The Global Experience of Laryngeal Transplantation: Series of Eleven Patients in Three Continents.

BACKGROUND: The loss of laryngeal function affects breathing, swallowing, and voice, thus severely compromises quality of life. Laryngeal transplantation has long been suggested as a solution for selected highly affected patients with complete laryngeal function loss. OBJECTIVE: To obtain insights regarding the advantages, weaknesses, and limitations of this procedure and facilitate future advances, we collected uniform data from all known laryngeal transplants reported internationally. METHODOLOGY: A case series. Patients were enrolled retrospectively by each institutional hospital or clinic. Eleven patients with complete loss of laryngeal function undergoing total laryngeal transplantation between 1998 and 2018 were recruited. RESULTS: After a minimum of 24 months follow-up, three patients had died (27%), and there were two graft explants in survivors, one total and one partial, due to chronic rejection. In the remaining cases, voice was functional in 62.5% and 50% achieved decannulation. Swallowing was initially restricted, but only one patient was gastrostomy-dependent by 6 months and all had normal or near-normal swallowing by the end of year two after transplantation. Median follow-up was 73 months. Functional (voice, swallowing, airway) recovery peaked between 12 and 24 months. CONCLUSIONS: Laryngeal transplantation is a complex procedure with significant morbidity. Significant improvements in quality of life are possible for highly selected individuals with end-stage laryngeal disorders, including laryngeal neoplasia, but further technical and pharmacological developments are required if the technique is to be more widely applicable. An international registry should be created to provide better quality pooled data for analysis of outcomes of any future laryngeal transplants. LEVEL OF EVIDENCE: IV Laryngoscope, 2024.

Cell therapies and its derivatives as immunomodulators in vascularized composite allotransplantation.

The adverse effects of traditional pharmaceutical immunosuppressive regimens have been a major obstacle to successful allograft survival in vascularized composite tissue allotransplantation (VCA) cases. Consequently, there is a pressing need to explore alternative approaches to reduce reliance on conventional immunotherapy. Cell therapy, encompassing immune-cell-based and stem-cell-based regimens, has emerged as a promising avenue of research. Immune cells can be categorized into two main systems: innate immunity and adaptive immunity. Innate immunity comprises tolerogenic dendritic cells, regulatory macrophages, and invariant natural killer T cells, while adaptive immunity includes T regulatory cells and B regulatory cells. Investigations are currently underway to assess the potential of these immune cell populations in inducing immune tolerance. Furthermore, mixed chimerism therapy, involving the transplantation of hematopoietic stem and progenitor cells and mesenchymal stem cells (MSC), shows promise in promoting allograft tolerance. Additionally, extracellular vesicles (EVs) derived from MSCs offer a novel avenue for extending allograft survival. This review provides a comprehensive summary of cutting-edge research on immune cell therapies, mixed chimerism therapies, and MSCs-derived EVs in the context of VCAs. Findings from preclinical and clinical studies demonstrate the tremendous potential of these alternative therapies in optimizing allograft survival in VCAs.

Reconstruction of a Pediatric Distal Phalanx Amputation With Stacked Integra Dermal Substitute: A Case Report.

Finger amputations in children present unique challenges and require special considerations compared to their adult counterparts. Maximizing length and preserving fingertip bulk and sensation is essential for maintaining a functional digit. Synthetic dermal substitutes have been recently used for soft tissue coverage for pediatric syndactyly as well as burn injuries; however, the literature discussing pediatric amputation cases with soft tissue damage proximal to the bony level is limited.In this case, we report a two-year-old patient who developed dry gangrene of her right index finger after multiple rabbit bites and underwent an amputation through the distal interphalangeal joint. Circumferential soft-tissue debridement proximal to the tip of the middle phalanx was required, leaving substantial exposed bone with no soft tissue envelope. We report our experience of single-stage stacking Integra dermal substitute directly onto the exposed bone to provide both finger bulk and soft tissue coverage.The patient displayed no functional limitations three years post-surgery.For instances when local or distant flap coverage may not be feasible, we present a novel technique to reconstruct, provide bulk, and preserve length in pediatric finger amputations. This case highlights that the utility of dermal substitutes is expanding and are providing more technical options.

Long-term outcomes and future challenges in face transplantation.

