Latest impact of engineered human liver platforms on drug development

Abstract

Drug-induced liver injury (DILI) is a leading cause of drug attrition, which is partly due to differences between preclinical animals and humans in metabolic pathways. Therefore, in vitro human liver models are utilized in biopharmaceutical practice to mitigate DILI risk and assess related mechanisms of drug transport and metabolism. However, liver cells lose phenotypic functions within 1–3 days in two-dimensional monocultures on collagen-coated polystyrene/glass, which precludes their use to model the chronic effects of drugs and disease stimuli. To mitigate such a limitation, bioengineers have adapted tools from the semiconductor industry and additive manufacturing to precisely control the microenvironment of liver cells. Such tools have led to the fabrication of advanced two-dimensional and three-dimensional human liver platforms for different throughput needs and assay endpoints (e.g., micropatterned cocultures, spheroids, organoids, bioprinted tissues, and microfluidic devices); such platforms have significantly enhanced liver functions closer to physiologic levels and improved functional lifetime to >4 weeks, which has translated to higher sensitivity for predicting drug outcomes and enabling modeling of diseased phenotypes for novel drug discovery. Here, we focus on commercialized engineered liver platforms and case studies from the biopharmaceutical industry showcasing their impact on drug development. We also discuss emerging multi-organ microfluidic devices containing a liver compartment that allow modeling of inter-tissue crosstalk following drug exposure. Finally, we end with key requirements for engineered liver platforms to become routine fixtures in the biopharmaceutical industry toward reducing animal usage and providing patients with safe and efficacious drugs with unprecedented speed and reduced cost.

The Role of Liver Zonation in Physiology, Regeneration, and Disease

“…Cell microenvironments that are three-dimensional (3D) are a closer representation of physiologic cell–cell and cell–ECM interactions; generally, 3D liver models support higher functions than 2D conventional monolayers cultures for several weeks in culture, 90 which allows for long-term appraisal of hepatic responses to molecular gradients. HepG2 cells cultured in a thin hydrogel using a paper-based culture platform demonstrated higher hepatic functions at physiologic O 2 as compared with 2D culture.…”

“…84 In Vitro Liver Platforms to Model Zonation Many in vitro liver models have been developed that can functionally stabilize hepatic functions for days to weeks and are advantageous for disease modeling, drug screening, and regenerative medicine. 90 Such models include conventional two-dimensional (2D) monocultures, micropatterned cocultures, self-assembled spheroids, bioprinted tissues, and microfluidic devices. Though throughput is compromised with more complex culture models, the increasing technological complexities allow for higher order control over physiological phenomenon (e.g., establishment of key gradients associated with the regulation of zonation).…”

In Vitro Models for Studying Chronic Drug-Induced Liver Injury

“…OoC technology recreates 3D organ microenvironments, such as multicellular architecture, vascular perfusion, fluid flow and other relevant physiological microenvironment of organs [ 111 ]. Microfluidic devices can be used to subject cells to shear forces and gradients as occurs in vivo as well as allowing the automated delivery of nutrients [ 5 ]. Previously, the OoC field was focused on the design and characterization of these microfluidic devices; however, at present, the challenge is to prove their superiority to animal models.…”

“…These in vitro platforms recapitulate aspects of the in vivo crosstalk between different tissues at a miniaturized scale. For instance, recently, intestinal and liver platforms have been connected to model first pass drug metabolism and intestine liver interactions [ 5 ]. These systems can display tissue specific functions up to 2 weeks [ 153 ]; therefore, they could be used in long-term DILI studies.…”

“…Thus, it would be desirable to remove drugs with an elevated risk of causing DILI early in the drug development process. Screening large sets of compounds in vivo for efficacy and toxicity is too costly and time-consuming [ 5 ]. Additionally, animal studies face important limitations since there are substantial differences between experimental animals and humans in drug metabolism and pharmacokinetics [ 6 , 7 ].…”