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IntroductionVascularized composite allotransplantation (VCA), with nerve repair/coaptation (NR) and tacrolimus (TAC) immunosuppressive therapy, is used to repair devastating traumatic injuries but is often complicated by inflammation spanning multiple tissues. We identified the parallel upregulation of transcriptional pathways involving chemokine signaling, T-cell receptor signaling, Th17, Th1, and Th2 pathways in skin and nerve tissue in complete VCA rejection compared to baseline in 7 human hand transplants and defined increasing complexity of protein-level dynamic networks involving chemokine, Th1, and Th17 pathways as a function of rejection severity in 5 of these patients. We next hypothesized that neural mechanisms may regulate the complex spatiotemporal evolution of rejection-associated inflammation post-VCA.MethodsFor mechanistic and ethical reasons, protein-level inflammatory mediators in tissues from Lewis rats (8 per group) receiving either syngeneic (Lewis) or allogeneic (Brown-Norway) orthotopic hind limb transplants in combination with TAC, with and without sciatic NR, were compared to human hand transplant samples using computational methods.ResultsIn cross-correlation analyses of these mediators, VCA tissues from human hand transplants (which included NR) were most similar to those from rats undergoing VCA + NR. Based on dynamic hypergraph analyses, NR following either syngeneic or allogeneic transplantation in rats was associated with greater trans-compartmental localization of early inflammatory mediators vs. no-NR, and impaired downregulation of mediators including IL-17A at later times.DiscussionThus, NR, while considered necessary for restoring graft function, may also result in dysregulated and mis-compartmentalized inflammation post-VCA and therefore necessitate mitigation strategies. Our novel computational pipeline may also yield translational, spatiotemporal insights in other contexts.

The use of autografted nerve in surgical repair of peripheral nerve injuries (PNI) is severely limited due to donor site morbidity and restricted tissue availability. As an alternative, synthetic nerve guidance channels (NGCs) are available on the market for surgical nerve repair, but they fail to promote nerve regeneration across larger critical gap nerve injuries. Therefore, such injuries remain unaddressed, result in poor healing outcomes and are a limiting factor in limb reconstruction and transplantation. On the other hand, a myriad of advanced biomaterial strategies to address critical nerve injuries are proposed in preclinical literature but only few of those have found their way into clinical practice. The design of synthetic nerve grafts should follow rational criteria and make use of a combination of bioinstructive cues to actively promote nerve regeneration. To identify the most promising NGC designs for translation into applicable products, thorough mode of action studies, standardized readouts and validation in large animals are needed. We identify design criteria for NGC fabrication according to the current state of research, give a broad overview of bioactive and functionalized biomaterials and highlight emerging composite implant strategies using therapeutic cells, soluble factors, structural features and intrinsically conductive substrates. Finally, we discuss translational progress in bioartificial conduits for nerve repair from the surgeon’s perspective and give an outlook toward future challenges in the field.

Severe trauma, tumor removal or congenital defects may result in composite tissue deficits, in which despite the best reconstructive efforts, functional and esthetic outcomes are poor, with increased morbidity, cost, and recovery time. Vascularized composite allotransplantation (VCA) is a new reconstructive option that involves transplantation of the composite tissues in one surgical procedure and allows to restore the appearance, anatomy, and function in the defects that cannot be repaired with conventional techniques. Unlike solid organ transplantation, the VCA is composed of heterogeneous tissues, including skin, fat, muscle, nerves, lymph nodes, bone, cartilage, ligaments, and bone marrow, all presenting different antigenicity. Thus, VCA may elicit different immune responses compared to solid organ transplants. Since the first successful clinical hand transplantation in 1998, and first face transplantation in 2005, over 100 hand and 40 face transplantations have been performed. Despite successful results, routine clinical application of VCA is limited due to known and unknown lifelong side effects of immunosuppressive protocols. Thus, VCA research is aiming to develop new, less toxic, tolerance-inducing strategies that will allow for routine clinical application of VCA. This chapter overviews the historical background, provides basic information on transplantation immunology, and summarizes the VCA experimental models and clinical applications, as well as the outcomes.

INTRODUCTION Research on tolerance has proven that development of donor-specific chimerism (DSC) may accompany tolerance induction in vascularized composite allotransplantation (VCA). In this study, we aimed to determine the effect of thymus transplantation on the induction of DSC in rat VCA model of osseomusculocutaneous sternum (OMCS) and osseomusculocutaneous sternum and thymus (OMCST) allotransplantation. MATERIALS AND METHODS A total of 20 Lewis-Brown Norway and Lewis rats, 5-6 weeks old, weighting between 120 and 150 g, were used in the study. OMCS (n = 5) and OMCST (n = 5) allografts were harvested from Lewis-Brown Norway donors (RT1l + n ) based on the common carotid artery and external jugular vein, and a heterotopic transplantation was performed to the inguinal region of the Lewis (RT1l ) recipients under cyclosporine A monotherapy (16 mg/kg) protocol tapered to 2 mg/kg and maintained for the duration of the study. The peripheral blood chimerism levels (T-cell, B-cell, and monocyte/granulocyte/dendritic cell-MGDC populations) were evaluated at days 7, 14, 35, 63, 100, and 150 posttransplant by flow cytometry. At Day 150, thymus, spleen, and liver samples were assessed by polymerase chain reaction (PCR) in the presence of DSC. RESULTS Total chimerism level increased in both OMCST and OMCS groups at all time points. At 150 days posttransplant, chimerism in OMCST group was significantly higher (12.91 ± 0.16%) than that in OMCS group (8.89 ± 0.53%%, p

The purpose of this review is to evaluate the recent literature about animal models for penile and lower limb transplantation, regarding their relevance to the clinical scenario. Although both penile and lower limb transplantations have been sharing same problems with all other vascularized composite allotransplantations, they have their unique issues that need to be addressed. There is no appropriate animal model to demonstrate functions of both penile and lower limb transplantation. We reevaluate and underline the interesting and important findings of the certain animal models of the penile and lower limb transplantation. Current and future clinical applicability and feasibility have also been discussed.

