Mohammed Alrakan

A Critical Analysis of Rejection in Vascularized Composite Allotransplantation: Clinical, Cellular and Molecular Aspects, Current Challenges, and Novel Concepts

Advances in microsurgical techniques and immunomodulatory protocols have contributed to the expansion of vascularized composite allotransplantation (VCA) with very encouraging immunological, functional, and cosmetic results. Rejection remains however a major hurdle that portends serious threats to recipients. Rejection features in VCA have been described in a number of studies, and an international consensus on the classification of rejection was established. Unfortunately, current available diagnostic methods carry many shortcomings that, in certain cases, pose a great diagnostic challenge to physicians especially in borderline rejection cases. In this review, we revisit the features of acute skin rejection in hand and face transplantation at the clinical, cellular, and molecular levels. The multiple challenges in diagnosing rejection and in defining chronic and antibody-mediated rejection in VCA are then presented, and we finish by analyzing current research directions and novel concepts aiming at improving available diagnostic measures.

Characterization, prophylaxis, and treatment of infectious complications in craniomaxillofacial and upper extremity allotransplantation: a multicenter perspective.

Background: Vascularized composite allotransplants consist of heterogeneous tissues from different germ layers, which include skin, muscle, bone, fat, nerves, and lymph nodes. The antigenic diversity of these tissues, particularly of the highly immunogenic skin component, necessitates potent immunosuppressive regimens similar to that of some solid organ transplants. Indeed, the lifelong, high-dose, multidrug immunosuppressive protocols expose vascularized composite allotransplant recipients to considerable risk of infectious, metabolic, and neoplastic sequelae. In this article, the authors review the infectious risk to patients after vascularized composite allotransplantation, with special attention to the somewhat limited experience with the prophylaxis and treatment of infections after this innovative reconstructive surgery. Methods: A review of the literature was undertaken to elucidate the characterization, prophylaxis, and treatment of all documented infectious complications. Results: Infections in face and hand vascularized composite allotransplants follow a course similar to that of solid organ transplants. Several differences exist, including the unique flora of craniomaxillofacial transplants, the increased risk of donor-derived infections, and the alteration of the risk-to-benefit ratio for cytomegalovirus infections. Conclusions: The patient with a face or limb transplant has many of the same infectious risks as a lung transplant recipient, which include bacterial, viral, and fungal infections. Because of the anatomy, mucosal exposure, and differing donor flora, however, the face or limb transplant is susceptible to invasive diseases from a variety of microbes.

Preoperative Anemia and Postoperative Outcomes in Immediate Breast Reconstructive Surgery: A Critical Analysis of 10,958 Patients from the ACS-NSQIP Database.

Background: Preoperative anemia is independently associated with adverse outcomes after general and cardiac surgery. Outcomes after breast reconstruction are not established. We assessed the effect of preoperative anemia on 30-day postoperative morbidity and length of hospital stay (LOS) in patients undergoing immediate breast reconstruction. Methods: We identified patients undergoing immediate breast reconstruction from 2008 to 2010 from the American College of Surgeons’ National Surgical Quality Improvement Program database (a prospective outcomes-based registry from hospitals worldwide). De-identified data were obtained for demographics, preoperative risk factors, 30-day morbidity, and LOS. Morbidity variables included flap/graft/prosthesis, cardiac, respiratory, neurological, urinary, wound, and venous thromboembolism outcomes. Logistic regression assessed the crude and adjusted effect of anemia (hematocrit <36%) on postoperative 30-day morbidity. Measures of central tendency of LOS were compared across increasing severities of anemia in patients developing adverse events versus controls. Results: The study population included 10,958 patients; 1556 (16.74%) had preoperative anemia. Crude odds ratio for 30-day morbidity was significantly higher in anemic patients, unadjusted odds ratio = 1.33 (P < 0.008). This prevailed after extensive adjustment for confounding, yielding an adjusted odds ratio = 1.38 (P < 0.03). Patients who experienced adverse effects had protracted LOS, and the presence of anemia significantly amplified this effect. Conclusions: These data provide new insight into the effect of anemia in immediate breast reconstruction, demonstrating an independent association between preoperative anemia and 30-day morbidity. These findings suggest treating anemia when possible; however, prospective studies should explore the efficacy, safety, and cost-effectiveness of such treatments.

