direct the blood flow and continuously wash the membrane body to prevent blood stagnation. (Other angles are also contemplated) More specifically, blood contacting the body portion of the membrane  50  in the open position will be directed upwardly, along the concave surface, thereby washing the membrane body to wash away clots to reduce the likelihood of clotting. In the closed position, blood contacting the membrane body will be directed downwardly along the angled body to wash the opposing side of the membrane to likewise reduce the likelihood of clotting. 
     As can be appreciated, the membrane  50  remains at substantially the same angle across the blood vessel in the open (flow allowing) and closed (flow inhibiting) positions/conditions. That is, as shown in  FIGS. 5A and 5B , the upper region of the membrane  50  is adjacent one side of the vessel wall in the open (flow allowing) position. The upper region remains adjacent the same wall in the closed (flow inhibiting) position. Similarly, the lower region of the membrane  50  is adjacent an opposite side of the vessel wall, and remains adjacent that wall in both the open and closed positions of  FIGS. 5A, 5B , respectively. Thus, the upper and lower attached regions of the membrane remain in substantially the same position. 
     One example of the location of placement of the flow regulating device in a patient&#39;s leg is shown in  FIG. 8  with areas A 1  and A 2  showing possible placement sites of the device, e.g. upstream or downstream of the native valve V. 
     If composed of shape memory, the device will automatically expand to the position shown either upon release from a delivery member or in response to temperature change. However, if composed of other materials, the device can be designed to automatically expand due to the springiness of the material or can alternatively be implanted in a blood vessel using a balloon catheter (not shown) as described in copending U.S. patent application Ser. No. 11/801,691, the entire contents of which are incorporated herein by reference. That is, rings  14  and  24  can be moved from a closed position to an expanded position by inflating the balloon or by use of a mechanical expander. Upon expansion, the rings  14  and  24  apply a force against the vessel wall, thereby being retained therein. The balloon or mechanical expander is then deflated and the catheter is removed from the blood vessel so the device  10  can regulate the flow of blood through the vessel in the manner described above. 
     In the embodiments disclosed herein showing substantially circular rings, it should be understood that the rings can be shaped to have a size larger than the diameter of the vessel and therefore, depending on the size of the vessel, may not assume a circular shape but have an oval shape pressing against the vessel wall toward a circular configuration. 
     Referring now to  FIGS. 9-11 , there is shown a frame for a flow regulating device constructed in accordance with another preferred embodiment of the subject invention, and designated generally by reference numeral  200 . Regulating device  200  includes an elongated frame  220  that consists of upper and lower substantially annular ring portions  240  and  260 , much as described above. Rings  240  and  260  are connected to one another by at least one connective member  280  in the form of an x-shaped bar or wire. In the exemplary embodiment of  FIGS. 9-14 , two x-shaped connective members  280  are shown. Connective members  280  are adapted and configured to follow the circumference of the host vessel. The individual cross-linked bars or wires of each x-shaped connective member  280  are attached to the opposed rings  240  and  260  of frame  220  at locations that are about 180° apart from one another, making device  200  substantially symmetrical. This gives frame  220  an inherent symmetrical flexibility and enables it to move with the natural movements (e.g., pulsitile) of the vein. 
       FIGS. 12-14  show device  200  with the membrane, much as described above, in place. Membrane or sail  250  attaches to portions of the x-shaped connective members  280 . Apertures  270  allow blood flow in one direction, and inhibit flow in the opposite direction much as described above. This frame and sail configuration gives device  200  more support and symmetry, allows for delivery using a simpler delivery device, distributes stress more evenly and reduces stress raisers between support portions. 
     The frame, described in the above and in the applications incorporated by reference above, can be made of a laser cut, heat set, smoothly micro-polished one piece Nitinol construct, a well known and well tolerated super elastic alloy, used for many years in the vasculature and more recently proven to be successfully implanted within the target valve anatomical location. See, e.g., Neglen et al, Journal of Vascular Surgery November 2007, which is incorporated by reference herein in its entirety. 
     The valve membrane or leaflet, as described above and in the applications incorporated by reference above, can be manufactured from an ePTFE (expanded polytetrafluoroethylene), which is a material with a long history of being well tolerated in the vasculature. This ePTFE leaflet is designed and built to have specific stress relieved and annealed characteristics and specific porosity designed to allow attachment and adherence of the attachment polymer, while maintaining the mechanical, functional, stability and biocompatibility requirements for this specific application, as described in further detail below. 
     The practical assembly of this device is based on a unique heat shaping process of the leaflet material combined with the micro thin application and impregnation of a proven biocompatible polycarbonate polyurethane material to the underside with respect to the orientation of  FIG. 3  of the leaflet in the seam area enabling the application of heat to seamlessly attach the leaflet to the frame, via the folding described above and in the applications incorporated by reference above. 
     These attachment techniques allow the polymer material to be attached to the frame without any perforation of the leaflet material (perforations of a thin polymer sheet under frequent cyclic movement lead to the potential for accelerated risk of tear propagation of the polymer sheet, as demonstrated in other medical device applications where tears were seen at suture hole locations after cyclical use). 
     The folding processes described above and in the applications incorporated by reference above can additionally include some or all of the following:
         1. Spraying the metal frame of the valve with silicone lubricant, to prevent adherence of the leaflet to the frame through the heat-welding process;   2. Wrapping the leaflet around the frame and welding of the leaflet material to itself, forming a continuous flexible seam around the metal frame, without the leaflet material being adhered to the frame;   3. Using a pre-shaped bi-axially stress relieved and annealed ePTFE material with the porosity range selected between 15 and 25 microns, these size pores are large enough to allow deep and uniform penetration of a Polycarbonate polyurethane adhesive, and/or other suitable adhesive, into the bulk of the leaflet; but small enough to prevent blood seepage through the leaflet;   4. Forming the leaflet from a thermally-fitted and fully annealed polymer sheet, reducing the risk of folds and creases in the leaflet that could harbor cellular adherence;   5. Melting the thinly applied and impregnated Polycarbonate polyurethane (the strongest and most flexible of the polyurethane elastomers), to smooth out the seam making it virtually invisible, reducing the potential for blood or cellular adherence; and   6. Using a pre-programmed laser cutting apparatus, and/or other suitable device, to cut out openings in the leaflet, to allow blood flow though the valve, as described in the applications incorporated by reference above. Laser cutting of the leaflet material causes the cut edge to be sealed and lowers the risk of the cut edge having the potential for tearing or ripping during use.       

     The methods and systems of the present invention, as described above and shown in the drawings, provide for flow regulating devices with superior properties including fatigue resistance, biocompatibility, and ease of manufacture. While the apparatus and methods of the subject invention have been shown and described with reference to preferred embodiments, those skilled in the art will readily appreciate that changes and/or modifications may be made thereto without departing from the spirit and scope of the subject invention.