4D Thermo-Responsive Smart hiPSC-CM Cardiac Construct for Myocardial Cell Therapy

PURPOSE: 4D fabrication techniques have been utilized for advanced biomedical therapeutics due to their ability to create dynamic constructs that can transform into desired shapes on demand. The internal structure of the human cardiovascular system is complex, where the contracting heart has a highly curved surface that changes shape with the heart’s dynamic beating motion. Hence, 4D architectures that adjust their shapes as required are a good candidate to readily deliver cardiac cells into the damaged heart and/or to serve as self-morphing tissue scaffolds/patches for healing cardiac diseases. In this proof-of-concept in vitro study, a two-in-one 4D smart cardiac construct that integrates the functions of minimally invasive cell vehicles and in situ tissue patches was developed for repairing damaged myocardial tissue. METHODS: For this purpose, a series of thermo-responsive 4D structures with different shapes and sizes were fabricated via the combination of fused deposition modeling (FDM)-printing and stamping molding. The thermo-responsive 4D constructs were firstly optimized to exhibit their shape transformation behavior at the designated temperature for convenient control. After which, the mechanical properties, shape recovery rate, and shape recovery speed of the 4D constructs at different temperatures were thoroughly evaluated. Also, the proliferation and functional prototype of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) on the 4D constructs were quantified and evaluated using F-actin staining and immunostaining. RESULTS: Our results showed that the 4D constructs possessed the desirable capability of shape-changing from spherical carriers to unfolded patches at human body temperature and exhibited excellent biocompatibility. Moreover, myocardial maturation in vitro with a uniform and printing pattern-specific cell distribution was observed on the surface of the unfolded 4D constructs. CONCLUSION: We successfully developed a 4D smart cardiac construct that integrates the functions of minimally invasive cell vehicles and in situ tissue patches for repairing damaged myocardial tissue.