Reconstruction of composite tissues or organs is challenging, with limited functional and esthetic outcomes. Nearly 100 years passed from the first penile reconstruction is performed; however, the outcomes were far from ideal. With the beginning of the reconstructive transplantation era, new choices became possible. Until now, four penis transplantations were performed worldwide, with encouraging short-term results. Although with a short follow-up, these penile transplantations reported success. However, the problems related to systemic lifelong immunosuppression remain as the major problem related to these life-enhancing transplantations. In this review, we revisit and evaluate the conventional methods of penis reconstruction, overview the up-to-date results of penis transplantation, and discuss advantages and disadvantages of these two techniques.

Background Traumatic nasal deformities have a wide spectrum of presentations, which further complicates their management and preoperative planning. Although many methods and algorithms have been proposed for management of specific posttraumatic nasal deformities, such as twisted, deviated, saddle, or short nose, these algorithms usually focus on a specific deformity in isolation from the remainder of the nose. Objectives The aim of this study is to present an algorithm for traumatic nasal deformities and to evaluate the functional and aesthetic outcomes of this new algorithm by a preoperative and postoperative quality-of-life questionnaire. Methods Patients with traumatic nasal deformity were operated on according to our surgical algorithm. Preoperative and postoperative Rhinoplasty Outcome Evaluation (ROE) scores, which is a rhinoplasty outcome survey, were evaluated. Results A total of 120 patients were included in the study. The mean preoperative ROE score was 3.3 ± 1.9 and mean postoperative ROE score was 20.4 ± 3.2. There was a statistically significant difference between preoperative and postoperative ROE scores (P < 0.001). There was a negative, mild to moderate, statistically significant correlation between preoperative scores and benefit (difference between postoperative and preoperative scores) (r = -0.465, P < 0.001), which means patients with lower scores had more improvement from the surgery. During the follow-up period, relapse of deviation, hypertrophic inferior turbinate, and intranasal synechia were found in 9% (n = 11), 6.6% (n = 8), and 3.3% (n = 4) of patients, respectively. Conclusions In this study, a comprehensive surgical algorithm applicable to all traumatic nasal deformities is suggested, and the results of 120 patients with traumatic nasal deformities are presented. Level of Evidence 2

Transplantation is a truly multidisciplinary specialty where a surgical procedure requires inputs from both, the specialists of the specific organ e.g. nephrologist for kidney transplant or hepatologist for liver transplant, as well as from experts of other specialties such as immunology, infectious diseases etc. It is also a rapidly grooving field with the advances in surgical techniques, immunological knowledge and pharmacology. A recent, major advance in the field of transplantation is the emergence of new procedure of vascularized composite allotransplantation, which includes transplantation of non-lifesaving organs such as face, hands, abdominal wall or uterus. Additionally, organ shortage in transplantation yielded a new area of research such as xenotransplantation and regenerative medicine. The specialty of transplantation may be difficult to comprehend for those entering the field; thus, the goal of this chapter is to provide a comprehensive overview of the most important aspects of transplantation. This review contains 2 figures, 3 tables, and 67 references. Keywords: transplantation, solid organ transplantation (SOT), vascularized composite allotransplantation (VCA), transplant immunology, allorecognition, acute rejection, chronic transplant rejection, principles of transplantation, transplantation terminology, immunosuppressive drugs

Purpose of review The advent of clinical vascularized composite allotransplantation (VCA), offers hope for whole eye transplantation (WET) in patients with devastating vison loss that fails or defies current treatment options. Optic nerve regeneration and reintegration remain the overarching hurdles to WET. However, the realization of WET may indeed be limited by our lack of understanding of the singular immunological features of the eye as pertinent to graft survival and functional vision restoration in the setting of transplantation. Recent findings Like other VCA, such as the hand or face, the eye includes multiple tissues with distinct embryonic lineage and differential antigenicity. The ultimate goal of vision restoration through WET requires optimal immune modulation of the graft for successful optic nerve regeneration. Our team is exploring barriers to our understanding of the immunology of the eye in the context of WET including the role of immune privilege and lymphatic drainage on rejection, as well as the effects ischemia, reperfusion injury and rejection on optic nerve regeneration. Summary Elucidation of the unique immunological responses in the eye and adnexa after WET will provide foundational clues that will help inform therapies that prevent immune rejection without hindering optic nerve regeneration or reintegration.

