Opportunities and challenges in the wider adoption of liver and interconnected microphysiological systems

Abstract

Liver disease represents a growing global health burden. The development of in vitro liver models which allow the study of disease and the prediction of metabolism and drug-induced liver injury in humans remains a challenge. The maintenance of functional primary hepatocytes cultures, the parenchymal cell of the liver, has historically been difficult with dedifferentiation and the consequent loss of hepatic function limiting utility. The desire for longer term functional liver cultures sparked the development of numerous systems, including collagen sandwiches, spheroids, micropatterned co-cultures and liver microphysiological systems. This review will focus on liver microphysiological systems, often referred to as liver-on-a-chip, and broaden to include platforms with interconnected microphysiological systems or multi-organ-chips. The interconnection of microphysiological systems presents the opportunity to explore system level effects, investigate organ cross talk, and address questions which were previously the preserve of animal experimentation. As a field, microphysiological systems have reached a level of maturity suitable for commercialization and consequent evaluation by a wider community of users, in academia and the pharmaceutical industry. Here scientific, operational, and organizational considerations relevant to the wider adoption of microphysiological systems will be discussed. Applications in which microphysiological systems might offer unique scientific insights or enable studies currently feasible only with animal models are described, and challenges which might be addressed to enable wider adoption of the technologies are highlighted. A path forward which envisions the development of microphysiological systems in partnerships between academia, vendors and industry, is proposed. Impact statement Microphysiological systems are in vitro models of human tissues and organs. These systems have advanced rapidly in recent years and are now being commercialized. To achieve wide adoption in the biological and pharmaceutical research communities, microphysiological systems must provide unique insights which translate to humans. This will be achieved by identifying key applications and making microphysiological systems intuitive to use.

A Microphysiological System for Studying Nonalcoholic Steatohepatitis

“…With further development, other cell types could be incorporated into the model to potentially enhance its translational relevance, but while it might be desirable for all cell types of the liver to be included in a model, to date no in vitro model exists that incorporates all of the cell types of the liver. (17) The model additionally does not recapitulate full hepatic zonation, as all of the hepatocytes are exposed to close to atmospheric levels of oxygen, something that is common for in vitro models. However, the model does feature an oxygen gradient across the microtissues and has been shown to consume physiologically relevant concentrations of oxygen.…”

“…However, longterm cultures (>1 week) of primary human hepatocytes (PHHs) are challenging, and only through recent technological advances (e.g., three-dimensional [3D] spheroidal cultures, microfluidic perfusion, co-cultures) has this become tractable. (17) Therefore, to date, most in vitro NAFLD studies involving PHHs have focused on short-term exposure (48-72 hours) to free fatty acids (FFAs), allowing the study of transient responses to triglyceride challenge. (14)(15)(16) Some studies using advanced in vitro platforms, including micropatterned co-cultures of primary hepatocytes and murine fibroblasts, (18) a hemodynamic co-culture system (19) or bioprinted cultures of primary liver cells, (20) have started to demonstrate how exposure to glucose and FFAs can affect human hepatic cell types.…”

A thermoplastic microfluidic microphysiological system to recapitulate hepatic function and multicellular interactions

“…The primary focus of in vitro hepatic cell culture systems has been primary human hepatocyte (PHH) stabilization and long‐term culture, achieved using collagen sandwich (Dunn, Tompkins, & Yarmush, ), spheroid (Messner, Agarkova, Moritz, & Kelm, ), 3D printing (Nguyen et al, ), and micropatterning (Khetani & Bhatia, ) techniques. In addition to static systems, high‐throughput in vitro models and advanced dynamic microfluidic systems are emerging as tools to predict ADMET attributes, and disease modeling in particular (Bale et al, ; Bale, Moore, et al, ; Bhatia & Ingber, ; Ewart et al, ; Hughes, Kostrzewski, & Sceats, ; Materne et al, ). Further, these organ‐on‐chip systems have the potential to elucidate molecular and cellular phenotypes of rare diseases, and aid in drug development (Low & Tagle, ; Low & Tagle, ).…”

Microfluidic Cell Culture Platforms to Capture Hepatic Physiology and Complex Cellular Interactions

“…Hepatotoxicity accounts for ;50% of cases of acute liver failure and remains a major factor responsible for withdrawal or restricted use of approved drugs (Olson et al, 2000;Schuster et al, 2005;Wilke et al, 2007;Kaplowitz, 2013). Apart from drug hepatotoxicity, liver-generated metabolites are transported to other tissues in the human body through the systemic circulation, resulting either in therapeutic effects (e.g., prodrugs) or unwanted side effects (Bale et al, 2016b;Hughes et al, 2017).…”

“…Key requirements for the development of such MPS platforms for capturing liver functionality are aimed at: 1) constructing complex microscale structures suitable for mimicking in vivo microarchitecture, cellular composition, and interactions; 2) simulating liver pathophysiology in an in vivo-like microenvironment; and 3) providing a rapid, easy, and high-throughput process for the screening of diverse treatment methods and toxic materials using a small number of human cells. Further, capturing hepatic responses in MPS models can drive the generation of multiorgan MPS systems that are capable of capturing inter-organ interactions and assaying for compounds and their metabolites, and drug responses (Bale et al, 2016b;Hughes et al, 2017).…”