Published online Jan 27, 2018. doi: 10.4254/wjh.v10.i1.22
Peer-review started: October 7, 2017
First decision: November 23, 2017
Revised: November 28, 2017
Accepted: December 28, 2017
Article in press: December 29, 2017
Published online: January 27, 2018
To develop appropriate humanized three-dimensional ex-vivo model system for drug testing.
Bioengineered humanized livers were developed in this study using human hepatic stem cells repopulation within the acellularized liver scaffolds which mimics with the natural organ anatomy and physiology. Six cytochrome P-450 probes were used to enable efficient identification of drug metabolism in bioengineered humanized livers. The drug metabolism study in bioengineered livers was evaluated to identify the absorption, distribution, metabolism, excretion and toxicity responses.
The bioengineered humanized livers showed cellular and molecular characteristics of human livers. The bioengineered liver showed three-dimensional natural architecture with intact vasculature and extra-cellular matrix. Human hepatic cells were engrafted similar to the human liver. Drug metabolism studies provided a suitable platform alternative to available ex-vivo and in vivo models for identifying cellular and molecular dynamics of pharmacological drugs.
The present study paves a way towards the development of suitable humanized preclinical model systems for pharmacological testing. This approach may reduce the cost and time duration of preclinical drug testing and further overcomes on the anatomical and physiological variations in xenogeneic systems.
Core tip: Liver is the central organ for absorption, distribution, metabolism, excretion and toxicity (ADMET) of pharmacological drugs and molecules. Available in vitro and in vivo preclinical models deals with several limitations including xenogeneic barrier, lack of natural humanized liver architecture and functional responses. Bioengineered humanized livers developed in present study can overcome on such limitations. This humanized liver model system provides better platform which could be used more efficiently to screen the ADMET of several pipeline drugs and other pharmacological molecules. This approach could reduce the time and cost of the total drug screening experiments as compared to the animal models. It provides enhanced dose response relationship by using drug concentrations relative to human exposure. Ease of ex-vivo access of cellular and molecular responses in humanized liver model system during pharmacological screening also offers high-throughput studies to determine the cellular response networks and toxicity pathways.