Use of a fibrin-based system for enhancing angiogenesis and modulating inflammation in the treatment of hyperglycemic wounds

Abstract The complex pathophysiology of chronic ulceration in diabetic patients is poorly understood; diabetes-related lower limb amputation is a major health issue, which has limited effective treatment regimes in the clinic. This study attempted to understand the complex pathology of hyperglycemic...

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Bibliographic Details
Published in:Biomaterials 2014-02, Vol.35 (6), p.2001-2010
Main Authors: Kulkarni, M, O'Loughlin, A, Vazquez, R, Mashayekhi, K, Rooney, P, Greiser, U, O'Toole, E, O'Brien, T, Malagon, Maria M, Pandit, A
Format: Article
Language:English
Subjects:
Advanced Basic Science
Angiogenesis
Animals
Cell Proliferation - drug effects
Dentistry
Diabetes
Fibrin - chemistry
Gene therapy
Humans
Hyperglycemia - drug therapy
Hyperglycemia - metabolism
Immunohistochemistry
Inflammation
Inflammation - metabolism
Keratinocyte
Keratinocytes - cytology
Keratinocytes - metabolism
Neovascularization, Physiologic - drug effects
Nitric Oxide Synthase Type III - metabolism
rab GTP-Binding Proteins - metabolism
Rabbits
Wound healing
Wound Healing - physiology
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Summary:Abstract The complex pathophysiology of chronic ulceration in diabetic patients is poorly understood; diabetes-related lower limb amputation is a major health issue, which has limited effective treatment regimes in the clinic. This study attempted to understand the complex pathology of hyperglycemic wound healing by showing profound changes in gene expression profiles in wounded human keratinocytes in hyperglycemic conditions compared to normal glucose conditions. In the hyper-secretory wound microenvironment of hyperglycemia, Rab18, a secretory control molecule, was found to be significantly downregulated. Using a biomaterial platform for dual therapy targeting the two distinct pathways, this study aimed to resolve the major dysregulated pathways in hyperglycemic wound healing. To complement Rab18, and promote angiogenesis eNOS was also targeted, and this novel Rab18-eNOS therapy via a dynamically controlled ‘fibrin-in-fibrin’ delivery system, demonstrated enhanced wound closure, by increasing functional angiogenesis and reducing inflammation, in an alloxan-induced hyperglycemic preclinical ear ulcer model of compromised wound healing.
ISSN:0142-9612
1878-5905
DOI:10.1016/j.biomaterials.2013.11.003