Face transplant (FT) has emerged as a groundbreaking option for patients with severe facial deformities, resulting from congenital disorders, trauma, or tumor ablation. Although reconstructive surgery has made significant strides, the challenges of restoring both form and function remain, particularly in centrally located defects. This review explored the long-term outcomes of FT, addressing its challenges and potential pitfalls. A systematic review following the PRISMA guidelines was conducted, encompassing articles published in English from November 2005 to January 2023, which were searched across PubMed, MEDLINE, and EMBASE databases. Keywords included "face transplant," "face transplant outcomes," and "face transplant long-term." Data on surgical teams, patient demographics, transplant specifics, rejection episodes, additional surgeries, and patient-reported outcomes were extracted and analyzed. In total, 34 articles met the inclusion criteria. Over the 2 decades, 48 FT procedures were performed, with 23 patients followed for at least 3 years. Predominantly, patients were men (80%), averaging 31 years in age. Ballistic trauma (44.6%) and burns (25.5%) were common causes of injury. Chronic rejection emerged as a significant concern, leading to graft loss and necessitating retransplantation in 2 patients. Additional surgical procedures were often required. FT offers a remarkable solution for individuals with extensive facial disfigurement. Successful outcomes depend on factors, such as patient selection, multidisciplinary collaboration, psychiatric evaluation, and post-operative care. Nevertheless, challenges persist, including the need for lifelong immunosuppression and risk of chronic rejection. Although FT has transformed lives, continued success in this evolving field hinges on the ongoing research and vigilant patient management.

One Year Experience of the Hand Allotransplantation First Performed after Korea Organ Transplantation Act (KOTA) Amendment.

The revision of the Korea Organ Transplantation Act (KOTA) in 2018 included hand/arm among the organs that can be transplanted. The first hand transplantation since the revision of KOTA took place in January 2021. A 62-year-old male patient experienced hand amputation on July 13, 2018, by a catapult injury. The patient first visited our institute 3 months after the injury. After serial interviews and an overall evaluation, the patient was registered on the hand transplantation waiting list in January 2020. On January 9, 2021, the patient underwent hand transplantation at the right distal forearm level. The total operation time was 17 hours 15 minutes, and the cold ischemic time was 4 hours 9 minutes. Postoperative immunosuppression was administered based on the protocol used for kidney transplantation. Two acute rejection episodes occurred, on postoperative days 33 and 41. Both rejection episodes were reversible with rescue therapy of a higher tacrolimus trough level, steroid pulse therapy, and topical immunosuppressants. Controlled passive range of motion exercise was started on postoperative day 10. Dynamic splint was applied on postoperative day 18. At 1 year, graft maintenance and functional improvement were satisfactory, and the patient showed a Disabilities of Arm, Shoulder and Hand score of 25.8. We successfully performed the first hand transplantation surgery under the KOTA amendment. It came from the organic and effective cooperation of plastic, orthopaedic, and transplantation departments and we believe it will guarantee the future ongoing success.

Psychosocial Risk Stratification in Upper Extremity Transplantation Candidates.

BACKGROUND: Candidate selection for upper extremity transplantation remains an inherently subjective process. This work evaluated the effect that psychosocial factors have on outcomes, both to standardize evaluation of potential candidates and in optimizing these factors prior to transplantation. Our goal was to measure and quantify the risk that various psychosocial factors have on transplant outcomes. METHODS: Given that we do not have sufficient post-transplant patients to examine specific factors, we chose to have experts in the field evaluate hypothetical patients based on their experience. We used a Generalized Estimating Equation to estimate and compare surgical candidacy scores using patient scenario vignettes based on the presence or absence of permutations of the following: (1) depression; (2) participation in occupational therapy (OT); (3) expectation of post-transplant function; (4) punctuality; and (5) family support were given to experts in the field. RESULTS: This work suggests there is a decrease in predicted success with increasing numbers of negative factors with participation in OT and realistic expectations of outcomes being most important. An increase in the summarizing risk score from 0 to 1.7 was associated with a decrease in the outcome surgical candidacy score from 8.6 to 5.3, meaning candidates with 2 risk factors would often observe a large drop in surgical candidacy score. CONCLUSIONS: Focusing on optimizing psychosocial variables in transplant candidates may help improve hand transplant success.

