Original Article Adipose-Derived Mesenchymal Stem Cells in the Treatment of Diabetic Foot Ulcers: A Review of Preclinical and Clinical Studies Francisco Javier A ´ lvaro-Afonso, PharmD, DPM, PhD 1 , Irene Sanz-Corbal ´ an, DPM, PhD 1 , Jos´ e Luis L´ azaro-Mart´ ınez, DPM, PhD 1 , Despoina Kakagia, MD, PhD 2 , and Nikolaos Papanas, MD, PhD 3 Abstract This review provides an outline of the use of adipose-derived mesenchymal stem cells (AMSCs) in the treatment of diabetic foot ulcers (DFUs). A systematic search of PubMed and the Cochrane database was performed on October 2, 2019. Eighteen studies were identified (14 preclinical and 4 clinical). Studies in animal models have demonstrated that AMSCs enhance diabetic wound healing, accelerate granulation tissue formation, and increase reepithelialization and neovascularization. Only 1 randomized control trial has been published so far. Patients (n ¼ 25) with DFUs were treated using an allogeneic AMSC directly on the wound bed as a primary dressing, and improvements were found in complete wound closure in the treatment group (n ¼ 16). Three clinical studies showed that autologous AMSC might be a safe alternative to achieve therapeutic angiogenesis in patients with diabetes and peripheral arterial disease. Based on the available evidence, AMSCs hold promise in the treatment of DFUs. However, this evidence requires confirmation by well-designed trials. Additional studies are also required to understand some issues regarding this treatment for DFUs. For example, the potential application of autologous or allogeneic AMSCs in different types of DFUs, optimal dose/infusion schedules, safety evaluations, and cost-effectiveness. Keywords adipose-derived stem cells, adipose-derived mesenchymal stem cells, diabetic foot, diabetic foot ulcers, treatment, diabetes Introduction Diabetic foot ulcers (DFUs) are a serious complication of dia- betes mellitus (DM). They affect approximately 19% and 34% of people with DM at least once in their life and are a leading cause of hospitalization and nontraumatic lower limb amputa- tions. 1 A DFU precedes 85% of nontraumatic lower limb amputations 2 and the 5-year mortality rate for patients under- going major amputation can be as high as 70%. 3,4 Above-the- knee amputation has the same 5-year mortality as common malignancies such as colon cancer. 5,6 Unfortunately, even after the successful treatment of a DFU, recurrence is common, 1 with recurrence rates varying widely in different regions. A recent systematic review and meta-analysis showed a pooled estimate for a recurrence rate of 22.1% per person-year (24.9% in Europe, 17.8% in North America, 16.9% in Africa, and 17.0% in Asia). 7 Considering these recurrence rates, people with DFUs have a significantly lower health-related quality of life, and these ulcers are associated with a high health care costs. 8,9 Management of DFUs requires a multidisciplinary approach to address many causal factors. The rate of wound closure within the first 4 weeks of treatment is a robust predictor of healing outcome and the Wound Healing Society guidelines recommend advanced wound therapies for DFUs if they do not shrink in size by 40% following standard therapy for 4 weeks. 10 Advanced therapies include negative pressure wound therapy, 11 hyperbaric oxygen therapy, 12 ultrasound-assisted debridement, 13 new wound dressings, some of them with potential antimicrobial/antiseptic activity, 14-16 negatively charged polystyrene microspheres, 17 or different types of der- moepidermal skin substitutes. 18 In addition, cell therapy was developed to overcome the limitations of conventional meth- ods. A recent characterization of dermal stem cells from dia- betic patients demonstrated that the gene expression profile of 1 Diabetic Foot Unit, University Podiatric Clinic, Edificio Facultad de Medicina, Complutense University of Madrid, Instituto de Investigaci ´ on Sanitaria del Hospital Cl´ ınico San Carlos (IdISSC), Madrid, Spain 2 Department of Plastic Surgery, Democritus University of Thrace, University Hospital of Alexandroupolis, Greece 3 Diabetes Centre-Diabetic Foot Clinic, Second Department of Internal Med- icine, Democritus University of Thrace, University Hospital of Alexan- droupolis, Greece Corresponding Author: Irene Sanz-Corbal´ an, Diabetic Foot Unit, University Podiatric Clinic, Com- plutense University of Madrid, Edificio Facultad de Medicina, Pabell ´ on 1, Avda. Complutense s/n, 28040 Madrid, Spain. Email: irsanz01@ucm.es Angiology 1-11 ª The Author(s) 2020 Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/0003319720939467 journals.sagepub.com/home/ang