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Microvasculature-on-a-chip for the long-term study of endothelial barrier dysfunction and microvascular obstruction in disease

Nature Biomedical Engineeringvolume 2pages453463 (2018) | Download Citation


Alterations in the mechanical properties of erythrocytes occurring in inflammatory and haematological disorders such as sickle-cell disease (SCD) and malaria often lead to increased endothelial permeability, haemolysis and microvascular obstruction. However, the associations among these pathological phenomena remain unknown. Here, we show that a perfusable, endothelialized microvasculature-on-a-chip featuring an interpenetrating-polymer-network hydrogel that recapitulates the stiffness of blood vessel intima, basement membrane self-deposition and self-healing endothelial barrier function for longer than one month enables the real-time visualization, with high spatiotemporal resolution, of microvascular obstruction and endothelial permeability under physiological flow conditions. We found that extracellular haem—a haemolytic by-product—induces delayed yet reversible endothelial permeability in a dose-dependent manner, and demonstrate that endothelial interactions with SCD or malaria-infected erythrocytes cause reversible microchannel occlusion and increased in situ endothelial permeability. The microvasculature-on-a-chip enables mechanistic insight into the endothelial barrier dysfunction associated with SCD, malaria and other inflammatory and haematological diseases.

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This work was performed in part at the Georgia Tech Institute for Electronics and Nanotechnology (a member of the National Nanotechnology Coordinated Infrastructure, which is supported by the National Science Foundation (grant ECCS-1542174)). We acknowledge the clinical research personnel at Emory University and the Children’s Healthcare of Atlanta who helped to obtain samples, and the patients for donating blood. We acknowledge D. Archer and L. A. Brown for valuable discussions. We acknowledge the rest of the Lam Lab for technical support and suggestions. Financial support was provided by National Science Foundation CAREER Award 1150235 (to W.A.L.), National Institutes of Health grants U01HL117721 (to S.F.O.-A., C.H.J. and W.A.L.), U54HL112309 (to W.A.L.) and R01HL121264 (to W.A.L.), and the National Institute for Neurological Disorders and Strokes grant R21NS085382 (to T.J.L.).

Author information


  1. Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA

    • Yongzhi Qiu
    • , Byungwook Ahn
    • , Yumiko Sakurai
    • , Reginald Tran
    • , Robert G. Mannino
    • , Jordan C. Ciciliano
    •  & Wilbur A. Lam
  2. Department of Pediatrics, Division of Pediatric Hematology/Oncology, Aflac Cancer Center and Blood Disorders Center of Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA

    • Yongzhi Qiu
    • , Byungwook Ahn
    • , Yumiko Sakurai
    • , Caroline E. Hansen
    • , Reginald Tran
    • , Robert G. Mannino
    • , Clinton H. Joiner
    •  & Wilbur A. Lam
  3. Winship Cancer Institute, Emory University, Atlanta, GA, USA

    • Yongzhi Qiu
    • , Byungwook Ahn
    • , Yumiko Sakurai
    • , Caroline E. Hansen
    • , Reginald Tran
    • , Robert G. Mannino
    • , Jordan C. Ciciliano
    •  & Wilbur A. Lam
  4. Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA

    • Yongzhi Qiu
    • , Byungwook Ahn
    • , Yumiko Sakurai
    • , Reginald Tran
    • , Robert G. Mannino
    • , Jordan C. Ciciliano
    •  & Wilbur A. Lam
  5. Department of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA, USA

    • Caroline E. Hansen
  6. Department of Pathology, University of Utah, Salt Lake City, UT, United States

    • Patrice N. Mimche
    •  & Tracey J. Lamb
  7. George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA

    • Jordan C. Ciciliano
  8. Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    • Solomon F. Ofori-Acquah
  9. Center for Translational and International Hematology, Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA

    • Solomon F. Ofori-Acquah
  10. School of Biomedical and Allied Health Sciences, College of Health Sciences, University of Ghana, Accra, Ghana

    • Solomon F. Ofori-Acquah


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Y.Q. and W.A.L. designed the device. Y.Q., W.A.L., S.F.O.-A., C.H.J. and T.J.L. conceived and designed the project. Y.Q., B.A., Y.S., C.E.H., R.T., P.N.M., R.G.M. and J.C.C. performed the experimental work. Y.Q., W.A.L., S.F.O.-A., C.H.J. and T.J.L. analysed the data. Y.Q., W.A.L., S.F.O.-A., C.H.J., T.J.L., P.N.M. and J.C.C. wrote the manuscript. All authors discussed the results.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Wilbur A. Lam.

Supplementary information

  1. Supplementary Information

    Supplementary figures, tables and video captions.

  2. Reporting Summary

  3. Supplementary Video 1

    3D rendering of confocal microscopy immunostaining images of the adherens-junction protein VE-cadherin in the IPN-hydrogel-based endothelialized microfluidic system.

  4. Supplementary Video 2

    Diffusion of BSA-AF594 from acellular (non-endothelialized) microchannels can be used as a positive control to measure permeability.

  5. Supplementary Video 3

    Perfused BSA-AF594 was maintained in the ‘vascular’ space of the endothelialized microchannels during the permeability assay.

  6. Supplementary Video 4

    Perfusion of RBCs isolated from the sickle-cell disease patients with lower percentages of ISCs (~2.5%) into the engineered microvasculature (4-hour perfusion).

  7. Supplementary Video 5

    Perfusion of RBCs isolated from the sickle-cell disease patients with higher percentages of ISCs into the engineered microvasculature (4-hour perfusion).

  8. Supplementary Video 6

    Perfusion of malaria-infected RBCs into the engineered microvasculature (4-hour perfusion).

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