Hand Therapy Regimen for Functional Recovery Following Combined Face and Bilateral Hand Transplantation.

Intensive postoperative rehabilitation therapy is associated with positive functional recovery in hand transplants (HTs). Our goal is to share the hand therapy protocol developed for our patient who underwent a combined face and bilateral HT. The patient is a 23-year-old right-hand-dominant male with a history of third-degree burns to 80% of his body following a motor vehicle accident. A multidisciplinary evaluation established his candidacy for a combined face and bilateral HT, and surgery took place in August 2020. Our individualized hand therapy protocol consisted of 4 phases. The pre-surgery phase focused on planning the orthotics and patient/caregivers' education on the rehabilitation process. The intensive care unit (ICU)/acute care phase involved hand allograft protection and positioning via orthotic fabrication, safe limb handling, and edema/wound management. The inpatient rehabilitation phase aimed to prepare the patient for independent living via neuromuscular and sensory re-education, improvement of upper extremities strength/flexibility, training basic activities of daily living, and providing a home exercise program (HEP). Finally, the outpatient phase aimed to maximize our patient's range of motion and independency in performing his routine activities and HEP. The patient's post-transplant functional outcomes showed a significant improvement compared to the pre-operative baseline. We hope this report sheds light on a comprehensive hand therapy program in HT.

Research status and progress on limb preservation technology / 器官移植

Limb replantation and transplantation is the optimal treatment for traumatic limb amputation. Safe and effective limb preservation is the key factor to determine the success of limb replantation and transplantation. Currently, static cold storage is the gold standard of limb preservation. However, the preservation time is short, which may no longer meet clinical requirements. With rapid development of organ preservation in recent years, novel preservation technologies, such as ultra-low temperature preservation, supercooling preservation and mechanical perfusion preservation, have successively emerged. However, at present, these techniques are primarily applied to the preservation of solid organs rather than composite tissue allografts with blood vessels including limbs. In this article, research status and progress on the application of static cold storage and mechanical perfusion preservation in limb preservation were reviewed, aiming to provide reference for clinical application of limb preservation technology and promote the development of limb replantation and transplantation.

Virtual Surgical Planning and 3D-Printed Surgical Guides in Facial Allotransplantation.

The complex three-dimensional (3D) anatomy in facial allotransplantation creates a unique challenge for surgical reconstruction. Evolution of virtual surgical planning (VSP) through computer-aided design and computer-aided manufacturing has advanced reconstructive outcomes for many craniomaxillofacial indications. Surgeons use VSP, 3D models, and surgical guides to analyze and to trial surgical approaches even prior to entering the operating room. This workflow allows the surgeon to plan osteotomies and to anticipate challenges, which improves surgical precision and accuracy, optimizes outcomes, and should reduce operating room time. We present the development, evolution, and utilization of VSP and 3D-printed guides in facial allotransplantation at our institution, from guide conception to first clinical case.

In the face of change: Which coping strategies predict better psychosocial outcomes in face transplant recipients?

Objectives: Face transplantation aims to improve patients' quality of life and psychosocial functioning in patients with a disfiguring injury. With 40 cases worldwide, little is known about coping strategies predicting resilient outcomes. Design: Six patients followed in Boston, completed the Brief COPE (Carver, 1997) along with validated measures of depression, self-esteem, and quality of life - every 3 months during the first year post-transplant and every 6 months thereafter, up to 36 months post-transplant. Analyses: Due to sample size and distribution of the data, nonparametric tests were used to characterize the relation of coping strategies with psychosocial outcomes. Results: As expected, active coping strategies were associated with better mental health pre-transplant, while avoidant coping strategies were associated with poorer mental health. Patients using support-based strategies reported better mental health at baseline. Post-transplant, the pattern reversed such that avoidant strategies appeared protective, when looking at mental health trajectories over 18 months. Importantly, trends identified during the first 18 months matched the trajectories of all patients with existing data up to 36 months post-transplant, for all outcomes measured. Conclusion: Different coping strategies support optimal outcomes in the pre-versus post-transplant phases. Pre-transplant data may better inform interventions supporting mental health of transplant candidates than predict post-transplant behavior. Early post-transplant data seems to provide promising insight in long term psychosocial outcomes. Clinical implications: Our data stresses the need for pre-transplant assessment of coping and post-transplant coping training. Research aiming to optimize post-transplant psychosocial outcomes should consider coping as a promising target for intervention.

