Diabetic foot ulcer is a very common complication of the diabetes due to diabetic neuropathy. The most common cause of diabetic foot ulcer is inappropriate footwear leading to excessive local pressure. The major physiological factors leading to development of foot ulcers are diabetes-induced sensory and motor neuropathies, which lead to progressive loss of protective sensation, alteration in the distribution of forces applied to the foot during walking and formation of local skin thickenings (callus). At the same time, diabetic ischemia and loss of the protective sweat function cause diabetic skin to be dry and fragile, reducing the ability of the callus region to withstand abnormal loads, resulting in broken skin wounds prone to inflammation. In general, wound healing is highly compromised in diabetes patients, where lesions remain in the inflammatory phase due to micro-vascular dysfunction leading to reduced oxygen and nutrition supply and altered immune responses. Specifically, diabetic foot ulcer might further deteriorate and healing can be significantly delayed when secondary bacterial inflammation is present. In case of inappropriate or delayed treatment, diabetic foot ulcer develops into chronic wound. Despite the rising understanding of high importance of diabetes foot ulcer prevention and treatment, the management provided to this disease is frequently insufficient, leading to delayed healing and eventually to leg amputation.
Currently, diabetic foot ulcer care provides limited healing, while the ultimate curative treatment is still under exploration.
An innovative approach to diabetic foot ulcer treatment includes application of stem cells in attempt to improve healing via stimulation of angiogenesis, supply of extracellular matrix components and production of cytokines and growth factors. Stem cell-based treatments can be roughly divided into cell injection and tissue-engineered skin-like construct implantation.
Allogeneic mixture of white blood cells, CureXcell™, was proved to be highly effective in treating deep sternal wound infections after open-heart surgery, and at the same time demonstrated a markedly improved healing rate when treating severe pressure ulcers. These cells are approved for clinical use and are injected into the diabetic foot ulcer every four weeks until the lesion is closed. The functionally active immune cells in CureXcell™ balance the inflammatory environment in the non-healing wound by releasing essential growth factors and cytokines.
Bone marrow-derived cells healing potential has been also explored in respect to diabetic foot ulcer. Various fractions of autologous cells, including bone marrow-derived mesenchymal stem cells (BM-MSCs), bone marrow-derived mononuclear cells (BM-MNCs) and expanded bone marrow mononuclear cells enriched with CD90+ mesenchymal stem cells (tissue repair cells, TRCs) have been assessed in diabetic foot ulcer therapy. Treatment proved to be safe and feasible, and some cell types improved microcirculation and wound healing.
Tissue-engineered skin-like construct implantation
Methods aimed to mimic unique skin microenvironment based on combination of cells and supportive scaffolds are widely explored in the past years. Several skin-like constructs exist on the market and are used for treatment of diabetic foot ulcer, such as: Grafix® - three-dimensional cellular matrix containing MSCs, growth factors and anti-inflammatory cytokines; Apligraf® - dermal patch that consists of two layers of living cells and structural proteins; Dermagraft® - a cryopreserved human fibroblast-derived dermal substitute composed of fibroblasts, extracellular matrix and a bio-absorbable scaffold.
In summary, stem cells therapy provides a novel and more effective means of curing diabetic foot ulcer and preventing limb amputation. The cell-based approach enables concomitant delivery of all the elements proved to be necessary for wound healing – growth factors, cytokines and extracellular matrix components. These therapies proved to be safe and feasible and to significantly improve chronic wound healing.