Autologous Bone Marrow Mesenchymal Stem Cells Improve the Quality and Stability of Vascularized Flap Surgery of Irradiated Skin in Pigs

Local, accidental, cutaneous overexposure to ionizing radiation has severe health consequences, especially when the absorbed dose exceeds 25 Gy and skin necrosis occurs 1. Lesions can rapidly extend beyond the skin surface alone, involving underlying tissue (muscle and bone). The injury evolves by successive but unpredictable inflammatory waves over the first few days to weeks after irradiation, and these lead to horizontal and vertical extension of a process of full‐thickness skin necrosis and ulceration 1. Long‐lasting cell dysfunction and stromal changes remain and impair cutaneous integrity. Radiation‐induced fibrosis and necrosis are usually considered intractable. Current therapeutic principles for local irradiation injury mostly involve nonspecific medical and surgical interventions with debridement of necrotic tissue, followed by different approaches including a skin graft, artificial derma application, or a rotation flap. Despite advances in modern plastic surgery techniques, such as skin grafting for the thermal injury, none has proved entirely satisfactory. The unpredictable spatio‐temporal course of the substantial inflammatory waves due to irradiation makes conventional surgical treatment often ineffective or even harmful: every surgical procedure appears to stimulate inflammation and the fibronecrotic process 2. In cases when healing is finally achieved, the scar remains fragile and unstable over time with a high risk of unpredictable upsurges. Preclinical studies of wound healing have focused on mesenchymal stem cells (MSCs)—nonhematopoietic, adherent fibroblast‐like cells with an intrinsic capacity for self‐renewal and differentiation—as a possible cell population within the bone marrow that might contribute to cutaneous repair 3, particularly in radiation burns 4, 5, 6, 7, 8. Optimum healing of skin wounds is orchestrated by several temporally processes that provide an anti‐inflammatory effect, cell proliferation, control of the extracellular matrix (ECM) deposition, angiogenesis, and remodeling 9. Impairment in this orderly progress of the healing process can lead to wound chronicity. The development of abnormal (e.g., hypertrophic or chronic) scarring may be one of the most common problems after radiation injury due to its functional consequences, especially when treatment includes surgery. Abnormal scars are probably due to overabundant collagen deposition—a cellular response by fibroblasts during the proliferation phase of wound healing 10. MSC treatment strongly enhances scar quality, which some authors attribute to the greater quantity of collagen within the healed tissue, which increases its tensile strength 9, 11, 12. The involvement of MSCs in the wound‐healing process appears to be crucial in injuries resulting from irradiation exposure, especially for nonhealing wounds resulting from fibronecrosis. Some patients with severe radiological syndrome have been treated with autologous MSCs injection combined with surgery 13. Most studies demonstrating the protective effects of MSCs 14 describe their short‐term (i.e., within a month) protection, but data about long‐term protection are sparse. Wound healing often demands significant long‐term medical attention and generally, a period of at least 6–18 months is required for maturation of burn scars 10. Particularly in radiation burns the important questions concern long‐term maintenance without inflammation and or renewed fibrosis. The healing process does not always go as planned, and some scars continue to remodel, grow, and expand, thereby becoming dysfunctional. Control of scar growth is thus important in clinical practice. Pigs are a preferred animal model for skin wounds, due to the similarity between their skin and human skin in architecture, structural epidermal thickness, dermal–epidermal thickness ratios, dermal collagen, and elastic content 15. Pig skin wounds heal primarily by re‐epithelialization rather than contraction, so they are especially useful in studying wound healing and burn lesions. The aim of this study is to evaluate the long‐term effects of bone marrow‐derived mesenchymal stromal cell (BM‐MSC) treatment on the preservation of wound‐healing quality after surgical resection to treat cutaneous radiation overexposure. Our findings show that all the specific surgical treatments of necrotic tissue resulted in the development of a hypertrophic scar and that, despite the placement of the vascularized flap, BM‐MSC was also required for remodeling to produce a lasting native dermal matrix.