Face Transplantation Research Articles

The Future of Microsurgery: Vascularized Composite Allotransplantation and Engineering Vascularized Tissue

BackgroundMicrosurgical techniques have revolutionized the field of reconstructive surgery and are the mainstay for complex soft tissue reconstruction. However, their limitations have promoted the development of viable alternatives. This article seeks to explore technologies that have the potential of revolutionizing microsurgical reconstruction as it is currently known, reflect on current and future vascularized composite allotransplantation (VCA) practices, as well as describe the basic science within emerging technologies and their potential translational applications. MethodsA literature review was performed of the technologies that may represent the future of microsurgery: vascularized tissue engineering (VCA) and flap-specific tissue engineering. ResultsVCA has shown great promise and has already been employed in the clinical setting (especially in face and limb transplantation). Immunosuppression, logistics, cost, and regulatory pathways remain barriers to overcome to make it freely available. Vascularized and flap-specific tissue engineering remain a laboratory reality but have the potential to supersede VCA. The capability of creating an off-the-shelf free flap matching the required tissue, size, and shape is a significant advantage. However, these technologies are still at the early stage and require significant advancement before they can be translated into the clinical setting. ConclusionVCA, vascularized tissue engineering, and flap-specific bioengineering represent possible avenues for the evolution of current microsurgical techniques. The next decade will elucidate which of these three strategies will evolve into a tangible translational option and hopefully bring a paradigm shift of reconstructive surgery.

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.

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.

Response to "The History of Uterus Transplantation, Rewritten."

Response to "The History of Uterus Transplantation, Rewritten."

427.3: Military Veterans’ Knowledge, Attitudes, and Interest in VCA Treatment for Disfiguring Service-Related Injuries

Background: Thousands of American service members have suffered catastrophic injuries to the head, face, and extremities resulting in functional limitations and significant disfigurement. The rise of vascularized composite allograft (VCA) procedures now allows for hand and face transplants, which can improve the functioning, mobility, and quality of life for these veterans, particularly those who have not responded well to available reconstructive procedures or prosthetics. Despite potentially life-enhancing outcomes, however, the awareness of and interest in this treatment option by VCA-eligible veterans is unknown. By examining this population’s receptivity to VCA, the study’s goal of identifying the assets and barriers to receiving a VCA will instruct more informed decision making about this treatment. Methods: In collaboration with the Veterans Affairs Medical Center (VAMC) in Coatesville, PA, and the Department of Defense Joint Trauma Registry, over 1,100 medical records from 2010-2019 were reviewed for applicable ICD-9 codes. In-depth semi-structured interviews were conducted via telephone or video conference with up to 60 military veterans to examine current health status, treatments and therapies, impact of their injuries on daily life, and reactions to VCA, as the primary domains of inquiry. Interviews were audio-recorded for accuracy, deidentified, and transcribed for analysis. The existing domains and emergent themes formed the basis of a codebook, and MAXQDA software was used to facilitate qualitative coding of the data. Results: Most participants interviewed to date, reported amputation of one or both hands. Although largely unfamiliar with the technical terminology of “Vascularized Composite Allotransplantation,” most expressed familiarity with the procedure when described in more detail. While initial reactions were largely positive, many participants did not see this treatment as necessary for themselves. Multiple participants indicated greater receptivity if they were less adapted to their injury or did not have at least one functioning upper limb. Reported concerns included possible graft rejection, recovery time, medical fatigue, side effects of immunosuppression, and the effectiveness of the VCA procedure. Respondents identified more functional independence as the most critical and desired outcome of receiving a VCA graft in addition to navigating their day-to-day environments with fewer accommodations and adaptive equipment. Conclusion: Participants viewed VCA as an interesting medical advancement and acknowledged its potential benefits but also expressed skepticism about its efficacy. These observations provide a knowledge base for researchers and practitioners engaged in growing the field of VCA. Further examination of the attitudes and experiences of the caregivers and healthcare providers of VCA-eligible patients would offer valuable perspectives in informing decision making about VCA. U.S. Department of Defense, Grant/Award Number: W81XWH-19-1-0274.

TH-115. Axonal and cortical excitability findings in hand and face transplant patients

TH-115. Axonal and cortical excitability findings in hand and face transplant patients

Maxillary and Mandibular Healing After Facial Allotransplantation.

