A Tri-Culture Heart-on-a-Chip Platform With iPSC-Derived Cardiac Cells for Predictive Cardiotoxicity Testing

Area of Science:

• Biomedical Engineering
• Cardiovascular Research
• Drug Discovery

Background:

• High attrition rates in drug development, particularly due to cardiotoxicity, significantly increase R&D costs and timelines.
• Current preclinical models often lack the physiological complexity, especially the vascular system, needed to accurately predict in vivo drug responses.
• The vascular component is crucial for understanding drug distribution and its impact on cardiac health.

Purpose of the Study:

• To develop and validate a physiologically relevant heart-on-a-chip (HoC) platform for improved cardiotoxicity assessment.
• To integrate key cardiac cell types, including endothelial cells, to better mimic the native cardiac microenvironment.
• To evaluate the platform's ability to predict drug-induced cardiotoxicity more accurately than conventional models.

Main Methods:

• Developed a heart-on-a-chip (HoC) platform using a tri-culture system of human induced pluripotent stem cell (iPSC)-derived cardiomyocytes, cardiac fibroblasts, and endothelial cells from a single genetic source.
• Maintained cell viability (>90%) and functional maturity under perfusion for 7 days.
• Assessed functional maturity via chronotropic responses to isoproterenol and evaluated cardiotoxicity using doxorubicin.

Main Results:

• The tri-culture HoC system demonstrated sustained cell viability and functional maturity, responding appropriately to pharmacological stimuli.
• The inclusion of endothelial cells in the HoC platform significantly mitigated doxorubicin-induced cardiotoxicity.
• This protective effect, absent in conventional models, underscores the importance of the vascular component in replicating in vivo drug responses.

Conclusions:

• The developed heart-on-a-chip platform offers enhanced physiological relevance by incorporating endothelial cells, crucial for accurate cardiotoxicity assessment.
• This scalable platform represents a transformative tool for improving preclinical drug safety evaluation and potentially reducing animal testing.
• The findings highlight the critical role of vascular integration in predicting drug-induced cardiac adverse events.