Quantitative prediction of human pharmacokinetic responses to drugs via fluidically coupled vascularized organ chips

Herland, Anna; Maoz, Ben M.; Das, Debarun; Somayaji, Mahadevabharath R.; Prantil‐Baun, Rachelle; Novak, Richard M.; Cronce, Michael J.; Huffstater, Tessa; Jeanty, Sauveur S. F.; Ingram, M.; Chalkiadaki, Angeliki; Chou, David B.; Marquez, Susan; Delahanty, Aaron; Baharvand, Hossein; Milton, Yuka; Sontheimer-Phelps, Alexandra; Swenor, Ben; Levy, Oren; Parker, Kevin Kit; Przekwas, Andrzej; Ingber, Donald E.

doi:10.1038/s41551-019-0498-9

Cited by 339 publications

(330 citation statements)

References 68 publications

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“…The ability to use a universal medium across Organ Chips dramatically increases experimental flexibility by leveraging the Interrogator platform for HuBoC linking with the potential to arbitrarily reconfigure the linkage scheme without the need to individually assess the viability of each new Organ Chip linkage. Importantly, we have recently confirmed the utility of this versatile Interrogator-enabled HuBoC approach coupled with MCRO modeling for evaluating drug PK/PD in a first-pass Organ Chip system and were able to recapitulate clinical drug profiles and PK parameters for two drugs (nicotine and cisplatin) previously observed in humans 48 .…”

Section: Discussionsupporting

confidence: 60%

“…This model and simplified reduced-order differential equation models were used to confirm the quantitative accuracy of the Interrogator-enabled HuBoC platform using an inert inulin-FITC tracer dye in the present study, which is focused on validation of the Interrogator instrument. However, in a parallel effort, this model has been extended to create an MCRO model that incorporates drug transport and metabolism with subsequent in vitro-in vivo translation 48 .…”

Section: Discussionmentioning

confidence: 99%

“…We also demonstrated that the Interrogator can be leveraged to create a viable HuBoC platform that maintains multi-organ function for at least 3 weeks in vitro. Although only a branched serial linkage scheme with 8 Organ Chips was used here, robotics-based organ linking can be readily reconfigured to include varying numbers of organs as well as an arterio-venous reservoir48 . The modular design of both the Interrogator hardware and control software enables rapid addition or removal of Organ Chips without disrupting the experiment, including, importantly, the perfusion of media.…”

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confidence: 99%

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A robotic platform for fluidically-linked human body-on-chips experimentation

Novak

Ingram

Clauson

et al. 2019

Preprint

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Here we describe of an 'Interrogator' instrument that uses liquid-handling robotics, a custom software package, and an integrated mobile microscope to enable automated culture, perfusion, medium addition, fluidic linking, sample collection, and in situ microscopic imaging of up to 10 Organ Chips inside a standard tissue culture incubator. The automated Interrogator platform maintained the viability and organ-specific functions of 8 different vascularized, 2-channel, Organ Chips (intestine, liver, kidney, heart, lung, skin, blood-brain barrier (BBB), and brain) for 3 weeks in culture when fluidically coupled through their endothelium-lined vascular channels using a common blood substitute medium. When an inulin tracer was perfused through the multi-organ Human Body-on-Chips (HuBoC) fluidic network, quantitative distributions of this tracer could be accurately predicted using a physiologically-based multi-compartmental reduced order (MCRO) in silico model of the experimental system derived from first principles. This automated culture platform enables non-invasive imaging of cells within human Organ Chips and repeated sampling of both the vascular and interstitial compartments without compromising fluidic coupling, which should facilitate future HuBoc studies and pharmacokinetics (PK) analysis in vitro.Vascularized human Organ Chips are microfluidic cell culture devices containing separate vascular and parenchymal compartments lined by living human organ-specific cells that recapitulate the multicellular architecture, tissue-tissue interfaces, and relevant physical microenvironments of key functional units of living organs, while providing vascular perfusion in vitro 1,2 . The growing recognition that animal models do not effectively predict drug responses in humans 3-5 and the related increase in demand for in vitro human toxicity and efficacy testing, has led to pursuit of time-course analyses of human Organ Chip models and fluidically linked,

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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A robotic platform for fluidically-linked human body-on-chips experimentation

