ABSTRACT
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease and strongly correlates with the growing incidence of obesity and type II diabetes. We have developed a human-on-a-chip model composed of human hepatocytes and adipose tissue chambers capable of modeling the metabolic factors that contribute to liver disease development and progression, and evaluation of the therapeutic metformin. This model uses a serum-free, recirculating medium tailored to represent different human metabolic conditions over a 14-day period. The system validated the indirect influence of adipocyte physiology on hepatocytes that modeled important aspects of NAFLD progression, including insulin resistant biomarkers, differential adipokine signaling in different media and increased TNF-α-induced steatosis observed only in the two-tissue model. This model provides a simple but unique platform to evaluate aspects of an individual factor's contribution to NAFLD development and mechanisms as well as evaluate preclinical drug efficacy and reassess human dosing regimens.
Subject(s)
Adipocytes/drug effects , Drug Discovery/instrumentation , Hepatocytes/drug effects , Hypoglycemic Agents/pharmacology , Lab-On-A-Chip Devices , Metformin/pharmacology , Non-alcoholic Fatty Liver Disease/drug therapy , Adipocytes/metabolism , Adipose Tissue, White/cytology , Cell Communication , Cells, Cultured , Culture Media/pharmacology , Culture Media, Serum-Free/pharmacology , Cytochrome P-450 CYP1A1/metabolism , Cytochrome P-450 CYP3A/metabolism , Equipment Design , Fatty Acids/metabolism , Fatty Acids/pharmacology , Glucose/pharmacology , Hepatocytes/metabolism , Humans , Inflammation , Insulin/pharmacology , Tumor Necrosis Factor-alpha/pharmacologyABSTRACT
Drug development for rare diseases, classified as diseases with a prevalence of < 200 000 patients, is limited by the high cost of research and low target population. Owing to a lack of representative disease models, research has been challenging for orphan drugs. Human-on-a-chip (HoaC) technology, which models human tissues in interconnected in vitro microfluidic devices, has the potential to lower the cost of preclinical studies and increase the rate of drug approval by introducing human phenotypic models early in the drug discovery process. Advances in HoaC technology can drive a new approach to rare disease research and orphan drug development.
