Engineering the aortic valve extracellular matrix through stages of development, aging, and disease

For such a thin tissue, the aortic valve possesses an exquisitely complex, multi-layered extracellular matrix (ECM), and disruptions to this structure constitute one of the earliest hallmarks of fibrocalcific aortic valve disease (CAVD). The native valve structure provides a challenging target for engineers to mimic, but the development of advanced, ECM-based scaffolds may enable mechanistic and therapeutic discoveries that are not feasible in other culture or in vivo platforms. This review first discusses the ECM changes that occur during heart valve development, normal aging, onset of early-stage disease, and progression to late-stage disease. We then provide an overview of the bottom-up tissue engineering strategies that have been used to mimic the valvular ECM, and opportunities for advancement in these areas.