Advances in Translational Regenerative Therapies.

Regenerative medicine aims to replace damaged cells and tissues following injury [...].

Nitric oxide-releasing gel accelerates healing in a diabetic murine splinted excisional wound model.

Introduction: According to the American Diabetes Association (ADA), 9-12 million patients suffer from chronic ulceration each year, costing the healthcare system over USD $25 billion annually. There is a significant unmet need for new and efficacious therapies to accelerate closure of non-healing wounds. Nitric Oxide (NO) levels typically increase rapidly after skin injury in the inflammatory phase and gradually diminish as wound healing progresses. The effect of increased NO concentration on promoting re-epithelization and wound closure has yet to be described in the context of diabetic wound healing. Methods: In this study, we investigated the effects of local administration of an NO-releasing gel on excisional wound healing in diabetic mice. The excisional wounds of each mouse received either NO-releasing gel or a control phosphate-buffered saline (PBS)-releasing gel treatment twice daily until complete wound closure. Results: Topical administration of NO-gel significantly accelerated the rate of wound healing as compared with PBS-gel-treated mice during the later stages of healing. The treatment also promoted a more regenerative ECM architecture resulting in shorter, less dense, and more randomly aligned collagen fibers within the healed scars, similar to that of unwounded skin. Wound healing promoting factors fibronectin, TGF-ß1, CD31, and VEGF were significantly elevated in NO vs. PBS-gel-treated wounds. Discussion: The results of this work may have important clinical implications for the management of patients with non-healing wounds.

Homeless Tent Fires: A Descriptive Analysis of Tent Fires in the Homeless Population.

Tent fires are a growing issue in regions with large homeless populations given the rise in homelessness within the United States and existing data that suggest worse outcomes in this population. The aim of this study was to describe the characteristics and outcomes of tent fire burn injuries in the homeless population. A retrospective review was conducted involving two verified regional burn centers with patients admitted for tent fire burns between January 2015 and December 2020. Variables recorded include demographics, injury characteristics, hospital course, and patient outcomes. Sixty-nine patients met the study inclusion criteria. The most common mechanisms of injury were by portable stove accident, assault, and tobacco or methamphetamine related. Median percent total body surface area (%TBSA) burned was 6% (interquartile range [IQR] 9%). Maximum depth of injury was partial thickness in 65% (n = 45) and full thickness in 35% (n = 24) of patients. Burns to the upper and lower extremities were present in 87% and 54% of patients, respectively. Median hospital length of stay (LOS) was 10 days (IQR = 10.5) and median ICU LOS was 1 day (IQR = 5). Inhalation injury was present in 14% (n = 10) of patients. Surgical intervention was required in 43% (n = 30) of patients, which included excision, debridement, skin grafting, and escharotomy. In-hospital mortality occurred in 4% (n = 3) of patients. Tent fire burns are severe enough to require inpatient and ICU level of care. A high proportion of injuries involved the extremities and pose significant barriers to functional recovery in this vulnerable population. Strategies to prevent these injuries are paramount.

All hands on deck: Hand replantation versus transplantation.

OBJECTIVES: Our hands play a remarkable role in our activities of daily living and the make-up of our identities. In the United States, an estimated 41,000 individuals live with upper limb loss. Our expanding experience in limb transplantation-including operative techniques, rehabilitation, and expected outcomes-has often been based on our past experience with replantation. Here, we undertake a systematic review of replantation with transplantation in an attempt to better understand the determinants of outcome for each and to provide a summary of the data to this point. METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we conducted PubMed searches from 1964 to 2013 for articles in English. In total, 53 primary and secondary source articles were found to involve surgical repair (either replantation or transplantation) for complete amputations at the wrist and forearm levels. All were read and analyzed. RESULTS: Hand replantations and transplantations were compared with respect to pre-operative considerations, surgical techniques, post-operative considerations and outcomes, including motor, sensation, cosmesis, patient satisfaction/quality of life, adverse events/side effects, financial costs, and overall function. While comparison of data is limited by heterogeneity, these data support our belief that good outcomes depend on patient expectations and commitment. CONCLUSION: When possible, hand replantation remains the primary option after acute amputation. However, when replantation fails or is not possible, hand transplantation appears to provide at least equal outcomes. Patient commitment, realistic expectations, and physician competence must coincide to achieve the best possible outcomes for both hand replantation and transplantation.