Monocyte derived macrophages (MDMs) infiltrate sites of infection or injury and upregulate cyclooxygenase-2 (COX-2), an enzyme that stimulates prostaglandin-E2 (PgE2). Nanotheranostics combine therapeutic and diagnostic agents into a single nanosystem. In previous studies, we demonstrated that a nanotheranostic strategy, based on theranostic nanoemulsions (NE) loaded with a COX-2 inhibitor (celecoxib, CXB) and equipped with near-infrared fluorescent (NIRF) reporters, can specifically target circulating monocytes and MDMs. The anti-inflammatory and anti-nociceptive effects of such cell-specific COX-2 inhibition lasted several days following Complete Freund's Adjuvant (CFA) or nerve injury in male mice. The overall goal of this study was to investigate the extended (up to 40 days) impact of MDM-targeted COX-2 inhibition and any sex-based differences in treatment response; both of which remain unknown. Our study also evaluates the feasibility and efficacy of a preclinical nanotheranostic strategy for mechanistic investigation of the impact of such sex differences on clinical outcomes. Methods: CFA was administered into the right hind paws of male and female mice. All mice received a single intravenous dose of NIRF labeled CXB loaded NE twelve hours prior to CFA injection. In vivo whole body NIRF imaging and mechanical hypersensitivity assays were performed sequentially and ex vivo NIRF imaging and immunohistopathology of foot pad tissues were performed at the end point of 40 days. Results: Targeted COX-2 inhibition of MDMs in male and female mice successfully improved mechanical hypersensitivity after CFA injury. However, we observed distinct sex-specific differences in the intensity or longevity of the nociceptive responses. In males, a single dose of CXB-NE administered via tail vein injection produced significant improved mechanical hypersensitivity for 32 days as compared to the drug free NE (DF-NE) (untreated) control group. In females, CXB-NE produced similar, though less prominent and shorter-lived effects, lasting up to 11 days. NIRF imaging confirmed that CXB-NE can be detected up to day 40 in the CFA injected foot pad tissues of both sexes. There were distinct signal distribution trends between males and females, suggesting differences in macrophage infiltration dynamics between the sexes. This may also relate to differences in macrophage turnover rate between the sexes, a possibility that requires further investigation in this model. Conclusions: For the first time, this study provides unique insight into MDM dynamics and the early as well as longer-term targeted effects and efficacy of a clinically translatable nanotheranostic agent on MDM mediated inflammation. Our data supports the potential of nanotheranostics as presented in elucidating the kinetics, dynamics and sex-based differences in the adaptive or innate immune responses to inflammatory triggers. Taken together, our study findings lead us closer to true personalized, sex-specific pain nanomedicine for a wide range of inflammatory diseases.

Biocompatibility is a very common word that is used within biomaterial science and used for description of the interactions between the foreign material and the body. However, the meaning of biocompatibility as well as the mechanisms that collectively constitutes is still unclear. With the advance of nanotechnology, new concerns have been observed related to biocompatibility of these biomaterials. Due to their small size and variability of their physical and chemical properties, nanoparticles’ (NP) distribution within the body and interactions with the target cells and tissues are highly variable. Here, we tried to provide an overview about NPs, the concept of biocompatibility and biocompatibility-related issues in nanomedicine and several different NPs.

Purpose of review It has been increasingly common to use adipose tissue for regenerative and reconstructive purposes. Applications of autologous fat transfer and different stem cell therapies have significant limitations and adipose tissue engineering may have the potential to be an important strategy in the reconstruction of large tissue defects. A better understanding of adipogenesis will help to develop strategies to make adipose tissue more effective for repairing volumetric defects. Recent findings We provide an overview of the current applications of adipose tissue transfer and cellular therapy methods for soft tissue reconstruction, cellular physiology, and factors influencing adipogenesis, and adipose tissue engineering. Furthermore, we discuss mechanical properties and vascularization strategies of engineered adipose tissue, and its potential applications in the clinical settings. Summary Autologous fat tissue transfer is the standard of care technique for the majority of surgeons; however, high resorption rates, poor perfusion within a large volume fat graft and widely inconsistent graft survival are the main limitations. Adipose tissue engineering is a promising field to reach the first goal of producing adipose tissue which has more predictable survival and higher graft retention rates. Advancements of scaffold and vascularization strategies will contribute to metabolically and functionally more relevant adipose tissue engineering.

The size of the thoracodorsal artery perforator (TDAP) flap or pedicle, in general, may be found to be inadequate. Pre-expansion of the flap before harvest can be a solution to increase the size of the TDAP flap in such instances. The pre-expanded TDAP flap can be used to reconstruct large-sized defects with the advantage of primary closure of the donor site. This article presents details on the surgical technique and provides discussion of the authors' experiences.

Summary Introduction Whole eye transplantation (WET) holds promise for vision restoration in devastating/disabling visual loss (congenital or traumatic) not amenable to surgical or neuroprosthetic treatment options. The eye includes multiple tissues with distinct embryonic lineage and differential antigenicity. Anatomically and immunologically, the eye is unique due to its avascular (cornea) and highly vascular (retina) components. Our goal was to establish technical feasibility, demonstrate graft viability, and evaluate histologic changes in ocular tissues/adnexae in a novel experimental model of WET that included globe, adnexal, optic nerve (ON), and periorbital soft tissues. Methods Outbred Sprague-Dawley rats (n = 5) received heterotopic vascularized WET from donors. Each WET included the entire globe, adnexa, ON, and periorbital soft tissues supplied by the common carotid artery and external jugular vein. Viability and perfusion were confirmed by clinical examination, angiography and magnetic resonance imaging (MRI). Globe, adnexal, and periorbital tissues were analyzed for histopathologic changes, and the ON was examined for neuro-regeneration at study endpoint (30 days) or Banff Grade 3 rejection in the periorbital skin (whichever was earlier). Results Gross examination confirmed transplant viability and corneal transparency. Average operative duration was 64.0 ± 5.8 min. Average ischemia time was 26.0 ± 4.2 min. MRI revealed loss of globe volume by 36.0 ± 2.8% after transplantation. Histopathology of globe and adnexal tissues showed unique and differential patterns of inflammatory cell infiltration. The ON revealed a neurodegeneration pattern. Conclusion The present study is the first in the literature to establish an experimental model of WET. This model holds significant potential in investigating mechanistic pathways, monitoring strategies or developing management approaches involving ocular viability, immune rejection, and ON regeneration after WET.

