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Review
. 2022 Aug;23(8):467-491.
doi: 10.1038/s41576-022-00466-9. Epub 2022 Mar 25.

Human organs-on-chips for disease modelling, drug development and personalized medicine

Donald E Ingber  1   2   3
Affiliations
Review

Human organs-on-chips for disease modelling, drug development and personalized medicine

Donald E Ingber. Nat Rev Genet. 2022 Aug.

Abstract

The failure of animal models to predict therapeutic responses in humans is a major problem that also brings into question their use for basic research. Organ-on-a-chip (organ chip) microfluidic devices lined with living cells cultured under fluid flow can recapitulate organ-level physiology and pathophysiology with high fidelity. Here, I review how single and multiple human organ chip systems have been used to model complex diseases and rare genetic disorders, to study host-microbiome interactions, to recapitulate whole-body inter-organ physiology and to reproduce human clinical responses to drugs, radiation, toxins and infectious pathogens. I also address the challenges that must be overcome for organ chips to be accepted by the pharmaceutical industry and regulatory agencies, as well as discuss recent advances in the field. It is evident that the use of human organ chips instead of animal models for drug development and as living avatars for personalized medicine is ever closer to realization.

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Conflict of interest statement

D.E.I. holds equity in Emulate, chairs its scientific advisory board and is a member of its board of directors.