Macrophage Subpopulation Dynamics Shift following Intravenous Infusion of Mesenchymal Stromal Cells.

Intravenous infusion of mesenchymal stromal cells (MSCs) is thought to be a viable treatment for numerous disorders. Although the intrinsic immunosuppressive ability of MSCs has been credited for this therapeutic effect, their exact impact on endogenous tissue-resident cells following delivery has not been clearly characterized. Moreover, multiple studies have reported pulmonary sequestration of MSCs upon intravenous delivery. Despite substantial efforts to improve MSC homing, it remains unclear whether MSC migration to the site of injury is necessary to achieve a therapeutic effect. Using a murine excisional wound healing model, we offer an explanation of how sequestered MSCs improve healing through their systemic impact on macrophage subpopulations. We demonstrate that infusion of MSCs leads to pulmonary entrapment followed by rapid clearance, but also significantly accelerates wound closure. Using single-cell RNA sequencing of the wound, we show that following MSC delivery, innate immune cells, particularly macrophages, exhibit distinctive transcriptional changes. We identify the appearance of a pro-angiogenic CD9+ macrophage subpopulation, whose induction is mediated by several proteins secreted by MSCs, including COL6A1, PRG4, and TGFB3. Our findings suggest that MSCs do not need to act locally to induce broad changes in the immune system and ultimately treat disease.

The impact of hospital volume on patient safety indicators following post-mastectomy breast reconstruction in the US.

INTRODUCTION: Despite the growing spotlight on value-based care and patient safety, little is known about the influence of patient-, reconstruction-, and facility-level factors on safety events following breast reconstruction. The purpose of this study is to characterize postoperative complications in light of hospital-level risk factors. METHODS: Using the National Inpatient Sample, all patients who underwent free flap and prosthetic breast reconstruction from 2012 to 2014 were identified. Predictor variables included patient demographic and clinical characteristics, type and timing of reconstruction, annual hospital reconstructive volume, hospital bed size, hospital setting (rural vs. urban), and length of stay. Patient safety indicators (PSIs) were based on the Agency for Healthcare Research and Quality's designation of preventable hospital complications: venous thromboembolism, bleeding, wound complications, pneumonia, and sepsis. Logistic models were used to analyze outcomes. RESULTS: The sample included 103,301 women, of which 27,695 (26.8%) underwent free flap reconstruction. 3.6% of patients experienced ≥ 1 PSI, most commonly wound PSI (4.9% and 2.5% for free flap and prosthetic reconstruction, respectively). Significant predictors of PSIs included rural setting (p < 0.01) and Elixhauser score ≥ 4 (p < 0.01) for the free flap group, and delayed reconstruction (p < 0.01) for the prosthetic group. Annual reconstructive facility volume was not associated with increased odds of PSIs in either prosthetic or free flap reconstruction (p > 0.05). CONCLUSION: PSIs were associated with rural hospitals and greater comorbidities for patients undergoing reconstruction with free flaps. Annual reconstructive facility volume was not associated with adverse inpatient outcomes with either method of reconstruction.

Homelessness and Inpatient Burn Outcomes in the United States.

Burn injuries are common in the homeless population. Little is known regarding whether homeless patients experience different outcomes when admitted for burns. We aim to 1) characterize the admitted homeless burn population, and 2) investigate differences in inpatient outcomes between the homeless and non-homeless populations. A retrospective cohort study was performed utilizing the Nationwide Inpatient Sample. Adult patients with complete data for burn characteristics were extracted. Variables included demographic, burn, and facility characteristics. Homelessness was identified with International Classification of Disease 9th edition codes. Outcomes were modeled with regression analysis and included length of stay, total operations, charges, disposition, and Patient Safety Indicators (PSIs). 43,872 encounters were included of which 0.76% were homeless. Homeless encounters were more likely to be male (P < .001) and Medicaid-insured (P < .001). Flame and frostbite injuries were more likely (P < .001), and the mean %TBSA was smaller (15.0 vs 16.8, P < .001). After adjustment, homeless patients had greater lengths of stay (11.5 vs 9.6, P = .046), greater charges ($73,597 vs $66,909, P = .030), fewer operations (P = .016), and three times higher likelihood leaving against medical advice (P = .002). There was no difference in PSIs or mortality. Homeless burn admissions represent a unique cohort that carries a higher comorbidity burden and experiences longer lengths of stay with greater difficulty in disposition. Ironically, these patients accumulate more charges with limited means to pay. Even though no differences were observed in PSIs or mortality, further research is needed to understand how the challenges within this population affect their recovery.

