Patent Publication Number: US-2006008497-A1

Title: Implantable apparatus having improved biocompatibility and process of making the same

Description:
TECHNICAL FIELD  
      The present invention relates to an implantable apparatus and more particularly to an implantable apparatus having improved biocompatibility and to a process of making an implantable apparatus to improve its biocompatibility.  
     BACKGROUND  
      Surgically implantable prostheses are widely used today to help patients affected by a variety of conditions including congenital, degenerative and traumatic afflictions of various body parts including, for example joints, blood vessels, heart valves and spinal tissue. The satisfactory performance of these prostheses can be affected by the level of biocompatibility with the body.  
      Biocompatibility is defined as the ability of a material to interface with a natural substance without provoking a biological response. In the human body, the typical response to contact with a synthetic material is the deposition of proteins and cells from body fluids on the surface of the material. The human body tolerates plastics such as PVC, polycarbonate, polyurethane and the like, for a short period of time but these materials are not considered biocompatible for long term usage.  
      The blood interfaces with a large surface area of the synthetic material and the initial reaction is the adsorption of a layer of protein onto these surfaces. The surface protein adsorption occurs in a short time (e.g., in minutes) and is triggered by chemical and physical phenomena related to surface features of the material and of the surrounding medium in contact with it, such as blood. The nature and quantity of this layer depends on the surface features and the composition of the blood.  
      Subsequently, activation of the blood and the formation of clots can set in, which may ultimately lead to thrombotic embolisation of body vessels. At present, blood coagulation is prevented or controlled by administering systemic anticoagulants, such as heparin. However, on going efforts focus on improving biocompatibility of implantable prostheses to minimize surface protein adsorption and thwart thrombus formation.  
     SUMMARY  
      One aspect of the invention provides an implantable apparatus which has a plurality of fixed and detoxified protein layers formed in situ overlying at least one surface of the implantable apparatus.  
      Another aspect of the present invention provides a process of making the implantable apparatus. At least one surface of the implantable apparatus is repeatedly exposed to a protein solution to form a multi-layered coating of protein. Each of the layers of protein is fixed with a fixation solution. The multi-layered protein coating undergoes a detoxification process, such as including heparin bonding.  
      Yet another aspect of the present invention provides a method for improving biocompatibility of an implantable article. At least one surface of the implantable article is exposed to a protein solution so that the protein adheres to form a protein layer on the at least one surface. The protein layered implantable device is cross-linked with a fixation solution, and the implantable article is substantially detoxified and to help resist formation of thrombus on the implantable article.  
      Still yet another aspect of the invention provides a prosthetic device with at least one layer of a fixed and detoxified protein adhering to the surface made by a process of exposing the surface to a protein solution to form a layer of protein and fixing the protein layer by exposing the protein layer to a fixation solution and detoxifying the fixed protein layer. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
      To the accomplishment of the foregoing and related ends, certain illustrative aspects of the invention are described herein in connection with the following description and the annexed drawings. These aspects are indicative, however, of but a few of the various ways in which the principles of the invention may be employed and the present invention is intended to include all such aspects and their equivalents. Other advantages and novel features of the invention will become apparent from the following detailed description of the invention when considered in conjunction with the drawings in which:  
       FIGS. 1-3  illustrate a process of making an implantable apparatus according to the invention.  
       FIG. 4  illustrates an isometric view of an apparatus according to an embodiment of the invention.  
       FIG. 5  illustrates a cross-sectional view of another embodiment of the apparatus according to the invention.  
       FIG. 6  illustrates a cross-sectional view of yet another embodiment of the apparatus according to the invention.  
       FIG. 7  is a flow diagram illustrating a process of making the implantable apparatus of the present invention. 
    
    
     DETAILED DESCRIPTION  
      Various illustrative aspects of the present invention will now be described in connection with the following figures.  
      The present invention provides a process to provide an implantable apparatus  10 , with one or more layers  12  of a fixed and detoxified protein so as to improve its biocompatibility when implanted into the human body.  
      While  FIG. 4  illustrates a schematic generic representation of an implantable apparatus  10  according to the present invention, such as a prosthesis, two specific exemplary embodiments are illustrated in  FIG. 5  (a stent), and in  FIG. 6  (a vascular graft).  
