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Dual-function injectable angiogenic biomaterial for the repair of brain tissue following stroke

Nature Materials volume 17, pages 642–651 (2018)Cite this article

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Abstract

Stroke is the primary cause of disability due to the brain's limited ability to regenerate damaged tissue. After stroke, an increased inflammatory and immune response coupled with severely limited angiogenesis and neuronal growth results in a stroke cavity devoid of normal brain tissue. In the adult, therapeutic angiogenic materials have been used to repair ischaemic tissues through the formation of vascular networks. However, whether a therapeutic angiogenic material can regenerate brain tissue and promote neural repair is poorly understood. Here we show that the delivery of an engineered immune-modulating angiogenic biomaterial directly to the stroke cavity promotes tissue formation de novo, and results in axonal networks along thee generated blood vessels. This regenerated tissue produces functional recovery through the established axonal networks. Thus, this biomaterials approach generates a vascularized network of regenerated functional neuronal connections within previously dead tissue and lays the groundwork for the use of angiogenic materials to repair other neurologically diseased tissues.

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Fig. 1: Post-stroke angiogenic response and vascular remodelling.
Fig. 2: Long-term post-stroke vascular growth.
Fig. 3: Post-stroke neurogenesis and axonal sprouting.
Fig. 4: Association between the vascular and axonal networks in the lesion site.
Fig. 5: Poststroke neurological recovery.
Fig. 6: Role of naked heparin particles in the hcV treatment at 2 weeks poststroke.

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References

  1. Go, A. S. et al. Heart disease and stroke statistics—2014 update: a report from the American Heart Association. Circulation 129, e28–e292 (2014).

    Article  Google Scholar 

  2. Larrivee, B., Freitas, C., Suchting, S., Brunet, I. & Eichmann, A. Guidance of vascular development: lessons from the nervous system. Circ. Res. 104, 428–441 (2009).

    Article  Google Scholar 

  3. Ohab, J. J., Fleming, S., Blesch, A. & Carmichael, S. T. A neurovascular niche for neurogenesis after stroke. J. Neurosci. 26, 13007–13016 (2006).

    Article  Google Scholar 

  4. Lindvall, O. & Kokaia, Z. Neurogenesis following stroke affecting the adult brain. Cold Spring Harb. Perspect. Biol. 7, a019034 (2015).

    Article  Google Scholar 

  5. Zhang, Z. G. et al. VEGF enhances angiogenesis and promotes blood–brain barrier leakage in the ischemic brain. J. Clin. Investig. 106, 829–838 (2000).

    Article  Google Scholar 

  6. Ergul, A., Alhusban, A. & Fagan, S. C. Angiogenesis: a harmonized target for recovery after stroke. Stroke 43, 2270–2274 (2012).

    Article  Google Scholar 

  7. Huang, L. et al. Glial scar formation occurs in the human brain after ischemic stroke. Int. J. Med. Sci. 11, 344–348 (2014).

    Article  Google Scholar 

  8. Sofroniew, M. V. & Vinters, H. V. Astrocytes: biology and pathology. Acta Neuropathol. 119, 7–35 (2010).

    Article  Google Scholar 

  9. Dirnagl, U., Iadecola, C. & Moskowitz, M. A. Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci. 22, 391–397 (1999).

    Article  Google Scholar 

  10. Fitch, M. T., Doller, C., Combs, C. K., Landreth, G. E. & Silver, J. Cellular and molecular mechanisms of glial scarring and progressive cavitation: in vivo and in vitro analysis of inflammation-induced secondary injury after CNS trauma. J. Neurosci. 19, 8182–8198 (1999).

    Article  Google Scholar 

  11. Nih, L. R., Carmichael, S. T. & Segura, T. Hydrogels for brain repair after stroke: an emerging treatment option. Curr. Opin. Biotechnol. 40, 155–163 (2016).

    Article  Google Scholar 

  12. Nih, L. R. et al. Engineered HA hydrogel for stem cell transplantation in the brain: biocompatibility data using a design of experiment approach. Data Brief. 10, 202–209 (2017).

    Article  Google Scholar 

  13. Moshayedi, P. et al. Systematic optimization of an engineered hydrogel allows for selective control of human neural stem cell survival and differentiation after transplantation in the stroke brain. Biomaterials 105, 145–155 (2016).