The Evolving Clinical Presentation of Acute Rejection in Facial Transplantation.

IMPORTANCE: Acute rejection is one of the most frequent complications in facial transplantation, with potentially severe consequences for the recipient if overlooked. Clinical signs, such as erythema or edema, are helpful to diagnose acute rejection in the early follow-up stage; however, it is not well known whether these clinical signs remain reliable markers of acute rejection beyond the second posttransplant year. OBJECTIVE: To determine the diagnostic value of clinical signs of acute rejection after facial transplantation over time. DESIGN, SETTING, AND PARTICIPANTS: A retrospective, single-center cohort study was conducted of patients who underwent facial transplantation at Brigham and Women's Hospital between April 2009 and October 2014, with up to an 8-year follow-up. Medical records were reviewed until September 30, 2017. The medical records from 104 encounters with 7 patients who underwent partial or full facial transplantation were analyzed for symptoms of rejection, immunosuppressive therapy, and histopathologic findings. MAIN OUTCOMES AND MEASURES: The occurrence of 5 clinical signs of acute rejection were evaluated: erythema, edema, exanthema, suture line erythema, and mucosal lesions. Odds ratios (ORs) were calculated to determine the statistically significant association of these signs with the histopathologic diagnosis of rejection. In addition, tacrolimus blood levels, as a surrogate marker of immunosuppressive therapy, were evaluated. RESULTS: Of the 7 patients included in the study, 5 were men. The mean follow-up was 66 months (range, 35-101). Of 104 clinical encounters, 46 encounters (44.2%) represented rejection episodes and 58 encounters (55.8%) represented no-rejection episodes. Beyond 2 years posttransplantation, only erythema (OR, 6.53; 95% CI, 1.84-20.11; P = .004) and exanthema (OR, ∞; 95% CI, 2.2-∞; P = .004) were demonstrated to be reliable clinical signs of acute rejection in facial transplantation. There was also a statistically significant association of subtherapeutic tacrolimus levels with late rejection episodes (OR, 3.79; 95% CI, 1.25-12.88; P = .03). In addition, the occurrence of subclinical rejection was more frequent during later follow-up times (7 [24.1%] late rejections vs 1 [5.9%] early rejection). Five of 8 subclinical rejections (62.5%) were associated with subtherapeutic tacrolimus levels. CONCLUSIONS AND RELEVANCE: Clinical signs of acute rejection in facial transplantation appear to be of limited diagnostic value, particularly after the second postoperative year. Until alternative biomarkers for rejection are identified, protocol skin biopsies will remain necessary for guiding assessments of allograft rejection. LEVEL OF EVIDENCE: 3.

Stem cell therapies for wound healing.

INTRODUCTION: Aberrant wound healing is a significant healthcare problem, posing a substantial burden on patients, their families, and the healthcare system. Existing treatment options remain only moderately effective and often fail to promote the closure of non-healing wounds in susceptible populations, such as aging and diabetic patients. Stem cell therapy has emerged as a promising treatment modality, with the potential to restore tissue to its pre-injured state. Of particular interest are mesenchymal stromal cells, which have been shown to accelerate wound healing by modulating the immune response and promoting angiogenesis. AREAS COVERED: This review provides an overview of wound healing and current methods for the management of chronic wounds, as well as the current state and considerations for optimizing stem cell therapy. Considerations include stem cell types, tissue source, donor selection, cell heterogeneity, delivery methods, and genetic engineering. EXPERT OPINION: A growing body of evidence has shown that delivery of stem cells, particularly mesenchymal stromal cells, has the potential to effectively improve the rate and quality of wound healing. However, significant additional basic and clinical research must be performed to optimize cell therapy, such as further elucidation of the therapeutic mechanisms of stem cells and standardization of clinical trial guidelines.

Increasing ambulatory treatment of pediatric minor burns-The emerging paradigm for burn care in children.

