Advanced tissue-engineered pulsatile conduit using human induced pluripotent stem cell-derived cardiomyocytes

Abstract

Single ventricle congenital heart defects (SVCHDs) are life-threatening defects that can lead to severe circulation issues and increased stress on the heart. Without prompt treatment, these defects can prove fatal in infancy. Fontan surgery is a conventional treatment for SVCHDs, which reroutes oxygen-poor blood directly to the lungs, bypassing the non-functioning ventricle. This procedure, however, can lead to circulation inefficiencies due to the absence of a natural, functional ventricle to pump blood to the pulmonary circulation. To address this issue, our team previously developed a tissue-engineered pulsatile conduit (TEPC) by wrapping engineered heart tissues (EHTs) derived from human induced pluripotent stem cell-derived cardiomyocytes (hiPSCCMs) around decellularized human umbilical artery (dHUA). This conduit has demonstrated the ability to produce a luminal pressure of 0.68 mmHg from spontaneous beating, which under 2 Hz electrical stimulation, increases to 0.83 mmHg. This offers a promising modular TEPC design that has the potential to provide active pumping function to the pulmonary circulation. We have since significantly optimized our approach by providing the conduit with electrical pacing training and an additional layer of EHT. These two enhancements have achieved markedly greater contractile productivity, where the spontaneous pressure generation reached 0.96 mmHg and the stimulated luminal pressure generation attained 1.87 mmHg with 2 Hz pacing. Our studies thus underscore the effectiveness of these TEPC design modifications, marking significant progress in the ongoing effort to improve treatments for patients with SVCHDs. STATEMENT OF SIGNIFICANCE: Single ventricle congenital heart defects (SVCHDs) are a life-threatening disorder, leading to severe circulation issues and heart failure. The Fontan procedure reroutes blood to the lung but lacks active pumping required for efficient circulation, often causing long-term complications. To address this challenge, we developed a tissue-engineered pulsatile conduit (TEPC) using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and decellularized human umbilical artery (dHUA) scaffolds. Our optimized design, with electrical pacing and enhanced engineered heart tissue (EHT) approaches, significantly increased luminal pressure development (up to 1.87 mmHg at 2 Hz frequency), offering a promising solution to improve outcomes for SVCHD patients.

Keywords: Cardiomyocytes; Engineered heart tissue; Human induced pluripotent stem cells; Tissue-engineered pulsatile conduit.