Background Vascularized composite allotransplantation offers a new hope for restoration of orbital content and perhaps vision. The aim of this study was to introduce a new composite eyeball-periorbital transplantation model in fresh cadavers in preparation for composite eyeball allotransplantation in humans. Methods The composite eyeball-periorbital transplantation flap borders included the inferior border, outlined by the infraorbital rim; the medial border, created by the nasal dorsum; the lateral border, created by the lateral orbital rim; and the superior border, created by the superior part of the eyebrow. The pedicle of the flap included the facial artery, superficial temporal artery, and external jugular vein. The skin and subcutaneous tissues of the periorbital region were dissected and the bony tissue was reached. A coronal incision was performed and the frontal lobe of the brain was reached by means of frontal osteotomy. Ophthalmic and oculomotor nerves were also included in the flap. After a "box osteotomy" around the orbit, the dissection was completed. Methylene blue and indocyanine green injection (SPY Elite System) was performed to show the integrity of the vascular territories after facial flap harvest. Results Adequate venous return was observed within the flap after methylene blue dye injection. Laser-assisted indocyanine green angiography identified a well-defined vascular network within the entire composite eyeball-periorbital transplantation flap. Conclusions For the first time, a novel composite eyeball-periorbital transplantation model in human cadavers was introduced. Good perfusion of the flap confirmed the feasibility of composite eyeball-periorbital transplantation in the clinical setting. Although harvesting of the flap is challenging, it introduces a new option for reconstruction of the periorbital region including the eyeball.

Introduction Vascularized composite allotransplantation (VCA), a new reconstructive option for patients suffering from extensive facial defects leads to superior functional and aesthetic outcomes compared to the standard autologous reconstruction. Among VCA recipients, each case involves different facial structures and tissues depending on the patient's injury, thus drawing conclusions on the mechanism of immune interactions between the donor and recipient is challenging. This study introduces a new total hemiface VCA model, including scalp, external ear, mystacial pad, premaxilla, upper/lower lids, nose, and upper/lower lips to evaluate the effect of transplantation of multitissue VCA on the recipient's immune response. Material and Methods Ten hemiface allotransplantations were performed in two groups between Lewis–Lewis (isograft) and LBN-Lewis (allograft) rats. Cyclosporine A (CsA) monotherapy was applied in the allograft group to prevent rejection. Results All flaps survived up to 100 days post-transplant. The mean warm ischemia time was 45 minutes. Histological analysis revealed normal bone, cartilage (ear and nose), conjunctiva, palpebra, and eyelashes. Flow cytometry confirmed donor-specific chimerism for T cells (CD4/RT1n and CD8/RT1n) and B cells (CD45RA/RT1n) in the peripheral blood of all rats in the allotransplantation group. At post-transplant day 7, chimerism levels were at 1.68% for CD4/RT1n, 0.46% for CD8/RT1n and 0.64% for CD45RA/RT1n. However, chimerism levels for CD4/RT1n, CD8/RT1n, and CD45RA/RT1n populations decreased at long-term follow-up (at post-transplant day 100) to 0.08%, 0.04%, and 0.23%, respectively. Conclusion The feasibility and long-term survival of the new hemiface VCA transplantation model was confirmed, donor-specific chimerism and post-transplant tissue changes were evaluated. © 2016 Wiley Periodicals, Inc. Microsurgery 36:230–238, 2016.

In the USA, 20 million patients suffer from neuropathy caused by peripheral nerve injuries, which costs approximately $150 billion annually. For longer nerve gaps and multiple injury sites, it is essential to use nerve guidance conduits for healthy pathfinding of regenerating axons. Here, extracellular matrix mimetic peptide nanofiber hydrogels were used for functionalizing guidance conduits to enhance neuronal regeneration in the distal stump of full transaction sciatic nerve injury in rats with functional repair. Conduits filled with heparan sulfate and laminin mimetic peptide nanofibers significantly improved electromyography response and promoted neuronal regeneration in a rat model of sciatic nerve defect. In addition, Schwann cells cultured on these nanofibers showed increased viability and significantly enhanced nerve growth factor (NGF) release. Overall, these results suggest that extracellular matrix mimetic peptide nanofibers present a promising treatment option for peripheral nerve injuries.

Background Achieving satisfactory results may be difficult in augmentation mammaplasty patients in the presence of breast, chest wall, or vertebral deformities. These deformities have not been classified previously, and the impact of each deformity or combination of deformities has not been defined. Objectives The aims of this study are to determine the complicating factors in augmentation mammaplasty, to classify these factors according to their influence on surgical outcome, and to develop an identification system for simplifying the recognition of challenging cases. Methods We retrospectively analyzed photographs and records of 100 consecutive patients who underwent augmentation mammaplasty. We observed suboptimal results in 18 cases. Preoperative deformities of the breast, chest wall, and vertebra were recorded in order to determine which factor or factors had complicated the surgeries. Eventually, the relationship between suboptimal surgical results and complicating factors was evaluated. Results We observed that some deformities alone caused suboptimal results, whereas others did not. Deformities that caused suboptimal results alone were called major complicating factors, and any others were called minor complicating factors. We observed that suboptimal results were also obtained in patients who had four minor complicating factors. Patients who had suboptimal results because of major or minor complicating factors were considered challenging cases. Conclusions In this study, complicating factors for augmentation mammaplasty were defined and classified as major or minor depending on their effect on the surgical outcome. We suggest an identification system that simplifies the recognition of challenging cases in breast augmentation. Level of Evidence: 4 ![Graphic][1] Therapeutic [1]: /embed/inline-graphic-1.gif

