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Objective: Single-stage laryngotracheal reconstruction (SSLTR) provides a definite surgical treatment for patients with complex glotto-subglottic stenosis. To date, the influence of SSLTR on the functional outcome after surgery has not been analyzed., Methods: A retrospective analysis of all patients receiving a SSLTR between November 2012 and October 2019 was performed. Preoperatively and 3 months postoperatively, patients received a full functional evaluation, including spirometry; voice measurements (eg, fundamental frequency; dynamic range, singing voice range, and perceptual voice evaluation using the Roughness-Breathiness-Hoarseness [RBH] score, and fiberoptic endoscopic evaluation of swallowing [FEES])., Results: A total of 15 patients with a mean age of 45 ± 17 years underwent SSTLR. Two (13%) patients were men and 13 (87%) were women. The majority of patients (67%) had undergone previous surgical or endoscopic treatment attempts that had failed. At the 3-month follow-up visit, none of the patients had signs of penetration or aspiration in their swallowing examination. Voice measurements revealed a significantly lower fundamental voice frequency (201.0 Hz vs 155.5 Hz; P = .006), whereas voice range (19.1 semitones vs 14.9 semitones; P = .200) and dynamic range (52.5 dB vs 53.0 dB; P = .777) was hardly affected. The median RBH score changed from R1 B0 H1 to R2 B1 H2. In spirometry, breathing capacity increased significantly (peak expiratory flow, 44% vs 87% [P < .001] and mean expiratory flow at 75% of vital capacity, 48% vs 90% [P < .001]). During a median follow-up of 32.5 months (range, 7-88 months), none of the patients developed re-stenosis., Conclusions: For complex glotto-subglottic stenoses, durable long-term airway patency together with reasonable voice quality and normal deglutition can be achieved by SSLTR., (Copyright © 2020. Published by Elsevier Inc.)

Osteochondral (OC) defects are debilitating joint injuries characterized by the loss of full thickness articular cartilage along with the underlying calcified cartilage through to the subchondral bone. While current surgical treatments can provide some relief from pain, none can fully repair all the components of the OC unit and restore its native function. Engineering OC tissue is challenging due to the presence of the three distinct tissue regions. Recent advances in additive manufacturing provide unprecedented control over the internal microstructure of bioscaffolds, the patterning of growth factors and the encapsulation of potentially regenerative cells. These developments are ushering in a new paradigm of 'multiphasic' scaffold designs in which the optimal micro-environment for each tissue region is individually crafted. Although the adoption of these techniques provides new opportunities in OC research, it also introduces challenges, such as creating tissue interfaces, integrating multiple fabrication techniques and co-culturing different cells within the same construct. This review captures the considerations and capabilities in developing 3D printed OC scaffolds, including materials, fabrication techniques, mechanical function, biological components and design.

