Founder's Award, 25th Annual Meeting of the Society for Biomaterials, perspectives. Providence, RI, April 28-May 2, 1999. Tissue heart valves: current challenges and future research perspectives.

Substitute heart valves composed of human or animal tissues have been used since the early 1960s, when aortic valves obtained fresh from human cadavers were transplanted to other individuals as allografts. Today, tissue valves are used in 40% or more of valve replacements worldwide, predominantly as stented porcine aortic valves (PAV) and bovine pericardial valves (BPV) preserved by glutaraldehyde (GLUT) (collectively termed bioprostheses). The principal disadvantage of tissue valves is progressive calcific and noncalcific deterioration, limiting durability. Native heart valves (typified by the aortic valve) are cellular and layered, with regional specializations of the extracellular matrix (ECM). These elements facilitate marked repetitive changes in shape and dimension throughout the cardiac cycle, effective stress transfer to the adjacent aortic wall, and ongoing repair of injury incurred during normal function. Although GLUT bioprostheses mimic natural aortic valve structure (a) their cells are nonviable and thereby incapable of normal turnover or remodeling ECM proteins; (b) their cuspal microstructure is locked into a configuration which is at best characteristic of one phase of the cardiac cycle (usually diastole); and (c) their mechanical properties are markedly different from those of natural aortic valve cusps. Consequently, tissue valves suffer a high rate of progressive and age-dependent structural valve deterioration resulting in stenosis or regurgitation (>50% of PAV overall fail within 10-15 years; the failure rate is nearly 100% in 5 years in those <35 years old but only 10% in 10 years in those >65). Two distinct processes-intrinsic calcification and noncalcific degradation of the ECM-account for structural valve deterioration. Calcification is a direct consequence of the inability of the nonviable cells of the GLUT-preserved tissue to maintain normally low intracellular calcium. Consequently, nucleation of calcium-phosphate crystals occurs at the phospholipid-rich membranes and their remnants. Collagen and elastin also calcify. Tissue valve mineralization has complex host, implant, and mechanical determinants. Noncalcific degradation in the absence of physiological repair mechanisms of the valvular structural matrix is increasingly being appreciated as a critical yet independent mechanism of valve deterioration. These degradation mechanisms are largely rationalized on the basis of the changes to natural valves when they are fabricated into a tissue valve (mentioned above), and the subsequent interactions with the physiologic environment that are induced following implantation. The "Holy Grail" is a nonobstructive, nonthrombogenic tissue valve which will last the lifetime of the patient (and potentially grow in maturing recipients). There is considerable activity in basic research, industrial development, and clinical investigation to improve tissue valves. Particularly exciting in concept, yet early in practice is tissue engineering, a technique in which an anatomically appropriate construct containing cells seeded on a resorbable scaffold is fabricated in vitro, then implanted. Remodeling in vivo, stimulated and guided by appropriate biological signals incorporated into the construct, is intended to recapitulate normal functional architecture.