Robotic fluidic coupling and interrogation of multiple vascularized organ chips

Richard Novak; Miles Ingram; Susan Marquez; Debarun Das; Aaron Delahanty; Anna Herland; Ben M. Maoz; Sauveur S.F. Jeanty; Mahadevabharath R. Somayaji; Morgan Burt; Elizabeth Calamari; Angeliki Chalkiadaki; Alexander Cho; Youngjae Choe; David Benson Chou; Michael Cronce; Stephanie Dauth; Toni Divic; Jose Fernandez-Alcon; Thomas Ferrante; John Ferrier; Edward A. FitzGerald; Rachel Fleming; Sasan Jalili-Firoozinezhad; Thomas Grevesse; Josue A. Goss; Tiama Hamkins-Indik; Olivier Henry; Chris Hinojosa; Tessa Huffstater; Kyung Jin Jang; Ville Kujala; Lian Leng; Robert Mannix; Yuka Milton; Janna Nawroth; Bret A. Nestor; Carlos F. Ng; Blakely O’Connor; Tae Eun Park; Henry Sanchez; Josiah Sliz; Alexandra Sontheimer-Phelps; Ben Swenor; Guy Thompson; George J. Touloumes; Zachary Tranchemontagne; Norman Wen; Moran Yadid; Anthony Bahinski; Geraldine A. Hamilton; Daniel Levner; Oren Levy; Andrzej Przekwas; Rachelle Prantil-Baun; Kevin K. Parker; Donald E. Ingber

doi:10.1038/s41551-019-0497-x

Robotic fluidic coupling and interrogation of multiple vascularized organ chips

Richard Novak, Miles Ingram, Susan Marquez, Debarun Das, Aaron Delahanty, Anna Herland, Ben M. Maoz, Sauveur S.F. Jeanty, Mahadevabharath R. Somayaji, Morgan Burt, Elizabeth Calamari, Angeliki Chalkiadaki, Alexander Cho, Youngjae Choe, David Benson Chou, Michael Cronce, Stephanie Dauth, Toni Divic, Jose Fernandez-Alcon, Thomas FerranteJohn Ferrier, Edward A. FitzGerald, Rachel Fleming, Sasan Jalili-Firoozinezhad, Thomas Grevesse, Josue A. Goss, Tiama Hamkins-Indik, Olivier Henry, Chris Hinojosa, Tessa Huffstater, Kyung Jin Jang, Ville Kujala, Lian Leng, Robert Mannix, Yuka Milton, Janna Nawroth, Bret A. Nestor, Carlos F. Ng, Blakely O’Connor, Tae Eun Park, Henry Sanchez, Josiah Sliz, Alexandra Sontheimer-Phelps, Ben Swenor, Guy Thompson, George J. Touloumes, Zachary Tranchemontagne, Norman Wen, Moran Yadid, Anthony Bahinski, Geraldine A. Hamilton, Daniel Levner, Oren Levy, Andrzej Przekwas, Rachelle Prantil-Baun, Kevin K. Parker, Donald E. Ingber

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Abstract

Organ chips can recapitulate organ-level (patho)physiology, yet pharmacokinetic and pharmacodynamic analyses require multi-organ systems linked by vascular perfusion. Here, we describe an ‘interrogator’ that employs liquid-handling robotics, custom software and an integrated mobile microscope for the automated culture, perfusion, medium addition, fluidic linking, sample collection and in situ microscopy imaging of up to ten organ chips inside a standard tissue-culture incubator. The robotic interrogator maintained the viability and organ-specific functions of eight vascularized, two-channel organ chips (intestine, liver, kidney, heart, lung, skin, blood–brain barrier and brain) for 3 weeks in culture when intermittently fluidically coupled via a common blood substitute through their reservoirs of medium and endothelium-lined vascular channels. We used the robotic interrogator and a physiological multicompartmental reduced-order model of the experimental system to quantitatively predict the distribution of an inulin tracer perfused through the multi-organ human-body-on-chips. The automated culture system enables the imaging of cells in the organ chips and the repeated sampling of both the vascular and interstitial compartments without compromising fluidic coupling.

Original language	English
Pages (from-to)	407-420
Number of pages	14
Journal	Nature Biomedical Engineering
Volume	4
Issue number	4
DOIs	https://doi.org/10.1038/s41551-019-0497-x
State	Published - 1 Apr 2020
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.

Funding

This research was sponsored by the Wyss Institute for Biologically Inspired Engineering at Harvard University and the Defense Advanced Research Projects Agency under Cooperative Agreement number W911NF-12-2-0036. The views and conclusions contained in this document are those of the authors and should not be interpreted as representing the official policies, either expressed or implied, of the Defense Advanced Research Projects Agency or the US government. This work was performed in part at the Center for Nanoscale Systems (CNS), a member of the National Nanotechnology Coordinated Infrastructure Network (NNCI), which is supported by the National Science Foundation under NSF award number 1541959. The CNS is part of Harvard University, the Harvard Materials Research Science and Engineering Center (DMR-1420570). The authors thank J. Caramanica and P. Machado for their machining expertise, M. Rosnach for his artwork, B. Fountaine and S. Kroll for their help with photography, M. Rousseau for help with videography, C. Vidoudez for mass spectrometry analysis, and J. Wikswo for helpful input at the start of this project.

