Novel cell-based strategies for immunomodulation in vascularized composite allotransplantation.

PURPOSE OF REVIEW: Vascularized composite allotransplantation (VCA) has become a clinical reality in the past two decades. However, its routine clinical applications are limited by the risk of acute rejection, and the side effects of the lifelong immunosuppression. Therefore, there is a need for new protocols to induce tolerance and extend VCA survival. Cell- based therapies have emerged as an attractive strategy for tolerance induction in VCA. This manuscript reviews the current strategies and applications of cell-based therapies for tolerance induction in VCA. RECENT FINDINGS: Cellular therapies, including the application of bone marrow cells (BMC), mesenchymal stem cells (MSC), adipose stem cells, regulatory T cells (Treg) cells, dendritic cells and donor recipient chimeric cells (DRCC) show promising potential as a strategy to induce tolerance in VCA. Ongoing basic science research aims to provide insights into the mechanisms of action, homing, functional specialization and standardization of these cellular therapies. Additionally, translational preclinical and clinical studies are underway, showing encouraging outcomes. SUMMARY: Cellular therapies hold great potential and are supported by preclinical studies and clinical trials demonstrating safety and efficacy. However, further research is needed to develop novel cell-based immunosuppressive protocol for VCA.

Functional Reconstruction of Arches of the Foot With Vascularized Fibula Flap.

ABSTRACT: The skeletal integrity of the foot is as important as the soft tissue coverage of the foot. In this article, we present reconstruction of arches of foot with free fibula flap. Three patients with composite foot defects underwent reconstruction a with vascularized fibula flap. Free fibula flap was used to reconstruct the transverse arch in 2 cases and longitudinal arch in 1 case. The mean follow-up period was 3.2 years. Functional outcome was evaluated with 3-dimensional motion analyses at 12 months postoperatively. No early or late complications were encountered, and all patients were satisfied with both cosmetic appearance and functional aspects of their foot. Fibular bone showed a very healthy course without any fracture, resorption, extrusion, or migration. Three-dimensional motion analyses revealed acceptable gait capability in all cases showing successful restoration of the foot arches. As a conclusion, osteocutaneous free fibula flap can provide functional and durable reconstruction of longitudinal and transverse arches of the foot, especially if preservation of the length or the width of the foot is desired.

Sex Differences Revealed in a Mouse CFA Inflammation Model with Macrophage Targeted Nanotheranostics.

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.

Adipogenesis for soft tissue reconstruction.

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.

Demonstration of technical feasibility and viability of whole eye transplantation in a rodent model.

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 ±â€¯5.8 min. Average ischemia time was 26.0 ±â€¯4.2 min. MRI revealed loss of globe volume by 36.0 ±â€¯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.

Late Correction of Traumatic Nasal Deformities: A Surgical Algorithm and Experience in 120 Patients.

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.

A New Composite Eyeball-Periorbital Transplantation Model in Humans: An Anatomical Study in Preparation for Eyeball Transplantation.

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.

The neurochemistry of peripheral nerve regeneration.

Peripheral nerve injuries (PNIs) can be most disabling, resulting in the loss of sensitivity, motor function and autonomic control in the involved anatomical segment. Although injured peripheral nerves are capable of regeneration, sub-optimal recovery of function is seen even with the best reconstruction. Distal axonal degeneration is an unavoidable consequence of PNI. There are currently few strategies aimed to maintain the distal pathway and/or target fidelity during regeneration across the zone of injury. The current state of the art approaches have been focussed on the site of nerve injury and not on their distal muscular targets or representative proximal cell bodies or central cortical regions. This is a comprehensive literature review of the neurochemistry of peripheral nerve regeneration and a state of the art analysis of experimental compounds (inorganic and organic agents) with demonstrated neurotherapeutic efficacy in improving cell body and neuron survival, reducing scar formation and maximising overall nerve regeneration.

The effect of in vivo created vascularized neurotube on peripheric nerve regeneration.

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.

Pre-expanded Thoracodorsal Artery Perforator Flap.

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.

Useful Method for Intraoperative Monitoring of Facial Nerve in a Scarred Bed.

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.

Fetal Cleft Lip/Palate Surgery: End of a Dream?

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.

Hemangioma of the Zygomatic Bone.

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.

