Microphysiology systems (MPS), also called organs-on-chips and tissue chips, are miniaturized functional units of organs constructed with multiple cell types under a variety of physical and biochemical environmental cues that complement animal models as part of a new paradigm of drug discovery and development. Biomimetic human liver MPS have evolved from simpler 2D cell models, spheroids and organoids to address the increasing need to understand patient-specific mechanisms of complex and rare diseases, the response to therapeutic treatments, and the absorption, distribution, metabolism, excretion and toxicity of potential therapeutics. The parallel development and application of transdisciplinary technologies, including microfluidic devices, bioprinting, engineered matrix materials, defined physiological and pathophysiological media, patient-derived primary cells, and pluripotent stem cells as well as synthetic biology to engineer cell genes and functions, have created the potential to produce patient-specific, biomimetic MPS for detailed mechanistic studies. It is projected that success in the development and maturation of patient-derived MPS with known genotypes and fully matured adult phenotypes will lead to advanced applications in precision medicine. In this Review, we examine human biomimetic liver MPS that are designed to recapitulate the liver acinus structure and functions to enhance our knowledge of the mechanisms of disease progression and of the absorption, distribution, metabolism, excretion and toxicity of therapeutic candidates and drugs as well as to evaluate their mechanisms of action and their application in precision medicine and preclinical trials.
Liver in vitro experimental models have a long history involving the use of 2D and 3D models that continue to have valuable roles in our understanding of liver physiology and pathophysiology.
Human microphysiology systems (MPS) have evolved from simple cell-based experimental models and have the potential to meet the need for human experimental models for basic biomedical research and the development of therapeutics.
Human biomimetic liver MPS (HBL-MPS) aim to improve the efficiency of developing biomarkers, repurposed drugs and novel therapeutics by maximally recapitulating the structure and functions of the liver acinus.
HBL-MPS are evolving based either on liver organoids derived from patient cells that self-assemble and differentiate or on the directed assembly or bioprinting of matrix materials and cells into microfluidic devices.
Organoid-derived MPS and structured MPS are next-generation HBL-MPS that are projected to enable applications of precision medicine, including preclinical trials, either as stand-alone liver models or as coupled, multi-organ MPS.
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A.S.-G. is co-founder and D.L.T. is an adviser for Von Baer Wolff Inc., a company focused on biofabrication of autologous human hepatocytes using stem cell technology and genetic reprogramming to overcome liver failure. Their interests are managed by the Conflict of Interest Office at the University of Pittsburgh, USA, in accordance with their policies. The other authors declare no competing interests.
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- Absorption, distribution, metabolism, excretion and toxicity
(ADMET). Studies conducted during the drug discovery, lead optimization and preclinical development phases to provide information for characterization and ranking of compounds based on their properties and to predict their fate after administration into the human body.
- Micropatterned cell arrays
Methodologies, often based on nanofabrication, to fix one or more cell types on a substrate with precisely controlled spatial distributions.
In vitro 3D spherical aggregates of cells of either a single cell type or a combination of cells generated by a variety of 3D culturing methods.
3D multicellular systems produced primarily from patient-specific stem cells and their progenies via in situ differentiation, cell sorting and self-organization processes.
- Plate-based platforms
Platforms designed around microplate standards from the Society of Biomolecular Sciences, available in 6–1,536-well formats.
A drug development tool that has been accepted for use in a specific application based on thorough evaluation of the information provided.
- Synthetic biology
An interdisciplinary area of science focused on the (re)design and construction of biological systems in a bottom-up fashion, often through the engineering of well-characterized genetic components, modules and devices to attain new functions or to correct dysregulated ones.
A set of proteins expressed by cells (organs) and secreted into the extracellular space, including cytokines, growth factors, extracellular matrix proteins mediating autocrine, paracrine, endocrine (via circulation) and/or exocrine (via ducts) physiological regulation or pathophysiological dysregulation.
The collection of processes by which the body removes a drug, generally categorized as metabolism or elimination.
- Pharmacokinetic models
Quantitative models that predict how an organism influences the absorption, distribution, metabolism and excretion of a drug.
- Pharmacodynamic models
A quantitative integration of pharmacokinetics, pharmacological systems and (patho-) physiological processes to understand the intensity and time course of drug effects on the body.
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Gough, A., Soto-Gutierrez, A., Vernetti, L. et al. Human biomimetic liver microphysiology systems in drug development and precision medicine. Nat Rev Gastroenterol Hepatol (2020). https://doi.org/10.1038/s41575-020-00386-1