Facial transplantation has emerged as a viable option in treating devastating facial injuries.Despite the high healing rate of Le Fort III and bilateral sagittal split osteotomies (BSSO) in nontransplant patients, few studies have reported assessment of maxillary and mandibular healing in face transplant patients compared with nontransplant patients. The aim of this study was to examine differences in bone healing in our patients. A retrospective chart review was conducted of facial allotransplantation patients at the Cleveland Clinic from December 2008 to inception. Demographics such as age, date of birth, and sex were recorded. Additional variables included procedures, revisions, reoperations, medications, and bone stability and healing. Computed tomography (CT) images assessed the alignment of skeletal components, bony union quality, and stability of fixation. Three patients were included: 2 had Le Fort III segment transplantation, and 1 had transplantation of both a Le Fort III segment and mandibular BSSO. The Le Fort III segment in all patients exhibited mobility and fibrous union at the Le Fort III osteotomy on CT. In contrast, the BSSO healed uneventfully after transplantation and revision surgery, with bony union confirmed by both CT and histology of the fixation area between the donor and recipient mandible bilaterally. No patients with midfacial fibrous union required revision of the nonunion as they were clinically asymptomatic. Le Fort osteotomy demonstrates inferior healing in facial transplantation compared with the nontransplant population. In contrast, the successful healing in the mandible is likely owing to the high density of rich cancellous bone.

Adipose-derived stem cells attenuate acne-related inflammation via suppression of NLRP3 inflammasome

BackgroundAcne is a chronic facial disease caused by Propionibacterium acnes, which proliferates within sebum-blocked skin follicles and increases inflammatory cytokine production. Several therapeutic drugs and products have been proposed to treat acne, yet no single treatment that ensures long-term treatment efficacy for all patients is available. Here, we explored the use of facial autologous fat transplant of adipose-derived stem cells (ADSCs) to dramatically reduce acne lesions.MethodsTHP-1 cells were treated with active P. acnes for 24 h at different multiplicities of infection, and alterations in inflammatory factors were detected. To study the effect of THP-1 on inflammasome-related proteins, we first co-cultured ADSCs with THP-1 cells treated with P. acnes and evaluated the levels of these proteins in the supernatant. Further, an acne mouse model injected with ADSCs was used to assess inflammatory changes.ResultsPropionibacterium acnes-mediated stimulation of THP-1 cells had a direct correlation with the expression of active caspase-1 and interleukin (IL)-1β in an infection-dependent manner. ADSCs significantly reduced the production of IL-1β induced by P. acnes stimulation through the reactive oxygen species (ROS)/Nod-like receptor family pyrin domain-containing 3 (NLRP3)/caspase-1 pathway. The results showed that ADSCs inhibit the skin inflammation induced by P. acnes by blocking the NLRP3 inflammasome via reducing the secretion of IL-1β in vivo.ConclusionsOur findings suggest that ADSCs can alter IL-1β secretion by restricting the production of mitochondria ROS, thereby inhibiting the NLRP3/caspase-1 pathway in P. acnes-induced inflammatory responses. This study indicates that anti‐acne therapy can potentially be developed by targeting the NLRP3 inflammasome.

Recipient Selection Criteria for Facial Transplantation: A Systematic Review.

Recipient selection is an important determinant of surgical outcomes in facial transplantation (FT). Appropriately, each FT program develops their own guidelines for recipient selection criteria. Currently, there is no resource to simultaneously assess and identify similarities and differences between these guidelines. Such information could be useful in distinguishing areas of FT that are well understood from those that could benefit from further exploration. We performed a systematic review of the scientific literature from inception to June 18, 2021, using Pubmed, Embase, Cochrane Library, and Scopus to identify articles pertaining to recipient selection criteria. Clinical trials were identified through the Clinicaltrials.gov registry. United States and international program websites were reviewed for patient-facing information. Our systematic review yielded 90 suitable articles, 8 clinical trials, and 7 program websites containing the recipient selection criteria of 24 different FT programs. The most reported on recipient criteria were age, positive human immunodeficiency viral status (HIV+), positive hepatitis C viral status, psychosocial stability, and medical compliance. Other criteria were rarely addressed, such as blindness and recipient immune status. Guidelines among different face transplant programs are changing over time. We found consensus on certain recipient selection criteria, but the majority remain program or surgeon dependent, emphasizing that FT is still an evolving procedure. Although most programs reported on their recipient selection criteria, the rationale was often missing. Further discussion about recipient selection criteria and the reasoning behind employing or changing them will help advance the field.

Special Considerations in Face Transplantation: A Systematic Review.

