Abstract

Assessing Contractility of 3D iPSC-derived Engineered Muscle Tissues for Safety and Drug Discovery Applications Using a High-throughput and Novel Label-free Method

Nicholas Geisse, Chief Science Officer, Curi Bio Inc.

Preclinical assays often fail to predict drug action, resulting in high clinical trial failure rates. Cellular models can screen for cardiotoxicity, but oftentimes utilize complex 3D systems that are challenging to deploy at sufficient scale. We designed, optimized, and validated a novel method to fabricate and measure the contractility of 24 3D Engineered Muscle Tissues (EMT) in parallel. Our approach allows for successful tissue casting rates >95% (n > 100) and produces consistently-sized constructs (confirmed across 6 laboratories). The consumable features embedded magnets. As tissues contract, the magnet’s displacement is quantitatively detected in a highly-parallel manner using specialized sensors. Displacement can be detected simultaneously across all 24 tissues with suitable acquisition rates for measuring contractility parameters such as upstroke velocity and decay time. Our platform can be used to detect changes in contractility, including those induced by structural cardiotoxicants like doxorubicin. EMTs treated with doxorubicin showed no differences over controls at acute (30 min) or chronic timepoints to Day 2 post exposure. The highest-dosed (1 µM) tissue slowed at Day 4 and Day 5 until complete cessation of twitching by Day 6. We also show phenotype stratification across EMTs from healthy and diseased individuals, demonstrating potential use in drug discovery studies.