    Article  Google Scholar 

  14. Zhu, S., Nih, L. R., Carmichael, S. T., Lu, Y. & Segura, T. Enzyme-responsive delivery of multiple proteins with spatiotemporal control. Adv. Mater. 27, 3620–3625 (2015).

    Article  Google Scholar 

  15. Carmichael, S. T. Cellular and molecular mechanisms of neural repair after stroke: making waves. Ann. Neurol. 59, 735–742 (2006).

    Article  Google Scholar 

  16. Chai, C. & Leong, K. W. Biomaterials approach to expand and direct differentiation of stem cells. Mol. Ther. 15, 467–480 (2007).

    Article  Google Scholar 

  17. Orive, G., Anitua, E., Pedraz, J. L. & Emerich, D. F. Biomaterials for promoting brain protection, repair and regeneration. Nat. Rev. Neurosci. 10, 682–692 (2009).

    Article  Google Scholar 

  18. Lau, L. W., Cua, R., Keough, M. B., Haylock-Jacobs, S. & Yong, V. W. Pathophysiology of the brain extracellular matrix: a new target for remyelination. Nat. Rev. Neurosci. 14, 722–729 (2013).

    Article  Google Scholar 

  19. Hou, S. et al. The repair of brain lesion by implantation of hyaluronic acid hydrogels modified with laminin. J. Neurosci. Methods 148, 60–70 (2005).

    Article  Google Scholar 

  20. Cook, D. J. et al. Hydrogel-delivered brain-derived neurotrophic factor promotes tissue repair and recovery after stroke. J. Cereb. Blood Flow. Metab. 37, 1030–1045 (2017).

    Article  Google Scholar 

  21. Fairbrother, W. J., Champe, M. A., Christinger, H. W., Keyt, B. A. & Starovasnik, M. A. Solution structure of the heparin-binding domain of vascular endothelial growth factor. Structure 6, 637–648 (1998).

    Article  Google Scholar 

  22. Walter, H. L. et al. In vivo analysis of neuroinflammation in the late chronic phase after experimental stroke. Neuroscience 292, 71–80 (2015).

    Article  Google Scholar 

  23. Anderson, M. A. et al. Astrocyte scar formation aids central nervous system axon regeneration. Nature 532, 195–200 (2016).

    Article  Google Scholar 

  24. Chen, Z. L. et al. Ablation of astrocytic laminin impairs vascular smooth muscle cell function and leads to hemorrhagic stroke. J. Cell Biol. 202, 381–395 (2013).

    Article  Google Scholar 

  25. Ferrara, N., Gerber, H. P. & LeCouter, J. The biology of VEGF and its receptors. Nat. Med. 9, 669–676 (2003).

    Article  Google Scholar 

  26. Conway, A. et al. Multivalent ligands control stem cell behaviour in vitro and in vivo. Nat. Nanotechnol. 8, 831–838 (2013).

    Article  Google Scholar 

  27. Lee, K. W. et al. Sustained release of vascular endothelial growth factor from calcium-induced alginate hydrogels reinforced by heparin and chitosan. Transplant. Proc. 36, 2464–2465 (2004).

    Article  Google Scholar 

  28. Chung, C. & Burdick, J. A. Influence of three-dimensional hyaluronic acid microenvironments on mesenchymal stem cell chondrogenesis. Tissue Eng. Part A 15, 243–254 (2009).

    Article  Google Scholar 

  29. Anderson, S. M. et al. VEGF internalization is not required for VEGFR-2 phosphorylation in bioengineered surfaces with covalently linked VEGF. Integr. Biol. Quant. Biosci. Nano Macro. 3, 887–896 (2011).

    Google Scholar 

  30. Lee, S., Jilani, S. M., Nikolova, G. V., Carpizo, D. & Iruela-Arispe, M. L. Processing of VEGF-A by matrix metalloproteinases regulates bioavailability and vascular patterning in tumors. J. Cell Biol. 169, 681–691 (2005).

    Article  Google Scholar 

  31. Wei, L., Erinjeri, J. P., Rovainen, C. M. & Woolsey, T. A. Collateral growth and angiogenesis around cortical stroke. Stroke 32, 2179–2184 (2001).

    Article  Google Scholar 

  32. Ma, Y., Zechariah, A., Qu, Y. & Hermann, D. M. Effects of vascular endothelial growth factor in ischemic stroke. J. Neurosci. Res. 90, 1873–1882 (2012).

    Article  Google Scholar 

  33. Eklund, L. & Olsen, B. R. Tie receptors and their angiopoietin ligands are context-dependent regulators of vascular remodeling. Exp. Cell Res. 312, 630–641 (2006).

