Existing and Evolving Bioethical Dilemmas, Challenges, and Controversies in Vascularized Composite Allotransplantation: An International Perspective From the Brocher Bioethics Working Group

Early results of hand and face transplants and other grafts such as those of uterus, penis, trachea, larynx, or abdominal wall have confirmed the potential for vascularized composite allotransplantation (VCA) to restore appearance, anatomy, function, independence, and social integration in patients suffering from devastating tissue deficits untreatable by conventional treatment options. Despite such promise, these novel and complex procedures face challenges and controversies that remain open to discussion and debate. Indeed, many barriers to clinical advancement and negative stakeholder perceptions still exist. The bioethical challenges surrounding VCA include but are not limited to justice and vulnerability of subjects, and their experiences with risks, benefits and outcomes, provider economy of fame, public awareness and attitudes toward transplantation, and policy and regulatory issues shaping progress of the field. The First International Workshop on Bioethical Challenges in Reconstructive Transplantation was organized by the Brocher Foundation in Hermance, Switzerland. VCA professionals representing teams from across the world examined bioethical issues in VCA related to standards for safety, efficacy, feasibility, privacy, confidentiality, and equitability. Key discussion topics from the workshop were included in a survey questionnaire implemented across VCA professionals attending the 13th Congress of International Society of VCA held in Salzburg, Austria. The insights from the Brocher workshop and International Society of VCA survey as presented here could help inform the future development of clinical practice and policy strategies in VCA to ensure value, accessibility, and acceptance of these procedures by potential donors, potential or actual recipients and their families, and providers and payers

Abdominal, perineal, and genital soft tissue reconstruction with pedicled anterolateral thigh perforator flaps

Background Pedicled perforator flaps have become a contemporary alternative to muscle flaps for soft tissue reconstruction as they have reduced donor site morbidity, avoid the need for microsurgical transfer, and are versatile and reliable. The anterolateral thigh (ALT) flap was first introduced as a free flap and has since gained popularity as a pedicled flap. Here we review our experience using pedicled ALT flaps for regional soft tissue reconstruction. Methods We retrospectively reviewed all patients who underwent loco-regional soft tissue reconstruction using pedicled ALT flaps between March 2014 and October 2018, with the goal of identifying potential applications of pedicled ALT flaps. The following aspects of each case were reviewed: patient demographics, defect location and size, comorbidities such as previous radiotherapy, flap details, clinical follow-up, and postoperative complications. Results Our analysis demonstrates the versatility of pedicled ALT flaps in a variety of indications to successfully cover large abdominal, perineal, and genital soft tissue defects. Depending on the patient’s needs to achieve more bulk or stability in the reconstruction, the ALT flap was individually tailored with underlying muscle or fascia. The average follow-up was 7 months (range: 3–13 months). Conclusions Pedicled ALT flaps are a valuable reconstructive option for soft tissue defects located within the pedicle’s range, from the lower abdomen to the perianal region. These flaps are usually raised from a non-irradiated donor site and are sufficient for covering extensive soft tissue defects. Three-dimensional reconstruction of the defect using pedicled ALT flaps allows for anatomical function and minor donor sites

The Significance of Vascular Alterations in Acute and Chronic Rejection for Vascularized Composite Allotransplantation.

Vascularized composite allotransplantation (VCA) has emerged as a useful reconstructive option for patients suffering from major tissue defects and functional deficits. While the technical feasibility has been optimized and more than 130 VCAs have been performed during the last two decades, hurdles such as acute and chronic allograft rejection, graft deterioration, and eventual functional impairment need to be addressed. Recently, chronic graft rejection and progressive failure have been linked to vascular alterations observed in the allografts. Graft vasculopathy (GV) may play a pivotal role in long-term graft deterioration. The understanding of the underlying pathophysiological processes and their initial triggers is of utmost importance in the prevention, attenuation, and therapy of GV. While there are reports on the etiology and development of GV in solid organ transplantation, there are limited data with respect to chronic rejection and GV in the realm of VCA. Nevertheless, recent reports from long-term VCA recipients suggest that GV could truly jeopardize allografts in the follow-up evaluation. Chronic rejection and GV include different entities and might have different pathways in distinct organs. Herein, we reviewed the current literature on vascular changes during both acute and chronic allograft rejection, with a focus on their clinical and translational significance for VCA

Predictors for limb amputation and reconstructive management in electrical injuries

BACKGROUND Electrical injuries follow a specific pathophysiology and may progressively damage both skin and deeper tissues, frequently ending in amputations. Type and timing of soft tissue reconstruction after electrical burns is crucial for proper outcome. The aim of this study was to assess surgical management and outcome of patients with electrical injuries treated at the Zurich Burn Center over the last 15 years, with emphasis on risk factors for amputation and reconstructive strategy. METHODS Patient charts were reviewed retrospectively to identify cases admitted at the Zurich Burns Center (2005-2019). Patient characteristics and surgical management, with a special focus on amputations, reconstruction and outcome were analyzed and risk factors for amputation were assessed. RESULTS Eighty-nine patients were identified and a total of 522 operations were performed. Escharotomy and fasciotomies were performed in 40.5% and 24.7% of cases, respectively, mainly at admission. The total amputation rate was 13.5% (23 amputations, 12 patients). Development of compartment syndrome, rhabdomyolysis, high myoglobin and CK blood levels, kidney failure, sepsis and respiratory complications during the course were related to higher risk of amputation (p < 0.001). Sixty-six flap-based reconstructions were performed (25% cases): 49 loco-regional flaps, 3 distant pedicled flaps, 14 free flaps. Two flaps were lost (flap failure rate 14%). Both flap losses occurred in cases of early reconstruction (within 5-21 days). CONCLUSIONS Electrical injuries are still cause of elevated morbidity and mortality, with high amputation rate. Predictors for amputation can support physicians in the surgical care and decision-making. Reconstruction remains challenging in this type of injury: the surgical management with early decompression, serial necrectomies and delayed early reconstruction remains the procedure of choice at our unit