INTRODUCTION: Innovations in topical burn treatment along with a drive toward value-based care are steering burn care to the outpatient setting. Little is known regarding what characteristics predict outpatient treatment of pediatric minor burns and whether there is a temporal trend toward this treatment paradigm. METHODS: A retrospective cohort study was performed using California's Office of Statewide Health Planning and Development linked emergency department and inpatient database (2005-2013). All patients under 18years of age with a primary burn diagnosis were extracted. Using patient and facility level variables, we used regression modeling to evaluate predictors of outpatient burn treatment and temporal trends. RESULTS: There were 16,480 pediatric minor burn encounters during the period. 56.4% were male, 85.3% had <10% total body surface area (TBSA), 76.3% were scald or contact, and 77.3% were at deepest depth 2nd degree. Multiple variables predicted an increased likelihood of discharge home including older age(p<0.001), smaller TBSA(p<0.001), and superficial/partial thickness burns(< 0.001). Children of Hispanic and Black race were less likely to be discharged home compared to White and Asian peers(p=<0.001). On Poisson modeling, the incidence rate ratio over the 9-year period for home discharge was 1.004 (95% CI 1.001-1.008, p=0.032). CONCLUSION: Older patients and those with more superficial burns were more likely to be treated as outpatients. Black and non-white Hispanic race was associated with inpatient admission. There is a growing trend toward ambulatory treatment of minor burns in the pediatric population. Further research is needed to assess whether outpatient treatment of pediatric minor burns results in greater readmissions.

Kidney Dysfunction After Vascularized Composite Allotransplantation.

BACKGROUND: Kidney dysfunction is a major complication after nonrenal solid organ transplants. Transplantation of vascularized composite allografts (VCA) has yielded successful midterm outcomes despite high rates of acute rejection and greater requirements of immunosuppression. Whether this translates in higher risks of kidney complications is unknown. METHODS: Ninety-nine recipients of facial or extremity transplants from the Brigham and Women's Hospital (BWH) and the International Registry on Hand and Composite Tissue Transplantation (IR) were reviewed. We assessed immunosuppression, markers of renal function over time, as well as pretransplant and posttransplant renal risk factors. RESULTS: Data were obtained from 10 patients from BWH (age at transplant, 42.5 ± 13.8 years) and 89 patients (37.8 ± 11.5 years) from IR. A significant rise in creatinine levels (BWH, P = 0.0195; IR, P < 0.0001) and drop in estimated glomerular filtration rate (GFR) within the first year posttransplant was observed. The BWH and IR patients lost a mean of 22 mL/min GFR and 60 mL/min estimated GFR in the first year, respectively. This decrease occurred mostly in the first 6 months posttransplant (BWH). Pretransplant creatinine levels were not restored in either cohort. A mixed linear model identified multiple variables correlating with renal dysfunction, particularly tacrolimus trough levels. CONCLUSIONS: Kidney dysfunction represents a major complication posttransplantation in VCA recipients early on. Strategies to mitigate this complication, such as reducing calcineurin inhibitor trough levels or using alternative immunosuppressive agents, may improve long-term patient outcomes. Standardizing laboratory and data collection of kidney parameters and risk factors in VCA patients will be critical for better understanding of this complication.

Perceived social support among patients with burn injuries: A perspective from the developing world.

BACKGROUND: Social support is among the most well-established predictors of post-burn psychopathology after burn. Despite a disproportionately large burden of burns in the developing world, the nature of social support among burn patients in this context remains elusive. We, therefore, seek to investigate social support and its biopsychosocial determinants among patients with burn injuries in Pakistan. METHODS: A cross-sectional study of 343 patients presenting with burn injuries at four teaching hospitals in the Punjab province of Pakistan was conducted. Patient evaluation consisted of a multi-part survey of demographic status, clinical features, and social support as measured by the validated Urdu translation of the Multidimensional Scale of Perceived Social Support (MSPSS). Multiple regression analysis was performed to evaluate associations between patient characteristics and MSPSS score. RESULTS: Mean overall MSPSS score was 57.64 (std dev 13.57). Notable positive predictors of social support include male gender, Punjabi ethnicity, burn surface area, and ego resiliency. CONCLUSION: Our study reveals a troubling pattern of inadequate social support among certain subgroups of Pakistani burn patients. Addressing these inequities in the provision of social support must be prioritized as part of the global burn care agenda.

