Ericka M. Bueno

Cell-free and cell-based approaches for bone regeneration

The clinical augmentation of bone currently involves the use of autogenous or allogeneic bone grafts and synthetic materials, all of which are associated with limitations. Research on the safe enhancement of bone formation concerns the potential value of scaffolds, stem cells, gene therapy, and chemical and mechanical signals. Optimal scaffolds are engineered to provide mechanical stability while supporting osteogenesis, osteoconduction and/or osteoinduction. Scaffold materials include natural or synthetic polymers, ceramics, and composites. The resorption, mechanical strength and efficacy of these materials can be manipulated through structural and chemical design parameters. Cell-seeded scaffolds contain stem cells or progenitor cells, such as culture-expanded marrow stromal cells and multipotent skeletal progenitor cells sourced from other tissues. Despite extensive evidence from proof-of-principle studies, bone tissue engineering has not translated to clinical practice. Much of the research involves in vitro and animal models that do not replicate potential clinical applications. Problem areas include cell sources and numbers, over-reliance on existing scaffold materials, optimum delivery of factors, control of transgene expression, vascularization, integration with host bone, and the capacity to form bone and marrow structures in vivo. Current thinking re-emphasizes the potential of biomimetic materials to stimulate, enhance, or control bones innate regenerative capacity at the implantation site.

Three Patients with Full Facial Transplantation

Unlike conventional reconstruction, facial transplantation seeks to correct severe deformities in a single operation. We report on three patients who received full-face transplants at our institution in 2011 in operations that aimed for functional restoration by coaptation of all main available motor and sensory nerves. We enumerate the technical challenges and postoperative complications and their management, including single episodes of acute rejection in two patients. At 6 months of follow-up, all facial allografts were surviving, facial appearance and function were improved, and glucocorticoids were successfully withdrawn in all patients.

The Management of Antibody‐Mediated Rejection in the First Presensitized Recipient of a Full‐Face Allotransplant

We report on the management of the first full‐face transplantation in a sensitized recipient with a positive preoperative crossmatch and subsequent antibody‐mediated rejection (AMR). The recipient is a 45‐year‐old female who sustained extensive chemical burns, with residual poor function and high levels of circulating anti‐HLA antibodies. With a clear immunosuppression plan and salvage options in place, a full‐face allotransplant was performed using a crossmatch positive donor. Despite plasmapheresis alongside a standard induction regimen, clinical signs of rejection were noted on postoperative day 5 (POD5). Donor‐specific antibody (DSA) titers rose with evidence of C4d deposits on biopsy. By POD19, biopsies showed Banff Grade III rejection. Combination therapy consisting of plasmapheresis, eculizumab, bortezomib and alemtuzumab decreased DSA levels, improved clinical exam, and by 6 months postop she had no histological signs of rejection. This case is the first to demonstrate evidence and management of AMR in face allotransplantation. Our findings lend support to the call for an update to the Banff classification of rejection in vascularized composite tissue allotransplantation (VCA) to include AMR, and for further studies to better classify the histology and mechanism of action of AMR in VCA.

Vascularized composite tissue allotransplantation--state of the art.

Vascularized composite tissue allotransplantation is a viable treatment option for injuries and defects that involve multiple layers of functional tissue. In the past 15 yr, more than 150 vascularized composite allotransplantation (VCA) surgeries have been reported for various anatomic locations including – but not limited to – trachea, larynx, abdominal wall, face, and upper and lower extremities. VCA can achieve a level of esthetic and functional restoration that is currently unattainable using conventional reconstructive techniques.

Novel surgical technique for full face transplantation.

Background: Full face transplantation raises a new set of ethical concerns and technical difficulties when compared with partial face transplantation. Previously, it was thought that full face allografts must include bilateral superficial temporal and facial arteries, dictating the need for inclusion of donor parotid glands. This would lead to poor aesthetic outcomes and limit facial nerve coaptation to the level of the main trunk, which often results in synkinesias. The authors present a new approach to full facial allograft recovery based on blood supply from facial arteries alone. This approach eliminates the need to include parotid glands, enabling more distal coaptation of facial nerve branches and targeted innervation of effector muscles. The recovery can be reproducibly performed within 4 hours. Methods: Three mock cadaver dissections and three full face transplantations were performed. Results: Donor facial allografts were dissected in cranio-caudal and lateral-to-medial fashion. Individual facial nerve branches were cut medial to parotid glands and coapted to corresponding recipient nerve branches. With the exception of one parotid gland used to add bulk, parotids were generally not included in the allografts. Relevant sensory nerves were coapted. External carotid arteries were dissected, leaving only bilateral facial arteries as the primary arterial supply. All full facial allografts were well perfused immediately following transplantation and are surviving. Conclusions: The authors describe a new, simple, and reproducible technique of full facial allograft recovery that allows perfusion using only bilateral facial arteries. Their technique follows critical principles of targeted sensory and motor nerve coaptation. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

Evolution of indications for facial transplantation

Face transplantation has the unique potential to restore facial form and function in patients with severe facial defects. Current indications for face transplantation remain limited by unknown long-term outcomes and the requirements for lifelong immunosuppression and substantial plans for reconstruction in case of failure. We initially obtained Institutional Review Board approval for partial face transplantation in patients with defects comprising 25% of the face and/or loss of one or more major facial features. We launched an outcome-oriented face transplantation study and screened 13 potential patients between February 2008 and January 2011. Experience gained during screening motivated the expansion of indications to include full facial defects and the consideration of patient-specific complex issues on a case-by-case basis. Although our programme focuses on restoring absent or severely compromised motor and sensory functions, we recognise aesthetic appearance as a crucial facial function. Patients are extensively educated on the risks and benefits of facial transplantation and then allowed to play the main role in the decision-making process, as long as no absolute exclusion criteria are present. As we learn more about the long-term outcomes of face transplantation and safe reduction of immunosuppression, face-transplant indications may expand from major unreconstructable defects towards potentially minor defects.

