Assessment of Novel, Non-Invasive Interventions for the Prevention of Foot Ulceration in Patients with Diabetes and a Mechanistic Study of Progenitor Cells from Diabetic Patients

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Abstract

Diabetic foot ulceration (DFU) is a known major complication of diabetes mellitus which contributes to lower extremities amputation. This study aimed to investigate the use of interventional devices either as a preventative or therapeutic strategy to improve clinical management of this pathology, as well as investigating the impaired function of endothelial progenitor cells in the diabetic condition. The first element targeted plantar callus formation among diabetic neuropathic (NRP) patients through the use of a SurroSenseRxTM biofeedback device. Reducing foot pressure with improved walking strategy in the 6 months study in diabetic neuropathy patients (n=20) appeared to minimise the size of non-ulcerative plantar callus (p<0.05), potentially reducing future ulcer recurrence. The 2nd study focused on the use of a GekoTM electrical stimulation device to enhance DFU healing in 24 patients. Wounds were characterised as being neuroischaemic (NRI) or neuropathic (NRP) based on standard parameters adopted in the Manchester diabetes clinic. The device was worn by 11 intervention subjects and compared to 13 controls without any electrical stimulus. Results suggested healing and wound closure have potentially increased in participants with electrical stimulation. In addition, Neuropathy Disability Score (NDS) was improved among intervention patients compared to control (p<0.0001). The 3rd, in vitro and mechanistic study focuses on the outgrowth of endothelial cells (OECs), abnormal angiogenic responses and inflammatory microenvironment which could contribute to impaired wound healing in diabetic patients. OECs were isolated from diabetic patients and healthy controls (HCs), characterised by immunohistochemistry and Polymerase Chain Reaction (PCR). The functions of the three OEC groups from NRI, NRP diabetic patients and healthy controls respectively were compared using in vitro proliferation, transwell migration and wound healing scratch assays, together with matrigel tube formation assays. Scratch assays showed 100% closure in HCs over 24 hours, while 86.6% closure was apparent in NRI vs 38.1% in NRP. Seahorse mitochondrial stress test was conducted and demonstrated mitochondrial dysfunction in NRP vs NRI vs HCs (p<0.05). Western blot analysis showed a lack of ERK phosphorylation by NRP OECs and an up-regulation of plasma inflammatory cytokines (TNFα and IL-6) in diabetic samples vs HC (p<0.0001), while the angiogenic factors ang-2, FGF-2, VEGF-D, HGF and IL-8, and nitric oxide bioavailability were all significantly reduced in diabetic samples vs HC (p<0.05). The functional defects of the diabetic OECs were partially restored through glycomimetic (synthesis compounds for endothelial damage protection) treatment (p<0.05). In summary, this study has highlighted areas worthy of future development both in terms of preventative and therapeutic strategies. With improvements in digital technology and the need to empower patients to take responsibility of their health and well-being as well as greater understanding of the cellular and molecular biological repair processes that may be exploited, there may be potentials to reduce the risk of future ulceration among patients using these novel approaches in the future.

Keyword(s)

Diabetic Foot Ulceration; Diabetic Neuroischaemia; Diabetic Neuropathy; Electrical Stimulation; Outgrowth Endothelial Cells; Plantar Pressure

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