Patrick Duhamel

Emerging therapy for improving wound repair of severe radiation burns using local bone marrow‐derived stem cell administrations

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 patients 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.

Cultured epithelial autografts in massive burns: A single-center retrospective study with 63 patients

UNLABELLED Cultured epithelial autografts (CEAs) have long been used to tackle limited donor site availability and difficulty of permanent skin coverage in massive burns, but this approach still has limited documentation. METHODS In this retrospective, single-center study, medical records of patients treated with CEAs in our burn center from 1991 until 2008 were analyzed in search of factors associated with outcome. RESULTS Out of 68 patients, 63 records were analyzable. Patients were aged 29 [17-41.5] years (seven children). Total body surface area (TBSA) burned was 81±10%, of which 69±14% TBSA full thickness. CEAs were first applied after 45±34 days, on a surface of 32±14% TBSA. Success rate at take down was 65±19%, correlating only with young age (r(2)=0.18; p=0.0006). At discharge, CEAs covered 26±15% TBSA. Infections (4.3±2 per patient), most frequently of skin, often complicated the clinical course. Mortality was 16% (10 patients). In multivariate analysis, the number of infections was the only factor associated with mortality (OR=2.05 per single infection, 95%CI 1.03-4.07, p=0.04). CONCLUSION Although complex and costly, CEAs can be used with reasonable success and satisfying survival results for the treatment of massive burns. In this study, favorable outcome was principally associated with young age and low number of infectious complications.

Anti-HLA sensitization in extensively burned patients: extent, associated factors, and reduction in potential access to vascularized composite allotransplantation

Extensively burned patients receive iterative blood transfusions and skin allografts that often lead to HLA sensitization, and potentially impede access to vascularized composite allotransplantation (VCA). In this retrospective, single‐center study, anti‐HLA sensitization was measured by single‐antigen‐flow bead analysis in patients with deep, second‐ and third‐degree burns over ≥40% total body surface area (TBSA). Association of HLA sensitization with blood transfusions, skin allografts, and pregnancies was analyzed by bivariate analysis. The eligibility for transplantation was assessed using calculated panel reactive antibodies (cPRA). Twenty‐nine patients aged 32 ± 14 years, including 11 women, presented with a mean burned TBSA of 54 ± 11%. Fifteen patients received skin allografts, comprising those who received cryopreserved (n = 3) or glycerol‐preserved (n = 7) allografts, or both (n = 5). An average 36 ± 13 packed red blood cell (PRBC) units were transfused per patient. In sera samples collected 38 ± 13 months after the burns, all patients except one presented with anti‐HLA antibodies, of which 13 patients (45%) had complement‐fixing antibodies. Eighteen patients (62%) were considered highly sensitized (cPRA≥85%). Cryopreserved, but not glycerol‐preserved skin allografts, history of pregnancy, and number of PRBC units were associated with HLA sensitization. Extensively burned patients may become highly HLA sensitized during acute care and hence not qualify for VCA. Alternatives to skin allografts might help preserve their later access to VCA.

Reconstruction of the Achilles Tendon with a Composite Anterolateral Thigh Free Flap with Vascularized Fascia Lata: A Case Report

Reconstruction of a segmental loss of the Achilles tendon combined with defects in soft-tissue coverage creates a challenge for the surgeon. We present the case of a patient who had combined loss of the Achilles tendon and overlying soft-tissue coverage. The patient was managed successfully with a single surgical procedure involving a composite anterolateral thigh free flap with vascularized fascia lata. The functional outcome of the reconstructed ankle and morbidity in the donor thigh were evaluated at one year with use of a kinetic dynamometer combined with magnetic resonance imaging. The patient was informed that data concerning the case would be submitted for publication, and he consented. A forty-eight-year-old man sustained a complete rupture of the left Achilles tendon during military service. Primary suture repair of the tendon was performed. Four months after that operation, a new rupture occurred when the patient returned to work, and a second tendon repair was performed to reconstruct the defect with the central part of the proximal part of the Achilles tendon (the Bosworth procedure). A large hematoma formed postoperatively, followed by skin necrosis, resulting in a 12-cm segmental tendon loss with an overlying soft-tissue defect measuring 8 × 3 cm. The wound site was debrided of all fibrous and necrotic tissue (Fig. 1). Because of the lack of suitable local tissue, a composite anterolateral thigh flap with attached vascularized fascia lata was harvested after a preoperative Doppler ultrasound examination. The main cutaneous perforator was located in the middle portion of a line between the anterior superior iliac spine and the lateral edge of the patella (Fig. 2). The skin paddle of the anterolateral thigh flap (17 × 8 cm) was designed to be slightly larger than the soft-tissue defect. It was harvested along with its vascular pedicle and a portion of the fascia …

Is the deltopectoral flap born again? Role in postburn head and neck reconstruction

After extensive use for head and neck reconstruction, the deltopectoral flap has been supplanted by alternative methods of reconstruction and relegated to historical references. However, it remains a very valuable skin flap and should keep its place in the armamentarium of reconstructive surgeons for postburn head and neck reconstruction. We report here five cases of head and neck reconstruction using the deltopectoral flap: one case of perioral reconstruction after ballistic trauma, one case of nasal reconstruction after burn and three cases of neck reconstruction after burn contracture. Technical simplicity and reliability are the main features of this flap. The skin paddle is thin and pliable, and its surface can be extended after a flap delay. Previous tissue expansion can minimize donor site morbidity. The flap division necessitates a second surgical procedure. The major burn contractures of the neck are, in our opinion, an excellent indication of the deltopectoral flap.

