Robotic fluidic coupling and interrogation of multiple vascularized organ chips.
Journal
Nature biomedical engineering
ISSN: 2157-846X
Titre abrégé: Nat Biomed Eng
Pays: England
ID NLM: 101696896
Informations de publication
Date de publication:
04 2020
04 2020
Historique:
received:
26
02
2019
accepted:
25
11
2019
pubmed:
29
1
2020
medline:
12
5
2020
entrez:
29
1
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31988458
doi: 10.1038/s41551-019-0497-x
pii: 10.1038/s41551-019-0497-x
pmc: PMC8057865
mid: NIHMS1682565
doi:
Types de publication
Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
407-420Subventions
Organisme : NCI NIH HHS
ID : T32 CA009216
Pays : United States
Références
Bhatia, S. N. & Ingber, D. E. Microfluidic organs-on-chips. Nat. Biotechnol. 32, 760–772 (2014).
pubmed: 25093883
doi: 10.1038/nbt.2989
Lee, S. et al. Microfluidic-based vascularized microphysiological systems. Lab Chip 18, 2686–2709 (2018).
pubmed: 30110034
doi: 10.1039/C8LC00285A
Bhushan, A., Martucci, N. J., Usta, O. B. & Yarmush, M. L. New technologies in drug metabolism and toxicity screening: organ-to-organ interaction. Expert Opin. Drug Metab. Toxicol. 12, 475–477 (2016).
pubmed: 26940609
pmcid: 4927438
doi: 10.1517/17425255.2016.1162292
Benigni, R. Predictive toxicology today: the transition from biological knowledge to practicable models. Expert Opin. Drug Metab. Toxicol. 12, 989–992 (2016).
pubmed: 27351633
doi: 10.1080/17425255.2016.1206889
Mak, I. W., Evaniew, N. & Ghert, M. Lost in translation: animal models and clinical trials in cancer treatment. Am. J. Transl. Res. 6, 114–118 (2014).
pubmed: 24489990
pmcid: 3902221
Ewart, L. et al. Application of microphysiological systems to enhance safety assessment in drug discovery. Annu. Rev. Pharmacol. Toxicol. 58, 65–82 (2018).
pubmed: 29029591
doi: 10.1146/annurev-pharmtox-010617-052722
Prantil-Baun, R. et al. Physiologically based pharmacokinetic and pharmacodynamic analysis enabled by microfluidically linked organs-on-chips. Annu. Rev. Pharmacol. Toxicol. 58, 37–64 (2018).
pubmed: 29309256
doi: 10.1146/annurev-pharmtox-010716-104748
Vernetti, L. et al. Functional coupling of human microphysiology systems: intestine, liver, kidney proximal tubule, blood–brain barrier and skeletal muscle. Sci. Rep. 7, 42296 (2017).
pubmed: 28176881
pmcid: 5296733
doi: 10.1038/srep42296
Sung, J. H. et al. Using PBPK guided “Body-on-a-Chip” systems to predict mammalian response to drug and chemical exposure. Exp. Biol. Med. 239, 1225–1239 (2014).
doi: 10.1177/1535370214529397
Wang, Y. I et al. Self-contained, low-cost Body-on-a-Chip systems for drug development. Exp. Biol. Med. 242, 1701–1713 (2017).
doi: 10.1177/1535370217694101
Edington, C. D. et al. Interconnected microphysiological systems for quantitative biology and pharmacology studies. Sci. Rep. 8, 4530 (2018).
pubmed: 29540740
pmcid: 5852083
doi: 10.1038/s41598-018-22749-0
Loskill, P., Marcus, S. G., Mathur, A., Reese, W. M. & Healy, K. E. μOrgano: a Lego®-like plug & play system for modular multi-organ-chips. PLoS ONE 10, e0139587 (2015).
pubmed: 26440672
pmcid: 4595286
doi: 10.1371/journal.pone.0139587
Maoz, B. M. et al. A linked organ-on-chip model of the human neurovascular unit reveals the metabolic coupling of endothelial and neuronal cells. Nat. Biotechnol. 36, 865–874 (2018).
pubmed: 30125269
doi: 10.1038/nbt.4226
Coppeta, J. R. et al. A portable and reconfigurable multi-organ platform for drug development with onboard microfluidic flow control. Lab Chip 17, 134–144 (2016).
