Progressive hypoxia‐on‐a‐chip: An in vitro oxygen gradient model for capturing the effects of hypoxia on primary hepatocytes in health and disease. Issue 3 (28th November 2019)

• Record Type: Journal Article
• Authors: Kang, Young Bok (Abraham); Eo, Jinsu; Bulutoglu, Beyza; Yarmush, Martin L.; Usta, O. Berk
• Is Part Of: Biotechnology and bioengineering. Volume 117:Issue 3(2020)
• Page Start: 763
• Page End: 775
• Publication Date: 2019-11-28
• Subjects: hepatocytes -- HIF -- hypoxia -- microfluidics -- oxygen gradient -- ROS; Biotechnology -- Periodicals; Bioengineering -- Periodicals; 660.6
• DOI: 10.1002/bit.27225
• Languages: English
• ISSNs: 0006-3592

Abstract

Abstract: Oxygen is vital to the function of all tissues including the liver and lack of oxygen, that is, hypoxia can result in both acute and chronic injuries to the liver in vivo and ex vivo. Furthermore, a permanent oxygen gradient is naturally present along the liver sinusoid, which plays a role in the metabolic zonation and the pathophysiology of liver diseases. Accordingly, here, we introduce an in vitro microfluidic platform capable of actively creating a series of oxygen concentrations on a single continuous microtissue, ranging from normoxia to severe hypoxia. This range approximately captures both the physiologically relevant oxygen gradient generated from the portal vein to the central vein in the liver, and the severe hypoxia occurring in ischemia and liver diseases. Primary rat hepatocytes cultured in this microfluidic platform were exposed to an oxygen gradient of 0.3–6.9%. The establishment of an ascending hypoxia gradient in hepatocytes was confirmed in response to the decreasing oxygen supply. The hepatocyte viability in this platform decreased to approximately 80% along the hypoxia gradient. Simultaneously, a progressive increase in accumulation of reactive oxygen species and expression of hypoxia‐inducible factor 1α was observed with increasing hypoxia. These results demonstrate the induction of distinct metabolic and genetic responses in hepatocytes upon exposure to an oxygen (/hypoxia) gradient. This progressive hypoxia‐on‐a‐chip platform can be used to study the role of oxygen and hypoxia‐associated molecules in modeling healthy and injured liver tissues. Its use can be further expanded to the study of other hypoxic tissues such as tumors as well as the investigation of drug toxicity and efficacy under oxygen‐limited conditions. Abstract : We demonstrated a progressive hypoxia‐on‐a‐chip model capable of actively creating a series of oxygen concentrations on a single continuous micro‐liver tissue. We were able to capture both physiologically relevant and severely hypoxic conditions relevant for injury and disease conditions. Our progressive hypoxia‐on‐a‐chip model, as presented here, can be used to study complex physiological and pathophysiological states, of the liver and other tissues where hypoxia can be an important modulator, and to assess the safety and efficacy of new drugs.