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Research Article

Diabetic wound regeneration using peptide-modified hydrogels to target re-epithelialization

Yun Xiao, Lewis A. Reis, Nicole Feric, Erica J. Knee, Junhao Gu, Shuwen Cao, Carol Laschinger, Camila Londono, Julia Antolovich, Alison P. McGuigan, and Milica Radisic
  1. aDepartment of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON M5S 3E5, Canada;
  2. bInstitute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada;
  3. cDepartment of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada;
  4. dDepartment of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada;
  5. eToronto General Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada

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PNAS October 4, 2016 113 (40) E5792-E5801; first published September 19, 2016; https://doi.org/10.1073/pnas.1612277113
Yun Xiao
aDepartment of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON M5S 3E5, Canada;
bInstitute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada;
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Lewis A. Reis
bInstitute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada;
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Nicole Feric
bInstitute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada;
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Erica J. Knee
bInstitute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada;
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Junhao Gu
aDepartment of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON M5S 3E5, Canada;
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Shuwen Cao
aDepartment of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON M5S 3E5, Canada;
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Carol Laschinger
bInstitute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada;
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Camila Londono
bInstitute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada;
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Julia Antolovich
cDepartment of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada;
dDepartment of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada;
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Alison P. McGuigan
aDepartment of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON M5S 3E5, Canada;
bInstitute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada;
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Milica Radisic
aDepartment of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON M5S 3E5, Canada;
bInstitute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada;
eToronto General Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada
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  • For correspondence: m.radisic@utoronto.ca
  1. Edited by Robert Langer, Massachusetts Institute of Technology, Cambridge, MA, and approved August 19, 2016 (received for review July 27, 2016)

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Significance

Current treatments for diabetic chronic wounds fail to achieve effective therapeutic outcomes. The majority of these treatments focus on angiogenesis, but diabetes often involves endothelial dysfunction. A hallmark of regenerative wound healing is rapid, effective re-epithelialization. In this study, we present QHREDGS (glutamine-histidine-arginine-glutamic acid-aspartic acid-glycine-serine), a prosurvival peptide derived from angiopoietin-1, as a therapeutic candidate that targets re-epithelialization. Immobilized QHREDGS peptide promoted cell survival against hydrogen peroxide stress and collective cell migration of both normal and diabetic human keratinocytes in vitro. The clinical relevance was demonstrated further in type 2 diabetic mice: A single treatment with a low QHREDGS dose immobilized in chitosan–collagen was effective in promoting wound healing, and a single high-dose peptide treatment outperformed a clinically approved porous collagen dressing.

Abstract

There is a clinical need for new, more effective treatments for chronic wounds in diabetic patients. Lack of epithelial cell migration is a hallmark of nonhealing wounds, and diabetes often involves endothelial dysfunction. Therefore, targeting re-epithelialization, which mainly involves keratinocytes, may improve therapeutic outcomes of current treatments. In this study, we present an integrin-binding prosurvival peptide derived from angiopoietin-1, QHREDGS (glutamine-histidine-arginine-glutamic acid-aspartic acid-glycine-serine), as a therapeutic candidate for diabetic wound treatments by demonstrating its efficacy in promoting the attachment, survival, and collective migration of human primary keratinocytes and the activation of protein kinase B Akt and MAPKp42/44. The QHREDGS peptide, both as a soluble supplement and when immobilized in a substrate, protected keratinocytes against hydrogen peroxide stress in a dose-dependent manner. Collective migration of both normal and diabetic human keratinocytes was promoted on chitosan–collagen films with the immobilized QHREDGS peptide. The clinical relevance was demonstrated further by assessing the chitosan–collagen hydrogel with immobilized QHREDGS in full-thickness excisional wounds in a db/db diabetic mouse model; QHREDGS showed significantly accelerated and enhanced wound closure compared with a clinically approved collagen wound dressing, peptide-free hydrogel, or blank wound controls. The accelerated wound closure resulted primarily from faster re-epithelialization and increased formation of granulation tissue. There were no observable differences in blood vessel density or size within the wound; however, the total number of blood vessels was greater in the peptide-hydrogel–treated wounds. Together, these findings indicate that QHREDGS is a promising candidate for wound-healing interventions that enhance re-epithelialization and the formation of granulation tissue.

  • diabetic wound healing
  • peptide
  • hydrogel
  • QHREDGS
  • re-epithelialization

Footnotes

  • ↵1To whom correspondence should be addressed. Email: m.radisic{at}utoronto.ca.
  • Author contributions: Y.X., A.P.M., and M.R. designed research; Y.X., L.A.R., and C. Londono performed research; M.R. supervised research; A.P.M. advised on experiments; Y.X., J.G., S.C., and C. Laschinger contributed new reagents/analytic tools; Y.X., L.A.R., N.F., E.J.K., J.G., S.C., C. Laschinger, and J.A. analyzed data; and Y.X., L.A.R., N.F., and M.R. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1612277113/-/DCSupplemental.

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Peptide-modified hydrogels for wound regeneration
Yun Xiao, Lewis A. Reis, Nicole Feric, Erica J. Knee, Junhao Gu, Shuwen Cao, Carol Laschinger, Camila Londono, Julia Antolovich, Alison P. McGuigan, Milica Radisic
Proceedings of the National Academy of Sciences Oct 2016, 113 (40) E5792-E5801; DOI: 10.1073/pnas.1612277113

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Peptide-modified hydrogels for wound regeneration
Yun Xiao, Lewis A. Reis, Nicole Feric, Erica J. Knee, Junhao Gu, Shuwen Cao, Carol Laschinger, Camila Londono, Julia Antolovich, Alison P. McGuigan, Milica Radisic
Proceedings of the National Academy of Sciences Oct 2016, 113 (40) E5792-E5801; DOI: 10.1073/pnas.1612277113
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