Vascularized composite allotransplantation of the face is an exceedingly complex procedure, requiring extensive planning and surgical precision in order to successfully manage patients with facial disfigurements. This review aims to present an overview of the salient anatomic considerations in facial transplantation, as well as give attention to unique patient populations and special considerations.A literature review was performed in search of articles pertaining to considerations in facial transplantation using the databases PubMed, Web of Science, and Cochrane. Articles selected for further review included full-text articles with an emphasis on specific anatomic defects and how they were addressed in the transplant process, as well as management of special patient populations undergoing facial transplantation. In total, 19 articles were deemed appropriate for inclusion.The use of computer-assisted technologies for the planning portion of the procedure, as well as intraoperative efficiency, has yielded favorable results and can be considered as part of the operative plan. The ultimate outcome is dependent upon the synchronization of subunits of the allograft and the desired functional outcomes, including osseous, ocular, oral, and otologic considerations. Management of specific pathology and subgroups of patients are critical aspects. Although pediatric face transplantation has not yet been performed, it is a likely a future step in the evolution of this procedure.When performing a face transplantation, many components must be considered pre-, intra-, and post-operatively. This systematic review presents specific anatomic considerations, as well as information about special patient populations within this crosssection of multidisciplinary microsurgery, psychiatry, and transplant immunology.

106. Tendon Tensioning in Hand Transplantation: Emerging Principles From the First Successful Full Face and Bilateral Hand Transplant

106. Tendon Tensioning in Hand Transplantation: Emerging Principles From the First Successful Full Face and Bilateral Hand Transplant

Evaluation of an eLearning System to Train Health Professionals to Communicate about Vascularized Composite Allotransplantation with Donor Families

Introduction: Vascularized composite allotransplantation (VCA) donation relies on obtaining surrogate authorization. Yet, many donor professionals have limited experience discussing composite allograft donation. Using virtual and interactive elements, the eLearning program, Communicating Effectively about Donation for Vascularized Composite Allotransplantation (CEaD-VCA), was developed to enhance the quality of donor professionals' communication approach. Research Questions: We tested the effectiveness of the eLearning program in improving donor professionals' knowledge, preparedness, and confidence leading discussions with families. Design: Donor professionals who primarily obtain family authorization for solid organ and tissue donation were recruited from 2 regional Organ Procurement Organizations. The training was evaluated using a nonrandomized pre-post design. Participants completed an online survey with items assessing their knowledge, preparedness, and confidence for donation discussions. Pre- and post-training responses were compared using paired sample t-tests. Results: The sample included 42 donor professionals. The majority (71.4%) had at least 3 years of work experience, and over half (52.4%) had no experience discussing VCA donation with families. Post-training, significant increases in mean knowledge scores (6.4 pre to 7.0 post, P < 0.01) and mean self-reported preparation (6.6 pre to 7.9 post, P < 0.0001) were observed. There were significant increases in mean confidence scores for discussing face (6.2 pre to 7.9 post, P < 0.0001) and hand (6.2 pre to 8.0 post, P < 0.0001) transplants. Conclusion: The CEaD-VCA program was effective in increasing donor professionals' knowledge, preparation, and confidence when discussing donation, and holds potential for improving donor professional communication during donation discussions.

The First Successful Combined Full Face and Bilateral Hand Transplant

Vascularized composite allotransplantation has redefined the frontiers of plastic and reconstructive surgery. At the cutting edge of this evolving paradigm, the authors present the first successful combined full face and bilateral hand transplant. A 21-year-old man presented for evaluation with sequelae of an 80 percent total body surface area burn injury sustained after a motor vehicle accident. The injury included full face and bilateral upper extremity composite tissue defects, resulting in reduced quality of life and loss of independence. Multidisciplinary evaluation confirmed eligibility for combined face and bilateral hand transplantation. The operative approach was validated through 11 cadaveric rehearsals utilizing computerized surgical planning. Institutional review board and organ procurement organization approvals were obtained. The recipient, his caregiver, and the donor family consented to the procedure. Combined full face (i.e., eyelids, ears, nose, lips, and skeletal subunits) and bilateral hand transplantation (i.e., forearm level) was performed over 23 hours on August 12 to 13, 2020. Triple induction and maintenance immunosuppressive therapy and infection prophylaxis were administered. Plasmapheresis was necessary postoperatively. Minor revisions were performed over seven subsequent operations, including five left upper extremity, seven right upper extremity, and seven facial secondary procedures. At 8 months, the patient was approaching functional independence and remained free of acute rejection. He had significantly improved range of motion, motor power, and sensation of the face and hand allografts. Combined face and bilateral hand transplantation is feasible. This was the most comprehensive vascularized composite allotransplantation procedure successfully performed to date, marking a new milestone in plastic and reconstructive surgery for patients with otherwise irremediable injuries.