A multidisciplinary protocol for face transplantation at Brigham and Women’s Hospital

Face transplantation introduces an unprecedented potential to restore form and function in patients with severe facial disfigurement. A successful face transplantation programme requires a sound research protocol, a solid infrastructure, expert personnel and adequate funding. There are only a few active face transplant programmes in the world and interest in the development of new such programmes continues to grow. After 2 years of working on the development of the face transplant programme, in 2009 the team at Brigham and Womens Hospital (BWH) performed the 2nd face transplant in the United States. Since then, the team has continued to evaluate several possible face transplant candidates and performed three additional facial transplants. These experiences have helped refine a highly effective multidisciplinary protocol that carries a patient through recruitment, informed consent, screening, preoperative planning, face transplantation surgery and postoperative long-term follow-up. The members of the BWH face transplantation team responsible for carrying out this protocol include a team leader, a programme manager/coordinator, clinical and rehabilitation specialists, social workers, bioethicists, nurses and administrative staff. The roles of each team member during the various stages of the face transplant process are presented here. Additional insight into the interaction between the face transplant team, the Institutional Review Board and the regional Organ Procurement Organization is given. The BWH teams experience has shown that true collaboration, creativity and a unique approach to each candidate translate into the optimal care of the face transplant patient both before and after surgery.

Functional Outcomes of Face Transplantation

In this study we provide a compilation of functional impairments before and improvements after face transplantation (FT) of five FT recipients of our institution and all FTs reported in current literature. Functional outcome included the ability to smell, breath, eat, speak, grimace and facial sensation. Before FT, all our patients revealed compromised ability to breath, eat, speak, grimace and experience facial sensation. The ability to smell was compromised in two of our five patients. Two patients were dependent on tracheostomy and one on gastrostomy tubes. After FT, all abilities were significantly improved and all patients were independent from artificial air airways and feeding tubes. Including data given in current literature about the other 24 FT recipients in the world, the abilities to smell, eat and feel were enhanced in 100% of cases, while the abilities of breathing, speaking and facial expressions were ameliorated in 93%, 71% and 76% of cases, respectively. All patients that required gastrostomy and 91% of patients depending on tracheostomy were decannulated after FT. Unfortunately, outcomes remain unreported in all other cases and therefore we are unable to comment on improvements.

CURRENT PRINCIPLES OF FACIAL ALLOTRANSPLANTATION: THE BRIGHAM AND WOMEN’S HOSPITAL EXPERIENCE

Background: Facial allotransplantation is a revolutionary operation that has at last introduced the possibility of nearly normal facial restoration to patients afflicted by the most severe cases of facial disfigurement. Methods: The facial transplantation team at Brigham and Women’s Hospital evaluated more than 20 patients as potential face transplant recipients; of these, six became face transplant candidates and underwent full screening procedures. The team performed facial allotransplantations in four of these patients between April of 2009 and May of 2011. This is the largest clinical volume of facial transplant recipients in the United States to date. Results: The authors have learned important lessons from each of these four unique cases and from the more than 20 patients that they have evaluated as potential face transplant recipients. The authors have translated lessons learned through direct experience into a set of fundamental surgical principles of the operation. Conclusions: The authors’ surgical principles emphasize safety, technical feasibility, preservation of functional facial units, and return of motor and sensory function. This article describes each of these principles along with their rationale and, in some instances, illustrates their application.

Vascularized composite allotransplantation: current standards and novel approaches to prevent acute rejection and chronic allograft deterioration.

The advent of more potent immunosuppressants led to the first successful human upper extremity transplantation in 1998. At this time, >100 upper extremity transplants, 30 face transplants, and a variety of other vascularized composite allotransplantation (VCA) procedures have been performed around the world. VCA recipients present unique challenges for transplantation. The incidence of acute rejection exceeds 80% in hand and face transplantation and is well documented, whereas reports about antibody‐mediated rejection and chronic rejection remain scarce. Immunosuppression protocols commonly used at US centers are derived from solid organ transplantation protocols. Novel approaches to minimize rejections in VCA may include improved HLA matching and considerations toward cytomegalovirus infection status. New graft preservation techniques may decrease immunogenicity prior to transplant. Novel monitoring methods such as valid biomarkers, ultrasound biomicroscopy, and sentinel flaps may enable earlier diagnosis of rejection. Cell‐based therapies are being explored to achieve immunosuppressive regimen minimization or even tolerance induction. The efficacy of local immunosuppression in clinical VCA remains controversial. In conclusion, although immunosuppressive strategies adapted from SOT have demonstrated good midterm results, focusing on the unique features of VCA grafts may enable additional, more specific treatment strategies in the future and improved long‐term graft outcomes.