pubmed: 27901159
pmcid: 5177565
doi: 10.1039/C6LC01236A
Xiao, S. et al. A microfluidic culture model of the human reproductive tract and 28-day menstrual cycle. Nat. Commun. 8, 14584 (2017).
pubmed: 28350383
pmcid: 5379057
doi: 10.1038/ncomms14584
Esch, M. B., Ueno, H., Applegate, D. R. & Shuler, M. L. Modular, pumpless body-on-a-chip platform for the co-culture of GI tract epithelium and 3D primary liver tissue. Lab Chip 16, 2719–2729 (2016).
pubmed: 27332143
doi: 10.1039/C6LC00461J
Oleaga, C et al. Multi-organ toxicity demonstration in a functional human in vitro system composed of four organs. Sci. Rep. 6, 20030 (2016).
pubmed: 26837601
pmcid: 4738272
doi: 10.1038/srep20030
Sances, S. et al. Human iPSC-derived endothelial cells and microengineered organ-chip enhance neuronal development. Stem Cell Rep. 10, 1222–1236 (2018).
doi: 10.1016/j.stemcr.2018.02.012
Maschmeyer, I. et al. A four-organ-chip for interconnected long-term co-culture of human intestine, liver, skin and kidney equivalents. Lab Chip 15, 2688–2699 (2015).
pubmed: 25996126
doi: 10.1039/C5LC00392J
Bauer, S. et al. Functional coupling of human pancreatic islets and liver spheroids on-a-chip: towards a novel human ex vivo type 2 diabetes model. Sci. Rep. 7, 14620 (2017).
pubmed: 29097671
pmcid: 5668271
doi: 10.1038/s41598-017-14815-w
Yu, F., Selva Kumar, N. D., Choudhury, D., Foo, L. C. & Ng, S. H. Microfluidic platforms for modeling biological barriers in the circulatory system. Drug Discov. Today 23, 815–829 (2018).
pubmed: 29357288
doi: 10.1016/j.drudis.2018.01.036
Poisson, J. et al. Liver sinusoidal endothelial cells: physiology and role in liver diseases. J. Hepatol. 66, 212–227 (2017).
pubmed: 27423426
doi: 10.1016/j.jhep.2016.07.009
Huh, D. et al. Microfabrication of human organs-on-chips. Nat. Protoc. 8, 2135–2157 (2013).
pubmed: 24113786
doi: 10.1038/nprot.2013.137
Novak, R et al. Scalable fabrication of stretchable, dual channel, microfluidic organ chips. J. Vis. Exp. 140, e58151 (2018).
Ewart, L. et al. Navigating tissue chips from development to dissemination: a pharmaceutical industry perspective. Exp. Biol. Med. 242, 1579–1585 (2017).
doi: 10.1177/1535370217715441
Brown, J. A. et al. Recreating blood–brain barrier physiology and structure on chip: a novel neurovascular microfluidic bioreactor. Biomicrofluidics 9, 054124 (2015).
pubmed: 26576206
pmcid: 4627929
doi: 10.1063/1.4934713
Griep, L. M. et al. BBB on chip: microfluidic platform to mechanically and biochemically modulate blood–brain barrier function. Biomed. Microdevices 15, 145–150 (2013).
pubmed: 22955726
doi: 10.1007/s10544-012-9699-7
Huh, D. et al. Reconstituting organ-level lung functions on a chip. Science 328, 1662–1668 (2010).
pubmed: 20576885
pmcid: 8335790
doi: 10.1126/science.1188302
Kim, H. J., Huh, D., Hamilton, G. & Ingber, D. E. Human gut-on-a-chip inhabited by microbial flora that experiences intestinal peristalsis-like motions and flow. Lab Chip 12, 2165–2174 (2012).
pubmed: 22434367
doi: 10.1039/c2lc40074j
Kim, H. J. & Ingber, D. E. Gut-on-a-Chip microenvironment induces human intestinal cells to undergo villus differentiation. Integr. Biol. 5, 1130–1140 (2013).
doi: 10.1039/c3ib40126j
Jang, K.-J. et al. Human kidney proximal tubule-on-a-chip for drug transport and nephrotoxicity assessment. Integr. Biol. 5, 1119–1129 (2013).
doi: 10.1039/c3ib40049b
Imura, Y., Asano, Y., Sato, K. & Yoshimura, E. A microfluidic system to evaluate intestinal absorption. Anal. Sci. 25, 1403–1407 (2009).
