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 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.

Keywords: Angiogenesis; Diabetes; Gene therapy; Inflammation; Keratinocyte; Wound healing.