Novak

Ingram

Clauson

et al. 2019

Preprint

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“…The challenges with preclinical models and tools have spurred the development of cell culture platforms comprising human primary cells in a microfluidic environment, commonly known as microphysiological systems (MPS) or organs-on-chips [20]. Over the past two decades, these devices have evolved from early toxicology platforms to today's wide range of technologies including multi-organ systems [21,22] and a variety of organ-specific models including airway or alveolar tissue systems [23,24]. While the integration of human primary cells or stem cell-derived populations in a physiologically-relevant microenvironment represents a tremendous advance over the use of cell lines in principle, in practice the application of these systems in pharmacological research and development has been severely gated by several factors.…”

Section: Introductionmentioning

confidence: 99%

High-Throughput Human Primary Cell-Based Airway Model for Evaluating Influenza, Coronavirus, or other Respiratory Virusesin vitro

Gard

Maloney

Cain

et al. 2020

Preprint

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Influenza and other respiratory viruses represent a significant threat to public health, national security, and the world economy, and can lead to the emergence of global pandemics such as the current COVID-19 crisis. One of the greatest barriers to the development of effective therapeutic agents to treat influenza, coronaviruses, and many other infections of the respiratory tract is the absence of a robust preclinical model. Preclinical studies currently rely on high-throughput, low-fidelity in vitro screening with cell lines and/or low-throughput animal models that often provide a poor correlation to human clinical responses. Here, we introduce a human primary airway epithelial cell-based model integrated into a highthroughput platform where tissues are cultured at an air-liquid interface (PREDICT96-ALI). We present results on the application of this platform to influenza and coronavirus infections, providing multiple readouts capable of evaluating viral infection kinetics and potentially the efficacy of therapeutic agents in an in vitro system. Several strains of influenza A virus are shown to successfully infect the human primary cell-based airway tissue cultured at an air-liquid interface (ALI), and as a proof-of-concept, the effect of the antiviral oseltamivir on one strain of Influenza A is evaluated. Human coronaviruses NL63 (HCoV-NL63) and SARS-CoV-2 enter host cells via ACE2 and utilize the protease TMPRSS2 for protein priming, and we confirm expression of both in our ALI model. We also demonstrate coronavirus infection in this system with HCoV-NL63, observing sufficient viral propagation over 96 hours post-infection to indicate successful infection of the primary cell-based model. This new capability has the potential to address a gap in the rapid assessment of therapeutic efficacy of various small molecules and antiviral agents against influenza and other respiratory viruses including coronaviruses.

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“…Self-organization of cells into three-dimensional multicellular organoid-like structures may be enhanced by advanced bioengineering strategies including 3D printing 23 . Towards scar-free skin regeneration, various improvements still need to be achieved to get regionalized skin comprizing loco-typic hairiness and appendages ideally also enabling creation of perfect organoid model systems to read-out complex transcriptional regulatory networks in their response to environmental or pharmacologic input signals 24,25 . It remains to be clarified to what extent the rather simplistic organoids can facilitate intercellular communication analysis and development of novel pharmacologic or diagnostic strategies 26 .…”

mentioning

confidence: 99%

Self-assembly of progenitor cells under the aegis of platelet factors facilitates human skin organoid formation and vascularized wound healing

Peking

Krisch

Wolf

et al. 2020

Preprint

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Stem/progenitor cells can self-organize into organoids modelling tissue function and regeneration. Here we demonstrate that human platelet-derived factors can orchestrate 3D self-assembly of clonally expanded adult skin fibroblasts, keratinocytes and endothelial progenitors forming skin organoids within three days. Organoids showed distinct signaling patterns in response to inflammatory stimuli that clearly differed from separated cell types. Human induced pluripotent stem cell (hiPSC)-derived skin cell progenitors also self-assembled into stratified human skin within two weeks, healing deep wounds of immune-deficient mice. Co-transplantation of endothelial progenitors significantly accelerated vascularization. Mechanistically, platelet-derived extracellular vesicles mediated the platelet-derived trophic effects. Long-term fitness of epidermal cells was accelerated further by keratinocyte growth factor mRNA transfection. No tumorigenesis was observed upon xenografting. This permits novel rapid 3D skin-related pharmaceutical testing opportunities and facilitates development of iPSC-based skin regeneration strategies.

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Quantitative prediction of human pharmacokinetic responses to drugs via fluidically coupled vascularized organ chips

Cited by 339 publications

References 68 publications

A robotic platform for fluidically-linked human body-on-chips experimentation

A robotic platform for fluidically-linked human body-on-chips experimentation

High-Throughput Human Primary Cell-Based Airway Model for Evaluating Influenza, Coronavirus, or other Respiratory Virusesin vitro

Self-assembly of progenitor cells under the aegis of platelet factors facilitates human skin organoid formation and vascularized wound healing

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