Reinforcement learning coupled with finite element modeling for facial motion learning

Background and ObjectiveFacial palsy patients or patients with facial transplantation have abnormal facial motion due to altered facial muscle functions and nerve damage. Computer-aided system and physics-based models have been developed to provide objective and quantitative information. However, the predictive capacity of these solutions is still limited to explore the facial motion patterns with emerging properties. The present study aims to couple the reinforcement learning and the finite element modeling for facial motion learning and prediction. MethodsA novel modeling workflow for learning facial motion was developed. A physically-based model of the face within the Artisynth modeling platform was used. Information exchange protocol was proposed to link reinforcement learning and rigid multi-bodies dynamics outcomes. Two reinforcement learning algorithms (deep deterministic policy gradient (DDPG) and Twin-delayed DDPG (TD3)) were used and implemented to drive the simulations of symmetry-oriented and smile movements. Numerical outcomes were compared to experimental observations (Bosphorus database) for evaluation and validation purposes. ResultsAs result, after more than 100 episodes of exploring the environment, the agent starts to learn from previous trials and can find the optimal policy after more than 300 episodes of training. Regarding the symmetry-oriented motion, the muscle excitations predicted by the trained agent help to increase the value of reward from R = -2.06 to R = -0.23, which counts for ∼89% improvement of the symmetry value of the face. For smile-oriented motion, two points at the edge of the mouth move up 0.35 cm, which is within the range of movements estimated from the Bosphorus database (0.4 ± 0.32 cm). ConclusionsThe present study explored the muscle excitation patterns by coupling reinforcement learning with a detailed finite element model of the face. We developed, for the first time, a novel coupling scheme to integrate the finite element simulation into the reinforcement learning process for facial motion learning. As perspectives, this present workflow will be applied for facial palsy and facial transplantation patients to guide and optimize the functional rehabilitation program.

Severe Self-Inflicted Gunshot Wound of the Face

A 26-year-old male was transported to the hospital with a severe self-inflicted gunshot wound of the middle and lower face (Panel A) due to the suicide attempt. Three-dimensional computed tomography (CT) showed multiple site comminuted fracture of the facial skeleton including maxilla, mandible, right zygomatic, ethmoid, and nasal bones (Panel B). Also, the sockets of multiple avulsed teeth were noted. The patient was transported from the region several days after the injury. Due to the osseous and soft tissue loss, this type of gunshot wounds typically poses a considerable challenge to the oral and maxillofacial and plastic surgeons. Acute management in such cases includes resuscitative and life-saving measures. Timing of each surgical procedure should be chosen according to the patient condition, extent of the injury, and international recommendations.1 Operative principles include: (1) general considerations (all reconstructive options are to be taking into account, moreover, the volume of bone and soft tissue loss, functional and aesthetic purposes should be analyzed and planned very precisely), (2) skeletal fixation, (3) bone grafts, (4) soft tissue coverage, and even (5) a facial transplantation in some cases. In our case, the right eye enucleation (removal of the entire globe with all intraocular contents, while preserving orbital/periorbital structures) was done due to the severely ruptured globe. Typical indications for enucleation are severe eye trauma and blind, intraocular tumors, painful, and cosmetically disfiguring eyes. In case of evisceration the intraocular contents are removed from an intact sclera, extraocular muscle attachments and the orbital adnexa are preserved, with placement of an implant within the scleral shell with a purpose to retain orbital volume. Common indications for enucleation are unresponsive endophthalmitis and for improvement of cosmesis in a blind eye. The most common indication for orbital exenteration (removal of the globe and all orbital contents, including muscles, fat, optic nerve, lacrimal gland, nerves, periorbital bone, upper and lower lid complexes) is malignancy.

Trends, Gaps, and Collaboration in Facial Transplantation: A Bibliometric Study.

We conducted a comprehensive bibliometric analysis of the published FT literature from 1994, the first year FT was mentioned in the literature, through July 2020. Co-authorship and keyword information were analyzed using VOSviewer. Articles were manually categorized based on keywords and their aim to provide insight on trends. A total of 2182 articles were identified. Analysis identified the top 50 publishing authors in the field and demonstrated co-authorship linkage between 84.8% of the top 1000 authors. Clinical surgical techniques, protocols, and experiments were the most frequently published category. Within clinical outcomes, immunologic outcomes were most frequent, while psychosocial were the lowest. Gaps were identified in long-term outcomes reporting and patient-reported outcomes, with physician-reported outcomes heavily outweighing patient-reported outcomes. As the field continues to evolve, rigorous tracking of publication patterns over time will encourage development of a more robust evidence base, identify gaps in the published literature, and highlight opportunities to enhance collaboration in the field. This data will provide surgeons and research institutions with information to further improve this life-changing procedure.