    Article  Google Scholar 

  34. Bramfeldt, H., Sabra, G., Centis, V. & Vermette, P. Scaffold vascularization: a challenge for three-dimensional tissue engineering. Curr. Med. Chem. 17, 3944–3967 (2010).

    Article  Google Scholar 

  35. Lorthois, S., Lauwers, F. & Cassot, F. Tortuosity and other vessel attributes for arterioles and venules of the human cerebral cortex. Microvasc. Res. 91, 99–109 (2014).

    Article  Google Scholar 

  36. Arai, K., Jin, G., Navaratna, D. & Lo, E. H. Brain angiogenesis in developmental and pathological processes: neurovascular injury and angiogenic recovery after stroke. FEBS J. 276, 4644–4652 (2009).

    Article  Google Scholar 

  37. Adams, R. H. & Eichmann, A. Axon guidance molecules in vascular patterning. Cold Spring Harb. Perspect. Biol. 2, a001875 (2010).

    Article  Google Scholar 

  38. Barami, K. Relationship of neural stem cells with their vascular niche: implications in the malignant progression of gliomas. J. Clin. Neurosci. 15, 1193–1197 (2008).

    Article  Google Scholar 

  39. Ruiz de Almodovar, C. et al. VEGF mediates commissural axon chemoattraction through its receptor Flk1. Neuron 70, 966–978 (2011).

    Article  Google Scholar 

  40. Nih, L. R. et al. Neuroblast survival depends on mature vascular network formation after mouse stroke: role of endothelial and smooth muscle progenitor cell co-administration. Eur. J. Neurosci. 35, 1208–1217 (2012).

    Article  Google Scholar 

  41. Allred, R. P. et al. The vermicelli handling test: a simple quantitative measure of dexterous forepaw function in rats. J. Neurosci. Methods 170, 229–244 (2008).

    Article  Google Scholar 

  42. Li, S. et al. GDF10 is a signal for axonal sprouting and functional recovery after stroke. Nat. Neurosci. 18, 1737–1745 (2015).

    Article  Google Scholar 

  43. Smith, K. S., Bucci, D. J., Luikart, B. W. & Mahler, S. V. DREADDS: use and application in behavioral neuroscience. Behav. Neurosci. 130, 137–155 (2016).

    Article  Google Scholar 

  44. Croll, S. D. et al. VEGF-mediated inflammation precedes angiogenesis in adult brain. Exp. Neurol. 187, 388–402 (2004).

    Article  Google Scholar 

  45. Busse, C. E., Krotkova, A. & Eichmann, K. The TCRβ enhancer is dispensable for the expression of rearranged TCRβ genes in thymic DN2/DN3 populations but not at later stages. J. Immunol. 175, 3067–3074 (2005).

    Article  Google Scholar 

  46. Wan, M. X., Zhang, X. W., Torkvist, L. & Thorlacius, H. Low molecular weight heparin inhibits tumor necrosis factor-α-induced leukocyte rolling. Inflamm. Res. 50, 581–584 (2001).

    Article  Google Scholar 

  47. Handel, T. M., Johnson, Z., Crown, S. E., Lau, E. K. & Proudfoot, A. E. Regulation of protein function by glycosaminoglycans—as exemplified by chemokines. Annu. Rev. Biochem. 74, 385–410 (2005).

    Article  Google Scholar 

  48. Lohmann, et al. Glycosaminoglycan-based hydrogels capture inflammatory chemokines and rescue defective wound healing in mice. Sci. Transl. Med. 9, aai9044 (2017).

    Article  Google Scholar 

  49. Anderson, S. M., Siegman, S. N. & Segura, T. The effect of vascular endothelial growth factor (VEGF) presentation within fibrin matrices on endothelial cell branching. Biomaterials 32, 7432–7443 (2011).

    Article  Google Scholar 

  50. Anderson, S. M., Chen, T. T., Iruela-Arispe, M. L. & Segura, T. The phosphorylation of vascular endothelial growth factor receptor-2 (VEGFR-2) by engineered surfaces with electrostatically or covalently immobilized VEGF. Biomaterials 30, 4618–4628 (2009).

    Article  Google Scholar 

  51. Lei, Y.,Gojgini, S. & Segura, T. The spreading, migration and proliferation of mouse mesenchymal stem cells cultured inside hyaluronic acid hydrogels. Biomaterials 32, 39–47 (2011).

