Prosthesis (i.e. – artificial body members) – parts thereof – or ai – Arterial prosthesis – Drug delivery
Reexamination Certificate
2001-04-27
2004-02-10
Isabella, David J. (Department: 3738)
Prosthesis (i.e., artificial body members), parts thereof, or ai
Arterial prosthesis
Drug delivery
C623S023720, C606S036000
Reexamination Certificate
active
06689161
ABSTRACT:
TECHNICAL FIELD
The present invention relates to decellularized vascular prostheses that are resistant to thrombus occlusion and have a low level of immunogenicity. The vascular prostheses are denuded of cells, and coated with an anti-thrombogenic agent and a growth factor that promotes recellularization and further reduces the immunogenicity.
BACKGROUND OF THE INVENTION
Chronic venous insufficiency is a major health problem in the United States and throughout the world. More than 7 million people are afflicted and at least 500,000 develop leg ulcerations as a consequence. An estimated 900,000 new cases arise annually. Chronic venous insufficiency is a general term that encompasses all causes of chronic venous disease. It occurs in a primary form with stretched valves and dilated venous walls, and in a secondary form following thrombophlebitis, with scarred and deformed valves and thickened venous walls with longitudinal septa and seriously compromised lumens. Other causes of venous insufficiency, such as valve aplasia, congenital malformations and external obstruction occur less often.
The clinical symptoms associated with venous insufficiency range from severe pain and recurrent ulcerations to no manifest symptoms. The site of involvement appears to be critical to the severity of the symptoms. Thus, varicosity of the superficial venous system is usually benign and the incidence of significant complications is low. In contrast, insufficiency of the deep veins or of the perforating vessels is more frequently associated with pain, swelling, ulceration, and long-term disability.
The current basic treatments for venous insufficiency rely on the prevention of reflux and a reduction of venous pressure. Conservative treatments, however, including bed rest, limb elevation, mild diuretic administration, and elastic compression stockings are aimed at the relief of symptoms rather than the underlying disease process. They are not particularly successful.
Direct valvuloplasty may be accomplished by tightening redundant cusp edges, whereas indirect valvuloplasty employs a DACRON or polytetrafluoroethylene (PTFE) cuff around the valve. Despite noticeable gains in hemodynamic measurements, clinical improvement is frequently less evident. Venous valve repair and replacement are attempts to restore competence to the deep venous system. Venous valve repair, however, suffers from the limitation that it is only suitable for those patients without prior deep venous thrombosis. In the event that the valve apparatus has been significantly degraded or destroyed, valve transplantation may be the only available option to offer symptomatic relief and a fall in venous pressure.
The quantity and quality of donor valves remain significant problems. In the typical patient as many as 30% to 40% of brachial or axillary valves are incompetent. Additionally, many patients have dilated venous systems that will not accommodate a smaller-caliber brachial or axillary vein graft. Accordingly, valve transplantation suffers from considerable constraints in its use as a surgical technique.
Small caliber vascular grafts with inner diameters of less than 6 mm are used extensively in aorta-coronary artery and infrapopliteal artery bypasses for the treatment of arterial occlusive diseases, and as arterio-venous conduits for hemodialysis access in the end stage of renal disease. At present, autogenous saphenous veins continue to be the most widely used vascular prostheses for small caliber arterial reconstructive procedures. Primary patency at four years for an arterial bypass with saphenous veins is 40-70%. A practical impediment to constructing such bypasses, however, is the fact that 10 to 40% of patients do not have an acceptable saphenous vein that can be transplanted for a successful graft.
Previous harvesting of vascular tissue for use in cardiac or vascular surgical procedures, varicose vein stripping, and prior thrombophlebitis are the most common reasons for unsuccessful autogenous saphenous vein grafting. Alternative sources of small-caliber vascular prostheses, with a patency rate comparable to or better than that of the autogenous saphenous vein, are urgently needed for clinical use.
Venous allografts from cadavers have also been used. They provide reasonable function early in the life of the graft, but yield poor results after 2 years. Modern cryopreservation techniques, including controlled-rate freezing, storage at −190° C., and cryoprotectants such as dimethyl sulfoxide and chondroitin sulfate, improve the viability of cryopreserved allograft saphenous veins. Successful results using unmodified cryopreserved allograft saphenous veins for infrainguinal tibial artery reconstructions have achieved a one-year patency rate in the range of 10 to 50%. Long-term benefits to the patient have been marred, however, by vein graft rejection and unheralded early graft closure. Complications related to the mechanical failure of the conduit itself, such as graft aneurysms or ruptures, have occurred with greater frequency and caused greater morbidity, compared to fresh autogenous veins.
Synthetic DACRON and PTFE vascular prostheses have achieved some degree of clinical success even though they are not ideal in large and mid-sized arterial reconstructions. In addition, vessel substitutes smaller than 6 mm in diameter are susceptible to early graft occlusion. The most frequently encountered failures of synthetic grafts result from thrombosis and anastomotic hyperplasia. The inherent properties of synthetic graft materials, and their limited spontaneous re-endothelialization in humans, contribute to high surface thrombogenicity.
The implantation of glutaraldehyde-fixed bovine and human umbilical vein grafts was extensively evaluated and largely discarded because of high rates of aneurysm formation occurring two years after implantation. Most of these grafts failed because of delayed vascular healing and degenerative changes. An immune response to the highly immunogenic, chemically modified venous material, was characterized by invasion of multinucleated giant cells and reduced implant recellularization. Furthermore, glutaraldehyde fixation disturbed the natural matrix protein configuration. The cytotoxic effect of glutaraldehyde inhibited cell migration into the graft wall. Degeneration in the grafts resulted in a highly thrombogenic surface and the consequent occlusion of the vessels by thrombosis.
Many factors contribute to the degree of patency achieved with a particular prosthesis. These include the inherent properties of the chosen materials, surface thrombogenicity, compliance, and porosity in the case of textile grafts. The surface properties of materials seem to be a key issue in securing the desired long-term patency of small vessel substitutes. Numerous researchers have attempted to optimize the clinical efficacy of small diameter vascular grafts by modifying the prosthetic materials to make them biologically inert, but such an inert material has yet to be developed. An alternative approach to optimize the biological components of the prosthesis-tissue complex has led to the development of biohybrid materials. Some examples include synthetic material seeded with viable cells, coatings of biological compounds such as albumin and collagen, and materials synthesized from polymers known to elicit favorable biological responses. This approach has also not yielded a practical or effective vascular prosthesis.
In general, biological materials obtained from animals or humans have unique and special microstructural, mechanical, hemodynamical, and biochemical properties that cannot be completely replicated by currently available technology. Therefore, biologically-derived materials have great potential as raw materials for implantable artificial organs. The use of porcine organs for xenotransplantation is an attractive option to overcome the shortage of available organs for transplantation into humans. However, the problem of acute rejection remains an unsolved barrier. Cell surface molecules of xenogenic organs are ma
Chen Changyi
Lumsden Alan B.
Baylor College of Medicine
Chattopadhyay Urmi
Fulbright & Jaworski L.L.P.
Isabella David J.
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