High throughput screening system for engineered cardiac tissues

Abstract

Introduction: Three dimensional engineered cardiac tissues (3D ECTs) have become indispensable as in vitro models to assess drug cardiotoxicity, a leading cause of failure in pharmaceutical development. A current bottleneck is the relatively low throughput of assays that measure spontaneous contractile forces exerted by millimeter-scale ECTs typically recorded through precise optical measurement of deflection of the polymer scaffolds that support them. The required resolution and speed limit the field of view to at most a few ECTs at a time using conventional imaging.Methods: To balance the inherent tradeoff among imaging resolution, field of view and speed, an innovative mosaic imaging system was designed, built, and validated to sense contractile force of 3D ECTs seeded on a 96-well plate. Results: The system performance was validated through real-time, parallel contractile force monitoring for up to 3 weeks. Pilot drug testing was conducted using isoproterenol.Discussion: The described tool increases contractile force sensing throughput to 96 samples per measurement; significantly reduces cost, time and labor needed for preclinical cardiotoxicity assay using 3D ECT. More broadly, our mosaicking approach is a general way to scale up image-based screening in multi-well formats.

Heart-on-a-chip systems: disease modeling and drug screening applications

“…To reduce time-to-market and improve success rate, HoC systems could provide a valuable link between pre-clinical animal studies and clinical trials or even serve as a standalone replacement to animal studies all together. One of the most popular drugs tested with HoC systems is the non-selective β-adrenergic receptor agonist isoproterenol, 143–145,155,160,168,172,181,224,225,357–368 which can help treat bradycardia. Isoproterenol is similar in structure and function to epinephrine, which has also been evaluated using HoC systems.…”

Harnessing 3D Printing and Electrospinning for Multiscale Hybrid Patches Mimicking the Native Myocardium

“…Collagen/fibrin-based microbundles, , decellularized extracellular matrix (dECM), and (bio)­printing , are three dominant techniques in manufacturing organized 3D cardiac patches using robust structural templates. Even though high-performance, standardized, and reproducible collagen/fibrin-based microbundles have been fabricated, , the limitations lie in nonarranged internal distribution, mismatched mechanical properties, and size (maximum length/width/thickness of 3 × 0.8 × 0.5 mm) ,,− with restraining feasibility for in vivo heart transplantation, especially for large animals. The emergence of heart-dECM opens a new avenue for overcoming these restraints.…”

Understanding spatiotemporal mechanical behavior, viscoelasticity, and functions of stem cell-derived cardiomyocytes

“…3 In vitro mechanical test platform allows measuring the influences of bio-environment factors, cardiovascular drugs, 7 substrate topology/stiffness, [8][9][10][11] aging, and pH on the viscoelasticity, adhesion, 12 and beating mechanics 13,14 of hiPSC-CM. Compared to 2D or 3D cardiac microbundles or patches, [15][16][17][18] this platform is simple and has data precision due to controllable cell quality and technical maturity.…”