Prostacyclin (PGI2) Pathway to Enhance Wound Healing in Diabetic Foot Ulcers
- Conditions
- Diabetic FootDiabetes Mellitus, Type 2
- Interventions
- Diagnostic Test: Microdialysis, current induced vasodilationDiagnostic Test: peri-ulcerated skin biopsyDiagnostic Test: Skin biopsy
- Registration Number
- NCT05099367
- Lead Sponsor
- University Hospital, Grenoble
- Brief 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
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 60
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Group 3 : diabetes with ulcer active or <2 years Skin biopsy 15 patients with diabetes type II and with foot ulcer (active or \<2years) Group 1 : healthy subject Skin biopsy 15 healthy subject without diabetes Group 1 : healthy subject Microdialysis, current induced vasodilation 15 healthy subject without diabetes Group 2 : diabetes without ulcer Microdialysis, current induced vasodilation 15 patients with diabetes type II and without foot ulcer Group 2 : diabetes without ulcer Skin biopsy 15 patients with diabetes type II and without foot ulcer Group 3 : diabetes with ulcer active or <2 years Microdialysis, current induced vasodilation 15 patients with diabetes type II and with foot ulcer (active or \<2years) Group 4 : Patients with type 2 diabetes, neuropathy and DFU undergoing lower limb peri-ulcerated skin biopsy Patients with type 2 diabetes and neuropathy and DFU undergoing lower lunb surgery for skin ulcer
- Primary Outcome Measures
Name Time Method Exploring PGI2 pathway in skin microvascular reactivity Day 1 Comparison of skin perfusion measured with laser speckle contrast imaging (LSCI) on the calf, and expressed as arbitrary perfusion units, in response to local cathodal current application, between the three groups
- Secondary Outcome Measures
Name Time Method Involvement of COX-1 and 2 in cutaneous current-induced vasodilation Day 1 1. Comparison of skin perfusion measured with LSCI on the calf, in response to local current application, during local infusion of ketorolac (COX-1 blocker), and meloxicam (COX-2 blocker), using skin microdialysis, between the three groups.
Expression of different components of PGI2 pathway in the skin : PTGIS Day 1 5. Comparison of the expression of PTGIS (CYP8A1) in the skin of the calf, between the three groups and a fourth group of foot skin biopsies from patients with diabetes, neuropathy and DFU undergoing lower-limb surgery.
IP receptor function Day 1 3. Comparison of skin perfusion measured with LSCI on the calf, in response to intradermal infusion of treprostinil using skin microdialysis, between the three groups.
Involvement of sensory nerves in cutaneous current-induced vasodilation Day 1 2. Comparison of skin perfusion measured with LSCI on the calf, in response to local current application, after local infusion of lidocaine, between the three groups.
Expression of different components of PGI2 pathway in the skin : PTGIR Day 1 5. Comparison of the expression of PTGIR (IP-receptor) in the skin of the calf, between the three groups and a fourth group of foot skin biopsies from patients with diabetes, neuropathy and DFU undergoing lower-limb surgery.
Involvement of NO et EETs pathways in cutaneous current-induced vasodilation Day 1 4. Comparison of skin perfusion measured with LSCI on the calf, in response to local current application, during local infusion of NG-Monomethyl-L-arginine (L-NMMA) and fluconazole using skin microdialysis, between the three groups.
Expression of different components of PGI2 pathway in the skin : PTGS1/2 Day 1 5. Comparison of the expression of Prostaglandin-Endoperoxide Synthase (PTGS1/2 (COX1/2)), in the skin of the calf, between the three groups and a fourth group of foot skin biopsies from patients with diabetes, neuropathy and DFU undergoing lower-limb surgery.
role of PGI2 pathway on cell migration in vitro Day 1 6. Cell migration observed on wounded 3D skin equivalents made from cells collected from the three groups and from a fourth group of patients undergoing lower-limb surgery. Fibroblasts and kératinocytes migration on 3D reconstructed skin models.
Expression of different components of PGI2 pathway in the skin : TBXA2R Day 1 5. Comparison of the expression of TXA2R (TP-receptor) in the skin of the calf, between the three groups and a fourth group of foot skin biopsies from patients with diabetes, neuropathy and DFU undergoing lower-limb surgery.
Trial Locations
- Locations (1)
CHU Grenoble Alpes Centre d'investigation clinique
🇫🇷Grenoble, France