In vitro platforms for evaluating liver toxicity.
The liver is a heterogeneous organ with many vital functions, including metabolism of pharmaceutical drugs and is highly susceptible to injury from these substances. The etiology of drug-induced liver disease is still debated although generally regarded as a continuum between an activated immune response and hepatocyte metabolic dysfunction, most often resulting from an intermediate reactive metabolite. This debate stems from the fact that current animal and in vitro models provide limited physiologically relevant information, and their shortcomings have resulted in "silent" hepatotoxic drugs being introduced into clinical trials, garnering huge financial losses for drug companies through withdrawals and late stage clinical failures. As we advance our understanding into the molecular processes leading to liver injury, it is increasingly clear that (a) the pathologic lesion is not only due to liver parenchyma but is also due to the interactions between the hepatocytes and the resident liver immune cells, stellate cells, and endothelial cells; and (b) animal models do not reflect the human cell interactions. Therefore, a predictive human, in vitro model must address the interactions between the major human liver cell types and measure key determinants of injury such as the dosage and metabolism of the drug, the stress response, cholestatic effect, and the immune and fibrotic response. In this mini-review, we first discuss the current state of macro-scale in vitro liver culture systems with examples that have been commercialized. We then introduce the paradigm of microfluidic culture systems that aim to mimic the liver with physiologically relevant dimensions, cellular structure, perfusion, and mass transport by taking advantage of micro and nanofabrication technologies. We review the most prominent liver-on-a-chip platforms in terms of their physiological relevance and drug response. We conclude with a commentary on other critical advances such as the deployment of fluorescence-based biosensors to identify relevant toxicity pathways, as well as computational models to create a predictive tool.
Center for Engineering in Medicine (CEM) at Massachusetts General Hospital, Harvard Medical School, Shriners Hospital for Children, Boston MA 02114.
Shyam Sundhar
SS
Bale
University of Pittsburgh Drug Discovery Institute, Pittsburgh PA 15260.|University of Pittsburgh Department of Computational and Systems Biology, Pittsburgh PA 15260.
Lawrence
L
Vernetti
University of Pittsburgh Drug Discovery Institute, Pittsburgh PA 15260.|University of Pittsburgh Department of Computational and Systems Biology, Pittsburgh PA 15260.
Nina
N
Senutovitch
Center for Engineering in Medicine (CEM) at Massachusetts General Hospital, Harvard Medical School, Shriners Hospital for Children, Boston MA 02114.
Rohit
R
Jindal
Center for Engineering in Medicine (CEM) at Massachusetts General Hospital, Harvard Medical School, Shriners Hospital for Children, Boston MA 02114.
Manjunath
M
Hegde
University of Pittsburgh Drug Discovery Institute, Pittsburgh PA 15260.|University of Pittsburgh Department of Computational and Systems Biology, Pittsburgh PA 15260.
Albert
A
Gough
Center for Engineering in Medicine (CEM) at Massachusetts General Hospital, Harvard Medical School, Shriners Hospital for Children, Boston MA 02114.
William J
WJ
McCarty
University of Pittsburgh Department of Computational and Systems Biology, Pittsburgh PA 15260.
Ahmet
A
Bakan
Center for Engineering in Medicine (CEM) at Massachusetts General Hospital, Harvard Medical School, Shriners Hospital for Children, Boston MA 02114.
Abhinav
A
Bhushan
University of Pittsburgh Drug Discovery Institute, Pittsburgh PA 15260.
Tong Ying
TY
Shun
Center for Engineering in Medicine (CEM) at Massachusetts General Hospital, Harvard Medical School, Shriners Hospital for Children, Boston MA 02114.
Inna
I
Golberg
University of Pittsburgh Drug Discovery Institute, Pittsburgh PA 15260.
Richard
R
DeBiasio
Center for Engineering in Medicine (CEM) at Massachusetts General Hospital, Harvard Medical School, Shriners Hospital for Children, Boston MA 02114.
Berk Osman
BO
Usta
University of Pittsburgh Drug Discovery Institute, Pittsburgh PA 15260.|University of Pittsburgh Department of Computational and Systems Biology, Pittsburgh PA 15260.
D Lansing
DL
Taylor
Center for Engineering in Medicine (CEM) at Massachusetts General Hospital, Harvard Medical School, Shriners Hospital for Children, Boston MA 02114.
Martin L
ML
Yarmush
D000818:Animals; D015374:Biosensing Techniques / Q000295:instrumentation / Q000379:methods; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology; D004353:Drug Evaluation, Preclinical / Q000295:instrumentation / Q000379:methods; D064420:Drug-Related Side Effects and Adverse Reactions; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D046210:Microfluidic Analytical Techniques / Q000295:instrumentation / Q000379:methods; D008954:Models, Biological
Drug-induced liver injury; hepatotoxicity; high content screening; liver on chip; predictive modeling