Serum Selenium-Binding Protein 1 (SELENBP1) in Burn Injury: A Potential Biomarker of Disease Severity and Clinical Course

Oxidative stress, systemic inflammation, and metabolic derangements are hallmarks of burn pathophysiology. Severely burned patients are highly susceptible to infectious complications. Selenium-binding protein 1 (SELENBP1) modulates intracellular redox homeostasis, and elevated serum concentrations have been associated with adverse clinical outcomes in trauma patients. We hypothesized that serum SELENBP1 at hospital admission and during hospitalization may constitute a meaningful biomarker of disease severity and the clinical course in burn injury, with pulmonary infection as primary endpoint. To this end, we conducted a prospective cohort study that included 90 adult patients admitted to the Burn Center of the University Hospital Zurich, Switzerland. Patients were treated according to the local standard of care, with high-dose selenium supplementation during the first week. Serum SELENBP1 was determined at nine time-points up to six months postburn and the data were correlated to clinical parameters. SELENBP1 was initially elevated and rapidly declined within the first day. Baseline SELENBP1 levels correlated positively with the Abbreviated Burn Severity Index (ABSI) (R = 0.408; p < 0.0001). In multiple logistic regression, a higher ABSI was significantly associated with increased pulmonary infection risk (OR, 14.4; 95% CI, 3.2-88.8; p = 0.001). Similarly, baseline SELENBP1 levels constituted a novel but less accurate predictor of pulmonary infection risk (OR, 2.5; 95% CI, 0.7-8.9; p = 0.164). Further studies are needed to explore the additional value of serum SELENBP1 when stratifying patients with respect to the clinical course following major burns and, potentially, for monitoring therapeutic measures aimed at reducing tissue damage and oxidative stress

Adipose-derived stem cells (ADSCs) and muscle precursor cells (MPCs) for the treatment of bladder voiding dysfunction

Purpose: Bladder outflow obstruction (BOO) is common in the elderly and can result in bladder voiding dysfunction (BVD) due to severe bladder muscle damage. The goal of this research was to evaluate the use of adult stem cells for the treatment of BVD due to decreased muscle contractility in a rat model. Materials and methods: Adipose-derived stem cells (ADSCs) and muscle precursor cells (MPCs) were harvested from male Lewis rats and expanded in culture. BOO was induced by tying a suture around the urethra. Six weeks after obstruction, the development of BVD was confirmed by cystometric analysis in conscious rats, histology and molecular investigations. Injection of ADSCs or MPCs into the bladder wall and synchronous deligation was performed 6weeks after the obstruction. After stem-cell treatment, morphological and functional changes were assessed. Age-matched rats and animals without cellular therapy but deligation-only served as controls. Results: Voiding pressures decreased progressively 6weeks after obstruction with increased bladder capacities. Structural changes of the detrusor muscle occurred during the time of obstruction with an increased connective tissue-to-smooth muscle ratio and decreased SMA/smoothelin expression. After stem-cell injection, improved voiding pressures and voiding volumes were observed together with recovered tissue architecture. RT-PCR and Western blotting showed an up-regulation of important contractile proteins. Conclusions: We established a reliable model for BVD and demonstrated that ADSCs and MPCs can prevent pathophysiological remodelling and provide regenerated bladder tissue and function

Characteristics and Immunomodulating Functions of Adipose-Derived and Bone Marrow-Derived Mesenchymal Stem Cells Across Defined Human Leukocyte Antigen Barriers

BackgroundVascularized composite allotransplantation opens new possibilities in reconstructive transplantation such as hand or face transplants. Lifelong immunosuppression and its side-effects are the main drawbacks of this procedure. Mesenchymal stem cells (MSCs) have clinically useful immunomodulatory effects and may be able to reduce the burden of chronic immunosuppression. Herein, we assess and compare characteristics and immunomodulatory capacities of bone marrow- and adipose tissue-derived MSCs isolated from the same human individual across defined human leukocyte antigen (HLA) barriers.Materials and methodsSamples of omental (o.) adipose tissue, subcutaneous (s.c.) adipose tissue, and bone marrow aspirate from 10 human organ donors were retrieved and MSCs isolated. Cells were characterized by flow cytometry and differentiated in three lineages: adipogenic, osteogenic, and chondrogenic. In mixed lymphocyte reactions, the ability of adipose-derived mesenchymal stem cells (ASCs) and bone marrow-derived mesenchymal stem cells (BMSCs) to suppress the immune response was assessed and compared within individual donors. HLA mismatched or mitogen stimulations were analyzed in co-culture with different MSC concentrations. Supernatants were analyzed for cytokine contents.ResultsAll cell types, s.c.ASC, o.ASC, and BMSC demonstrated individual differentiation potential and cell surface markers. Immunomodulating effects were dependent on dose and cell passage. Proliferation of responder cells was most effectively suppressed by s.c.ASCs and combination with BMSC resulted in highly efficient immunomodulation. Immunomodulation was not cell contact-dependent and cells demonstrated a specific cytokine secretion.ConclusionWhen human ASCs and BMSCs are isolated from the same individual, both show effective immunomodulation across defined HLA barriers in vitro. We demonstrate a synergistic effect when cells from the same biologic system were combined. This cell contact-independent function underlines the potential of clinical systemic application of MSCs