NCT05099367

Prostacyclin (PGI2) Pathway to Enhance Wound Healing in Diabetic Foot Ulcers

• Status: Unknown
• Phase: N/A
• Study type: Interventional
• Enrollment: 60 (estimated)
• Sponsor: University Hospital, Grenoble · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Accepted

Summary

Prospective, monocentric, pathophysiological study, comparing 3 parallel groups: healthy controls; patients with diabetes and without DFU; patients with diabetes and with DFU. To address secondary objectives, samples from a fourth group will be collected.

Detailed description

Diabetic foot ulcers (DFUs) are a common and serious complication of diabetes mellitus, and associated with major morbidity. Indeed, diabetes is the primary cause of non-traumatic lower-limb amputation, and the rise in the prevalence of type 2 diabetes worldwide increases the global burden of DFUs. The treatment of DFUs is particularly challenging. Besides etiologic measures, local therapy of foot ulcers mainly relies on debridement of the wound and dressings. Essential complementary measures include pressure off-loading and infection control. However, despite these treatments, complications are frequent, stressing the need for new treatments. The microcirculation has a key role in tissue survival, and several classical pathways explain how hyperglycemia damages the microvessels. There is growing evidence that the PGI2 pathway is dysregulated in diabetes, which contributes to microvascular dysfunction. Besides its vasodilator effect, recent data has revealed the major role of PGI2 in angiogenesis. In the skin, such effect on healing might be enhanced by the role of PGI2 in the regulation of fibroblast and keratinocytes migration and proliferation. In the past few decades, studies in diabetic patients with ulcers have shown numerous structural and functional abnormalities of the cutaneous microcirculation, supporting its critical role in the pathophysiology of DFUs. However, the detailed mechanisms underlying endothelial dysfunction in the skin of diabetic patients remain largely unexplored in vivo. A better understanding of the specificities of microvascular changes in the diabetic foot is essential to developing new treatments for this pressing clinical need. Objectives are * to explore the role of the PGI2 pathway in skin microvascular reactivity, in healthy subjects and in diabetic patients with and without DFU * To determine the involvement of COX-1 and COX-2 in cutaneous current-induced vasodilation (CIV), in healthy subjects and in diabetic patients with and without DFU. * To determine the involvement of sensory nerves in cutaneous CIV, in healthy subjects and in diabetic patients with and without DFU. * To compare the function of the IP receptor between healthy subjects and diabetic patients with and without DFU. * To determine the involvement of the nitric oxide (NO) and epoxyeicosatrienoic acids (EETs) pathway in cutaneous CIV, in healthy subjects and in diabetic patients with and without DFU. * To assess cutaneous expression of the different components of the PGI2 pathway in the skin of healthy subjects and of diabetic patients with and without DFU. * To assess the role of the PGI2 pathway on cell migration in vitro

Conditions

• Diabetes Mellitus, Type 2
• Diabetic Foot

Interventions

Type	Name	Description
DIAGNOSTIC_TEST	Microdialysis, current induced vasodilation	CIV will be applied over all microdialysis fibers: one perfused with saline, one perfused with a preferential COX-1 blocker; and one perfused with a preferential COX-2 blocker. CIV will be applied over all fibers in the following conditions: one perfused with saline, one perfused with fluconazole and L-NMMA, and the last one perfused with lidocaine.Dialysate collection will be performed after each CIV: dermal PGI2 metabolite (6-ketoPGF1α) and other COX-dependent prostanoids or metabolite (e.g. 11-dehydroTXB2) will be collected in the dialysate fluid and quantified. One hour after the last condition, treprostinil will be perfused over all fibers.
DIAGNOSTIC_TEST	Skin biopsy	Skin biopsy will be proposed. It will be performed on the internal superior calf (medial gastrocnemius), at a reasonable distance from the foot
DIAGNOSTIC_TEST	peri-ulcerated skin biopsy	Non-ulcerated skin from the peri-wound area will be collected. These patient will not undergo all the procedures included in this protocol.

Timeline

• Start date: 2021-10-01
• Primary completion: 2025-02-28
• Completion: 2025-08-31
• First posted: 2021-10-29
• Last updated: 2023-12-06

Locations

1 site across 1 country: France