Project Applications

Small Diameter Vascular Grafts, Endovascular Devices, and Blood-Contacting Artificial Organs

As we enter the 21st century, atherosclerosis remains a serious source of morbidity and death despite advances in preventive measures and pharmacological therapeutics. Nearly 700,000 vascular surgical procedures are performed annually in the United States along with several hundred thousand peripheral and coronary angioplasties. Prosthetic bypass grafts and, more recently, arterial stents and other endovascular prostheses have been utilized in association with these reconstructive procedures. Although large diameter vascular grafts (> 6 mm internal diameter) have been successfully developed from polymers such as polytetrafluoroethylene (PTFE) and polyethylene terephthalate, the fabrication of durable small diameter prostheses (< 6 mm internal diameter) remains unsolved. Furthermore, while prosthetic bypass grafting can be performed in the infrainguinal position with reasonable short-term success, within 5 years 30% to 60% of these grafts will fail. It is recognized that the adverse events leading to the failure of many vascular prostheses are related to maladaptive biological reactions at the blood-material and tissue-material interface. In response to these problems, and particularly thrombosis of the small caliber prosthesis, grafts and stents have been coated with albumin, heparin, or prostacyclin analogues, which inhibit the clotting cascade and platelet reactivity, or with relatively inert materials, such as polyethylene oxide. Despite promising early reports, these strategies have yet to produce a small diameter prosthesis with acceptable clinical performance characteristics. Opportunities at the interface of biology, biomolecular engineering, and materials science, as well as mechanical/chemical engineering offer new strategies to solve this challenge.

 

Artificial Heart Valves

On annual basis 250,000 heart valve replacements are performed in the United States equally divided between mechanical and bioprosthetic implants that are derived either from bovine pericardial tissue or porcine native valves. Although mechanical valves exhibit better durability than bioprosthetic valves, patients must remain anticoagulated for the remainder of their lives due to an increased risk of thrombosis and thromboembolism. Bioprosthetic heart valves do not require anticoagulation presumably due to superior hemocompatibility and improved hemodynamics associated with an unobstructed central flow pattern. Nevertheless, bioprosthetic valves often fail due to leaflet calcification and tearing. At least 20-30% of bioprostheses become dysfunctional within 10 years and more than 50% fail due to degeneration within 12 to 15 years after implantation. Both valve types have an inherent risk of infection, require major surgery for implantation, and often present abruptly with late failure as evident by a clinically deteriorating condition. Many of these limitations can be addressed by innovative strategies at the interface of biology, biomolecular and mechanical engineering, and materials science.

 

Atherosclerosis and Aneurysm Formation

Atherosclerosis, aneurysm formation, and diverse vascul ar wall injury responses, including postangioplasty restenosis and neointimal hyperplasia that follows arterial bypass grafting, are all initiated, orchestrated, or otherwise modulated by local inflammatory responses. F or example, the recruitment of monocytes into the arterial wall is considered a critical step in the earliest stages of atherosclerosis and mature plaques are particularly rich in activated immune cells. Restenosis following angioplasty and vascular bypass can also be considered an inflammatory-relate d process and a significant body of evidence suggests that an inflammatory cascade, which leads to cytokine-mediated stimulation of metalloproteinase expression, is an important contributing factor in aneurysm expansion. Numerous clinical and epidemiological reports, as well as fundamental molecular and cellular studies support the notion that both hypertension and increased levels of oxidized lipids are dominant and interactive factors that induce aneurysm formation by potentiating local inflammatory and proteolytic responses. However, the underlying molecular and cellular mechanisms that eventually lead to a pathologic endpoint as a consequence of these stimuli remain largely undefined. It has been recently recognized that cell surface heparan sulfates are important regulators of tissue repair and local inflammatory responses and their dysregulated expression may lead to a range of maladaptive responses that likely play a critical role in aneurysm formation and atherosclerosis. Opportunities at the interface of cell and molecular biology, as well as biomolecular and mechanical engineering offer new strategies to decipher the etiology of these processes.

 

Islet Transplantation

Whole organ pancreatic allografts using current immunosuppresive protocols have an expected graft survival as high as 86% at one year and 74% at 5 years after transplantation. Despite these encouraging results, the risk of major perioperative morbidity, the associated complications of chronic immunosuppresion therapy, and the persistent shortage of donor organ tissue remain limitations of this approach. As a consequence, pancreas transplantation continues to have a limited role in the management of diabetes. As an alternative approach, islet transplantation offers several important advantages over whole organ transplantation. First, islets can be maintained and manipulated more easily than whole organ grafts and may be harvested from donor grafts that otherwise would not be suitable for whole organ transplantation. Second, islet transplantation, in comparison to whole organ grafting, is associated with a considerable reduction in morbidity and mortality, a decrease in intensive care unit utilization, shorter hospital stays, with the promise of achieving major reductions in overall healthcare costs. Significant limitations remain in islet transplantation that can be addressed by innovative strategies at the interface of biology, bioengineering, and biomolecular engineering.