Microfabricated Tissue Strip Device for Cardiotoxicity Screening
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Solution Overview
Problem
Current drug screening platforms for cardiotoxicity, particularly those using human pluripotent stem cell-derived cardiomyocytes, face limitations in throughput, making them inadequate for high-throughput screening necessary in pharmaceutical development, and often fail to predict human cardiac responses due to interspecies differences.
Innovation Solution
Microfabricated devices with flexible posts to anchor tissue strips, allowing for measurement of force changes and compatible with high-throughput assay formats, including 96-well plates, enabling automated monitoring and electrical stimulation, which improves force output and electrophysiology over previous ring-based systems.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If tissue strips are anchored at two points to create aligned elongated tissue, then force measurement capability is improved, but device complexity increases
Solution Approach 1:
The device is segmented into modular components: a substrate layer, flexible posts, and attachment features. Each component performs a specific function (substrate provides base, posts provide flexibility and force transmission, attachment features secure tissue). This segmentation allows for simplified manufacturing while maintaining the two-point anchoring capability for accurate force measurement.
Solution Approach 2:
The posts are designed as flexible elements that can deflect in response to tissue force. This flexibility allows the posts to accurately transmit and measure forces exerted by the tissue strips while maintaining a simple overall device structure. The flexible posts are integrated into the substrate, creating a unified yet functional component system.
2Ease of manufacture
If ring-based systems are used for tissue anchoring, then ease of manufacture is improved, but measurement precision deteriorates due to uncoordinated force contraction
Solution Approach 1:
The device transitions from symmetric ring-based anchoring to asymmetric linear tissue strip anchoring at two distinct points. This asymmetric configuration ensures that force is applied in a controlled manner at specific locations, preventing the uncoordinated contraction that occurs in ring systems. The asymmetric design also simplifies the manufacturing process while improving signal accuracy for force measurement.
Solution Approach 2:
Instead of using a circular ring structure that naturally forms closed loops, the invention inverts the approach by using linear tissue strips anchored at two points. This inversion of the geometric configuration (from closed circular to open linear arrangement) eliminates the circular electrical wave problem and ensures coordinated tissue contraction, thereby improving measurement precision while maintaining ease of manufacture.
3Productivity
If high-throughput screening is implemented, then productivity is improved, but device complexity increases due to need for automated monitoring compatibility
Solution Approach 1:
The device is designed with universal compatibility with standard high-throughput screening formats, including 96-well, 384-well, and 1536-well plates. The same basic device structure can be used across different plate formats, allowing the system to accommodate various automation platforms and reading devices. This universality enables high-throughput screening without requiring device-specific customization for each application type.
Solution Approach 2:
The device replaces complex mechanical measurement systems with optical or electrical sensing methods that are compatible with automated plate readers. Instead of requiring complex mechanical linkages or manual measurement systems, the device uses sensors that can be read optically or electrically, enabling integration with automated high-throughput screening equipment and reducing overall device complexity while maintaining high productivity.
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
Enhances the capability for high-throughput screening of drug effects on cardiac tissue strips, providing accurate and efficient measurements of contractile force and electrophysiology, thereby improving the prediction of cardiotoxicity and reducing drug attrition in clinical trials.
Implementation Method 1
The anchors are flexible to allow movement of the tissue strip, which allows measurement of any change in force exerted by the tissue strip
Implementation Method 2
a trough is provided for seeding that allows electrical stimulation by concentrating seeding in specific location due to surface tension
Implementation Method 3
The microfabricated devices are also compatible with electrical stimulation of tissue strips attached to the anchors
Data Source
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Figure 3A~3C
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AI summary
The disclosure provides a device for developing organized tissue strips, such as cardiac tissue strips, for high-throughput assays of functional performance and the methods involved in fabricating, assembling, implementing, utilizing and analyzing data from such assays. The disclosure further provides systems for constructing such devices, systems comprising those devices comprising cells and extracellular matrix material for developing organized tissue strips or comprising the devices and organized tissue strips. The disclosure further provides methods for assaying a property of a tissue strip, such as contractile force.