The therapeutic management of severe radiation burns remains a challenging issue today. Conventional surgical treatment including excision, skin autograft, or flap often fails to prevent unpredictable and uncontrolled extension of the radiation‐induced necrotic process. In a recent very severe accidental radiation burn, we demonstrated the efficiency of a new therapeutic approach combining surgery and local cellular therapy using autologous mesenchymal stem cells (MSC), and we confirmed the crucial place of the dose assessment in this medical management. The patient presented a very significant radiation lesion located on the arm, which was first treated by several surgical procedures: iterative excisions, skin graft, latissimus muscle dorsi flap, and forearm radial flap. This conventional surgical therapy was unfortunately inefficient, leading to the use of an innovative cell therapy strategy. Autologous MSC were obtained from three bone marrow collections and were expanded according to a clinical‐grade protocol using platelet‐derived growth factors. A total of five local MSC administrations were performed in combination with skin autograft. After iterative local MSC administrations, the clinical evolution was favorable and no recurrence of radiation inflammatory waves occurred during the patient's 8‐month follow‐up. The benefit of this local cell therapy could be linked to the “drug cell” activity of MSC by modulating the radiation inflammatory processes, as suggested by the decrease in the C‐reactive protein level observed after each MSC administration. The success of this combined treatment leads to new prospects in the medical management of severe radiation burns and more widely in the improvement of wound repair.

Severe burns remain a life-threatening local and general inflammatory condition often with serious sequelae, despite remarkable progress in their treatment over the past three decades. Cultured epidermal autografts, the first and still most up-to-date cell therapy for burns, plays a key role in that progress, but drawbacks to this need to be reduced by using cultured dermal-epidermal substitutes. This review focuses on what could be, in our view, the next major breakthrough in cell therapy of burns -use of mesenchymal stromal cells (MSCs). After summarizing current knowledge, including our own clinical experience with MSCs in the pioneering field of cell therapy of radiation-induced burns, we discuss the strong rationale supporting potential interest in MSCs in treatment of thermal burns, including limited but promising pre-clinical and clinical data in wound healing and acute inflammatory conditions other than burns. Practical options for future therapeutic applications of MSCs for burns treatment, are finally considered. Severe burns and their treatmentBurns are traumatic destruction of the skin and sometimes underlying tissues, usually caused by a heat source, less often by electricity or chemicals and rarely by ionizing radiation.1 Necrosis-triggered release of inflammatory mediators and in situ formation of toxic lipid-protein complexes generate local inflammation. In the most severe cases, potentially lethal acute toxaemia with systemic inflammatory response (SIR) and organ dysfunction, with a threshold around 20-30% total body surface area burnt, and dose (burn depth and extension)-dependent severity (1). Severe burns evolve in three phases:• In the early shock phase, hyperinflammation causes intense plasma leakage into the interstitium, organ dysfunction and injury aggravation. • In the following hypermetabolic phase, a long-lasting inflammatory status sustains organ dysfunctions and slows the wound-healing process, while cell-mediated immunity is impaired. • In the late local remodelling phase, cell ⁄ matrix interactions promote fibrotic, hypertrophic and ⁄ or retractile scarring.Besides aggressive supportive therapy, treating burns demands that the toxic eschar be quickly removed and that structure and function of the destroyed skin be restored. This is usually achieved through surgical eschar excision and split thickness autografts from healthy skin areas of the same patient. Despite providing epidermis and also a thin layer of dermal tissue, that technique cannot restore fully functional dermis nor epidermal appendages, and its applicability is limited by available amounts of healthy skin still present. Thus, burn treatment strategies often involve a combination of mesh expanded epidermal autografts, temporary or preparative skin substitutes including skin allografts and bio-engineered products (2), topical treatments and techniques to improve wound healing, and cell therapy in selected cases. Cell therapy for burns: background

When possible, early conversion from external to internal fixation improves bone union and functional recovery after war limb injuries in properly selected patients.

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Cultured epithelial autografts (CEAs) produced from a small, healthy skin biopsy represent a lifesaving surgical technique in cases of full-thickness skin burn covering >50% of total body surface area. CEAs also present numerous drawbacks, among them the use of animal proteins and cells, the high fragility of keratinocyte sheets, and the immaturity of the dermal-epidermal junction, leading to heavy cosmetic and functional sequelae. To overcome these weaknesses, we developed a human plasma-based epidermal substitute (hPBES) for epidermal coverage in cases of massive burn, as an alternative to traditional CEA, and set up critical quality controls for preclinical and clinical studies. In this study, phenotypical analyses in conjunction with functional assays (clonal analysis, long-term culture, or in vivo graft) showed that our new substitute fulfills the biological requirements for epidermal regeneration. hPBES keratinocytes showed high potential for cell proliferation and subsequent differentiation similar to healthy skin compared with a well-known reference material, as ascertained by a combination of quality controls. This work highlights the importance of integrating relevant multiparameter quality controls into the bioengineering of new skin substitutes before they reach clinical development. STEM CELLS TRANSLATIONAL MEDICINE 2015;4:643-654 SIGNIFICANCEThis work involves the development of a new bioengineered epidermal substitute with pertinent functional quality controls. The novelty of this work is based on this quality approach.