Abstract P1140: Scaling Up Engineered Cardiac Tissue For Clinical Translation As A Regenerative Therapy

• Published in: Circulation research Vol. 131; no. Suppl_1; p. AP1140
• Main Authors: Dwyer, Kiera, Kant, Rajeev, Coulombe, Kareen L
• Format: Journal Article
• Language: English
• Published: Lippincott Williams & Wilkins 05-08-2022
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/res.131.suppl_1.P1140

Advances in cardiovascular interventions have significantly decreased mortality due to acute myocardial infarction (MI). However, heart failure (HF) as a main sequela remains a major and devastating health burden. Globally, ~13 million people suffer from HF with systolic dysfunction and have no clinically available treatment to remuscularize their failing heart. Regenerative therapies using cardiomyocytes derived from embryonic or human-induced pluripotent stem cells (hiPSC-CMs) have emerged in large animal models and clinical trials to stabilize cardiac function post MI. Delivery of CMs through epicardially-implanted engineered cardiac tissues (ECTs) is advantageous as increased CM maturity, improved engraftment and increased mechanical support of the cardiac wall have been reported as compared to intramuscular CM injection. To date, however, the lack of rigorous studies exploring ECTs scaled to clinically relevant size (>3x3cm) poses an immense hurdle to their use in clinical trials. To this end, we are focused on understanding how such ECT scale up impacts the electromechanical function of the tissue. Our work details the differentiation and proliferative expansion of hiPSC-CMs to achieve the quantity and quality of hiPSC-CMs required for clinically scaled ECTs. We fabricate ECTs by mixing hiPSC-CMs with 5% human cardiac fibroblasts in a collagen-1 hydrogel with electromechanical function assessed through optical mapping of action potential and tensile mechanical testing. We report compromised electromechanical function and structural organization of ECTs with scale up, which is ameliorated by maturation of hiPSC-CMs using drug and metabolic interventions. Because larger animals will require higher CM density in implants, we evaluated the impact of CM density on ECT formation and function. Increasing CM density (30x106 vs 5x106 hiPSC-CMs/mL) decreased ECT compaction by 70% while increasing active force generation by 5.5-fold and contractile upstroke velocity by 4.3-fold. In conclusion, we have identified the design space for fabricating ECT of clinically relevant size. By understanding the space and its functional impact, this work supports the translational feasibility of ECTs as a regenerative treatment for the failing heart.