Reflectance confocal microscopy as a useful diagnostic tool for monitoring of skin containing vascularized composite allograft rejection: A preliminary study on rats.

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.

Challenging Breast Augmentations: The Influence of Preoperative Anatomical Features on the Final Result.

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.

The Future of Plastic Surgery: Surgeon's Perspective.

Since the days of Sushruta, innovation has shaped the history of plastic surgery. Plastic surgeons have always been known as innovators or close followers of innovations. With this descriptive international survey study, the authors aimed to evaluate the future of plastic surgeons by analyzing how plastic surgery and plastic surgeons will be affected by new trends in medicine. Aesthetic surgery is the main subclass of plastic surgery thought to be the one that will change the most in the future. Stem cell therapy is considered by plastic surgeons to be the most likely "game changer." Along with changes in surgery, plastic surgeons also expect changes in plastic surgery education. The most approved assumption for the future of plastic surgery is, "The number of cosmetic nonsurgical procedures will increase in the future." If surgeons want to have better outcomes in their practice, they must at least be open minded for innovations if they do not become innovators themselves. Besides the individual effort of each surgeon, international and local plastic surgery associations should develop new strategies to adopt these innovations in surgical practice and education.

Late oropharyngeal functional outcomes of suicidal maxillofacial gunshot wounds.

PURPOSE: The aim of this study was to evaluate the long-term aesthetic and functional results of suicidal gunshot injuries using objective methods to identify the residual problems after one-stage reconstruction. METHODS: Twenty male patients with gunshot injuries resulting from suicide attempts who were treated in the Department of Plastic and Reconstructive Surgery at Gulhane Military Medical Academy were included in the study. The control group was composed of 10 male volunteers. The reconstructions of all involved structures were performed within 1-3 days of the injury. The patients were evaluated both aesthetically and functionally. The Body Satisfaction Scale was used for evaluation of aesthetic appearances of the facial structures. To evaluate swallowing, videofluoroscopy, cine-magnetic resonance imaging, submental electromyography, Functional Endoscopic Evaluation of Swallowing, and submental ultrasound were performed. Perceptual speech analysis was used for speech evaluation. RESULTS: The Body Satisfaction Scale score was statistically higher in the control group than in patients with both ongoing and completed reconstructions (P < 0.05). Swallowing disturbances and their frequencies were higher in the study group than in the control group. The most frequently observed swallowing disturbance was stasis in the sinuses. The laryngeal elevation and geometric angle of the epiglottis in the study group were statistically lower than in the control group (P < 0.05). The mean amplitude of contraction of submental muscles was lower in the study group than in the control group (P < 0.05). The Multidimensional Voice Program showed statistically significant differences between the treatment and control groups (P < 0.01). CONCLUSION: Objective assessment methods enabled us to retrospectively evaluate the treatment and identify the specific problem underlying functional and aesthetic morbidities.

Palmar contracture release with arterialized venous instep flap: An anatomical and clinical study.

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.

Evaluation of the results of simultaneous open rhinoplasty and Abbe flap for the reconstruction of the secondary bilateral cleft and nasal deformity.

AIMS: We aimed to evaluate the results of simultaneous rhinoplasty and Abbe flap for the reconstruction of the secondary bilateral cleft and nasal deformity by means of a newly developed software-based method. PATIENTS AND METHODS: A total of 16 patients with the bilateral cleft lip nasal deformity received Abbe flap and simultaneous open rhinoplasty between 2004 and 2010. The mean age of the patients was 21 years, and the average follow-up time was 2.4 years. After the open rhinoplasty procedure, the upper lip was reconstructed with the Abbe flap. Preoperative and postoperative photographs that had been taken laterally were evaluated by using Adobe Photoshop(®) CS4 and Adobe InDesign(®) software. The length of the columella and the relative changes of the most anterior point of the upper lip to the vertical plane tangent to the most anterior point of the lower lip were measured in pixels on standardized preoperative and postoperative images. The differences were calculated and compared as a percentage (%). RESULTS: There was no flap loss and associated problems. The measurements of columellar length revealed an average increase of 51.8 ± 11.3%, while the relative change of the most anterior point of the upper lip revealed an average increase of 68.6 ± 11.2%. CONCLUSION: The results of the treatment modality were successfully evaluated by a newly developed software-based method.