Ancillary procedures necessary for translational research in experimental craniomaxillofacial surgery.

Introduction Swine are often regarded as having analogous facial skeletons to humans and therefore serve as an ideal animal model for translational investigation. However, there is a dearth of literature describing the pertinent ancillary procedures required for craniomaxillofacial research. With this in mind, our objective was to evaluate all necessary procedures required for perioperative management and animal safety related to experimental craniomaxillofacial surgical procedures such as orthotopic, maxillofacial transplantation. Methods Miniature swine (n = 9) were used to investigate perioperative airway management, methods for providing nutrition, and long-dwelling intravenous access. Flap perfusion using near-infrared laser angiography and facial nerve assessment with electromyoneurography were explored. Results Bivona tracheostomy was deemed appropriate versus Shiley because soft, wire-reinforced tubing reduced the incidence of tracheal necrosis. Percutaneous endoscopic gastrostomy tube, as opposed to esophagostomy, provided a reliable route for postoperative feeding. Femoral venous access with dorsal tunneling proved to be an ideal option being far from pertinent neck vessels. Laser angiography was beneficial for real-time evaluation of graft perfusion. Facial electromyoneurography techniques for tracing capture were found most optimal using percutaneous leads near the oral commissure. Experience shows that ancillary procedures are critical, and malpositioning of devices may lead to irreversible sequelae with premature animal death. Conclusions Face-jaw-teeth transplantation in swine is a complicated procedure that demands special attention to airway, feeding, and intravascular access. It is critical that each ancillary procedure be performed by a dedicated team familiar with relevant anatomy and protocol. Emphasis should be placed on secure skin-level fixation for all tube/lines to minimize risk for dislodgement. A reliable veterinarian team is invaluable and critical for long-term success.

Abstract 9: selectively permeable nanofiber constructs to prevent inflammatory scarring and enhance nerve regeneration in peripheral nerve injury.

ConClusion: Endothelial cell-stromal interactions, mediated by SDF-1, play a pivotal role in maintaining ASC niche transcriptional homeostasis and preserving the functional capacity of ASCs. In the absence of SDF-1, ASCs are shunted towards adipogenesis, with reduced proliferative and proangiogenic capacity, impacting their physiological role within the adipose niche environment and their therapeutic potential in treating ischemia. The dysfunction of ASCs in diabetes may be related to downregulation of SDF-1 and subsequent disruption of the physiological cytokine milieu. Further investigation of the role of SDF-1 in ASC homeostasis and function, particularly in the context of diabetes, is ongoing to inform the development of autologous cell based therapies for diabetic wound healing. 9 Selectively Permeable nanofiber constructs to Prevent inflammatory Scarring and enhance nerve regeneration in Peripheral nerve injury

Costimulatory Blockade in Combination with Donor Bone Marrow Infusion Induces Immune Tolerance Across A Full MHC Barrier In A Translational Large Animal Vascularized Composite Allotransplantation Model

Fully MHCand gender mismatched MGH miniature swine underwent heterotopic hind-limb transplantation. Recipient animals received a short course of tacrolimus monotherapy, C/¡ donor BM infusion (60x10cells/kg), and CTLA4Ig (abatacept). Short course tacrolimus only and untreated animals served as controls. Chimerism was assessed by SRY-gene PCR analysis. Alloreactivity against donor antigens was assessed in vitro using CFSE-based Mixed Lymphocyte Reaction (CFSE-MLR) assays. Robust immune tolerance in vivo was assessed by secondary skin grafting. Tolerance maintenance upon allograft removal was tested in vitro by CFSE-MLR. Donor-specific antibodies (DSA) production was assessed using flow cytometry. Results

Abstract 11: the role of donor antigen persistance in maintaining immune tolerance to a vascularized composite allograft.

PurPose: We have recently shown that indefinite graft survival can be achieved in a fully MHC mismatched swine hind limb transplantation model using a combined donor bone marrow infusion and co-stimulatory blockade regimen. The role of antigen persistence in the maintenance of tolerance in this setting, however, is still unknown. In this study we thus aimed to provide in vitro evidence supporting the clinical observation of tolerance and investigate whether donor-derived antigen persistence is necessary to maintain tolerance to a VCA.