A multi-organ chip with matured tissue niches linked by vascular flow

Kacey Ronaldson-Bouchard, Diogo Teles, Keith Yeager, Daniel Naveed Tavakol, Yimu Zhao, Alan Chramiec, Somnath Tagore, Max Summers, Sophia Stylianos, Manuel Tamargo, Busub Marcus Lee, Susan P. Halligan, Erbil Hasan Abaci, Zongyou Guo, Joanna Jacków, Alberto Pappalardo, Jerry Shih, Rajesh K. Soni, Shivam Sonar, Carrie GermanAngela M. Christiano, Andrea Califano, Karen K. Hirschi, Christopher S. Chen, Andrzej Przekwas, Gordana Vunjak-Novakovic

Research output: Contribution to journalArticlepeer-review

173 Scopus citations

Abstract

Engineered tissues can be used to model human pathophysiology and test the efficacy and safety of drugs. Yet, to model whole-body physiology and systemic diseases, engineered tissues with preserved phenotypes need to physiologically communicate. Here we report the development and applicability of a tissue-chip system in which matured human heart, liver, bone and skin tissue niches are linked by recirculating vascular flow to allow for the recapitulation of interdependent organ functions. Each tissue is cultured in its own optimized environment and is separated from the common vascular flow by a selectively permeable endothelial barrier. The interlinked tissues maintained their molecular, structural and functional phenotypes over 4 weeks of culture, recapitulated the pharmacokinetic and pharmacodynamic profiles of doxorubicin in humans, allowed for the identification of early miRNA biomarkers of cardiotoxicity, and increased the predictive values of clinically observed miRNA responses relative to tissues cultured in isolation and to fluidically interlinked tissues in the absence of endothelial barriers. Vascularly linked and phenotypically stable matured human tissues may facilitate the clinical applicability of tissue chips.

Original languageEnglish
Pages (from-to)351-371
Number of pages21
JournalNature Biomedical Engineering
Volume6
Issue number4
DOIs
StatePublished - Apr 2022
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.

Funding

We gratefully acknowledge funding of this research by the NIH (UG3 EB025765, P41 EB027062 and R01 CA249799 to G.V.-N.; R35 CA197745, S10 OD012351 and S10 OD021764 to An.C.; UL1 TR001873 to the Irving Institute for Clinical and Translational Research; P30 CA013696 to the Confocal and Specialized Microscopy Shared Resource), NSF (Engineering Reseach Center EEC-1647837 to C.S.C. and G.V.-N., Graduate Research Fellowship DGE1644869 to D.N.T.) and F.C.T. (PD/BD/105819/2014 to D.T.). We thank P. L. Graney, E. Öztürk, M. C. Samaritano, N. Valerio Dorrello and B. Fine for helpful discussions; R. Nandakumar and C. Qiao (Biomarkers Core Laboratory at the Irving Institute for Clinical Translational Research), M. Kissner (Columbia Stem Cell Initiative Flow Cytometry Core), C. Damoci (Oncology Precision Therapeutics and Imaging Core Shared Resource), the Molecular Pathology, Confocal and Specialized Microscopy, and the Oncology Precision Therapeutics and Imaging Core Shared Resources at the Columbia University Herbert Irving Comprehensive Cancer Center for technical support. We gratefully acknowledge funding of this research by the NIH (UG3 EB025765, P41 EB027062 and R01 CA249799 to G.V.-N.; R35 CA197745, S10 OD012351 and S10 OD021764 to An.C.; UL1 TR001873 to the Irving Institute for Clinical and Translational Research; P30 CA013696 to the Confocal and Specialized Microscopy Shared Resource), NSF (Engineering Reseach Center EEC-1647837 to C.S.C. and G.V.-N., Graduate Research Fellowship DGE1644869 to D.N.T.) and F.C.T. (PD/BD/105819/2014 to D.T.). We thank P. L. Graney, E. ?zt?rk, M. C. Samaritano, N. Valerio Dorrello and B. Fine for helpful discussions; R. Nandakumar and C. Qiao (Biomarkers Core Laboratory at the Irving Institute for Clinical Translational Research), M. Kissner (Columbia Stem Cell Initiative Flow Cytometry Core), C. Damoci (Oncology Precision Therapeutics and Imaging Core Shared Resource), the Molecular Pathology, Confocal and Specialized Microscopy, and the Oncology Precision Therapeutics and Imaging Core Shared Resources at the Columbia University Herbert Irving Comprehensive Cancer Center for technical support.

FundersFunder number
Engineering Reseach CenterEEC-1647837, PD/BD/105819/2014, DGE1644869
Irving Institute for Clinical Translational Research
National Science Foundation
National Institutes of HealthP41 EB027062, R35 CA197745, UL1 TR001873, S10 OD012351, UG3 EB025765, P30 CA013696, S10 OD021764
National Cancer InstituteR01CA249799

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