title: Diabetic wound regeneration using peptide-modified hydrogels to target re-epithelialization.
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 MAPKp42/44The 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.
authors.affiliation: Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON M5S 3E5, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada.
authors.forename: Yun
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada.
authors.forename: Lewis A
authors.initials: LA
authors.lastname: Reis
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada.
authors.forename: Nicole
authors.initials: N
authors.lastname: Feric
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada.
authors.forename: Erica J
authors.initials: EJ
authors.lastname: Knee
authors.affiliation: Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON M5S 3E5, Canada.
authors.forename: Junhao
authors.initials: J
authors.lastname: Gu
authors.affiliation: Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON M5S 3E5, Canada.
authors.forename: Shuwen
authors.initials: S
authors.lastname: Cao
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada.
authors.forename: Carol
authors.initials: C
authors.lastname: Laschinger
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada.
authors.forename: Camila
authors.initials: C
authors.lastname: Londono
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Julia
authors.initials: J
authors.lastname: Antolovich
authors.affiliation: Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON M5S 3E5, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada.
authors.forename: Alison P
authors.initials: AP
authors.lastname: McGuigan
authors.affiliation: Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON M5S 3E5, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada; Toronto General Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada m.radisic@utoronto.ca.
authors.forename: Milica
authors.initials: M
authors.lastname: Radisic
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D048271:Chitosan / Q000494:pharmacology; D003094:Collagen / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000473:pathology*; D006801:Humans; D020100:Hydrogels / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000633:toxicity; D055767:Immobilized Proteins / Q000494:pharmacology; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D062326:Re-Epithelialization / Q000187:drug effects
chemical_list: D020100:Hydrogels; D055767:Immobilized Proteins; D010455:Peptides; D003094:Collagen; D048271:Chitosan; D006861:Hydrogen Peroxide; D051057:Proto-Oncogene Proteins c-akt
keywords: QHREDGS; diabetic wound healing; hydrogel; peptide; re-epithelialization