Current Challenges in Translating Tissue-Engineered Heart Valves

Heart valve disease is a major health burden. The disease encompasses various defects of one or more of the four heart valves that, when in a severe state, can hamper proper blood flow through the heart. In the adult, the mitral valve and the aortic valve are the most commonly affected, with the main defects of the valves being either stenosis (incomplete opening) or regurgitation (incomplete closing). There are multiple causes of heart valve disease, with the most prevalent causes being bacterially induced acute rheumatoid fever (predominantly in lower-income countries) to age-related degeneration of the aortic and mitral valve (predominantly in higher-income countries) [ 1 ]. The main current therapeutic options are valve replacement or valve repair, with valve repair being an increasingly preferred therapy for mitral valve regurgitation [ 2 ]. Valves can be replaced by a mechanical valve or a bioprosthetic allograft (porcine) valve, or, in rare cases, a homograft (donor) valve. This replacement procedure is performed nearly 300,000 times globally each year [ 3 ]. Valve replacements are lifesaving, but not without complications: mechanical valves require lifelong anticoagulation, whereas allografts can undergo calcification or mechanical failure. This can result in a 50% structural valve degeneration rate within 10 years [ 4 ]. In addition, both the mechanical replacement, the allograft, and the homograft have no capacity for growth, a major problem in the pediatric population suffering from congenital heart valve disease. To address this issue, the tissue-engineered heart valve (TEHV) has been under investigation for over 30 years as an alternative replacement therapy, starting with in vitro endothelialization of biological valves [ 5 ]. Initial trileaflet TEHV consisting of autologous cells seeded in vitro on a preshaped biodegradable scaffold to form a non-immunogenic heart valve graft mimicking the native valve with a capacity to grow maintained functional up to 20 weeks [ 6 ]. In the development of TEHV, there has been much attention to the load-bearing function, extracellular matrix (ECM) formation, remodeling, and cellular behavior of TEHVs, all on a macroscopic scale of the tissue. This allowed the TEHVs to be improved for materials used, scaffold design, cells used for seeding, and culturing conditions, to obtain the most robust valve for implantation [ 7 ].