Skip to main content
  • Submit
  • About
    • Editorial Board
    • PNAS Staff
    • FAQ
    • Rights and Permissions
    • Site Map
  • Contact
  • Journal Club
  • Subscribe
    • Subscription Rates
    • Subscriptions FAQ
    • Open Access
    • Recommend PNAS to Your Librarian
  • Log in
  • My Cart

Main menu

  • Home
  • Articles
    • Current
    • Latest Articles
    • Special Features
    • Colloquia
    • Collected Articles
    • PNAS Classics
    • Archive
  • Front Matter
  • News
    • For the Press
    • Highlights from Latest Articles
    • PNAS in the News
  • Podcasts
  • Authors
    • Information for Authors
    • Purpose and Scope
    • Editorial and Journal Policies
    • Submission Procedures
    • For Reviewers
    • Author FAQ
  • Submit
  • About
    • Editorial Board
    • PNAS Staff
    • FAQ
    • Rights and Permissions
    • Site Map
  • Contact
  • Journal Club
  • Subscribe
    • Subscription Rates
    • Subscriptions FAQ
    • Open Access
    • Recommend PNAS to Your Librarian

User menu

  • Log in
  • My Cart

Search

  • Advanced search
Home
Home

Advanced Search

  • Home
  • Articles
    • Current
    • Latest Articles
    • Special Features
    • Colloquia
    • Collected Articles
    • PNAS Classics
    • Archive
  • Front Matter
  • News
    • For the Press
    • Highlights from Latest Articles
    • PNAS in the News
  • Podcasts
  • Authors
    • Information for Authors
    • Purpose and Scope
    • Editorial and Journal Policies
    • Submission Procedures
    • For Reviewers
    • Author FAQ

New Research In

Physical Sciences

Featured Portals

  • Physics
  • Chemistry
  • Sustainability Science

Articles by Topic

  • Applied Mathematics
  • Applied Physical Sciences
  • Astronomy
  • Computer Sciences
  • Earth, Atmospheric, and Planetary Sciences
  • Engineering
  • Environmental Sciences
  • Mathematics
  • Statistics

Social Sciences

Featured Portals

  • Anthropology
  • Sustainability Science

Articles by Topic

  • Economic Sciences
  • Environmental Sciences
  • Political Sciences
  • Psychological and Cognitive Sciences
  • Social Sciences

Biological Sciences

Featured Portals

  • Sustainability Science

Articles by Topic

  • Agricultural Sciences
  • Anthropology
  • Applied Biological Sciences
  • Biochemistry
  • Biophysics and Computational Biology
  • Cell Biology
  • Developmental Biology
  • Ecology
  • Environmental Sciences
  • Evolution
  • Genetics
  • Immunology and Inflammation
  • Medical Sciences
  • Microbiology
  • Neuroscience
  • Pharmacology
  • Physiology
  • Plant Biology
  • Population Biology
  • Psychological and Cognitive Sciences
  • Sustainability Science
  • Systems Biology

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
PNAS October 4, 2016 113 (40) E5792-E5801; published ahead of print 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;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lewis A. Reis
bInstitute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nicole Feric
bInstitute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Erica J. Knee
bInstitute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Junhao Gu
aDepartment of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON M5S 3E5, Canada;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shuwen Cao
aDepartment of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON M5S 3E5, Canada;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Carol Laschinger
bInstitute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Camila Londono
bInstitute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
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;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
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;
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
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
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • 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)

  • Article
  • Figures & SI
  • Info & Metrics
  • PDF
Loading

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.

View Full Text
PreviousNext
Back to top
Article Alerts
Email Article

Thank you for your interest in spreading the word on PNAS.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Diabetic wound regeneration using peptide-modified hydrogels to target re-epithelialization
(Your Name) has sent you a message from PNAS
(Your Name) thought you would like to see the PNAS web site.
Citation Tools
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

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Request Permissions
Share
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
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Mendeley logo Mendeley
Proceedings of the National Academy of Sciences: 116 (8)
Current Issue

Submit

Sign up for Article Alerts

Jump to section

  • Article
    • Abstract
    • Results
    • Discussion
    • Materials and Methods
    • Acknowledgments
    • Footnotes
    • References
  • Figures & SI
  • Info & Metrics
  • PDF

You May Also be Interested in

News Feature: Cities serve as testbeds for evolutionary change
Urban living can pressure flora and fauna to adapt in intriguing ways. Biologists are starting to take advantage of this convenient laboratory of evolution.
Image credit: Kristin Winchell (Washington University in St. Louis, St. Louis).
Several aspects of the proposal, which aims to expand open access, require serious discussion and, in some cases, a rethink.
Opinion: “Plan S” falls short for society publishers—and for the researchers they serve
Several aspects of the proposal, which aims to expand open access, require serious discussion and, in some cases, a rethink.
Image credit: Dave Cutler (artist).
Featured Profile
PNAS Profile of NAS member and biochemist Hao Wu
 Nonmonogamous strawberry poison frog (Oophaga pumilio).  Image courtesy of Yusan Yang (University of Pittsburgh, Pittsburgh).
Putative signature of monogamy
A study suggests a putative gene-expression hallmark common to monogamous male vertebrates of some species, namely cichlid fishes, dendrobatid frogs, passeroid songbirds, common voles, and deer mice, and identifies 24 candidate genes potentially associated with monogamy.
Image courtesy of Yusan Yang (University of Pittsburgh, Pittsburgh).
Active lifestyles. Image courtesy of Pixabay/MabelAmber.
Meaningful life tied to healthy aging
Physical and social well-being in old age are linked to self-assessments of life worth, and a spectrum of behavioral, economic, health, and social variables may influence whether aging individuals believe they are leading meaningful lives.
Image courtesy of Pixabay/MabelAmber.

More Articles of This Classification

  • CD4+ T help promotes influenza virus-specific CD8+ T cell memory by limiting metabolic dysfunction
  • Lateral transfers of large DNA fragments spread functional genes among grasses
  • Assembly and cryo-EM structures of RNA-specific measles virus nucleocapsids provide mechanistic insight into paramyxoviral replication
Show more

Related Content

  • PNAS Plus Significance Statements
  • Scopus
  • PubMed
  • Google Scholar

Cited by...

  • Potent laminin-inspired antioxidant regenerative dressing accelerates wound healing in diabetes
  • Biophysical stimulation for in vitro engineering of functional cardiac tissues
  • Scopus (20)
  • Google Scholar

Similar Articles

Site Logo
Powered by HighWire
  • Submit Manuscript
  • Twitter
  • Facebook
  • RSS Feeds
  • Email Alerts

Articles

  • Current Issue
  • Latest Articles
  • Archive

PNAS Portals

  • Classics
  • Front Matter
  • Teaching Resources
  • Anthropology
  • Chemistry
  • Physics
  • Sustainability Science

Information

  • Authors
  • Editorial Board
  • Reviewers
  • Press
  • Site Map

Feedback    Privacy/Legal

Copyright © 2019 National Academy of Sciences. Online ISSN 1091-6490