pubmed: 20009325
doi: 10.2116/analsci.25.1403
Leclerc, E., Sakai, Y. & Fujii, T. Microfluidic PDMS (polydimethylsiloxane) bioreactor for large-scale culture of hepatocytes. Biotechnol. Prog. 20, 750–755 (2004).
pubmed: 15176878
doi: 10.1021/bp0300568
Kim, H. J., Li, H., Collins, J. J. & Ingber, D. E. Contributions of microbiome and mechanical deformation to intestinal bacterial overgrowth and inflammation in a human gut-on-a-chip. Proc. Natl Acad. Sci. USA 113, E7–E15 (2016).
pubmed: 26668389
Huh, D. et al. A human disease model of drug toxicity-induced pulmonary edema in a lung-on-a-chip microdevice. Sci. Transl Med. 4, 159ra147 (2012).
pubmed: 23136042
pmcid: 8265389
doi: 10.1126/scitranslmed.3004249
Herland, A. et al. Quantitative prediction of human drug pharmacokinetic responses enabled by fluidically coupled vascularized organ chips. Nat. Biomed. Eng. https://doi.org/10.1038/s41551-019-0498-9 (2020).
Toto, R. D. Conventional measurement of renal function utilizing serum creatinine, creatinine clearance, inulin and para-aminohippuric acid clearance. Curr. Opin. Nephrol. Hypertens. 4, 505–509 (1995); discussion 4, 503–504 (1995).
pubmed: 8591059
doi: 10.1097/00041552-199511000-00009
Rahn, K. H., Heidenreich, S. & Brückner, D. How to assess glomerular function and damage in humans. J. Hypertens. 17, 309–317 (1999).
pubmed: 10100067
doi: 10.1097/00004872-199917030-00002
Rose, G. A. Measurement of glomerular filtration rate by inulin clearance without urine collection. BMJ 2, 91–93 (1969).
pubmed: 5775456
pmcid: 1982852
doi: 10.1136/bmj.2.5649.91
Musah, S. et al. Mature induced-pluripotent-stem-cell-derived human podocytes reconstitute kidney glomerular-capillary-wall function on a chip. Nat. Biomed. Eng. 1, 0069 (2017).
pubmed: 29038743
pmcid: 5639718
doi: 10.1038/s41551-017-0069
Kujala, V. J., Pasqualini, F. S., Goss, J. A., Nawroth, J. C. & Parker, K. K. Laminar ventricular myocardium on a microelectrode array-based chip. J. Mater. Chem. B 4, 3534–3543 (2016).
pubmed: 32263387
doi: 10.1039/C6TB00324A
Géraud, C. et al. Unique cell type-specific junctional complexes in vascular endothelium of human and rat liver sinusoids. PLoS ONE 7, e34206 (2012).
pubmed: 22509281
pmcid: 3317944
doi: 10.1371/journal.pone.0034206
Wikswo, J. P. et al. Scaling and systems biology for integrating multiple organs-on-a-chip. Lab Chip 13, 3496–3511 (2013).
pubmed: 23828456
pmcid: 3818688
doi: 10.1039/c3lc50243k
Low, L. A. & Tagle, D. A. Organs-on-chips: progress, challenges, and future directions. Exp. Biol. Med. 242, 1573–1578 (2017).
doi: 10.1177/1535370217700523
Benam, K. H. et al. Small airway-on-a-chip enables analysis of human lung inflammation and drug responses in vitro. Nat. Methods 13, 151–157 (2016).
pubmed: 26689262
doi: 10.1038/nmeth.3697
Benam, K. H. et al. Matched-comparative modeling of normal and diseased human airway responses using a microengineered breathing lung chip. Cell Syst. 3, 456–466.e4 (2016).
pubmed: 27894999
doi: 10.1016/j.cels.2016.10.003
Bein, A. et al. Microfluidic organ-on-a-chip models of human intestine. Cell. Mol. Gastroenterol. Hepatol. 5, 659–668 (2018).
pubmed: 29713674
pmcid: 5924739
doi: 10.1016/j.jcmgh.2017.12.010
Jalili-Firoozinezhad, S. et al. Modeling radiation injury-induced cell death and countermeasure drug responses in a human Gut-on-a-Chip. Cell Death Dis. 9, 223 (2018).
