16 Chapter 1 many strategies have been invented to induce a mature phenotype of hiPSC-CMs. These strategies include 1) biochemical strategies such as; prolonged culture time; alterations in energy sources (Figure 3); hormones; cell-cell interactions/co-culturing; genetic manipulation and 2) biophysical strategies including extracellular matrices/substrate stiffness; biophysical stimulation; in vivo maturation; mechanical stretch and 3D cell culture have been described.46,47 These different maturation methods can improve the modeling of complex adult cardiac physiology and disease. Figure 3. Maturation of hiPSC-CMs by modulating the physiologically appropriate levels of glucose and albuminbound fatty acids. Created with BioRender.com 1.6 hiPSC-CM models Next to cardiomyocyte generation, expansion, and maturation developments, the human- induced pluripotent stem cell (hiPSC) technology has yielded patient-derived cardiomyocytes that exhibit some of the hallmarks of cardiovascular disease and are therefore being used to model disease states. Some of the technical challenges were solved, such as the scaled production of pure cardiomyocytes in a quality-controlled way and the long-term cryopreserved hiPSC-CM biobanks. The generated ‘more mature’ cardiomyocytes have been used to study physiological and disease states, screen for novel therapeutic targets, and generate heart tissue for pharmaceutical testing. However, with the unlimited production of hiPSC-CMs, challenges arise for the scalability, sensitivity, and costs of hiPSC-CM disease modeling and robotic functional screening platforms. Each technique has its strengths, such as scalability or sensitivity, and needs to be considered carefully or combined to develop a full phenotypic screening (Table 1). By combining the different hiPSC-CM models, a full phenotypic screening would make it possible to study physiological disease states or to screen pharmaceutical or novel therapeutic compounds.
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