Funders	Funder number
National Science Foundation	1541959
National Cancer Institute	T32CA009216
Defense Advanced Research Projects Agency	W911NF-12-2-0036
Hansjörg Wyss Institute for Biologically Inspired Engineering, Harvard University

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Novak, R., Ingram, M., Marquez, S., Das, D., Delahanty, A., Herland, A., Maoz, B. M., Jeanty, S. S. F., Somayaji, M. R., Burt, M., Calamari, E., Chalkiadaki, A., Cho, A., Choe, Y., Chou, D. B., Cronce, M., Dauth, S., Divic, T., Fernandez-Alcon, J., ... Ingber, D. E. (2020). Robotic fluidic coupling and interrogation of multiple vascularized organ chips. Nature Biomedical Engineering, 4(4), 407-420. https://doi.org/10.1038/s41551-019-0497-x

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abstract = "Organ chips can recapitulate organ-level (patho)physiology, yet pharmacokinetic and pharmacodynamic analyses require multi-organ systems linked by vascular perfusion. Here, we describe an {\textquoteleft}interrogator{\textquoteright} that employs liquid-handling robotics, custom software and an integrated mobile microscope for the automated culture, perfusion, medium addition, fluidic linking, sample collection and in situ microscopy imaging of up to ten organ chips inside a standard tissue-culture incubator. The robotic interrogator maintained the viability and organ-specific functions of eight vascularized, two-channel organ chips (intestine, liver, kidney, heart, lung, skin, blood–brain barrier and brain) for 3 weeks in culture when intermittently fluidically coupled via a common blood substitute through their reservoirs of medium and endothelium-lined vascular channels. We used the robotic interrogator and a physiological multicompartmental reduced-order model of the experimental system to quantitatively predict the distribution of an inulin tracer perfused through the multi-organ human-body-on-chips. The automated culture system enables the imaging of cells in the organ chips and the repeated sampling of both the vascular and interstitial compartments without compromising fluidic coupling.",

author = "Richard Novak and Miles Ingram and Susan Marquez and Debarun Das and Aaron Delahanty and Anna Herland and Maoz, {Ben M.} and Jeanty, {Sauveur S.F.} and Somayaji, {Mahadevabharath R.} and Morgan Burt and Elizabeth Calamari and Angeliki Chalkiadaki and Alexander Cho and Youngjae Choe and Chou, {David Benson} and Michael Cronce and Stephanie Dauth and Toni Divic and Jose Fernandez-Alcon and Thomas Ferrante and John Ferrier and FitzGerald, {Edward A.} and Rachel Fleming and Sasan Jalili-Firoozinezhad and Thomas Grevesse and Goss, {Josue A.} and Tiama Hamkins-Indik and Olivier Henry and Chris Hinojosa and Tessa Huffstater and Jang, {Kyung Jin} and Ville Kujala and Lian Leng and Robert Mannix and Yuka Milton and Janna Nawroth and Nestor, {Bret A.} and Ng, {Carlos F.} and Blakely O{\textquoteright}Connor and Park, {Tae Eun} and Henry Sanchez and Josiah Sliz and Alexandra Sontheimer-Phelps and Ben Swenor and Guy Thompson and Touloumes, {George J.} and Zachary Tranchemontagne and Norman Wen and Moran Yadid and Anthony Bahinski and Hamilton, {Geraldine A.} and Daniel Levner and Oren Levy and Andrzej Przekwas and Rachelle Prantil-Baun and Parker, {Kevin K.} and Ingber, {Donald E.}",

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doi = "10.1038/s41551-019-0497-x",

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Novak, R, Ingram, M, Marquez, S, Das, D, Delahanty, A, Herland, A, Maoz, BM, Jeanty, SSF, Somayaji, MR, Burt, M, Calamari, E, Chalkiadaki, A, Cho, A, Choe, Y, Chou, DB, Cronce, M, Dauth, S, Divic, T, Fernandez-Alcon, J, Ferrante, T, Ferrier, J, FitzGerald, EA, Fleming, R, Jalili-Firoozinezhad, S, Grevesse, T, Goss, JA, Hamkins-Indik, T, Henry, O, Hinojosa, C, Huffstater, T, Jang, KJ, Kujala, V, Leng, L, Mannix, R, Milton, Y, Nawroth, J, Nestor, BA, Ng, CF, O’Connor, B, Park, TE, Sanchez, H, Sliz, J, Sontheimer-Phelps, A, Swenor, B, Thompson, G, Touloumes, GJ, Tranchemontagne, Z, Wen, N, Yadid, M, Bahinski, A, Hamilton, GA, Levner, D, Levy, O, Przekwas, A, Prantil-Baun, R, Parker, KK & Ingber, DE 2020, 'Robotic fluidic coupling and interrogation of multiple vascularized organ chips', Nature Biomedical Engineering, vol. 4, no. 4, pp. 407-420. https://doi.org/10.1038/s41551-019-0497-x