Extensively burned patients still need blood transfusions and skin allografts: unavoidable HLA sensitization requires optimization of VCA access

Dear Sirs, We thank Gaucher and Jarraya [1] for their comments on our study [2]. This first Single Antigen Flow Bead (SAFB) analysis of the strength and breadth of human leukocyte antigen sensitization (supporting information in our study [2]) in extensively burned patients was initiated after facing reduced access to Vascularized Composite Allograft (VCA) transplants for burned candidates. We described its impact on future VCA access and addressed the sensitizing factors and their alternatives. A recent report confirmed this risks of humoral rejection of VCA on sensitized patients [3]. Transfusions are unavoidable in acute care of extensively burned patients. Blood salvage procedures despite feasible have not been widespread due to their poor efficiency/risk (major sepsis) ratio after burns [4]. Red blood cells (RBC) present some HLA molecules that remain a cause of sensitization. In Leffell et al.’s study [5] kidney transplant candidates receiving leucoreduced transfusions presented a 20% risk of HLA sensitization versus 2.4% for nontransfused patient. In our study, all burns patients excepted one (not 100% of the patients, as mentioned by Gaucher and Jarraya) were sensitized, with a relative risk to be hypersensitized 3.3 fold higher when compared to kidney transplantation candidates. This could be explained by quantitative differences in RBC transfusions; however, the amounts of RBC received by the kidney transplant candidates were unavailable, as in Leffell’s study. Skin allografts keep a role after extensive burns, provided a risk benefit ratio analysis in the light of a potential VCA indication. Burns surface under or over 70% TBSA are, respectively, led to use CPSA as overlay on skin autograft (widely meshed or micrografted) [6] or for woundbed preparation before application of cultured autologous keratinocytes (CAK) [7]. As overlay, skin xenografts offer comparable efficacy and cost to CPSA [8], while dermal matrix offers poor adherence to CAK. If Kua et al. [9] compared glycerol (GPSA) with cryopreserved (CPSA) skin allografts for full-thickness burns, it retrieved no significant difference neither for mortality rates nor for length of stay. Richters et al. [10] study reported a very low T-cell response to allogenic glycerol-treated epidermal cells. No immunogenic comparison had been reported between GPSA and CPSA; however, such clinical comparison would require extensive multicentric assessment for a limited clinical relevance. The question of the potentiation between RBC and CPSA would require an animal study. The transfusion of HLA-matched RBC is not clinically applicable due to the number of units required for the acute care. It requires the development of transfusion components lacking the expression of HLA alloantigens. Skin banks with CPSA stocks allowing for HLA-matched skin grafting are not realistic. Antibody reductions by desensitization protocols in highly sensitized kidney transplant candidates are not long lasting and frequently recur. The limited number of patients to survive such extensive burns might limit the development and validation of any HLA sensitization multiparametric score. Gaucher and Jarraya stated that HLA sensitization must be avoided to keep open the option for VCA. This should be moderated as HLA sensitization do not preclude any VCA transplantation but increase the proportion of potential transplants carrying higher risks of humoral rejection. The priority to life-saving procedures for extensive face or hand burns patients should be combined with effort to reduce their sensitization. Their access to transplants can be optimized significantly by replacing the gender-matching usually applied for VCA by a size/morphological one.

Bioengineering a Human Plasma-Based Epidermal Substitute With Efficient Grafting Capacity and High Content in Clonogenic Cells

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.

Extensively burns patients are not unsuitable candidates to vascularized composite allotransplantations but require optimization in access to suitable transplants

We have read with a great interest the report from Win TS et al. on HLA sensitization in 14 extensively burns patients (TBSA over 40%) who received cryopreserved skin allografts. Over 30 face transplantations have been done worldwide, including one third of burns patients and we congratulate Win et al. for their interest on this topic. Their study is of importance when considering the reduced access to vascularized composite allografts (VCA) in general and not only for face transplant or burns candidates and deserves some comments. VCA requirements in extensively burns patients should not be reduced to face transplantations as upper limbs are often involved. Those patients will often require combined VCA with higher risks of technical failure and medical complications that cumulate to the risks related to the high sensitization. We reported the withdraw from the waiting list of a burned face transplant candidate due to a high (cPRA> 85%) HLA sensitization. We also previously reported the intense and wide HLA sensitization of 29 extensively burns patients with a subsequent extremely reduced access to VCA transplantation with acceptable risks. The concept of “transplant with acceptable risks” is important, as the HLA sensitization is not an absolute contra indication to VCA transplantion, contrary to a positive crossmatch, depending on the risks of early severe rejection as reported by Dr Pomahac’s team (Boston) that the team and patients will opt to face for those procedures. The reported average cPRA value of 87,7 27,6% is comparable to the one we noticed. More than the average