Skin tissue engineering advances in severe burns: review and therapeutic applications

Harnessing allogeneic mesenchymal stem cells

During the past decade, adult tissue-derived MSCs have rapidly moved from in-vitro and animal studies into human trials as a therapeutic modality for a diverse range of clinical applications. MSCs raise great expectations in regenerative medicine, not only because of their multipotent differentiation characteristics, trophic and immunomodulatory effects but also for their extensive sources and biostability when cultured and expanded in vitro [124]. Apart from bone marrow and adipose tissues, human MSCs can also be isolated from a variety of other tissues such as the amniotic membrane [125], umbilical cord [126, 127], cord blood [128] as well as the hair follicle dermal papilla [129] and sheath [130, 131].

MSCs have demonstrated a number of properties in-vitro that can promote tissue repair, including the production of multiple growth factors, cytokines, collagens, and matrix metalloproteinases [132, 133] in addition to the ability to promote migration of other skin cells such as keratinocytes [134]. MSCs have also been reported to enhance wound healing through differentiation and angiogenesis [135]. In the current literature, several clinical cases on the use of cultured autologous bone marrow MSCs for localized and topical treatment of chronic wounds have been reported. Yoshikawa et al. treated twenty patients with various non-healing wounds (i.e., burns, lower extremity ulcers, and decubitus ulcers) using autologous bone marrow–derived mesenchymal stem cells expanded in culture and a dermal replacement with or without autologous skin graft [136]. The authors reported that 18 of the 20 wounds appeared healed completely with the cell-composite graft transfer, and the addition of mesenchymal stem cells facilitated regeneration of the native tissue by histologic examination. For allogeneic MSCs usage, Hanson et al. [137] reported the use allogeneic bone marrow- or adipose-derived, MSCs to treat partial-thickness wounds of Göttingen Minipigs and demonstrated the safety, feasibility and potential efficacy of these MSCs for treatment of wounds.

In our opinion, the immunomodulatory effect of MSCs is key to the immediate utilization of these cells for rapid treatment of severe burns. It is now clear that MSCs modulate both innate and adaptive responses and evidence is now emerging that the local microenvironment is important for the activation or licensing of MSCs to become immunosuppressive [138]. Without this property, there is no way we can harness the regenerative and pro-angiogenic effects of the MSCs in the first place. Thankfully, we can have this off-the-shelf option to use MSCs as an allogeneic source of cells which can be pre-tested for safety and potency before use. And as vascularization of dermal template is crucial for permanent skin graft take – whether in a one-stage or two-stage procedure, the presence of allogeneic MSCs would definitely give that extra edge towards angiogenesis.

It is therefore not surprising to learn that the first worldwide clinical trial which uses allogeneic bone marrow MSCs to treat 10 patients with large severe deep burns is in progress in Argentina. This is done by treating the wound with the application of MSCs through a fibrin-based polymer spray over an acellular dermal biological matrix [139]. The same group, Mansilla et al. has just reported their preliminary experience treating a patient with 60 % total body surface burned with positive results [140]. A search using “allogeneic mesenchymal stem cells for burns” in ClinicalTrials.gov (as at Nov 2015) also revealed that two of such trials have been filed [141] which further reinforce the hypothesis that allogeneic MSCs might have a role in major burn treatment.