Saami Khalifian

Facial transplantation: the first 9 years

Since the first facial transplantation in 2005, 28 have been done worldwide with encouraging immunological, functional, psychological, and aesthetic outcomes. Unlike solid organ transplantation, which is potentially life-saving, facial transplantation is life-changing. This difference has generated ethical concerns about the exposure of otherwise young and healthy individuals to the sequelae of lifelong, high-dose, multidrug immunosuppression. Nevertheless, advances in immunomodulatory and immunosuppressive protocols, microsurgical techniques, and computer-aided surgical planning have enabled broader clinical application of this procedure to patients. Although episodes of acute skin rejection continue to pose a serious threat to face transplant recipients, all cases have been controlled with conventional immunosuppressive regimens, and no cases of chronic rejection have been reported.

Clinical outcomes in cranioplasty: risk factors and choice of reconstructive material.

Background: Continuing advances in cranioplasty have enabled repair of increasingly complicated cranial defects. However, the optimal materials and approaches for particular clinical scenarios remain unclear. This study examines outcomes following cranioplasty for a variety of indications in patients treated with alloplastic material, autogenous tissue, or a combination of both. Methods: The authors conducted a retrospective analysis on 180 patients who had 195 cranioplasties performed between 1993 and 2010. Results: Materials used for cranioplasty included alloplastic for 42.6 percent (83 of 195), autologous for 19.0 percent (37 of 195), and both combined for 38.5 percent (75 of 195). Mean defect size was 70.5 cm2. A subset of patients had undergone previous irradiation (12.2 percent; 22 of 180) or had preoperative infections (30.6 percent; 55 of 180). The most common complication was postoperative infection (15.9 percent; 31 of 195). Factors that significantly predisposed to complications included preoperative radiation, previous infection, and frontal location. Preoperative radiation was the strongest predictor of having any postoperative complications, with an adjusted odds ratio of 6.91 (p < 0.005). Irradiated patients (OR, 7.96; p < 0.05) and patients undergoing frontal cranioplasties (OR, 2.83; p < 0.05) were more likely to require repeated operation. Preoperative infection predisposed patients to exposure of hardware in alloplastic reconstructions (OR, 3.13; p < 0.05). Conclusions: Despite the evolution of cranioplasty techniques and materials, complications are not uncommon. The choice of reconstructive material may modify the risk of developing postoperative complications but appears less important than the clinical history in affecting outcome. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Immunomodulatory Effects of Adipose-Derived Stem Cells: Fact or Fiction?

Adipose-derived stromal cells (ASCs) are often referred to as adipose-derived stem cells due to their potential to undergo multilineage differentiation. Their promising role in tissue engineering and ability to modulate the immune system are the focus of extensive research. A number of clinical trials using ASCs are currently underway to better understand the role of such cell niche in enhancing or suppressing the immune response. If governable, such immunoregulatory role would find application in several conditions in which an immune response is present (i.e., autoimmune conditions) or feared (i.e., solid organ or reconstructive transplantation). Although allogeneic ASCs have been shown to prevent acute GvHD in both preclinical and clinical studies, their potential warrants further investigation. Well-designed and standardized clinical trials are necessary to prove the role of ASCs in the treatment of immune disorders or prevention of tissue rejection. In this paper we analyze the current literature on the role of ASCs in immunomodulation in vitro and in vivo and discuss their potential in regulating the immune system in the context of transplantation.

Computer-aided design and manufacturing in craniosynostosis surgery.

BackgroundConsiderable operative time is expended during the planning, shaping, and reconfiguring of the cranial vault in the pursuit of symmetry during open craniosynostosis surgery. Computer-aided design and manufacturing has recently been implemented in orthognathic surgery and complex craniomaxillofacial reconstruction as a means of optimizing operative accuracy and efficiency. In this report, we highlight our growing experience with this promising modality for the preoperative planning and intraoperative execution of cranial vault remodeling in patients with both simple and complex forms of craniosynostosis. MethodsComputer-assisted surgical planning begins with acquisition of high-resolution computed tomography scans of the craniofacial skeleton. An Internet-based teleconference is then held between the craniofacial and biomedical engineering teams and provides a forum for virtual manipulation of the patient’s preoperative three-dimensional computed tomography with real-time changes and feedback. Through virtual surgical planning, osteotomies are designed and calvarial bones reconfigured to achieve the desired cranial vault appearance. Cutting and positioning guides are manufactured to transform the virtual plan into a reality. ResultsFrom February to March 2012, 4 children (aged 9 months to 6 years) with craniosynostosis underwent computer-assisted simulation and surgery. Diagnoses included metopic, unicoronal (n = 2), and multisutural synostoses (sagittal and left unicoronal). Open craniofacial repairs were performed as virtually planned, including front o-orbital remodeling, fronto-orbital advancement, and anterior two-thirds calvarial remodeling, respectively. Cutting and final positioning guides demonstrated excellent fidelity and ease of use. ConclusionsComputer-aided design and manufacturing may offer a platform for optimizing operative efficiency, precision, and accuracy in craniosynostosis surgery, while accelerating the learning curve for future trainees.

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.

Donor age negatively affects the immunoregulatory properties of both adipose and bone marrow derived mesenchymal stem cells.