Background: Flap-based limb salvage surgery balances the morbidity and complexity of soft tissue transfer against the potential benefit of preserving a functional limb when faced with a traumatized extremity with composite tissue injury. These composite tissue injuries are well suited for multidisciplinary management between orthopaedic and plastic surgeons. Thus, it makes intuitive sense that a collaborative, orthoplastic approach to flap-based limb salvage surgery can result in improved outcomes with decreased risk of flap failure and other complications, raising the question of whether this orthoplastic team approach should be the new standard of care in limb salvage surgery., Questions/purposes: (1) Is there an association between increased annual institutional volume and perioperative complications to include free and local flap failure (substantial flap viability loss necessitating return to the operating room for debridement of a major portion or all of the flap or amputation)? (2) Is an integrated orthoplastic collaborative approach to managing combat-related traumatic injuries of the extremities individually associated with a decreased risk of flap failure and overall flap-related complications? (3) What other factors, such as location of injury, injury severity score, and initial inpatient length of stay, were associated with flap necrosis and flap-related complications?, Methods: We performed a retrospective review of the electronic medical records of all patients who underwent flap-based limb salvage for combat-related extremity trauma in the United States Military Health System's National Capital Region between January 1, 2003 and December 31, 2012. In total, 307 patients underwent 330 flap procedures. Of the 330 flaps, 59% (195) were local or pedicled flaps and 41% (135) were free flaps. Patients were primarily male (99% [303]), with a median (interquartile range) age of 24 years old (IQR 21 to 29), and 87% (267 of 307) of injuries were sustained from a blast mechanism. We collected data on patient demographics, annual case volume involving flap coverage of extremities, mechanism of injury, flap characteristics, perioperative complications, flap failure, flap revision, isolated orthopaedic management versus an integrated orthoplastic approach, and other salvage procedures. For the purposes of this study, orthoplastic management refers to operative management of flap coverage with microvascular surgeons present for soft tissue transfer after initial debridement and fixation by orthopaedic surgery. The orthoplastic management was implemented on a case-by-case basis based on individual injury characteristics and the surgeon's discretion with no formal starting point. When implemented, the orthoplastic team consisted of an orthopaedic surgeon and microvascular-trained hand surgeons and/or plastic surgeons. In all, 77% (254 of 330) of flaps were performed using this model. We considered perioperative flap complications as any complication (such as infection, hematoma, dehiscence, congestion, or necrosis) resulting in return to the operating room for re-evaluation, correction, or partial debridement of the flap. We defined flap failure as a return to the operating room for debridement of a major portion of the flap or amputation secondary to complete or near-complete loss of flap viability. Of the flap procedures, 12% (40 of 330) were classified as a failure and 14% (46 of 330) experienced complications necessitating return to the operating room. Over the study period, free flaps were not more likely to fail than pedicled flaps (11% versus 13%; p = 0.52) or have complications necessitating additional procedures (14% versus 16%; p = 0.65)., Results: Our multiple linear regression model demonstrated that an increased number of free flaps performed in our institution annually in any given year was associated with a lower likelihood of failure per case (r = -0.17; p = 0.03) and lower likelihood of reoperation for each flap (r = -0.34; p < 0.001), after adjusting for injury severity and team type (orthoplastic or orthopaedic only). We observed a similar relationship for pedicled flaps, with increased annual case volume associated with a decreased risk of flap failure and reoperation per case after adjusting for injury severity and team type (r = -0.21; p = 0.003 and r = -0.22; p < 0.001, respectively). Employment of a collaborative orthoplastic team approach was associated with decreased flap failures (odds ratio 0.4 [95% confidence interval 0.2 to 0.9]; p = 0.02). Factors associated with flap failure included a lower extremity flap (OR 2.7 [95% CI 1.3 to 6.2]; p = 0.01) and use of muscle flaps (OR 2.3 [95% CI 1.1 to 5.3]; p = 0.02)., Conclusion: Although prior reports of combat-related extremity trauma have described greater salvage success with the use of pedicled flaps, these reports are biased by institutional inexperience with free tissue transfer, the lack of a coordinated multiservice effort, and severity of injury bias (the most severe injuries often result in free tissue transfer). Our institutional experience, alongside a growing body of literature regarding complex extremity trauma in the civilian setting, suggest a benefit to free tissue coverage to treat complex extremity trauma with adequate practice volume and collaboration. We demonstrated that flap failure and flap-related complications are inversely associated with institutional experience regardless of flap type. Additionally, a collaborative orthoplastic approach was associated with decreased flap failures. However, these results must be interpreted with consideration for potential confounding between the increased case volume coinciding with more frequent collaboration between orthopaedic and plastic surgeons. Given these findings, consideration of an orthoplastic approach at high-volume institutions to address soft tissue coverage in complex extremity trauma may lead to decreased flap failure rates., Level of Evidence: Level III, therapeutic study., Competing Interests: Each author certifies that there are no funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article related to the author or any immediate family members. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request., (Copyright © 2021 by the Association of Bone and Joint Surgeons.)