Cytomegalovirus-related Complications and Management in Facial Vascularized Composite Allotransplantation: An International Multicenter Retrospective Cohort Study.

There is a paucity of data on the impact of cytomegalovirus (CMV) serostatus and CMV infection on outcomes in facial vascularized composite allotransplantation. This international, multicenter, retrospective cohort study presents data on CMV and basic transplant-related demographics, including pretransplant viral D/R serostatus, and duration of antiviral prophylaxis. CMV-related complications (viremia, disease), allograft-related complications (rejection episodes, loss), and mortality were analyzed. We included 19 patients, 4 of whom received CMV high-risk transplants (D+/R-). CMV viremia was noted in 6 patients (all 4 D+/R- patients and 2 D-/R+), mostly within the first-year posttransplant, shortly after discontinuation of antiviral prophylaxis (median 2 mo). CMV disease occurred in 2 D+/R- patients. The high-risk group experienced relatively more rejection episodes per month follow-up. None of D+/R- patients suffered allograft loss due to rejection (longest follow-up: 121 mo). D+/R- patients were at increased risk of CMV-related complications. Although a higher number of rejections was noted in this group, none of the D+/R- patients lost their allograft or died because of CMV or rejection. Thus, CMV D+/R- face transplantation can likely be safely performed with prophylaxis, active surveillance, and prompt treatment.

P29. DEVELOPING A LONG-TERM SURVIVAL HEMI-FACIAL VASCULARIZED COMPOSITE ALLOTRANSPLANTATION SWINE MODEL TO STUDY FACIAL NERVE REGENERATION

PURPOSE: We present a survival large animal model for preclinical facial transplant research to evaluate facial nerve regeneration. METHODS: 19 survival surgeries (16 auto-transplant, 3 allotransplant) were performed to develop and validate a hemi-facial composite flap based on the external carotid artery and vein. Assessment of nerve regeneration using serial compound muscle action potentials (CMAP), electroneurograms (ENG) and histology in a 3-4 month survival model was established. Immunosuppression in allotransplanted pigs started on POD-3 and maintained with weight-based Cyclosporin (CSA) (target levels of 200-300), mycophenolic acid and prednisone. Postoperative course and complications were documented. RESULTS: The buccal branch was selected to assess nerve regeneration using nerve conduction studies. In our allotransplant and auto-transplant models, minor wound breakdown and sialoceles in early postoperative period were managed conservatively or with superficial debridement. There were no flap losses. No systemic infections were experienced in the allotransplanted pigs (n=3); one pig developed an abscess requiring debridements, extended antibiotics usage, but had complete resolution at 8 weeks. At 3 months nerve regeneration reached 75% distance to target muscle with comparable ENG to normal side in auto-transplanted Sinclair mini-pig group (n=5), but a slower rate of regeneration in the allotransplanted group (n=3). CONCLUSION: This study demonstrates proof of concept for an allotransplant large experimental animal model for research to inform post-surgical care to improve facial nerve regeneration and functional outcomes.

A Reliable Porcine Fascio-Cutaneous Flap Model for Vascularized Composite Allografts Bioengineering Studies.

Vascularized Composite Allografts (VCA) such as hand, face, or penile transplant represents the cutting-edge treatment for devastating skin defects, failed by the first steps of the reconstructive ladder. Despite promising aesthetic and functional outcomes, the main limiting factor remains the need for a drastically applied lifelong immunosuppression and its well-known medical risks, preventing broader indications. Therefore, lifting the immune barrier in VCA is essential to tip the ethical scale and improve patients' quality of life using the most advanced surgical techniques. De novo creation of a patient-specific graft is the upcoming breakthrough in reconstructive transplantation. Using tissue engineering techniques, VCAs can be freed of donor cells and customized for the recipient through perfusion-decellularization-recellularization. To develop these new technologies, a large-scale animal VCA model is necessary. Hence, swine fascio-cutaneous flaps, composed of skin, fat, fascia, and vessels, represent an ideal model for preliminary studies in VCA. Nevertheless, most VCA models described in the literature include muscle and bone. This work reportsa reliable and reproducible technique for saphenous fascio-cutaneous flap harvest in swine, a practical tool for various research fields, especially vascularized composite tissue engineering.

VCA in the Era of the COVID-19 Pandemic.

VCA in the Era of the COVID-19 Pandemic.