Face Transplant: Indications, Outcomes, and Ethical Issues-Where Do We Stand?

Background: The addition of face allotransplantation (FT) to the head and neck reconstructive surgery arsenal has started a true revolution. This study is aimed at providing an extensive analysis of the current practice of composite tissue allotransplantation. Moreover, a thorough description of pre-procedural, intra-operative, and post-procedural settings, indications, contraindications, outcomes, ethical considerations, and future perspectives is provided. Methods: The authors' experience was supplemented with a literature review performed by using the PubMed, MEDLINE, and Embase databases on 21 February 2022. The search terms used were "face transplantation indications", "face transplantation complications", and "face transplantation ethical issues". Results: The most recent achievements and long-term clinical sequelae of FT are classified and summarized. A large number of records (4435) were identified. Seventy-five articles were assessed for eligibility. Publications without new data and reports with a patient follow-up < 5 years were excluded. Nineteen articles met the criteria for inclusion. Conclusions: The most recent achievements in the field of FT may be combined with cutting-edge regenerative medicine procedures and innovative immunological processing. It is paramount to build strong international networks between the world FT experts in order to achieve higher-level outcomes and reduce the complication rate. Nevertheless, the utmost caution is required in patient selection, clinical assessment, strict follow-up, and rejection management.

Manipulating adrenergic stress receptor signalling to enhance immunosuppression and prolong survival of vascularized composite tissue transplants.

BACKGROUND: Vascularized composite tissue allotransplantation (VCA) to replace limbs or faces damaged beyond repair is now possible. The resulting clear benefit to quality of life is a compelling reason to attempt this complex procedure. Unfortunately, the high doses of immunosuppressive drugs required to protect this type of allograft result in significant morbidity and mortality giving rise to ethical concerns about performing this surgery in patients with non-life-threatening conditions. Here we tested whether we could suppress anti-graft immune activity by using a safe ß2 -adrenergic receptor (AR) agonist, terbutaline, to mimic the natural immune suppression generated by nervous system-induced signalling through AR. METHODS: A heterotopic hind limb transplantation model was used with C57BL/6 (H-2b) as recipients and BALB/c (H-2d) mice as donors. To test the modulation of the immune response, graft survival was investigated after daily intraperitoneal injection of ß2 -AR agonist with and without tacrolimus. Analyses of immune compositions and quantification of pro-inflammatory cytokines were performed to gauge functional immunomodulation. The contributions to allograft survival of ß2 -AR signalling in donor and recipient tissue were investigated with ß2 -AR-/- strains. RESULTS: Treatment with the ß2 -AR agonist delayed VCA rejection, even with a subtherapeutic dose of tacrolimus. ß2 -AR agonist decreased T-cell infiltration into the transplanted grafts and decreased memory T-cell populations in recipient's circulation. In addition, decreased levels of inflammatory cytokines (IFN-γ, IL-6, TNF-α, CXCL-1/10 and CCL3/4/5/7) were detected following ß2 -AR agonist treatment, and there was a decreased expression of ICAM-1 and vascular cell adhesion molecule-1 in donor stromal cells. CONCLUSIONS: ß2 -AR agonist can be used safely to mimic the natural suppression of immune responses, which occurs during adrenergic stress-signalling and thereby can be used in combination regimens to reduce the dose needed of toxic immunosuppressive drugs such as tacrolimus. This strategy can be further evaluated for feasibility in the clinic.

Diagnostic criteria and research progress on Banff classification of allograft pathology in composite tissue allotransplantation / 器官移植

Composite tissue allotransplantation (CTA) is a novel transplantation discipline to treat functional tissue or limb defects. Since a majority of CTA grafts were vascularized grafts, it is also known as vascularized composite allotransplantation (VCA). The grafts of CTA/VCA consist of two or more types of allogeneic skin, subcutaneous tissue, bone, muscle, nerve and vessel, etc. Most of CTA/VCA grafts contain skin tissues, which possess the highest antigenicity. Acute rejection after transplantation is the primary obstacle leading to CTA/VCA graft failure and primary graft dysfunction. Hence, histopathological characteristics of skin rejection in CTA/VCA grafts have become the primary hotspot. In this article, pathological features of CTA/VCA rejection, Banff classification in 2007 and related research progress were reviewed, aiming to provide reference for the diagnosis and treatment of rejection and other complications of CTA/VCA.

