Article

Hydrogels with precisely controlled integrin activation dictate vascular patterning and permeability

  • Nature Materials volume 16, pages 953961 (2017)
  • doi:10.1038/nmat4954
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Abstract

Integrin binding to bioengineered hydrogel scaffolds is essential for tissue regrowth and regeneration, yet not all integrin binding can lead to tissue repair. Here, we show that through engineering hydrogel materials to promote α3/α5β1 integrin binding, we can promote the formation of a space-filling and mature vasculature compared with hydrogel materials that promote αvβ3 integrin binding. In vitro, α3/α5β1 scaffolds promoted endothelial cells to sprout and branch, forming organized extensive networks that eventually reached and anastomosed with neighbouring branches. In vivo, α3/α5β1 scaffolds delivering vascular endothelial growth factor (VEGF) promoted non-tortuous blood vessel formation and non-leaky blood vessels by 10 days post-stroke. In contrast, materials that promote αvβ3 integrin binding promoted endothelial sprout clumping in vitro and leaky vessels in vivo. This work shows that precisely controlled integrin activation from a biomaterial can be harnessed to direct therapeutic vessel regeneration and reduce VEGF-induced vascular permeability in vivo.

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Acknowledgements

The authors would like to thank Y. Chen and X. Chen for their help with flow cytometry. The authors would like to acknowledge Developmental Studies Hybridoma Bank (DSHB) for providing antibodies P3G8, AIIB2, BIIG2 and 9H5. This work was supported by National Institutes of Health R01NS079691 (T.S.).

Author information

Affiliations

  1. Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, California 90095, USA

    • Shuoran Li
    • , Lina R. Nih
    • , Eunwoo Nam
    • , Robert Dimatteo
    •  & Tatiana Segura
  2. Department of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332, USA

    • Haylee Bachman
  3. School of Optical and Electronic Information, Huazhong University of Science and Technology, Wuhan 430074, China

    • Peng Fei
  4. Department of Mechanical and Aerospace Engineering, University of California, Los Angeles, California 90095, USA

    • Peng Fei
  5. Department of Electrical Engineering, University of California, Los Angeles, California 90095, USA

    • Yilei Li
  6. NovuMind Inc., Santa Clara, California 95054, USA

    • Yilei Li
  7. Department of Medicine, Neurology, University of California, Los Angeles, California 90095, USA

    • S. Thomas Carmichael
  8. Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22908, USA

    • Thomas H. Barker
  9. Department of Medicine, Dermatology, University of California, Los Angeles, California 90095, USA

    • Tatiana Segura
  10. Department of Bioengineering, University of California, Los Angeles, California 90095, USA

    • Tatiana Segura

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Contributions

S.L. contributed to conceptual design, experimental execution, and troubleshooting. L.R.N. contributed to conceptual design, experimental execution, and troubleshooting for experiments involving the middle cerebral artery occlusion stroke model (Fig. 5). H.B. contributed to conceptual design, troubleshooting and production of the Fn910 and Fn9(4G)10 fibronectin fragments. P.F. contributed to conceptual design and troubleshooting of sheet confocal imaging for the modified Matrigel plug assay. Y.L. contributed to the conceptual design and experimental execution of the Matlab code used for cell migration analysis in Supplementary Fig. 1e, f. E.N. contributed to experimental execution and troubleshooting for experiments involving VE-cadherin quantification. R.D. contributed to the conceptual design and experimental execution of the Matlab code used for space-filling analysis in Fig. 4d. S.T.C. contributed to the conceptual design, and data interpretation for Fig. 5. T.H.B. contributed to conceptual design and troubleshooting of the Fn910 and Fn9(4G)10 fibronectin fragments. T.S. contributed to conceptual design, and oversaw all experimental design and interpretation. While S.L. and T.S. wrote the first draft of the manuscript all authors read and gave comments, especially with regards to their experimental section and analysis.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Tatiana Segura.

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