Figures

Fig. 1
Fig. 1. The range of microfluidic organ chip designs.
a | An optically clear, two-channel, mechanically actuable, organ chip fabricated from polydimethylsiloxane (PDMS) using soft lithography with two parallel channels separated by a flexible microporous membrane (now sold by Emulate). Different tissue cells are cultured on the top and bottom of the central extracellular matrix (ECM)-coated membrane with micrometre-sized pores to recreate a tissue–tissue interface that permits cell transmigration, and air can be introduced above the epithelium to create an air–liquid interface (for example, in lung) or fluid can be perfused through this channel. Application of cyclic suction to hollow side chambers results in rhythmic distortion of the flexible membrane and attached tissues, thereby mimicking organ-level mechanical distortions (such as breathing motions). b | A multiplexed array of three-channel plastic (polystyrene) chips that contain a thick ECM gel in the central channel, which lacks solid sidewalls and instead restrains the gel using a phase guide. Cells can be cultured in one or both of the flow channels as well as within the ECM gel (now sold by Mimetas). c | One or more hollow channels are created within a thick 3D ECM gel material by removing cylindrical mandrels after gelling has occurred, and cells can be cultured on the inner surface of the channels as well as within the ECM gel in these plastic devices (now sold by Nortis). d | A multiplexed PDMS microfluidic device containing two endothelium-lined channels separated by a third diamond-shaped chamber filled with ECM gel that can be used to support capillary ingrowth and 3D microvascular network formation surrounded by cells such as tumour cells in the gel (now sold by Aracari Biosciences). e | A plastic, multiwell-format organ chip system that incorporates multiple bioreactor chambers, each with a rigid porous membrane and lower microfluidic chamber linked to a fluid reservoir that can be cultured individually under flow or fluidically linked together through the lower compartment. Tissue–tissue interfaces are created by plating different cell types on either side of the membrane, and air or fluid can be included in the upper chamber (now sold by CN Bio Innovations). f | A higher-throughput (384-well) format plastic organ chip that includes two parallel channels separated by a rigid microporous membrane, and air or fluid can be introduced into the upper channel. g | Organ chips created using 3D printing to deposit sacrificial material in a cylindrical form in any desired pattern within an ECM gel with or without embedded cells. Once gelation is complete, the material is removed and epithelial or endothelial cells are cultured on the inner surface of the channel. h | A plastic multi-chamber organ chip system in which multiple mini-bioreactor chambers positioned on a flat plate can be cultured individually or fluidically coupled through a shared underlying fluidic channel. The cells may be cultured at bottom of the chamber in the flow path (left) or on top of the rigid porous membrane within a Transwell insert that placed within a chamber (right) so that they are separated from the flow path (now sold by TissUse). Part a adapted with permission from ref., AAAS. Part e adapted with permission from ref., RSC. Part g adapted with permission from ref., CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Part h adapted with permission from ref. RSC.
Fig. 2
Fig. 2. Schematics showing different multi-organ human body-on-chips formats.
a | A simple fluidic coupling between multiple chambers lined by different organotypic cell types and a common flow chamber in two-chamber organ chip designs; a porous membrane within each chamber separates the overlying cell type from the fluid flow path or transwell inserts containing cells may be placed within open chambers as shown in Fig. 1h. To mimic intravenous (IV) adminstration, the drug can be introduced into the lower flow path. b | A similar multiwell configuration, except that the surface of the shared flow chamber is lined by endothelium. c | A diagram of linked two-channel organ chips containing both parenchymal cells and an endothelium-lined flow channel that are fluidically coupled using a robotic liquid handler to transfer fluids drop-by-drop between the chips and an arteriovenous mixing reservoir. The reservoir is integrated into the system to mimic blood mixing in the central circulation, and it also allows fluid sampling that is more analogous to sampling peripheral blood in a patient. Red arrows indicate the directional fluid flow or transfer path, and the circled ‘I’ depicts points in the circuit where a liquid-handling robot is used to move fluid into or out of the organ models or the arteriovenous reservoir; small blue arrows indicate independent transfers of fluids to and from the parenchymal channels of each chip. In this configuration, IV adminstration is modelled by injecting the drug into the arteriovenous reservoir, whereas oral adminstration is accomplished by introducing the drug into the lumenal channel of an intestine chip. Part c adapted from ref., Springer Nature Limited.
Fig. 3
Fig. 3. Modelling drug pharmacokinetics and pharmacodynamics in human body-on-chips.
a | Multi-organ chip systems linked by common flow channels can mimic the physiological linking of organs in our bodies, and hence drug absorption, distribution, metabolism and excretion (ADME) that occurs in the human body as a result of whole body-level physiology can be modelled using this approach. Aerosolized, oral and intravenous (IV) delivery of drugs that occurs in our bodies can be modelled by introducing them into the air space of a lung chip, the lumen of an intestine chip or the vascular channel, respectively; however, IV dosing can be complicated by organ chips immediately downstream from the injection site abnormally experiencing higher doses than other chips due to the lack of mixing that normally occurs in human vasculature. Linked liver and kidney chips can be used to quantify drug metabolism and clearance, respectively, and by linking other relevant chips (for example, a bone marrow chip for myelotoxins), efficacy and potency can be measured as well. b | A schematic diagram showing the fluidic linkages among two-channel intestine, liver and kidney chips corresponding to flow through respective in vivo organ-feeding vessels mimicked by robotic fluid transfers (long arrows indicating flow direction) along with an arteriovenous (AV) reservoir that is fluidically linked to the vascular channels of the organ chips to model blood mixing for more physiologically relevant drug exposures across all chips and to enable experimental sampling analogous to peripheral blood sampling. A common blood substitute is flowed through the vascular channels and the AV reservoir while organ-specific medium is flowed through the parenchymal channel of each chip (small arrows). c | Because the drug levels in effluents of both the vascular and parenchymal channels can be measured over time, pharmacokinetics and pharmacodynamics (PK/PD) parameters — such as area under the curve (AUC), maximum drug concentration in blood (Cmax), and time to reach half-maximal levels (t1/2) — can be determined in vitro using computational physiologically based PK modelling along with scaling approaches. d | This approach has been used to quantitatively predict PK/PD parameters observed in humans in vivo, for example, as shown for cisplatin, using the body-on-chips linking configuration shown in part b. Squares and triangles indicate PK data obtained from patients in which cisplatin was infused for 1 hour or 3 hours, and dotted lines indicate computational PK predictions generated using data obtained from the human body-on-chips model. The vertical error bars represent the standard deviation. Parts a and b are adapted with permission from ref., Annual Reviews. Part c is reprinted with permission from ref., Annual Reviews. Part d is reprinted with permission from ref., Springer Nature Limited.
Fig. 4
Fig. 4. Human organ chip applications for personalized medicine.
Organ chips lined by patient-derived cells may be used to model rare genetic disorders, to identify toxicities difficult to study clinically (for example, effects of lethal radiation exposure or exposure of pregnant women to potential teratogens) or to compare drug responses in different subpopulations (such as women versus men or young versus old individuals). When multiple chips are created, each lined with cells from a different donor representing a different subpopulation or a patient with a different comorbidity, they might also be used to design and optimize drugs for specific subgroups whose members could be used as participants in future targeted clinical trials to increase the likelihood of success. Individualized single-organ chips and multi-organ chip systems lined by one or more organotypic cell types from the same patient (for example, using induced pluripotent stem (iPS) cell technology), from a population of genetically related individuals, or from patients with similar comorbidities, could also be used to personalize drug selection to optimize drug efficacy, minimize toxicity, determine optimal delivery routes, and when combined with pharmacokinetics and pharmacodynamics (PK/PD) predictions, to design optimal dosing regimens for use in targeted phase I clinical trials.
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