Microfabrication of liver and heart tissues for drug development

Abstract

Drug-induced liver- and cardiotoxicity remain among the leading causes of preclinical and clinical drug attrition, marketplace drug withdrawals and black-box warnings on marketed drugs. Unfortunately, animal testing has proven to be insufficient for accurately predicting drug-induced liver- and cardiotoxicity across many drug classes, likely due to significant differences in tissue functions across species. Thus, the field of human tissue engineering has gained increasing importance over the last 10 years. Technologies such as protein micropatterning, microfluidics, three-dimensional scaffolds and bioprinting have revolutionized platforms as well as increased the long-term phenotypic stability of both primary cells and stem cell-derived differentiated cells. Here, we discuss advances in engineering approaches for constructing human liver and heart models with utility for drug development. Design features and validation data of representative models are presented to highlight major trends followed by the discussion of pending issues. Overall, bioengineered liver and heart models have significantly advanced our understanding of organ function and injury, which will prove useful for mitigating the risk of drug-induced organ toxicity to human patients, reducing animal usage for preclinical drug testing, aiding in the discovery of novel therapeutics against human diseases, and ultimately for applications in regenerative medicine.This article is part of the theme issue 'Designer human tissue: coming to a lab near you'.

Mechanobiology Assays with Applications in Cardiomyocyte Biology and Cardiotoxicity

“…The use of EHTs in drug screening and developmental assays is of increasing interest with commercial systems now coming to market. [ 141,142 ] The hiPSC‐CMs in EHTs “trained” with intervals of electrical pacing more closely resemble CMs in an intact heart compared to CMs in 2D monolayer and unstructured single‐cell models. [ 143 ] In the past decade, there have been several studies that have reported changes in the contractile forces produced by EHTs in response to cardiotoxic agents identified by the CiPA initiative as well as cancer drugs using micropost displacements (Table 1).…”

Novel microfluidic platform accelerates processing of tissue into single cells for molecular analysis and primary culture models

“…In fact, liver damage is one of the leading causes of post-approval drug withdrawal. 22,74,75 Thus, in vitro screening of drugs against primary liver tissue is a critical component of preclinical testing. Increasingly, organ-on-a-chip systems are being employed to better maintain hepatocyte functionality and activity in culture settings and to enable personalized testing on patient-derived primary cells.…”

“…Heart failure is another leading cause of drug withdrawal from the market, combining with liver failure to account for ~ 70% of withdrawals. 74,75 Thus, there is robust interest in developing heart-on-chip technologies using primary cardiomyocytes for preclinical drug screening. 30,74,75,82,83 Cardiomyocytes have been shown to be highly sensitive to mechanical and enzymatic dissociation techniques.…”

“…74,75 Thus, there is robust interest in developing heart-on-chip technologies using primary cardiomyocytes for preclinical drug screening. 30,74,75,82,83 Cardiomyocytes have been shown to be highly sensitive to mechanical and enzymatic dissociation techniques. 84,85 In addition, they are disproportionately long in one direction, on the order of 100 µm and more.…”

Advanced bioengineering technologies for preclinical research

“…Currently, microtissues are successfully applied to predict drug-induced liver and cardiac toxicity, which is among the main causes of drug attrition and market withdrawal [33]. While animal testing has shown severe predictive limitations, in vitro testing has traditionally been hampered by the poor survival of both primary hepatocytes and cardiomyocytes as 2D monolayers.…”