Summary Background Plantar skin has similar histologic features to the palmar area and appears to be the ideal tissue for reconstruction of the palmar region. In this study, an anatomic examination was performed to determine the superficial venous architecture of the instep area, and the use of arterialized venous instep flaps for palmar contracture release was assessed. Methods The anatomical study was performed on 12 fresh cadaver feet. The arterialized venous instep flap, including the skin, subcutaneous tissue and superficial venous plexus, was harvested. To determine the venous structure, dissection (n = 6) and injection-corrosion (n = 6) techniques were used. In the clinical study, nine arterialized venous instep flaps were used for palmar contracture release. All flaps were harvested above the deep fascia and included skin, subcutaneous fat, and the superficial venous plexus. At the plantar site of the flap, two or three veins, one of which was used, were dissected for a sufficient length for the arterial anastomosis. The saphenous vein was used for the venous anastomosis. Results Dissection and injection-corrosion techniques revealed that the flap had 7–12 and 4–6 veins at its plantar and superior edges, respectively, with numerous anastomoses and interconnections between the veins. The flap dimensions were between 3 × 5 cm and 4 × 6 cm. All flaps survived, with two partial flap necrosis that healed with spontaneous epithelization. No debulking procedures were undertaken and all flaps adapted well to the recipient site. Conclusions The arterialized venous instep flap is a good alternative to reconstruct palmar contractures by adding similar tissue that is thin and pliable with minimal donor site morbidity.

Vascularized composite allografts can undergo immune-mediated rejection, and skin biopsies are needed for monitoring of the transplant. However it is an invasive method, and requires processing time and pathological assessment. The purpose of this study is to use a new noninvasive monitoring method of the reflectance confocal microscopy (RCM) to determine severity of the allograft rejection on rats. Five groin flap allotransplantation were performed between 10 male Sprague-Dawley rats. Immunosuppressive therapy with cyclosporine A was given to the recipients during 10 days after surgery and was ended at the 10th postoperative days to allow acute transplant rejection. Following cessation of CsA, concomitant RCM evaluation and skin biopsy was performed every other day from each animal until total rejection of the allograft. Complete rejection of the allograft took nearly about 10 days and 4 or 5 RCM evaluation and skin biopsy was performed from each rat during this period. A total of 17 specimens were evaluated. A scoring system was developed based on the RCM findings. Skin biopsies were evaluated according to the Banff 2007 working classification criteria. RCM evaluation revealed epidermal irregularity and collagen destruction, however mild perivascular inflammation and degeneration of the basal epidermal layer were observed in early and late rejection period respectively with histopathologic evaluation. High correlation was found between the RCM scores and histopathologic grading. The RCM may be the useful tool to reduce the need for skin biopsy for monitoring of the skin containing vascularized composite allograft.

Benign masses arising from facial bones have been reported several times in the literature. Hemangiomas are one of the uncommon benign tumors. In this study, the authors aimed to present a rare patient of zygomatic intraosseos hemangioma and their management. A 40-year-old woman with a mass in her left lateral cantus admitted to our clinic. Preoperative computed tomography and magnetic resonance imaging revealed an osseos mass in her left zygoma. The authors conclude that it should be kept in mind that although they are very rare benign tumors, intraosseos hemangiomas can cause facial masses. Meticulous radiologic examination can give important clues for differential diagnosis before the surgery.

Adipose tissue engineering is a promising field for regeneration of soft tissue defects. However, vascularization is needed since nutrients and oxygen cannot reach cells in thick implants by diffusion. Obtaining a biocompatible scaffold with good mechanical properties is another problem. In this study, we aimed to develop thick and vascularized adipose tissue constructs supporting cell viability and adipose tissue regeneration. Hydrogels were prepared by mixing rat decellularized adipose tissue (DAT) and silk fibroin (Fib) at different v/v ratios (3:1, 1:1 and 1:3) and vortexing. Gelation times decreased with increasing fibroin ratio Among hydrogel groups 1:3-DAT: Fib ratio group showed similar mechanical properties with adipose tissue. Both pre-adipocytes and pre-endothelial cells, pre-differentiated from adipose derived stem cells (ASCs), were encapsulated in hydrogels at a 1:3 ratio. In vitro analyses showed that hydrogels with 1:3 (v/v) DAT: Fib ratio supported better cell viability. Pre-adipocytes had lipid vesicles, and pre-endothelial cells formed tubular structures inside hydrogels only after 3 days in vitro. When endothelial and adipogenic pre-differentiated ASCs (for 7 days before encapsulation) were encapsulated together into 1:3-DAT: Fib hydrogels both cell types continued to differentiate into the committed cell lineage. Vascularization process in the hydrogels implanted with adipogenic and endothelial pre-differentiated ASCs took place between the first and second week after implantation which was faster than observed in the empty hydrogels. ASCs pre-differentiated towards adipogenic lineage inside hydrogels had begun to accumulate lipid vesicles after 1 week of subcutaneous implantation Based on these results, we suggest that 1:3-DAT: Fib hydrogels with enhanced vascularization hold promise for adipose tissue engineering.

This study aimed to evaluate the osteometric boundaries of the ilium, fibula, and scapula beyond which reconstruction of oromandibular and craniofacial defects, using these free flaps, may not be optimal. Fibula, scapula, and iliac bones were obtained bilaterally from 33 female and 27 male European adult cadavers (n = 60). Adapting classical anthropometric methods to surgical needs by modifying the measuring bone localizations and measurement points, a measuring system of osteometry and morphometry was used, to quantify the usable bone length of the iliac crest, fibula, and lateral border of the scapula and to localize an oval region (OR) in the ilium. The thin, translucent OR of ilium was localized 62.4 ± 5.6 mm posterior to the maximum concavity between the anterior superior (ASIS) and anterior inferior iliac spine and 26.7 ± 6 mm caudal to the intermediate line of the iliac crest. The available iliac crest was measured from ASIS to the posterior superior iliac spine (PSIS) 247.5 ± 12.6 mm, fibula supplied 170.2 ± 19.1 mm harvestable bone, and the lateral border of the scapula 94.3 ± 8.5 mm [Corrected]. The OR influenced the harvestable bone shape and volume of the ilium. Measuring of the localization points of OR, we found that the size of the OR was very variable and that the height of the neomandible reconstructed with iliac crest might alter with aging. Our findings contribute with knowledge of detailed morphometric measurements on commonly used donor bones to the planning strategies of volumetric defects in oral and maxillofacial region by precise osteometric localization method of OR and relativized length measurements.

