3D Human Heart Microtissues for Arrhythmia Risk Screening
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Solution Overview
Problem
Current cardiotoxicity testing methods, including in silico, in vitro, and animal models, are inadequate in predicting human responses to chemical compounds, leading to high drug-induced cardiotoxicity rates and unnecessary drug withdrawals due to false positives in HERG assays, and lack the ability to accurately assess arrhythmogenic risk.
Innovation Solution
A three-dimensional human heart engineered tissue model (TEEM) using human pluripotent stem cell-derived cardiomyocytes and cardiac fibroblasts for quantifying dose-dependent changes in electromechanical function, metabolic activity, and cellular structure, enabling high-resolution signal extraction and automated quantification of cardiotoxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If traditional in silico, in vitro, and animal models are used for cardiotoxicity testing, then testing can be performed with existing methods, but prediction accuracy of human responses is inadequate leading to high false positive rates
Solution Approach 1:
The patent transitions from traditional two-dimensional cell culture models to three-dimensional engineered heart tissue models. This dimensional change enables more physiologically relevant cardiac tissue architecture, improved cell-cell interactions, and better prediction of human cardiac responses to chemical compounds, thereby reducing false positives while maintaining testing feasibility
Solution Approach 2:
The patent creates composite engineered heart tissue by combining human induced pluripotent stem cell-derived cardiomyocytes with extracellular matrix components and supporting cell types. This composite structure mimics native heart tissue more accurately than single-cell-type cultures, improving prediction accuracy of cardiotoxicity while maintaining reliability
2Measurement precision
If three-dimensional engineered heart tissue models are used, then prediction accuracy and human response assessment improve, but device complexity and manufacturing difficulty increase
Solution Approach 1:
The patent performs preliminary differentiation of human induced pluripotent stem cells into cardiomyocytes before assembling the three-dimensional tissue structure. This pre-differentiation step simplifies the overall tissue engineering process by preparing cells in advance with the desired phenotype, reducing on-site complexity while maintaining high assessment accuracy
Solution Approach 2:
The patent utilizes the self-organizing and self-assembling properties of cardiomyocytes to form functional three-dimensional tissue structures. The cells naturally organize into syncytia with proper electrical coupling when provided with appropriate scaffolding, reducing the need for complex external control mechanisms and simplifying device design
Data Source
AI summary
The Cardio-Tox Tissue Engineered Model (TEEM) invention provides a robust in vitro model for cardiotoxicity evaluation using three-dimensional (3D) human heart microtissues to quantify dose-dependent changes in electromechanical activity, resulting in a comprehensive cardiotoxicity and arrhythmia risk assessment of test compounds. The invention also provides a predictive in vitro screening platform for pro-arrhythmic toxicity testing using human three-dimensional cardiac microtissues. The invention enables the screening of environmental and pharmaceutical compounds, chemicals, and toxicants to establish safe human exposure levels.