Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1180-1191 |
| Number of pages | 12 |
| Journal | Experimental Biology and Medicine |
| Volume | 239 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 1 2014 |
| Externally published | Yes |
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Keywords
- Drug-induced liver injury
- hepatotoxicity
- high content screening
- liver on chip
- predictive modeling
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Medicine(all)
Cite this
In vitro platforms for evaluating liver toxicity. / Bale, Shyam Sundhar; Vernetti, Lawrence; Senutovitch, Nina; Jindal, Rohit; Hegde, Manjunath; Gough, Albert; McCarty, William J.; Bakan, Ahmet; Bhushan, Abhinav; Shun, Tong Y.; Golberg, Inna; DeBiasio, Richard; Usta, O. Berk; Taylor, D. Lansing; Yarmush, Martin L.
In: Experimental Biology and Medicine, Vol. 239, No. 9, 01.09.2014, p. 1180-1191.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - In vitro platforms for evaluating liver toxicity
AU - Bale, Shyam Sundhar
AU - Vernetti, Lawrence
AU - Senutovitch, Nina
AU - Jindal, Rohit
AU - Hegde, Manjunath
AU - Gough, Albert
AU - McCarty, William J.
AU - Bakan, Ahmet
AU - Bhushan, Abhinav
AU - Shun, Tong Y.
AU - Golberg, Inna
AU - DeBiasio, Richard
AU - Usta, O. Berk
AU - Taylor, D. Lansing
AU - Yarmush, Martin L.
PY - 2014/9/1
Y1 - 2014/9/1
N2 - 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.
AB - 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.
KW - Drug-induced liver injury
KW - hepatotoxicity
KW - high content screening
KW - liver on chip
KW - predictive modeling
UR - http://www.scopus.com/inward/record.url?scp=84907016464&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84907016464&partnerID=8YFLogxK
U2 - 10.1177/1535370214531872
DO - 10.1177/1535370214531872
M3 - Article
C2 - 24764241
AN - SCOPUS:84907016464
VL - 239
SP - 1180
EP - 1191
JO - Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N. Y.)
JF - Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N. Y.)
SN - 1535-3702
IS - 9
ER -