A Change of Heart: Human Cardiac Tissue Engineering as a Platform for Drug Development

Abstract

Purpose of Review Human cardiac tissue engineering holds great promise for early detection of drug-related cardiac toxicity and arrhythmogenicity during drug discovery and development. We describe shortcomings of the current drug development pathway, recent advances in the development of cardiac tissue constructs as drug testing platforms, and the challenges remaining in their widespread adoption. Recent Findings Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have been used to develop a variety of constructs including cardiac spheroids, microtissues, strips, rings, and chambers. Several ambitious studies have used these constructs to test a significant number of drugs, and while most have shown proper negative inotropic and arrhythmogenic responses, few have been able to demonstrate positive inotropy, indicative of relative hPSC-CM immaturity. Summary Several engineered human cardiac tissue platforms have demonstrated native cardiac physiology and proper drug responses. Future studies addressing hPSC-CM immaturity and inclusion of patient-specific cell lines will further advance the utility of such models for in vitro drug development.

FRESH™ 3D Bioprinted Cardiac Tissue, a Bioengineered Platform for in vitro Toxicology and Pharmacology

“…Not only did this enable us to demonstrate our platform with one of the most widely used hiPSC-CM cell lines in academic and industry research, but it also decoupled the timeline of the cell culture process from the bioprinting process. Overall, this builds off of previous work leveraging FRESH™ bioprinting for the fabrication of functional cardiac tissues 30 together with other studies working towards utilization of engineered heart tissue for in vitro models in drug discovery 38 . With this platform, we were able to expand upon this previous work by creating a tissue strip designed to be reproducibly manufactured in a multi-well plate format (Figure 1), form cardiac tissue with high density and alignment characteristic of human myocardium (Figure 2), achieve high conduction velocity (Figure 3), and demonstrate positive chronotropic and inotropic response to β adrenoceptor agonist (Figure 4).…”

Validating the Arrhythmogenic Potential of High-, Intermediate-, and Low-Risk Drugs in a Human-Induced Pluripotent Stem Cell-Derived Cardiac Microphysiological System

“…Recently, enormous progress has been made in 3D cardiac tissue cultivation and new culture formats as application notes are published frequently. 35 Several studies have demonstrated the benefits of 3D culture formats over simple 2D cell layers. 3D cultures of various formats such as tissue strips, tissue rings, and chambers yielded more mature phenotypes regarding gene expression, electrophysiology, and tissue mechanics.…”

“…Recently, enormous progress has been made in 3D cardiac tissue cultivation and new culture formats as application notes are published frequently . Several studies have demonstrated the benefits of 3D culture formats over simple 2D cell layers.…”

Advances in 3D Organoid Models for Stem Cell-Based Cardiac Regeneration

“…Utilization of automated and high-throughput liquid handling systems has become an excellent approach to yield large-scale numbers of reproducible cardiac organoids [ 49 , 73 ]. Similar research has indicated that the production of thousands of cardiac organoids can be highly reproducible among different cell lines with limited batch variability [ 60 ], a platform that in the future holds promise for industry standard scalability, as reviewed elsewhere [ 74 ]. However, the number of cardiac organoids needed for human implantation would be at least an order of magnitude higher, and further research is needed into improving these scalability methods.…”