      Those skilled in the art will understand and appreciate that other specific examples of implantable apparatuses or prostheses may also be formed in accordance with the present invention, including, but not limited to surgical implants, and any artificial part or device which replaces or augments a part of a living body or comes into contact with bodily fluids, particularly blood. The substrates can be in any shape or form including tubular sheet, rod and articles of proper shape.  
      Various examples usable in accordance with the invention are known in the art. Examples include catheters, suture material, tubing, fiber membranes, bone growth stimulators, bone screws, grafts, implantable pumps, impotence and incontinence implants, intra-ocular lenses, nasal buttons, cranial implants such as cranial buttons and cranial caps, orbital implants, cardiac insulation pads, cardiac jackets, embolic devices, fracture fixation devices such as screws, nasal petal splints, nasal tampons, ophthalmic devices, periodontal fiber adhesives, staples, stomach ports, urethra stents, vaginal contraceptives, valves, vessel loops, annuloplasty rings, aortic/coronary locators, artificial pancreas, cosmetic or reconstructive surgery implants such as breast implants and facial implants, cardiac materials, such as fabric, felts, mesh, patches, cement spacers, cochlear implants, orthopedic implants, pacemakers, pacemaker leads, guide wires, patellar buttons, penile implant, prosthetic heart valves, coronary stents, vascular stents, sheeting shunts, valved conduits, joint and bone replacements such as hip bone and knee joint replacements, and spinal implants such as bone screws and inter-vertebral implants.  
      Turning now to  FIGS. 1-3 , a process for improving the biocompatibility of the implantable apparatus  10  is illustrated. The implantable apparatus  10  may be formed from a substrate  12  of a surgically useful textile material such as DACRON, polyethylene (PE) polyethylene tetraphthalate (PET), silk, Rayon, or the like or may also be formed of a surgically-useful polymeric material such as urethane, polytetrafluoroethylene (PTFE) or expanded polytetrafluoroethylene (ePTFE), or may be formed of a biological biocompatible material, such as animal pericardium (equine, bovine, porcine, etc.) or a collagen material (e.g., a remodeled collagen or fibrin biomatrix) or a surgically-useful metal such as titanium/titanium alloys, TiNi (shape memory/superelastic), aluminum oxide, platinum/platinum alloys, stainless steels. Substrates made using these materials may be coated or uncoated with a layer of a material prior to undergoing the process of  FIGS. 1-3 . For example, the substrate  12  can be covered with layer of a material that provides at least a portion of an outer exposed surface of the substrate, such as a polymeric material layer or a biological material layer (e.g., formed of remodeled biomatrix, such as collagen or fibrin, or animal pericardium).  
      The process of  FIGS. 1-3  can be conducted in an ambient temperature environment, such as in a range from about 25 to about 37° C. or another other suitable temperature. The process is schematically represented in  FIGS. 1-3  to include exposing the implantable apparatus  10  to a layer of a plasma protein solution  16  ( FIG. 1 ) in a container  24  by (e.g., immersing in or flushing with) the solution for a predetermined time (e.g., 30 seconds to 2 hours). The plasma protein solution  16  may contain albumin, fibrinogen or any suitable animal plasma protein. The plasma protein solution may also contain other biomolecules such as antibacterial and antimicrobial agents; anti-inflammatories; enzymes; catalysts; hormones; growth factors; drugs; vitamins; antibodies; antigens; nucleic acids; DNA and RNA segments and proteins and peptides. The biomolecules can be synthetically derived or naturally occurring.  
      The protein coated apparatus  10  is then exposed to a fixation solution  18  in container  26  (e.g., by immersing or flushing with the solution  18 ) to fix the layer of plasma protein  14  relative to the substrate surface  12  of the apparatus  10  ( FIG. 2 ). The fixation solution  18  may be an aldehyde solution, such as including glutaraldehyde and/or formaldehyde, such as at a solution concentration ranging from about 0.2% to about 1.0% aldehyde. The fixation process of  FIG. 2  results in cross linking of the protein layer(s) of the apparatus  10  by binding of amine groups of the protein. Those skilled in the art will understand and appreciate suitable time periods and other fixation solutions that can be utilized according to an aspect of the present invention.  
