AFC-ECM Maturation of hiPSC Cardiomyocytes for Arrhythmia Screening
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Solution Overview
Problem
Current preclinical drug candidate testing methods using genetically modified heterologous cells and animal models fail to accurately predict cardiotoxicity and proarrhythmia in humans, as they rely on immature human stem cell-derived cardiomyocytes that lack structural and functional maturity, and existing screening technologies provide inconsistent results for drug-induced arrhythmia patterns.
Innovation Solution
The use of an extracellular matrix derived from amniotic fluid (AFC-ECM) for culturing human induced pluripotent stem cell-derived cardiomyocytes to induce maturation, forming a cellular construct that mimics adult cardiac tissue, allowing for more accurate cardiotoxicity and proarrhythmic screening.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If genetically modified heterologous cells and animal models are used for preclinical drug candidate testing, then cardiotoxicity and proarrhythmia risk can be assessed, but the results do not accurately predict human cardiotoxicity
Solution Approach 1:
The patent uses human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to create an in vitro model that copies human cardiac tissue structure and function. This human-based cellular model replaces genetically modified heterologous cells and animal models, providing a more accurate representation of human cardiac electrophysiology and ion channel function, thereby improving predictive accuracy for human cardiotoxicity
Solution Approach 2:
The patent induces maturation of hiPSC-CMs through extended culture periods and optimization of culture conditions, changing the developmental stage parameter from immature to mature phenotype. This maturation process alters cellular parameters such as ion channel expression profiles, action potential characteristics, and contractile function to better match adult human cardiomyocytes, thereby improving the reliability of cardiotoxicity predictions
2Productivity
If immature human stem cell-derived cardiomyocytes are used, then cell availability is improved, but structural and functional maturity is insufficient leading to inconsistent screening results
Solution Approach 1:
The patent implements preliminary maturation actions by extending the culture period of hiPSC-CMs and optimizing culture conditions before conducting cardiotoxicity screening. This preliminary maturation process allows cells to develop mature phenotypic characteristics including appropriate ion channel expression, action potential duration, and contractile function, ensuring that screening is performed on cells with sufficient structural and functional maturity for reliable results
Solution Approach 2:
The patent dynamically adjusts culture conditions and monitoring parameters during the maturation process to track cellular development. By implementing time-dependent culture protocols and monitoring maturation markers, the system optimizes the transition from immature to mature phenotype, balancing cell availability with achieving the necessary structural and functional maturity for consistent screening outcomes
Data Source
AI summary
Disclosed are methods of using a cell-derived extracellular matrix derived in-vitro from cells isolated from amniotic fluid (AFC-ECM) for the maturation of immature cardiomyocytes derived from human induced pluripotent stem cells (immature hiPSC-CMs) in culture forming mature cardiomyocytes. Also disclosed is a cell construct comprising a monolayer of these mature cardiomyocytes on an AFC-ECM useful for cardiotoxicity and/or proarrhythmic screening assays of drug compounds. Also disclosed are methods for determining the cardiotoxicity and/or proarrhythmic effect of a drug compound in vitro using such cell constructs.