Experience With Patient Referrals for Upper Extremity Transplantation at a U.S. Academic Medical Center.

PURPOSE: To date, there have been over 100 upper extremity transplantations (UET) performed worldwide. However, little data are available regarding institutional screening practices or description of the population of patients that seek transplantation as a treatment modality for their upper extremity disabilities. We performed a review of our institutional experience in an attempt to better understand our referral patterns and identify factors that may be associated with successful screening. METHODS: Contact demographic data, injury characteristics, and mode of referral were retrospectively reviewed from 2010 through 2015. Differences in demographic data, injury-related characteristics, and clinical trial outcomes were assessed with the Chi-square test or Fisher exact test. RESULTS: There were a total of 89 UET contacts. The average age was 35.2 years, with most contacts being white (n = 24). The majority were male (n = 66; 75.0%) and the most common indication for referral was trauma (n = 43; 55.8%). Of the 89 contacts, 20 (22.5%) were physician referrals and 69 (77.5%) were self-referrals. Physician referrals led to the most screened and accepted contacts, whereas self-referrals more often led to immediate exclusion. CONCLUSIONS: This study gives an overview of the demographic composition of our UET contacts, with a specific emphasis on mode of referral. We have identified that physician referrals have led to more screened and accepted patients versus self-referred individuals. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic, Level IV.

Tissue conservation for transplantation.

Pathophysiological changes that occur during ischemia and subsequent reperfusion cause damage to tissues procured for transplantation and also affect long-term allograft function and survival. The proper preservation of organs before transplantation is a must to limit these injuries as much as possible. For decades, static cold storage has been the gold standard for organ preservation, with mechanical perfusion developing as a promising alternative only recently. The current literature points to the need of developing dedicated preservation protocols for every organ, which in combination with other interventions such as ischemic preconditioning and therapeutic additives offer the possibility of improving organ preservation and extending it to multiple times its current duration. This review strives to present an overview of the current body of knowledge with regard to the preservation of organs and tissues destined for transplantation.

Quality of Life after Face Transplantation: Outcomes, Assessment Tools, and Future Directions.

BACKGROUND: Face transplantation has emerged as a clinical reality for the restoration of complex facial defects. Critical to the advancement of the burgeoning field of reconstructive transplantation is the quality of the methods used to measure and report the impact of face transplantation on quality of life. METHODS: A systematic search using PubMed and EMBASE was conducted for all studies matching the a priori inclusion criteria from 2005 through 2015. Bibliographies of included studies were also reviewed. Two authors (M.A.A and H.K) independently performed screening of titles. RESULTS: The authors identified 17 articles reporting on quality-of-life outcomes among 14 face transplant recipients. Combinations of objective and subjective measures were used to assess quality of life. Instruments used to assess quality of life after face transplantation included over 25 different instruments. Four centers, comprising eight patients, have reported using prospective, systematic data with validated instruments. Overall, there is reported improvement in quality of life after face transplantation. Heterogeneity and a paucity of data between articles preclude a quantitative analysis. CONCLUSIONS: Anecdotal and subjective reports of improvements in quality of life after face transplantation constitute the majority of reported outcomes in the English peer-reviewed literature. Improved efforts in methods and standardization of collection and reporting of quality-of-life data after face transplantation are needed to better appreciate the impact of face transplantation on quality of life and justify lifelong immunosuppression and its attendant risks and morbidity.

The role of face transplantation in the self-inflicted gunshot wound.

BACKGROUND: Facial self-inflicted gunshot wounds (SIGSWs) cause a devastating midfacial defect and pose a challenging problem to the reconstructive surgeon. Face transplantation (FT) has the potential for near-normal restoration in otherwise non-reconstructible defects. Two out of 7 FT recipients at Brigham and Women's Hospital (BWH) sustained SIGSWs. In this study, we illustrate the role of FT in the management of SIGSWs through an aesthetic, functional, and psychosocial examination of outcomes. METHODS: We performed a retrospective analysis of individuals with SIGSWs who were screened at BWH between 2008 and 2015. We then collected data of the injuries, modes of conventional reconstruction (CR), and deficits. For the FT recipients, we critically reviewed the psychosocial screening process and post-transplantation aesthetic, functional, and psychosocial outcomes. RESULTS: A total of six individuals post-SIGSWs were screened for FT. All of them had undergone CR, with five receiving loco-regional flaps and free tissue transfers, and one undergoing serial debridement and primary soft-tissue repair. Following CR, all suffered from residual functional and aesthetic deficits. Two underwent partial FT and one is currently undergoing FT screening. We describe the pre-transplant psychosocial screening process and the aesthetic, functional, and psychosocial outcomes of the SIGSW FT recipients. CONCLUSIONS: We examined the facial SIGSW injury, outcomes of CR, and the mechanism of FT to offer a potential solution to the shortcomings of CR. More importantly, we highlight the critical nature of the psychosocial component of the multidisciplinary evaluation given the history of mental illness and suicidal behavior in this subset of patients.