Acute neuropathic pain (ANP) resulting from civilian and combat traumatic injuries has dramatic impact on society at large as it poses with significant personal and economic burden. With opioid abuse epidemic currently in public eye across all levels of society, it is pertinent new therapeutic modalities are needed to effectively treat and resolve ANP. Neuroinflammation is recognized as one of the primary drivers of acute neuropathic to chronic pain transition leading to prolonged disability and loss of productivity. We hypothesize that the lack of molecular and cellular targeting specificity to effectively engage key cellular players in the neuronal injury milieu leads to non-opioid and local analgesia pain control failures in some patients. Here we present novel nanomedicine strategies for targeted non-opioid drug delivery directly to the key cells at the site of injury, immune cells and nerves. Since drug delivery is cell targeted, smaller drug doses are expected to produce similar or improved therapeutic effects over non-targeted therapies. Further we achieve overall dramatically decreased systemic exposure (up to 1000 fold), which can diminish unwanted side effects. Presented nanomedicine formulations provide sustained drug release leading to dosing frequency decrease and extended duration of therapeutic effects (up to 30 days or longer). As designed, these pain directed nanomedicines could improve patient response to treatment while minimizing systemic exposure/overdose risk, tolerance and/or dependency. To the best of our knowledge this is the first example of dual administration (systemic and local) nanomedicine design for acute post-trauma pain applicable to both civilian and military settings. We present fabrication and optimization of immune cell and nerve targeted nanoformulations. Evaluation for controlled release kinetics and safety of the these systems with optimized drug payloads in vivo in rat models of nerve injury and mouse inflammatory pain models following local and systemic administration is also presented.

We assessed the morphological characteristics and dimensions of the ilium and fibula to evaluate the suitability of particular areas of bone for use as donor sites for dental reconstructions that carry implants. We measured the dimensions of 130 bilaterally harvested ilium and fibula bones from 65 adult cadavers using osteometric methods, and analysed the effects of age, sex, and side. Dimensions at measuring points, overall suitability for implantation, and relations among age, sex, and side, were evaluated statistically. We report observations of bone morphology involving cross-sections, and clinical relevance. Although the mean dimensions of the fibula and iliac crest were adequate, some segments would not support an implant 10 mm long and 3.5 mm wide. The overall suitability of parts of the iliac block fell to 30%. Fibular morphology is characterised by constant height and width, and relation of cortical and cancellous bone. Bony dimensions on the iliac fossa and fibula were significantly greater in men than in women. Age had a negative impact in one area of the iliac fossa, but nowhere on the iliac crest. Side was not significant. We found differences in dimensions and morphology between measuring points on the same bone. Precise knowledge about which areas of the donor sites can reliably provide sufficient bone to carry implants after reconstructions will allow greater flexibility and safety when reconstructions are designed. © 2013 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

Functional nerve regeneration after reconstructive nerve surgery remains unsatisfying. In this study, vascular endothelial growth factor (VEGF) gene therapy combined with a hyaluronic acid (HA)-enriched microenvironment in nerve regeneration was investigated. Sciatic nerve was transected, and end-to-end neurorrhaphy was performed on 32 male Sprague-Dawley rats, which were randomly divided into four groups (n = 8 per group): nerve coaptation without treatment (group I); nerve coaptation covered with HA film sheath (group II); nerve coaptation with intramuscular VEGF gene in plasmid injection (group III); and nerve coaptation combined with HA film sheath and intramuscular VEGF gene in plasmid injection (group IV). Contralateral sciatic nerves were used as control. VEGF expression was verified from gluteal muscle biopsies surrounding the sciatic nerve by reverse transcriptase-PCR. Electrophysiological, histopathological, and electron microscopic evaluations were performed after 4 weeks. Mean peak amplitude of groups I–IV and nonoperated sciatic nerve were 4.5 ± 0.6 mV, 6.4 ± 0.4 mV, 6.7 ± 0.5 mV, 8.5 ± 0.4 mV, and 9.8 ± 0.5 mV, respectively. Mean myelinated axonal counts of groups I–IV and nonoperated sciatic nerve were 105 ± 24, 165 ± 19, 181 ± 22, 271 ± 23, and 344 ± 17, respectively. Treatment with HA film sheath coverage combined with intramuscular VEGF gene in plasmid injection yielded statistically significant higher peak amplitudes and myelinated axonal counts (P < 0.001). In addition, significantly less scar formation with HA administration (groups II and IV; P < 0.001) was found. Thus, it was found that VEGF might crucially regulate nerve regeneration processes and that HA can reduce the scar formation. This study showed that the combination of HA film sheath and VEGF gene may synergistically promote peripheral nerve regeneration. © 2013 Wiley Periodicals, Inc. Microsurgery 34:209–216, 2014.

Reconstructive transplantation with vascularized composite allografts is an emerging frontier, with more than 200 procedures performed worldwide over the past decade. Lower extremity transplantation may be a superior treatment alternative in stringently selected patients who have failed, rejected, or are ineligible to use conventional prosthetics. Despite its potential for sensorimotor nerve regeneration, proprioception, and reflex feedback control of balance and independent ambulation, early outcomes of lower extremity transplantation have been disappointing due to morbidity or mortality. Broader feasibility of this promising procedure will be realized only if perioperative and immunosuppressive complications are minimized and long-distance neurodegeneration is optimized.

