402–442 (c) and (d) reproduced by permission from Schoen FJ. “Valvular heart disease: General principles and stenosis,” IN: Cardiovascular Pathology, 3rd Ed, Silver MD, Gotlieb AI, Schoen FJ (eds.), WB Saunders 2001, pp. (a) and (b) reproduced by permission from Schoen FJ. (d) Schematic depiction of layered aortic valve cuspal structure and configuration of collagen and elastin during systole and diastole. (c) Biomechanical cooperativity between elastin and collagen during valve motion. (b) Aortic valve histology emphasizing trilaminar structure and presence of valvular interstitial and endothelial cells. (a) Photograph of the aortic valve in open and closed position (from the aorta). Specialized ECM enables dynamic aortic valve function. Only autografts (such as Ross valves transplanted from the pulmonary-to-aortic position in an individual) presently are viable, 120 but the Ross procedure is technically difficult, risky, only serves a small patient subset, and has controversial results, including uncertainty over whether the grafts will grow commensurate with recipient growth. 35, 68 Most exciting is the possibility of growth, repair, and remodeling as a child recipient matures, thus eliminating the repetitive surgeries typically necessitated by the inability of a valve substitute to enlarge as an individual grows. The most immediate need for heart valve tissue engineering and regeneration technology is in the pediatric and young adult population in which the results of valve replacement are not as favorable as those in older adults. The design criteria and characteristics for conventional and tissue engineered replacement heart valves are summarized and compared in Table Table1. 50, 64, 146Īdvantages of an engineered tissue heart valve would likely include nonthrombogenicity, infection resistance, and cellular viability. 127 Nevertheless, each of these valve types has its limitations-in particular, mechanical valves require anticoagulation to control thromboembolism, while bioprosthetic and allograft valves frequently undergo calcification and structural deterioration. 14, 119, 122, 176 This review focuses on the application of tissue engineering technology to heart valves.Ĭurrently, adults who undergo replacement of diseased valves by either mechanical prosthetic or tissue valves (including bioprosthetic valves, cadaveric allograft, or pulmonary-to-aortic autograft valves ) generally have enhanced survival and quality of life. Cardiovascular tissue engineering has primarily considered blood vessels, 58, 102, 103, 104, 114, 178 myocardium, 27, 36, 74, 80, 123 and heart valves. In each case, there are limitations to conventional surgical approaches and existing prosthetic devices, serious complications associated with transplantation, and critical shortages of available donor tissues. Potential applications of tissue engineering in regenerative medicine range from structural tissues (e.g., skin, cartilage, bone) to complex organs (e.g., heart and other components of the cardiovascular system, liver, kidney, pancreas). Although modest progress has been made toward the goal of a clinically useful tissue engineered heart valve, further success and ultimate human benefit will be dependent upon advances in biodegradable polymers and other scaffolds, cellular manipulation, strategies for rebuilding the extracellular matrix, and techniques to characterize and potentially non-invasively assess the speed and quality of tissue healing and remodeling. Lastly, we analyze challenges to the field and suggest future directions for both preclinical and translational (clinical) studies that will be needed to address key regulatory issues for safety and efficacy of the application of tissue engineering and regenerative approaches to heart valves. Following a discussion of the fundamental principles of tissue engineering applicable to heart valves, we examine three approaches to achieving the goal of an engineered tissue heart valve: (1) cell seeding of biodegradable synthetic scaffolds, (2) cell seeding of processed tissue scaffolds, and (3) in-vivo repopulation by circulating endogenous cells of implanted substrates without prior in-vitro cell seeding. To provide a framework for understanding the enabling scientific principles, we first examine the elements and features of normal heart valve functional structure, biomechanics, development, maturation, remodeling, and response to injury. We emphasize basic concepts, approaches and methods, progress made, and remaining challenges. This review focuses on the engineering of heart valve tissue, a goal which involves a unique combination of biological, engineering, and technological hurdles. Potential applications of tissue engineering in regenerative medicine range from structural tissues to organs with complex function.
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