      If multiple protein layers are desired, for a greater thickness, the process of soaking the apparatus  10  in the plasma protein solution  16  ( FIG. 1 ) and fixing the plasma protein  14  to the substrate surface  12  of the apparatus  10  is repeated a desired number of times until the desired thickness is reached. Alternatively or additionally, the time period for immersion in the protein solution  16  can be increased to increase the thickness of the protein layer(s).  
      After a desired thickness of the protein layer(s) has been formed on the substrate surface  12 , the apparatus  10  undergoes a detoxification process, which is schematically illustrated at  FIG. 3 . As an example, the detoxification process can include exposing the cross-linked fixed protein layer  14  to antithrombotic materials, such as a solution  20  that contains heparin or another antithrombotic solution, to inhibit the coagulation of blood by interacting with thrombin to inhibit the conversion of fibrinogen to fibrin. The detoxification renders the resulting protein layer  14  durable, non-absorbable and resistant to infection. This detoxification treatment is schematically represented in  FIG. 3  by exposing the fixed protein layer  14  on the substrate  12  of the apparatus  10  to a heparin solution  20  in container  28 , such as including immersing in or flushing with the heparin solution  20 .  
      By way of example, the detoxification process can include the detoxification and heparin bonding, which is commercially available from Shelhigh, Inc., of Union, N.J., namely, the NO-REACT® process that is utilized to provide the NO-REACT® line of implantable tissue products. The detoxification further can promote covering of the substrate with endothelial cells (e.g., a thin layer of one or more cells) after the implanted apparatus has been exposed to blood.  
      Alternatively, prior to implanting the apparatus  10 , the exposed surface (or at least the surface(s) that is to contact blood) can be seeded with a patient&#39;s own endothelial cells, as is known in the art, to promote endothelial growth. For example, endothelial cells can be extracted from a vein or other anatomic structure of the patient. The extracted endothelial cells can be cultured and grown. The cultured cells then can be seeded onto the surface of the apparatus, such as the surface portions that are to come into direct contact with blood after being implanted.  
      Turning now to  FIG. 4 , a schematic cross-sectional representation of an implantable apparatus  10  is illustrated. The implantable apparatus  10  includes at least one plasma protein layer  14  which has been fixed and substantially detoxified to improve biocompatibility, such as according to the process illustrated in  FIGS. 1-3 .  
      While the representation of  FIG. 4  appears as a single layer, it will be appreciated that the protein layer  14  covering the surface of the apparatus  10  is intended to schematically illustrate any number of one or more protein layers  14  overlying the substrate surface  12  of the apparatus  10 . That is, the apparatus  10  can include a plurality of protein layers or only a single protein layer to provide the apparatus  10  with a desired thickness.  
      The protein layer  14  can cover all of the visible surfaces of the apparatus  10 . It should be understood however that under certain circumstances, it may be desirable to cover less than all of the visible surfaces of the apparatus  10  so that the surface is only partially covered with the protein layer  14 .  
       FIG. 5  illustrates a cross-sectional view of a stent  100  according to an alternative embodiment of the invention. The particular type of stent  100  shown in  FIG. 5  is for a heart valve, although the process is equally applicable to other types of stents, including, for example, coronary stents and vascular stents. The stent  100  is typically formed of a substrate of a resilient material such as plastic or metal. The stent  100  can be covered with a layer  102  of a biocompatible material, such as a textile material (e.g., a DACRON cloth) or with a biological material (e.g., remodeled collagen, remodeled fibrin, a cross-linked collagen gel, animal pericardium, dura matter, and the like).  