Introduction Creating vascularized nerve conduits for treatment of nerve gaps have been researched, however, these methods need microsurgical anastomosis thereby complicating the nerve repair process. Thus, the concept of vascularized nerve conduits has not popularized up till now. The aim of this study is to evaluate the effects of vascularized and non-vascularized biological conduits on peripheral nerve regeneration. Material and methods Following ethical board approval, 15 Sprague-Dawley rats were used in the study. The rats were equally divided into three groups. In group I, a silicon rod was inserted next to the sciatic nerve of the rat and connective tissue generated around this rod was used as a vascularized biological conduit. In group II, a silicon rod was inserted into the dorsum of the rat and connective tissue generated around this rod was used as a non-vascularized biological conduit. In group III, autogenic nerve graft was used to repair the nerve gap. The contralateral sciatic nerve is used as a control in all rats. Macroscopic, electrophysiological and histomorphometric evaluations were performed to determine the nerve regeneration. Results There was no statistically significant difference between groups, in terms of latency. However, the mean amplitude of group I was found to be higher than other groups. The difference between group I and II was statistically significant. Myelinated axonal counts in group I was significantly higher than groups II and III. Conclusion Our results showed that vascularized biological conduits provided better nerve regeneration when compared to autografts and non-vascularized biological conduits. Creation and application of vascularized conduits by using the technique described here is easy. Although this method is not an alternative to autogenic nerve grafts, our results are promising and encouraging for further studies.

Facial nerve is the main cranial nerve for the innervation of facial expression muscles. Main trunk of facial nerve passes approximately 1 to 2 cm deep to tragal pointer. In some patients, where a patient has multiple operations, fibrosis due to previous operations may change the natural anatomy and direction of the branches of facial nerve. A 22-year-old male patient had 2 operations for mandibular reconstruction after gunshot wound. During the second operation, there was a possible injury to the marginal mandibular nerve and a nerve stimulator was used intraoperatively to monitor the nerve at the tragal pointer because the excitability of the distal segments remains intact for 24 to 48 hours after nerve injuries. Thus, using a nerve stimulator at the operational site may lead to false-positive muscle movements in case of injuries. Using the nerve stimulator to stimulate the main trunk at the tragal point may help to distinguish the presence of possible injuries. A reliable method for intraoperative facial nerve monitoring in a scarred operational site was introduced in this letter.

Recognition that a fetus can scarlessly heal in intrauterine life led to various animal studies in the mid 1980s exploring the possibility of fetal cleft lip/palate surgery. The idea of scarless cleft repair seemed like a possible dream after the promising results from the early animal studies. In this review, we analyze the progress made in the 30 years since our first experience with animal models.

Cellular and vascularized bone marrow cells have been used to induce donor-specific chimerism in various models of composite tissue allotransplantation. Although thymus transplantation has been reported in the literature, the effect of thymus transplantation on chimerism levels in vascularized bone containing composite tissue allotransplantation has not been reported. In this study, a new method for composite vascularized sternal bone marrow transplant model is descried that can be applied to augment chimerism after transplantation. A total of seven composite osseomusculocutaneous sternum, ribs, thymus, pectoralis muscles, and skin transplantations were performed in two groups. The first group (n = 5) was designed as an allotransplantation group and the second group (n = 2) was designed as an isotransplantation group. Composite osseomusculocutaneous sternum, ribs, thymus, and pectoralis muscles allografts were harvested on the common carotid artery and external jugular vein and a heterotopic transplantation was performed to the inguinal region of the recipient rat. Cyclosporine A monotherapy was administered in order to prevent acute and chronic allograft rejection. Animals sacrificed when any sign of rejection occurred. The longest survival was 156 day post-transplant. Assessment of bone marrow cells within sternum bone component and flow cytometry analysis of donor-specific chimerism in the peripheral blood of recipients were evaluated. Our results showed that this composite allograft carried 7.5 × 10(6) of viable hematopoietic cells within the sternum component. At day 7 post-transplant chimerism was developed in T-cell population and mean level was assessed at 2.65% for RT1(n) /CD4 and at 1.0% for RT1(n) /CD8. In this study, a new osseomusculocutaneous sternum, ribs, thymus, pectoralis muscle, and skin allotransplantation model is reported which can be used to augment hematopoietic activity for chimerism induction after transplantation.

Background: Corrugator resection is an integral part of periorbital rejuvenation and can be accomplished through the open coronal, endoscopic, or transpalpebral technique. While most authors concur about the importance of corrugator resection during brow lift surgery, considerable debate remains regarding the efficacy and technical ease of muscle resection with these approaches. Objectives: The authors conducted a cadaver study to compare the completeness of resection of the corrugator muscle with the transpalpebral and endoscopic techniques. Methods: A split-face study was performed in 10 fresh cadavers. On one side, the corrugator muscle was resected through an endoscopic approach, and on the opposite side of the face, a transpalpebral resection was performed. After the completion of both procedures, a coronal incision was made; gross observations were noted; photographs were taken; and muscle weights were recorded. Results: In 19 of 20 cadaver halves, subtotal or total resection of the corrugator muscle was accomplished. In only one endoscopic instance was any muscle left in continuity. This occurred along the superior aspect of the arcus marginalis release when the corrugator muscle was hidden by the upper edge of the cut periosteum. Conclusions: Unlike the previous reports, the authors found that transpalpebral and endoscopic techniques both allow subtotal or total resection of the corrugator muscle. Inadequate resection is technique dependent rather than procedure dependent.

