Scaffold-based and scaffold-free cardiac constructs for drug testing

The safety and therapeutic efficacy of new drugs are tested in experimental animals. However, besides being a laborious, costly process, differences in drug responses between humans and other animals and potential cardiac adverse effects lead to the discontinued development of new drugs. Thus, alternative approaches to animal tests are needed. Cardiotoxicity and responses of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to drugs are conventionally evaluated by cell seeding and two-dimensional (2D) culture, which allows measurements of field potential duration and the action potentials of CMs using multielectrode arrays. However, 2D-cultured hiPSC-CMs lack 3D spatial adhesion, and have fewer intercellular and extracellular matrix interactions, as well as different contractile behavior from CMs in vivo. This issue has been addressed using tissue engineering to fabricate three-dimensional (3D) cardiac constructs from hiPSC-CMs cultured in vitro. Tissue engineering can be categorized as scaffold-based and scaffold-free. In scaffold-based tissue engineering, collagen and fibrin gel scaffolds comprise a 3D culture environment in which seeded cells exhibit cardiac-specific functions and drug responses, whereas 3D cardiac constructs fabricated by tissue engineering without a scaffold have high cell density and form intercellular interactions. This review summarizes the characteristics of scaffold-based and scaffold-free cardiac tissue engineering and discusses the applications of fabricated cardiac constructs to drug screening.