Collagen-based composite hydrogels as medicated wound dressings to promote skin wound healing – COLLAG-HEAL

Skin wound healing is impaired in chronic wounds such as foot diabetic ulcers. The absence of wound closure sometimes leads to infection and amputation. Current treatments of skin wounds rely on their debridement followed by a compression method. In some cases, this treatment is not sufficient and required the wound coverage by dressings. To date, no dressings are appropriated to treat the different kinds and stages of wounds. Current research is oriented towards medicated wound dressings incorporating therapeutic molecules in order to favor skin repair or to prevent infection.
We have recently shown the key role of the mineralocorticoid receptor (MR) in the re-epithelialization process and discovered that an antagonist for this receptor promoted skin tissue repair. This project aims at preparing novel biological wound dressings allowing the controlled and sustained delivery of this antagonist.
Our strategy is based on the synthesis of composite wound dressings based on dense collagen hydrogels, for which we have a high expertise. Our goal of this composite approach is to load a larger quantity of the antagonist and to deliver this molecule in a more sustained and controlled manner than for pure hydrogels. For this purpose, several methodologies for composite formation will be established and evaluated. Swelling properties, stability against enzymatic degradation and sterilization processes will be studied. Release kinetic of the antagonist will be analyzed over 2 weeks and compared with that obtained in a proteolytic environment which mimics wound. In parallel, structural (by optical and electronic microscopy) and mechanical analyses (by compression and traction tests) will permit a better understanding and control of the composite hydrogels. The performance of composites will be compared to that of commercial collagen based materials. Medicated wound dressings possessing the best properties in terms of controlled release, mechanical properties, structure and stability will be selected for in vitro toxicity assays on human fibroblasts and keratinocytes.Biological activity of the released antagonist will be analyzed by its ability to inhibit the mineralocorticoid receptor. The ability of hydrogels to promote re-epithelialization will be studied using a scratch test. Keratinocyte migration will be analyzed in a model of altered epithelialization. An organotypic culture of diabetic mouse skin (type II diabetes) will be performed to measure the drug effect in ex-vivo conditions. The outgrowth of keratinocytes around explants will be observed after treatment with the antagonist-loaded composite hydrogels. The in vivo evaluation of the medicated wound dressings will be performed on an impaired wound model in diabetic mouse (type I or II diabetes) over 7 days. Wound closure will be observed macroscopically and on histological sections. We will focus on wound re-epithelialization, modulation of inflammation, cellular colonization and stability of implants.