      The stent  100  includes one or more layers  114  of protein, which have been formed in-situ over an outer surface thereof. In the example of  FIG. 5 , the layer(s)  114  are formed overlying the surface of the exposed outer layer  102  of the stent  100 . That is, the protein layer(s)  114  adhere to the layer  102  that covers the stent  100 , such as by exposing the exposed surfaces of the stent to a plasma protein solution, fixing the protein layer(s) and then detoxifying the fixed protein layer(s) (e.g., according to the process of  FIGS. 1-3 ). The entire exposed surface may be covered with covered with the protein layer  114  or alternatively, only a selected portion of the surface of the stent  100  may be covered. Additionally, those skilled in the art will understand and appreciate that the exposed surfaces of the stent can include the layer  102  as well as exposed surface portions of the underlying substrate (e.g., a metal or plastic material), such as when the layer  102  does not cover the entire stent  102 .  
       FIG. 6  illustrates a partial cross-sectional view of a vascular graft  150  according to another alternative embodiment of the present invention. While a partial sectional view is shown in  FIG. 6 , those skilled in the art will appreciate that the graft  150  typically will be implemented a complete generally cylindrical member for fluidly connecting two spaces via the graft. The vascular graft  150  thus can be employed to replace a missing or degenerative blood vessel, for example. The vascular graft  150  typically includes a tubular substrate  152  of a substantially flexible material having a desired diameter and length. As an example, the material of the substrate  152  can be formed of natural or synthetic materials, such as a cloth-like material (e.g., a plastic (PTFE), DACRON or TEFLON). The substrate material can be generally porous, such that, absent processing according to an aspect of the present invention, the structure would not be sufficiently fluid-tight for use as a graft. The substrate  152  can be dimensioned and configured to provide any desired shape or length of graft  150 . For instance, in the example of  FIG. 6 , the graft  150  includes a curved portion  154  extending arcuately from an elongated generally straight portion  156 .  
      The vascular graft  150  includes a layer  158  of a cross-liked and detoxified protein overlying its interior and exterior surfaces  152 . The protein layer  158  may include any number of one or a plurality of fixed and detoxified protein layers, such as can be formed by the process shown and described with respect to  FIGS. 1-3 . Alternatively, only a portion of an interior or exterior surface of the substrate  152  may be covered by the one or more layers  158 .  
       FIG. 7  illustrates a flow diagram of a process  200  that can be employed to improve biocompatibility of an implantable apparatus. The process  200  may be automated (e.g., implemented using a conveyor belt type machine in a sterile environment). Alternatively, the process can be implemented by one or more technicians, manually and/or as part of an automated process.  
      The process  200  begins at  210 , which can include providing one or more implantable apparatuses that are to be treated to improve biocompatibility according to an aspect of the present invention. The apparatus being treated defines a substrate for the process and includes one or more exposed surfaces. The exposed surfaces can include a surface layer of a biocompatible material, such as a fabric material (e.g., DACRON) or a biological material (e.g., a remodeled biomatrix or pericardium), such as described herein.  
      At  220 , the apparatus is exposed to a plasma protein solution. During exposure to the plasma protein, a layer of protein adheres to the exposed one or more surfaces. The thickness of the layer formed at  220  generally will depend on, for example, the length of exposure time and the concentration of the protein in the solution. As described herein, the protein in the solution can include a combination of one or more animal proteins, such as albumin, fibrinogen or other plasma protein.  
      At  230 , the layer of protein adhering to one or more surfaces is fixed. For example, the protein layer can be fixed by cross-linking the layer in a fixation solution, such as an aldehyde solution (e.g., glutaraldehyde or formaldehyde).  
      At  240 , a determination is made as to whether a desired thickness of protein layer has reached a desired thickness. If the determination is made that the thickness of the protein layer has not reached a desired thickness, to process can return to  220  for repeating the exposure at  220  and fixation at  230 . The process exposure and fixation can be repeated until the desired thickness is reached.  
      If the determination is made that the thickness has reached the desired thickness, the one or more fixed protein layers of the apparatus is substantially detoxified at  250 . The detoxification can include heparin bonding of the fixed layer(s) of the apparatus. As one example, the detoxification can include heparin boding according to the NO-REACT® tissue treatment process, which is commercially available from Shelhigh, Inc., of Union, N.J. The process terminates at  260  after the apparatus has been detoxified.  
      From the above description of the invention, those skilled in the art will perceive improvements, changes and modifications. Such improvements, changes and modifications within the skill of the art are intended to be covered by the appended claims.