    Article  Google Scholar 

  52. Lam, J. & Segura, T. The modulation of MSC integrin expression by RGD presentation. Biomaterials 34, 3938–3947 (2013).

    Article  Google Scholar 

  53. Liu, S., Zhen, G., Meloni, B. P., Campbell, K. & Winn, H. R. Rodent stroke model guidelines for preclinical stroke trials. J. Exp. Stroke Transl. Med. 2, 2–27 (2009).

    Article  Google Scholar 

  54. Fluri, F., Schuhmann, M. K. & Kleinschnitz, C. Animal models of ischemic stroke and their application in clinical research. Drug Des. Dev. Ther. 9, 3445–3454 (2015).

    Google Scholar 

  55. Carmichael, S. T. Rodent models of focal stroke: size, mechanism, and purpose. NeuroRx 2, 396–409 (2005).

    Article  Google Scholar 

  56. Carmichael, S. T. Emergent properties of neural repair: elemental biology to therapeutic concepts. Ann. Neurol. 79, 895–906 (2016).

    Article  Google Scholar 

  57. Carmichael, S. T. The 3 Rs of stroke biology: radial, relayed, and regenerative. Neurotherapeutics 13, 348–359 (2016).

    Article  Google Scholar 

  58. Clarkson, A. N., Huang, B. S., Macisaac, S. E., Mody, I. & Carmichael, S. T. Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke. Nature 468, 305–309 (2010).

    Article  Google Scholar 

  59. Scott, A. K. et al. Magnetic resonance elastography of the brain. NeuroImage 39, 231–237 (2008).

    Article  Google Scholar 

  60. Salhia, B. et al. Expression of vascular endothelial growth factor by reactive astrocytes and associated neoangiogenesis. Brain Res 883, 87–97 (2000).

    Article  Google Scholar 

  61. Tsai, P. T. et al. A critical role of erythropoietin receptor in neurogenesis and post-stroke recovery. J. Neurosci. 26, 1269–1274 (2006).

    Article  Google Scholar 

  62. Li, S. et al. Hydrogels with precisely controlled integrin activation dictate vascular patterning and permeability. Nat. Mater. 16, 953–961 (2017).

    Article  Google Scholar 

  63. Fukui, S., Fazzina, G., Amorini, A. M., Dunbar, J. G. & Marmarou, A. Differential effects of atrial natriuretic peptide on the brain water and sodium after experimental cortical contusion in the rat. J. Cereb. Blood Flow. Metab. 23, 1212–1218 (2003).

    Article  Google Scholar 

  64. Rogan, S. C. & Roth, B. L. Remote control of neuronal signaling. Pharmacol. Rev. 63, 291–315 (2011).

    Article  Google Scholar 

  65. Schallert, T., Fleming, S. M., Leasure, J. L., Tillerson, J. L. & Bland, S. T. CNS plasticity and assessment of forelimb sensorimotor outcome in unilateral rat models of stroke, cortical ablation, parkinsonism and spinal cord injury. Neuropharmacology 39, 777–787 (2000).

    Article  Google Scholar 

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Acknowledgements

This work was supported through the US National Institutes of Health NIH RO1NS079691. The Bioplex experiment was done at the UCLA IMT core, Center for Systems Biomedicine, which is supported by CURE/P30 DK041301.

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Authors and Affiliations

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

    Lina R. Nih, Shiva Gojgini & Tatiana Segura

  2. Department of Neurology David Geffen School of Medicine, University of California, Los Angeles, USA, CA

    Lina R. Nih & S. Thomas Carmichael

  3. Department of Biomedical Engineering, Neurology, Dermatology, Duke University, Durham, NC, USA

    Tatiana Segura

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  1. Lina R. Nih
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  2. Shiva Gojgini
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Contributions

L.R.N. was responsible for the conceptual design of the in vivo study, troubleshooting, experimental execution, interpretation of in vivo data, manuscript writing and figure creation. S.G. performed in vitro studies and interpretation, sample preparation and characterization. T.S. and S.T.C. contributed equally to overseeing experimental design and interpretation.

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Correspondence to S. Thomas Carmichael or Tatiana Segura.

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Nih, L.R., Gojgini, S., Carmichael, S.T. et al. Dual-function injectable angiogenic biomaterial for the repair of brain tissue following stroke. Nature Mater 17, 642–651 (2018). https://doi.org/10.1038/s41563-018-0083-8

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