Hand Transplantation-Risks and Benefits.

Composite tissue allotransplantation (CTA) is the culmination of progress in transplantation, allowing the reconstruction of the hand in amputees. Worldwide, more than 100 procedures have been performed. The aim of this work was to understand the hand allotransplantation approach, making known current aspects, risks, and benefits. A PubMed research was realized between October 2018 and March 2019, including terms like "Hand transplantation" AND "Composite tissue allotransplantation," "Hand transplantation" AND "Functional outcomes," "Hand transplantation" AND "Immunosuppression," "Hand prosthetics," "Hand Transplantation" AND "Ethics." There were included papers between 1995 and 2018, with English language, amputee human adults, systematic reviews, and clinical studies. Seventy-two papers were fully evaluated. There are technical aspects that influence the procedure like team coordination or surgical technique. It requires a long-life treatment, which has risks such as toxicity or infections. However, it allows the recovery of fine movements, and independence, to perform detailed tasks. The indications must be carefully considered, because some patients benefit from the use of prosthesis. CTA has become an option for amputees so it is important to do more research, to determine the benefits of this procedure. It is not considered a life-saving procedure, so there is an ethical debate because of the risks.

Facial Transplantation: Complications, Outcomes, and Long-Term Management Strategies.

Within the past two decades, vascularized facial composite allotransplantation has evolved into a viable option in the reconstructive surgeons' armamentarium for patients with extensive facial disfigurements. As it has expanded the frontiers of microsurgical reconstructive techniques, facial transplantation has come to garner widespread interest within both the medical community and the general public. The procedure has established itself as an amalgamation of the forefronts of reconstructive microsurgery, immunology, and transplantation science. Therein too lies its complexity as multifaceted scientific developments are met with ethical and social issues. Both patients and physicians are faced with the everlasting challenges of immunosuppression regimens and their inherent complications, long-term aesthetic and functional considerations, the role of revision procedures, and the inevitable psychosocial implications. This article reflects on the medical and surgical advancements in facial transplantation surgery and highlights anticipated future challenges. It aims to encourage discussion regarding anticipated barriers to current practice and suggest future directions as we transition into the next phase of facial allograft transplantation.

Tracheal Allotransplantation-Lessons Learned.

Reconstruction of long tracheal defects still proves to be a challenge. Free fasciocutaneous flaps with cartilaginous struts or an allotransplant trachea have been reported but not been widely performed. This article reports with the experience of using a tracheal allotransplant in such a defect. A 43-year-old lady presented with adenoid cystic carcinoma involving the entire trachea from subglottic area up to the carina, leading to a life-threatening airway occlusion. After preliminary stenting, allotransplant trachea obtained from a brain-dead individual was revascularized in the forearm of the patient after mechanical decellularization to reduce the immune load and fulfil the need for immunosuppression in the background of active cancer. Subsequently, the trachea and larynx were resected. The vascularized neotrachea was transferred successfully into the neck. The patient did well initially but succumbed to a fatal hemorrhage due to innominate vein aneurysmal rupture on the 22nd day after the transplant. The technical details of resection, fabrication of the neotrachea, its transfer, and the lessons learnt in this tracheal allotransplant are described.

Ex-vivo treatment of allografts using adipose-derived stem cells induced prolonged rejection-free survival in an allogenic hind-limb transplantation model.

