3D Human Heart Microtissues for Predictive Cardiotoxicity Screening
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Solution Overview
Problem
Current methods for cardiotoxicity testing, including animal models and two-dimensional cell-based assays, are inadequate in predicting human cardiotoxicity, leading to high false positives and negatives, and are not effective in identifying arrhythmogenic risks, resulting in unnecessary drug discontinuation and increased development costs.
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 to assess cardiotoxicity, with high-resolution detection and automated quantification.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If animal models and two-dimensional cell-based assays are used for cardiotoxicity testing, then testing can be performed, but the predictive accuracy for human cardiotoxicity is poor, leading to high false positives and negatives
Solution Approach 1:
The patent transitions from two-dimensional cell-based assays to three-dimensional engineered heart tissues, adding a spatial dimension that better recapitulates human cardiac physiology. This dimensional change enables more accurate prediction of human cardiotoxicity by incorporating tissue-level architecture and cell-cell interactions that are absent in 2D models.
Solution Approach 2:
The patent creates engineered heart tissues that copy and replicate the structure and function of native human heart tissue. By using human pluripotent stem cell-derived cardiomyocytes assembled into 3D constructs, the model provides a human-specific copy of cardiac tissue that accurately predicts human cardiotoxicity responses without relying on animal models.
2Reliability
If current cardiotoxicity testing methods are used, then drug development can proceed, but arrhythmogenic risks are not effectively identified, resulting in unnecessary drug discontinuation and increased development costs
Solution Approach 1:
The patent implements a feedback mechanism by using non-invasive optical detection to continuously monitor electromechanical function of engineered heart tissues in real-time. This feedback enables dynamic assessment of drug-induced arrhythmogenic effects, allowing for accurate identification of arrhythmia risks and reducing false positives that lead to unnecessary drug discontinuation.
Solution Approach 2:
The patent replaces invasive mechanical or electrical measurement systems with non-invasive optical detection methods. This substitution enables continuous, real-time monitoring of cardiac tissue function without disrupting tissue integrity or requiring physical contact, thereby improving both arrhythmia detection accuracy and experimental throughput.
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.