Mechanisms Involved in the Development and Healing of Diabetic Foot Ulceration

Abstract

We examined the role of vascular function and inflammation in the development and failure to heal diabetic foot ulcers (DFUs). We followed 104 diabetic patients for a period of 18.4 ± 10.8 months. At the beginning of the study, we evaluated vascular reactivity and serum inflammatory cytokines and growth factors. DFUs developed in 30 (29%) patients. DFU patients had more severe neuropathy, higher white blood cell count, and lower endothelium-dependent and -independent vasodilation in the macrocirculation. Complete ulcer healing was achieved in 16 (53%) patients, whereas 13 (47%) patients did not heal. There were no differences in the above parameters between the two groups, but patients whose ulcers failed to heal had higher tumor necrosis factor-α, monocyte chemoattractant protein-1, matrix metallopeptidase 9 (MMP-9), and fibroblast growth factor 2 serum levels when compared with those who healed. Skin biopsy analysis showed that compared with control subjects, diabetic patients had increased immune cell infiltration, expression of MMP-9, and protein tyrosine phosphatase-1B (PTP1B), which negatively regulates the signaling of insulin, leptin, and growth factors. We conclude that increased inflammation, expression of MMP-9, PTP1B, and aberrant growth factor levels are the main factors associated with failure to heal DFUs. Targeting these factors may prove helpful in the management of DFUs.

Self‐Assembled Wound Dressings Silence MMP‐9 and Improve Diabetic Wound Healing In Vivo

“…Integration into the surrounding tissue is key in promoting the infiltration of cells into the forming granulation tissue, and in diabetic ulcers this integration is significantly impaired [3,6] . The wound edges of siMMP-9 treated mice exhibit significantly higher collagen content, with large collagen bundles leading from the uninjured dermis into the granulation tissue.…”

“…In ulcerative wound healing this process is interrupted and the wound persists in an inflamed state for weeks to months and in many cases never resolves. The pathology of the diabetic ulcer results from this chronic inflammation, due in part to the overexpression of extracellular matrix (ECM) proteases in the wound bed [3][4][5] . As a result, ECM accumulation within the DFU is dramatically reduced, impeding epithelial closure of the wound and significantly increasing the risk of infection [6] .…”

Substance P Promotes Wound Healing in Diabetes by Modulating Inflammation and Macrophage Phenotype

“…15,16 However, there is little information regarding its effect in diabetic skin wounds that are characterized by chronic inflammation, neuroischemia, and increased expression of MMPs that degrade proteins, including growth factors. 4 During normal wound healing, macrophages demonstrate transitions in phenotype and function in tissue repair progression, although the factors that regulate these transitions remain poorly defined. Thus, during the inflammatory phase, M1 activated macrophages initiate an acute inflammatory response, whereas during the proliferative phase M2 macrophages promote angiogenesis and granulation tissue formation.…”

“…1 Peripheral neuropathy associated with deficiency of neuropeptides, 2,3 vascular disease, chronic inflammation, increased expression of matrix metalloproteinase (MMP)-9, and aberrant growth factor expression has been associated with diabetic foot ulceration development and failure to heal. 4 Substance P (SP) belongs to the tachykinin neuropeptide family encoded by the Tac1 gene and is one of the main neuropeptides released by C-nociceptive fibers in response to injury. SP exerts its effects mainly via its high-affinity neurokinin-1 receptor (NK1R) and is degraded by the enzyme neutral endopeptidase (NEP).…”

An intelligent telemedicine system for detection of diabetic foot complications

“…Spectral imaging is a promising technology for our desired TM system, as it provides a hybrid modality for optical diagnosis with spectral data of the entire area under measurement and rendered in image form [41][42][43][44]. …”