BACKGROUND: Vascularized composite tissue allotransplantation (VCA) has increasingly been adopted for the reconstruction of tissues following severe injury. However, the side effects of the post-operative use of immunosuppressants may outweigh the benefits of VCA. In order to overcome this obstacle, ex-vivo pretreatment of allografts combined with mesenchymal stem cell-based therapy may help induce immunotolerance in composite tissue allotransplantation. METHODS: A hind-limb allotransplantation model of Brown-Norway to Lewis rats was established, and the allografts were infused with adipose-derived stem cells (ADSCs) and hypoxia primed ADSCs, which were injected through the vascular system along with short-term immunosuppressant treatment. The rejection-free survival of the allografts was monitored, and the histopathological examination of allografts was performed. The peripheral T lymphocytes and cytokines were analyzed using flow cytometry and ELISA, while Tregs infiltration in allotissue was detected using immunohistochemical staining (IHC). RESULTS: This study found that the ex-vivo treatment of allografts using ADSCs prolonged the survival of the allografts, compared with the medium control, suppressed the proliferation and infiltration of T lymphocytes and improved the secretion of immunomodulatory cytokines, such as IL-10, as well as induced regulatory T cells (Tregs) expression in the allografts. CONCLUSIONS: The ex-vivo pretreatment of allografts using ADSCs may function as an important adjunctive therapy for the induction of immunotolerance in VCA.

"Auricular reconstruction: A sociocultural, surgical and scientific perspective".

The functional and sociocultural role of the auricle has been prevalent in art, literature and history for millennia. It is no surprise, therefore, that auricular anomalies can be associated with affective disorders and impaired academic performance in children. The challenge of auricular reconstruction has captured the attention of surgical innovators for millennia with the earliest records of auricular reconstruction documented in the Edwin Smith Surgical Papyrus dating back to 3000 BCE. Since the 19th century, however, the interest in the ambition partial and total auricular reconstruction witnessed a rebirth, with refinements in frame construction, projection and skin coverage improving exponentially over the last two centuries. The gold standard auricular reconstruction practices today have their roots in these historical milestones, and form a solid foundation for the introduction of technological advancements such as 3D bioprinting and composite tissue allotransplantation into future auricular reconstruction practice. The aim of this review is to outline the sociocultural role of the auricle, the history and evolution of auricular reconstruction surgery and to provide an insight into potential future avenues of restoring auricular form and function.

Distal Digital Nerve Repair Using Nerve Allograft With a Dermal Substitute: A Case Report.

Background: Distal digital nerve repairs can present unique challenges for hand surgeons due to their sensitive location and ongoing difficulty obtaining soft tissue coverage in this region. Although autografts and nerve conduits have been shown to be of benefit with nerve gaps, they can have morbidities associated with their use. Nerve allografts have become a viable option over the past decade as their use has increased and data are now showing similar outcomes, particularly in short gap segments. Flaps and skin grafts are traditional coverage options for full thickness wounds but can pose challenges with multiple digit involvement, depth of wound, and critical structures exposed. Methods: We present a case where nerve allograft was used for distal digital nerve repair. Due to the distal nature of the nerve repair in the index digit distal to the trifurcation, the distal end of the nerve graft was connected to multiple small nerve ends. Dermal substitute was placed to achieve distal coverage of the affected digits. Results: At 6-month follow-up, the patient demonstrated improved strength, normal sensation, and full return of digital function. Conclusion: Nerve allograft can be used in combination with dermal skin substitute to achieve normal sensation and return of digital function following distal digital nerve injuries.

Building a Hand and Upper Extremity Transplantation Program: Lessons Learned From the First 20 Years of Vascularized Composite Allotransplantation.

Background: Upper extremity transplantation is a quality-of-life enhancing treatment for select patients with upper extremity loss. This article reviews the preoperative, intraoperative, and postoperative challenges in the upper extremity transplantation process and the lessons learned from the first 2 decades of hand transplantation. Methods: Key components of the author's hand transplantation protocol including patient selection, donor screening, surgical rehearsal, donor procurement, transplantation, immunosuppression, and patient outcome reporting/follow-up are reported to assist other teams who wish to establish a hand transplantation program. Results: There have been many advancements in the first 20 years of hand transplantation including better patient selection criteria, the recent addition of pediatric patients, improved surgical techniques such as the use of virtual surgical planning, and improved immunosuppression protocols. Improvement has also taken place in the tracking and reporting of hand transplant outcomes, but more work is clearly needed to fully define the benefits of transplantation, especially for pediatric patients. Conclusions: Over the past 20 years, significant progress has been made in upper extremity transplantation although a number of challenges remain including how to best document and share outcome measures, optimize immunosuppression, and diagnose/treat rejection. The authors encourage upper extremity transplant programs to report their experience and protocols to advance hand transplantation as standard of care for properly selected individuals.