## 7 Use of Biomaterials in the Release of Extracellular Vesicles for Treatment of Cutaneous Wounds  
As discussed in the previous section, clearance of MSC-EV occurs rapidly when systemically delivered. Therefore, local administration of damaged tissues could improve their efficiency. However, proteases and pH changes in these tissues also produce a high degradation of MSC-EV. Those that remain are rapidly taken up by cells, such as endothelial ones and macrophages [82]. On the other hand, regenerative processes, such as skin healing, consist of different phases, as described above. Each of these phases needs a series of factors and molecules for its development. Therefore, a simple administration of MSC-EV for regenerative purposes may not be the most appropriate approach. This, together with the short half-life of EV forces the need for repeated applications, for the treatment to be efficient. However, high wound manipulation can be counterproductive, delaying the healing process. Therefore, in recent years, different types of biomaterialshave been developed and tested for their encapsulation, progressive release and creation of a suitable microenvironment that favors healing. Properties that these biomaterials should include an extracellular matrix-like, tissue-adhesive structure, high porosity and good permeability [83]. They are called modern wound dressings. Unlike more traditional or inert ones, such as cotton, gauze, pads and bandages, the new ones have better biocompatibility, degradability and moisture retention. This not only protects the wound from external factors, but also creates a more favorable microenvironment for healing [84]. Among the modern dressings, currently used in the clinic, are the following: (i) hydrogels, consisting of a three-dimensional network of hydrophilic polymers; (ii) hydrocolloids, made of hydrogel, mixed with adhesive materials and synthetic rubber; (iii) alginate, which is a polysaccharide derived from brown seaweed; (iv) foams from silicone or polyurethane; and (v) porous and transparent films based on polyurethane [84]. Synthetic and natural polymers have been used to make some of these dressings. Among the latter are alginate, chitosan, collagen, hyaluronic acid and gelatin [83]. Current treatments are still not sufficiently effective for healing difficult-to-heal skin ulcers. Thus, traditional clinical treatments of diabetic wounds include control of blood glucose, surgical debridement, graft transplantation, as well as a wound dressing. Although these measures can be successfully applied in the most severe cases, in many instances they are not sufficient, and the wounds do not heal, or heal after very long periods of time. It is, therefore, necessary to develop new treatments that favor tissue regeneration, with adequate progress of healing. Thus, it has been proposed that products to promote skin healing must meet one or more of the following properties: (i) stable under room temperature storage; (ii) suitable for topical or injectable delivery; (iii) antimicrobial, analgesic or hemostatic properties; and (iv) accelerate wound repair, by promoting conductive or inductive regenerative mechanisms [85]. The new products based on a combination of multifunctional wound dressings with EV meet these properties. Their potential clinical applications are expected to result in shortening the healing period, and improving the functionality of scar tissues. Among the dressings used as VE vehicles for wound treatment, hydrogels stand out. In addition to acting as a barrier to external wound agents, they are semi-permeable to water and oxygen, being biodegradable. They reduce pain in patients and dressing frequency, avoiding second trauma during dressing changes. Additionally, they reduce scar formation, promoting autolytic debridement [86]. In addition, active pharmaceutical ingredients or bioactive factors can be incorporated into hydrogels, which are thus more stable, and can be progressively released when the gel is biodegraded, as opposed to direct administration [87].