Patient Recruitment and Referral Patterns in Face Transplantation: A Single Center's Experience.

BACKGROUND: Face transplantation has been shown to improve the functional and aesthetic deficits of facially disfigured individuals. Given promising short-term results, it is important to examine whether face transplantation centers are effectively reaching the targeted facial disfigurement population. The authors' center reviewed their face transplantation contacts to assess patient recruitment and outreach performance. METHODS: The authors performed a retrospective review of their face transplantation contacts from the time of their institutional review board protocol approval (February of 2008) to October of 2015. They investigated the relationship between referral pattern (i.e., physician versus self) with the contact's demographic characteristics (i.e., age, sex, race, mechanism of injury, and geographic location) and clinical trial status. RESULTS: There were a total of 72 face transplantation contacts. The average age of the contacts was 38 years, and the majority were men [n = 41 (56.9 percent)]. Most were white (n = 33), and the most prevalent mechanism of injury was burns (46.4 percent). The majority of the contacts resided within the United States (n = 47), with most from the Northeastern United States (n = 21). Of the 72 contacts, 35 (48.6 percent) were physician referrals and 37 (51.4 percent) were self-referrals. Physician referrals have led to the most screened and transplanted contacts in their center, whereas self-referral often led to immediate exclusion. CONCLUSIONS: The authors show the diversity of patient characteristics and referral patterns in their clinical trial. Furthermore, they describe the relationship of characteristics to outcomes in their cohort and identify areas of improvement, such as patient and physician education. Lastly, they are reminded of the potential impact on the burn community.

A Mobile Extracorporeal Extremity Salvage System for Replantation and Transplantation.

BACKGROUND: Traumatic amputation is the second leading cause of limb loss in the United States. The preferred treatment is salvage and replantation of the amputated limb, whenever possible, and allotransplantation is a novel procedure whereby healthy limbs are procured from deceased organ donors and transplanted into the amputee recipient. A major restriction for both procedures is the irrecoverable muscle damage occurring due to ischemia. We investigated the feasibility of using a novel lightweight, mobile perfusion device specifically designed to perfuse amputated porcine limbs with an acellular perfusion solution to delay ischemic muscle damage prior to transplantation or replantation. METHODS: Bilateral hind limbs of Yorkshire pigs were amputated; one of the limbs was preserved by perfusion in the mobile perfusion device, and the other by storage in ice slurry for 12 hours. RESULTS: Five sets of bilateral limbs were preserved as described previously. A defined pressure of 30 mm Hg was reliably maintained in the arterial system without loss of flow. Comparison of the perfusate composition before and after limb passage revealed significant differences. Muscle biopsies showed a consistent progression of clusters of hypoxic cells in the control limbs with time. Similar changes could not be observed in the perfused tissue. CONCLUSIONS: We have designed and built a small, mobile perfusion device that is operational and that more closely mimics the normal physiological environment when compared with the current standard of preservation in ice slurry. This project may have far-reaching implications for the treatment of limb loss through replantation and transplantation.

Common postburn deformities and their management.

This article describes a practical, clinically based approach to classification of postburn deformities. Burn scar contractures are of either the broad diffuse type or linear band-like type. The former generally respond well to release and insertion of a skin graft or substitute, whereas the latter are generally repaired using a simple or modified Z-plasty or a transpositional flap technique. The pulsed dye laser is a promising technique used to reduce scar thickness and redness. Postburn deformities of the face, upper and lower extremities, and trunk are discussed, in addition to novel techniques for vascularized composite allotransplantation of the face.