PURPOSE Age negatively impacts the biologic features of mesenchymal stem cells (MSCs), including decreased expansion kinetics and differentiation potential. Clinically, donor-age may be within a wide spectrum; therefore, investigation of the role of donors age on immunoregulatory potential is of critical importance to translate stem cell therapies from bench to bedside. METHODS Adipose and bone marrow derived MSCs (ASCs and BMSCs) were isolated in parallel from Lewis and Brown Norway rats of young (less than 4-week old) and senior groups (older than 15-month). The presentation of cells and time required for growth to 90% confluence was recorded. FACS sorting based on the expression of CD90 and CD29 double positive and CD45 CD11 double negative quantified the proportions of MSCs. After expansion, ASCs and BMSCs from different age groups were co-cultured in mixed lymphocyte reaction (MLR; Lewis vs. Brown Norway) assays. The suppression of CD3(+)CD4(+) and CD3(+)CD8(+) T cell populations by different sources of MSCs were compared. RESULTS The kinetics of cell growth was slower in old animals (17.3±2days) compared with young animals (8.8±3days), and cell morphology was irregular and enlarged in the senior groups. The yield of MSCs by FACS sorting was significantly higher in young groups compared to senior groups (p<0.02). With regard to immunoregulatory potential, senior ASCs failed to induce any CD3(+)CD4(+) T cell suppression (p>0.05). In addition, young BMSCs-induced suppression was more prominent than seniors (p<0.05). CONCLUSIONS Donor age should be taken into consideration when using recipient MSC of either bone marrow or adipose origin in clinical applications.

Defining Predictable Patterns of Craniomaxillofacial Injury in the Elderly: Analysis of 1,047 Patients

PURPOSE Currently, nearly 1 in 5 Americans is at least 60 years of age. Bone atrophy, decreased capacity for tissue repair, and chronic disease are known to influence fracture patterns and operative algorithms in this age group. This study presents craniofacial trauma injury patterns and treatment in an elderly population at a major urban trauma center. METHODS Patient records were retrospectively reviewed from February 1998 through December 2010. Patients at least 60 years of age who met the inclusion criteria for craniofacial fractures identified by International Classification of Diseases, Ninth Revision code review and confirmed by author review of available computed tomograms were studied. Demographic information, fracture type, concomitant injuries, and management were recorded. RESULTS Of 11,084 patients presenting with facial fracture, 1,047 were older than 60 years. The most common mechanism of injury was falls (50%), and most patients were men (59%). Commonly fractured areas included the nose (n = 452, 43%), maxilla (316, 30%), zygoma (312, 30%), orbital floor (280, 27%), and mandible (186, 18%), with 51 patients (5%) having a concomitant basilar skull fracture. Inpatient mortality and length of stay were significantly increased compared with the nongeriatric population (P < .01), although only 5% of all fractures were treated operatively. CONCLUSIONS Fractures in the elderly tend to be minimally displaced midfacial fractures that do not warrant surgical intervention. Despite conservative management, the elderly are hospitalized longer than their younger counterparts, have increased critical care needs, and have higher mortality. These data support national medical preparedness in anticipating the craniofacial trauma needs of the aging US population and can be used to update treatment algorithms for these patients.

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.

Classification of mandible defects and algorithm for microvascular reconstruction

Background: Composite mandibular tissue loss results in significant functional impairment and cosmetic deformity. This study classifies patterns of mandibular composite tissue loss and describes a microvascular treatment algorithm. Methods: A retrospective review of microvascular composite mandibular reconstruction from July of 2005 to April of 2013 by the senior surgeon at the R Adams Cowley Shock Trauma Center and at The Johns Hopkins Hospital yielded 24 patients with a mean follow-up of 17.9 months. Causes of composite mandibular defects included tumors, osteoradionecrosis, trauma, infection, and congenital deformity. Patients with composite tissue loss were classified according to missing subunits. Results: A treatment algorithm based on composite mandibular defects and microvascular reconstruction was developed and used to treat 24 patients. A type 1 defect is a unilateral dentoalveolar defect not crossing the midline and not extending into the angle of the mandible. A type 2 defect is a unilateral defect extending beyond the angle. A type 3 defect is a bilateral defect not involving the angles. A type 4 defect is a bilateral defect with extension into at least one angle. Type 2 defects were the predominant group. Patients had microvascular reconstruction using either fibula flaps (n = 19) or iliac crest flaps (n = 5). Complications included infection, partial necrosis, plate fracture, dehiscence, and microvascular thrombosis. Conclusion: This novel classification system and treatment algorithm allows for a consistent and reliable method of addressing composite mandibular defects and focuses on recipient vasculature and donor free flap characteristics. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Immunosuppression and monitoring of rejection in hand transplantation.

Advances in vascularized composite allotransplantation over the last decade have achieved significant milestones in basic science and translational research, as well as clinically with highly encouraging functional and immunologic outcomes. However, certain immunologic challenges remain. In particular, although tolerance has been induced to nearly all components of a hand allograft in experimental models, the skin component may still be subject to acute rejection episodes. Currently, conventional immunosuppressive protocols have been successful at preventing allograft loss; however, they have not prevented episodes of acute skin rejection. Furthermore, the profound side effect profile of the life-long, high-dose, multidrug immunosuppression regimen that is necessary to maintain a viable graft alters the risk to benefit ratio of this non–life-saving procedure. Therefore, there must be a concerted effort in the scientific community to develop novel protocols to either minimize immunosuppression or to induce tolerance to the allograft to promote the widespread application of this life-changing procedure.