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T1 - Robotic fluidic coupling and interrogation of multiple vascularized organ chips

AU - Novak, Richard

AU - Ingram, Miles

AU - Marquez, Susan

AU - Das, Debarun

AU - Delahanty, Aaron

AU - Herland, Anna

AU - Maoz, Ben M.

AU - Jeanty, Sauveur S.F.

AU - Somayaji, Mahadevabharath R.

AU - Burt, Morgan

AU - Calamari, Elizabeth

AU - Chalkiadaki, Angeliki

AU - Cho, Alexander

AU - Choe, Youngjae

AU - Chou, David Benson

AU - Cronce, Michael

AU - Dauth, Stephanie

AU - Divic, Toni

AU - Fernandez-Alcon, Jose

AU - Ferrante, Thomas

AU - Ferrier, John

AU - FitzGerald, Edward A.

AU - Fleming, Rachel

AU - Jalili-Firoozinezhad, Sasan

AU - Grevesse, Thomas

AU - Goss, Josue A.

AU - Hamkins-Indik, Tiama

AU - Henry, Olivier

AU - Hinojosa, Chris

AU - Huffstater, Tessa

AU - Jang, Kyung Jin

AU - Kujala, Ville

AU - Leng, Lian

AU - Mannix, Robert

AU - Milton, Yuka

AU - Nawroth, Janna

AU - Nestor, Bret A.

AU - Ng, Carlos F.

AU - O’Connor, Blakely

AU - Park, Tae Eun

AU - Sanchez, Henry

AU - Sliz, Josiah

AU - Sontheimer-Phelps, Alexandra

AU - Swenor, Ben

AU - Thompson, Guy

AU - Touloumes, George J.

AU - Tranchemontagne, Zachary

AU - Wen, Norman

AU - Yadid, Moran

AU - Bahinski, Anthony

AU - Hamilton, Geraldine A.

AU - Levner, Daniel

AU - Levy, Oren

AU - Przekwas, Andrzej

AU - Prantil-Baun, Rachelle

AU - Parker, Kevin K.

AU - Ingber, Donald E.

PY - 2020/4/1

Y1 - 2020/4/1

N2 - Organ chips can recapitulate organ-level (patho)physiology, yet pharmacokinetic and pharmacodynamic analyses require multi-organ systems linked by vascular perfusion. Here, we describe an ‘interrogator’ that employs liquid-handling robotics, custom software and an integrated mobile microscope for the automated culture, perfusion, medium addition, fluidic linking, sample collection and in situ microscopy imaging of up to ten organ chips inside a standard tissue-culture incubator. The robotic interrogator maintained the viability and organ-specific functions of eight vascularized, two-channel organ chips (intestine, liver, kidney, heart, lung, skin, blood–brain barrier and brain) for 3 weeks in culture when intermittently fluidically coupled via a common blood substitute through their reservoirs of medium and endothelium-lined vascular channels. We used the robotic interrogator and a physiological multicompartmental reduced-order model of the experimental system to quantitatively predict the distribution of an inulin tracer perfused through the multi-organ human-body-on-chips. The automated culture system enables the imaging of cells in the organ chips and the repeated sampling of both the vascular and interstitial compartments without compromising fluidic coupling.

AB - Organ chips can recapitulate organ-level (patho)physiology, yet pharmacokinetic and pharmacodynamic analyses require multi-organ systems linked by vascular perfusion. Here, we describe an ‘interrogator’ that employs liquid-handling robotics, custom software and an integrated mobile microscope for the automated culture, perfusion, medium addition, fluidic linking, sample collection and in situ microscopy imaging of up to ten organ chips inside a standard tissue-culture incubator. The robotic interrogator maintained the viability and organ-specific functions of eight vascularized, two-channel organ chips (intestine, liver, kidney, heart, lung, skin, blood–brain barrier and brain) for 3 weeks in culture when intermittently fluidically coupled via a common blood substitute through their reservoirs of medium and endothelium-lined vascular channels. We used the robotic interrogator and a physiological multicompartmental reduced-order model of the experimental system to quantitatively predict the distribution of an inulin tracer perfused through the multi-organ human-body-on-chips. The automated culture system enables the imaging of cells in the organ chips and the repeated sampling of both the vascular and interstitial compartments without compromising fluidic coupling.

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JF - Nature Biomedical Engineering

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Robotic fluidic coupling and interrogation of multiple vascularized organ chips

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