pubmed: 29445080
pmcid: 5833800
doi: 10.1038/s41419-018-0304-8
Agarwal, A., Goss, J. A., Cho, A., McCain, M. L. & Parker, K. K. Microfluidic heart on a chip for higher throughput pharmacological studies. Lab Chip 13, 3599–3608 (2013).
pubmed: 23807141
pmcid: 3786400
doi: 10.1039/c3lc50350j
Hubatsch, I., Ragnarsson, E. G. E. & Artursson, P. Determination of drug permeability and prediction of drug absorption in Caco-2 monolayers. Nat. Protoc. 2, 2111–2119 (2007).
pubmed: 17853866
doi: 10.1038/nprot.2007.303
Lehr, C.-M. Cell Culture Models of Biological Barriers: In vitro Test Systems for Drug Absorption and Delivery (CRC Press, 2003).
Roberts, M. S. & Rowland, M. A dispersion model of hepatic elimination. 1. Formulation of the model and bolus considerations. J. Pharmacokinet. Biopharm. 14, 227–260 (1986).
pubmed: 3783446
doi: 10.1007/BF01106706
Dong, J. & Park, M. S. Discussions on the hepatic well-stirred model: re-derivation from the dispersion model and re-analysis of the lidocaine data. Eur. J. Pharm. Sci. 124, 46–60 (2018).
pubmed: 30102979
doi: 10.1016/j.ejps.2018.08.011
Somayaji, M. R., Das, D. & Przekwas, A. Computational approaches for modeling and analysis of human-on-chip systems for drug testing and characterization. Drug Discov. Today 21, 1859–1862 (2016).
pubmed: 27871942
doi: 10.1016/j.drudis.2016.11.002
Robinson, D. E., Balter, N. J. & Schwartz, S. L. A physiologically based pharmacokinetic model for nicotine and cotinine in man. J. Pharmacokinet. Biopharm. 20, 591–609 (1992).
pubmed: 1302764
doi: 10.1007/BF01064421
Miller, P. G. & Shuler, M. L. Design and demonstration of a pumpless 14 compartment microphysiological system. Biotechnol. Bioeng. 113, 2213–2227 (2016).
pubmed: 27070809
doi: 10.1002/bit.25989
Jalili-Firoozinezhad, S et al. A complex human gut microbiome cultured in an anaerobic intestine-on-a-chip. Nat. Biomed. Eng. 3, 520–531 (2019).
pubmed: 31086325
pmcid: 6658209
doi: 10.1038/s41551-019-0397-0
Phan, D. T. T. et al. A vascularized and perfused organ-on-a-chip platform for large-scale drug screening applications. Lab Chip 17, 511–520 (2017).
pubmed: 28092382
pmcid: 6995340
doi: 10.1039/C6LC01422D
Kasendra, M. et al. Development of a primary human Small Intestine-on-a-Chip using biopsy-derived organoids. Sci. Rep. 8, 2871 (2018).
pubmed: 29440725
pmcid: 5811607
doi: 10.1038/s41598-018-21201-7
Benam, K. H. et al. Human lung small airway-on-a-chip protocol. Methods Mol. Biol. 1612, 345–365 (2017).
pubmed: 28634955
doi: 10.1007/978-1-4939-7021-6_25
Jang, K.-J. et al. Reproducing human and cross-species drug toxicities using a Liver-Chip. Sci. Transl. Med. 11, eaax5516 (2019).
pubmed: 31694927
doi: 10.1126/scitranslmed.aax5516
Tran, T. T. et al. Exact kinetic analysis of passive transport across a polarized confluent MDCK cell monolayer modeled as a single barrier. J. Pharm. Sci. 93, 2108–2123 (2004).
pubmed: 15236458
doi: 10.1002/jps.20105
Maddocks, O. D. K. et al. Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature 493, 542–546 (2013).
pubmed: 23242140
doi: 10.1038/nature11743
Przekwas, A., Friend, T., Teixeira, R., Chen, Z. J. & Wilkerson, P. Spatial Modeling Tools for Cell Biology (CFD Research Corporation, 2006).
Wang, G. et al. Modeling the mitochondrial cardiomyopathy of Barth syndrome with iPSC and heart-on-chip technologies. Nat. Med. 20, 616–623 (2014).
pubmed: 24813252
pmcid: 4172922
doi: 10.1038/nm.3545