Cardiac Anisotropic Sheet for In Vitro Cardiotoxicity Detection
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Solution Overview
Problem
Current pre-clinical testing methods for cardiotoxicity, such as those using immortalized transgenic Chinese Hamster Ovary (CHO) cells and human embryonic kidney (HEK293) cells, are sub-optimal for accurately predicting multi-cellular arrhythmias, leading to the release of unsafe drugs or faulty termination of useful candidates, and existing single-cell assays fail to detect cell-to-cell properties or sustain reentrant arrhythmic events.
Innovation Solution
A bio-hybrid material composed of human cardiomyocytes on a microfabricated substrate forms a cardiac anisotropic sheet (CAS) that replicates the anisotropic properties of human heart cells, allowing for in vitro assays to assess cardiotoxicity by detecting electrical signal propagation and reentrant wave formation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If immortalized transgenic CHO cells or HEK293 cells genetically modified to overexpress hERG are used for evaluating arrhythmogenicity, then the assay can be performed with a single ion channel protein, but the results are sub-optimal and do not accurately predict multi-cellular arrhythmias
Solution Approach 1:
The patent uses composite cell cultures combining multiple cell types (hPSC-CMs, hiPSC-CMs, or hESC-CMs with hiPSC-NCCs or hESC-NCCs) to create a more physiologically relevant model that accurately predicts multi-cellular arrhythmias while maintaining assay feasibility
2Device complexity
If single-cell assays are used to detect pro-arrhythmic properties, then the assay is simpler and more cost-effective, but the assays cannot detect cell-to-cell properties such as conduction or sustain reentrant arrhythmic events
Solution Approach 1:
The patent transitions from single-cell (0D) to multi-cellular (2D/3D) cultures, enabling detection of cell-to-cell conduction properties and reentrant arrhythmic events while maintaining relative assay simplicity through standardized culture protocols
3Reliability
If animal models are used for pre-clinical testing, then the models can provide in vivo physiological data, but significant species differences exist that reduce their predictive value for human cardiotoxicity
Solution Approach 1:
The patent creates in vitro copies of human cardiac tissue using human pluripotent stem cell-derived cardiomyocytes that replicate human cardiac electrophysiology, conduction, and arrhythmia mechanisms, providing human-relevant data without species differences
4Measurement precision
If conventional electrophysiological assays of hPSC-CMs are used, then the assays can identify pro-arrhythmic properties, but the variability commonly seen in these assays reduces their reliability
Solution Approach 1:
The patent combines multiple cell types (cardiomyocytes with neural crest cells) in co-culture systems that reduce variability through cell-cell interactions and create more stable, physiologically relevant electrophysiological environments
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The bio-hybrid material accurately reflects in vivo physiological effects, providing a reliable and cost-effective method to assess cardiotoxicity of therapeutics, including anti-arrhythmic compounds, by mimicking the electrophysiological features of the native human heart and minimizing variability.
Implementation Method 1
a microfabricated substrate providing an attachment point for the growth and ordered development of the human cardiomyocytes
Implementation Method 2
detecting electrical signal propagation in the anisotropic layer of cells
Data Source
AI summary
The disclosure provides a substrate for the ordered growth and development of cardiomyocytes such as ventricular cardiomyocytes derived from pluripotent stem cells along with methods of culturing the cells on the substrates for use in assays such as cardiotoxicity assays. Further provided are methods for assessing cardiotoxicity using one or more criteria disclosed herein.