###### Abstract  
Hard-to-head chronic wounds associated with aging and high-prevalence pathologies, such as diabetes, are a global health problem. Therefore, it is necessary to advance effective treatments to accelerate wound healing. Among these potential treatments are new therapies based on mesenchymal stem cells (MSC) and their secretomes, including extracellular vesicles (EV). They have an important therapeutic potential for the treatment of chronic ulcers, due to their immunomodulatory activity, as well as their ability to induce angiogenesis, cell proliferation and cell migration. The use of MSC-derived EV in regenerative medicine involves cell-free therapies that decrease risks associated with cell therapies, such as the potential development of tumors. However, the short half-life of MSC-EV is a limitation for their clinical use. A therapeutic strategy to increase the regenerative efficiency of EV in wounds is to encapsulate them in biomaterials. The latter must protect and progressively release EV in damaged tissues, optimizing healing. Biomaterials that can be used include hydrogels. These, in addition to acting as a vehicle for sustained application of EV, can create favorable environments for wound healing. Thus, the aim of this review is to critically describe the latest advances in the development of such therapeutic strategies. It highlights the significance and clinical potential of these new therapies, as well as the need to develop clinical trials, to ascertain their performance. mscenchymal stem cells; extracellular vesicles; wound healing; skin; wound dressings; biomaterials; hydrogels; diabetes +
Footnote †: journal: Medical  
glands and hair follicles. The dermis also contains interdigitations called dermal papillae, located in the area of contact with the epidermis [2]. Among the pathologies that can affect the skin are wounds caused by trauma or damage. Under normal physiological conditions, the regenerative process for the formation of new tissue occurs after a series of phases, in which different cell types intervene, until tissue similar to the original is formed [3]. However, under certain conditions, the healing process slows down and becomes chronic, resulting in difficult-to-heal or chronic wounds. Among the main risks for this to occur are aging, diabetes and recalcitrant infections [4]. Also, excessive fibrosis in the later stages of healing can generate hypertrophic scars, that under more extreme conditions can degenerate into keloids [5; 6]. The number of difficult-to-heal skin ulcers is increasing, mainly in the most economically developed countries. This is due in part to the aging of the population, and the increased prevalence of pathologies such as diabetes [7]. The latter is estimated that will be suffered by 629 million people worldwide by 2045, with an increase of 48% since 2017 [8]. That also leads to an increase in the number of skin ulcers. It is considered that open wounds represent a problem for 3% of the population over 65 years of age in the USA. So, with the aging of the population, the number of chronic wounds is expected to increase in the coming years [9]. This has a significant impact on healthcare spending, because these types of wounds require frequent care and treatment by physicians and nurses. Thus, the cost and management of diabetic foot ulcers, which have a 15-25% prevalence in diabetes, is between 9 and 13 million dollars in the USA [10]. Although conventional treatments, such as skin grafts, have reduced the mortality rate in patients, they are limited due to a lack of tissue sources. Also, the outcome of other treatments, such as surgical removal, dressing changes, hyperbaric-oxygen therapy, and negative-pressure wound therapy in many patients, is not satisfactory. Hence, the current quest for the development of more effective therapeutic approaches [11].