Background The mini- and micro-grafting method is still one of the most current treatment methods for male pattern baldness and female androgenic alopecia. The preparation of the recipient area with 16G needle has been reported in the literature. However, during the insertion of grafts, the neighboring grafts tend to `pop out'. The study presents our experience in the hair implantation for recipient site preparation with 16G epidural needle. Methods The 16G epidural needle was used during preparation of the recipient field in eight patients. Approximately 500 micrografts were grafted in each patient to reconstruct the anterior hairline. Results During insertion of the micrografts, almost none of the previously inserted grafts tended to `pop out'. The anterior hairline of the patients was natural without obvious scarring. The mean follow-up period of these patients was 1.5 years. The amount of graft survival was found to be satisfactory. Conclusion According to the surgeon’s clinical observations, application of this technique was found to be easier than standard needle techniques. It can be used by inexperienced surgeons. Use of epidural needle for recipient hole preparation works well in reducing the popping out, and the curved fashion of the holes reduced the angle of the hair follicle.

Background. Numerous experiments in composite tissue allotransplantation (CTA) have identified skin as the most antigenic, with recent experimentation from our laboratory finding a direct correlation between large antigenic skin loads and chimerism. Therefore, in preparation for clinical application of concomitant upper extremity (UExt) and face transplantation, we aimed to identify the exact skin quantities accompanying various upper UExt and concomitant scenarios using a cadaver study. Methods. Five fresh cadavers were obtained and dissections were performed to simulate five different UExt transplant levels. Exact skin quantities (cm 2 ) and total body surface area (TBSA) percentages were calculated using digital image analysis for both unilateral and bilateral hand transplant levels. UExt measurements were then cross-analyzed with our laboratory's facial/scalp alloflap data for similar evaluation of various concomitant CTA scenarios. Results. Skin quantities for unilateral hand transplants ranged from 335 ( ± 58) to 787 (±82) cm 2 , and from 670 (± 117) to 1575 (±163) cm 2 for bilateral. Concomitant CTA quantities (from "unilateral wrist-level with face" to "bilateral elbow-level with face/scalp") extended from 1010 (±81) to 2766 (±202) cm 2 , totaling a range of 5.6% to 15.4% TBSA. Conclusion. The findings presented here, for the first time, define exact skin quantities and TBSA percentages accompanying unilateral, bilateral, and concomitant hand/face transplant scenarios. Unilateral UExt transplants contain between 335 and 787 cm 2 and bilateral between 670 and 1575 cm 2 . Concomitant face/scalp and UExt transplants contain between 1000 and 2800 cm 2 , equating 5% to 15% TBSA. Furthermore, there exists a tremendous void in research and some inconsistencies between animal investigation and clinical experience related to large skin-bearing CTAs. These concerns warrant further investigation by all teams pursuing concomitant CTA.

Coal stoves that are used for heating purposes are more popular in economically developing and undeveloped countries because of their lower operational costs. Unfortunately, they may cause serious burn injuries when flammable liquids are misused to kindle or to accelerate a fire within them. Every year, particularly in the winter, many citizens in Turkey have suffered burn injuries caused by this dangerous practice. During the period from January 1989 to January 2009, 82 patients sustained burn injuries as a consequence of coal stove fires and were admitted to burn units. Efforts to inform the public about the danger of using flammable liquids with these kinds of stoves are recommended to minimize the incidence, morbidity, mortality, and cost of this relatively common and preventable type of injury.

From its origination involving successful rat hind-limb allograft studies using cyclosporine, face and upper extremity composite tissue allotransplantation has since developed into an exciting and promising subset of reconstructive transplant surgery. Current surgical technique involving composite tissue allotransplantation has allowed optimal outcomes in patients with massive facial and/or upper extremity defects; however, with its coexisting immunologic barrier, obligatory lifelong immunosuppression commits each patient to a daily risk of transplant-related complications with many unanswered questions. Since 1998, nearly 50 hand transplantations in 40 patients have been performed around the world at various levels ranging from wrist level to shoulder level. However, the risk-to-benefit ratio remains controversial in bilateral versus unilateral transplantation and has yet to be determined. From recent experience, the two most important determinants of the success of each patient's upper extremity transplant are patient compliance and intense rehabilitation. A total of nine face transplants have been performed since 2005. Multiple aesthetic subunits (i.e., nose, lips, eyelids) with or without underlying craniofacial skeletal defects (i.e., maxilla, mandible) have been successfully restored, thereby providing restoration of vital facial functions (i.e., smiling) in an unprecedented manner. As of today, face transplantation carries an estimated 2-year mortality of 20 percent. Concomitant composite tissue allotransplantation, which involves a variable combination of allograft subtypes, has been performed in two of the nine face transplant patients. These have included simultaneous bilateral hand transplants and tongue with mandible. Future study is warranted to investigate the potential advantages and disadvantages of using this approach versus a staged approach for reconstruction.

Pain management during burn dressing changes is a critical part of treatment in acute burn injuries. Although several treatment options have been suggested, it is still a challenge in a clinical setting. This study is aimed at finding out an ideal analgesic, sedative and/or anxiolytic combination that would minimise the unwanted effects of ketamine. A total of 24 patients, with burns up to 20-50% of total body surface area (TBSA), were included in the study and randomly divided into three groups. In group I, 2 mg kg(-1) ketamine was administered. In group II, 1 mg kg(-1) tramadol was administered and 30 min later, 1 microg kg(-1) dexmedetomidine and 2 mg kg(-1) ketamine was administered. In group III, 1 mg kg(-1) tramadol was applied and 30 min later, 0.05 mg kg(-1) midazolam and 2 mg kg(-1) ketamine was administered. The evaluation was performed with cardiopulmonary monitoring, sedation and visual analogue pain scores and overall patient satisfaction. Any adverse effects of ketamine were recorded. The results showed that group II had better outcomes with respect to pain management during dressing changes. As a conclusion, the use of the combination of ketamine, tramadol and dexmedetomidine was found to be a good treatment option for the prevention of the procedural pain suffered by adult patients during dressing changes.