Introduction:  The aim of this study is to report our experience with modified staged buccal mucosa graft urethroplasty for the repair of proximal hypospadias in children and adolescents., Materials and Methods:  A total of 183 patients were treated at the Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College between 2010 and 2019. The patients were grouped according to age: (1) within 1.5-year-old group, (2) prepuberty group (Tanner stage 1), and (3) puberty group., Results:  In total, 153 patients were included in this study. Thirty-six patients had complications: seven after stage one; 29 after stage two; one patient had two complications. Maximum flow rates were 11.80 ± 1.46 mL/s in the 1.5-year-old group, 13.24 ± 2.61 mL/s in the prepuberty group, and 13.60 ± 2.20 mL/s in the puberty group ( p  = 0.199). Average flow rates were 6.86 ± 1.37, 7.94 ± 1.74, and 7.88 ± 1.22 mL/s, respectively ( p  = 0.203). The optimal hypospadias objective scoring evaluation score of 16 was seen in 117 patients (76%), the score of 15 in 23 patients (15%), 14 in 10 (7%), and 13 in 3 patients (2%). Patients with an uncomplicated treatment (no complication) had a higher clinical outcome than patients with a complication (15.8 ± 0.53 vs. 15.3 ± 0.97, with or without complication, p  = 0.000). Multivariable analyses showed that previous treatment was closely related to the complication rate ( p  = 0.016)., Conclusion:  The modified procedure allows for two-stage repair of proximal hypospadias with good results with a low complication rate and good functional results. Delaying operation did not increase complication rates in our research., Competing Interests: None declared., (Thieme. All rights reserved.)

It is difficult to regenerate mammalian retinal cells once the adult retina is damaged, and current clinical approaches to retinal damages are very limited. The introduction of the retinal organoid technique empowers researchers to study the molecular mechanisms controlling retinal development, explore the pathogenesis of retinal diseases, develop novel treatment options, and pursue cell/tissue transplantation under a certain genetic background. Here, we revisit the historical background of retinal organoid technology, categorize current methods of organoid induction, and outline the obstacles and potential solutions to next-generation retinal organoids. Meanwhile, we recapitulate recent research progress in cell/tissue transplantation to treat retinal diseases, and discuss the pros and cons of transplanting single-cell suspension versus retinal organoid sheet for cell therapies.

Prevascularized artificial three-dimensional (3D) tissues are effective biomaterials for regenerative medicine. We have previously established a scaffold-free 3D artificial vascular tissue from normal human dermal fibroblasts (NHDFs) and umbilical vein-derived endothelial cells (HUVECs) by layer-by-layer cell coating technique. In this study, we constructed an artificial vascular tissue constructed by human adipose tissue-derived stromal cells (hASCs) and HUVECs (ASCVT) by a modified technique with cryopreservation. ASCVT showed a higher thickness with more dense vascular networks than the 3D tissue based on NHDFs. Correspondingly, 3D-cultured ASCs showed higher expression of several angiogenesis-related factors, including vascular endothelial growth factor-A and hepatic growth factor, compared to that of NHDFs. Moreover, perivascular cells in ASCVT were detected by pericyte markers, suggesting the differentiation of hASCs into pericyte-like cells. Subcutaneous transplantation of ASCVTs to nude mice resulted in an engraftment with anastomosis of host's vascular structures at 2 weeks after operation. In the engrafted tissue, the vascular network was surrounded by mural-like structure-forming hASCs, in which some parts developed to form vein-like structures at 4 weeks, suggesting the generation of functional vessel networks. These results demonstrated that cryopreserved human cells, including hASCs, could be used directly to construct the artificial transplantable tissue for regenerative medicine., (© 2021. The Author(s).)

Nitric oxide synthase (NOS) is a critical enzyme that catalyzes nitric oxide biosynthesis and orchestrates various immunological responses mediated by nitric oxide (NO) in host animals. In this study, the NOS gene was identified in the triangle shell mussel (Hyriopsis cumingii) (HcNOS). HcNOS was highly conserved in the characteristic gene structures of NOS. Phylogenetic analysis suggested that HcNOS was a typical invertebrate NOS. Further gene expression analysis, NOS activity assays and nitric oxide content measurements demonstrated the inducibility of HcNOS in responses to lipopolysaccharide (LPS) challenge and during tissue transplantation. Of note, mantle grafting induced a prolonged HcNOS/NO response, suggesting that through the HcNOS/NO system, multiple immunomodulators may play decisive roles in tissue grafting in triangle shell mussels. Thus, HcNOS appears to be a crucial player in responding to both bacterial infection and tissue transplantation., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

(1) Background: The aim of the present study was the biocompatibility analysis of a novel xenogeneic vascular graft material (PAP) based on native collagen won from porcine aorta using the subcutaneous implantation model up to 120 days post implantationem. As a control, an already commercially available collagen-based vessel graft (XenoSure ® ) based on bovine pericardium was used. Another focus was to analyze the (ultra-) structure and the purification effort. (2) Methods: Established methodologies such as the histological material analysis and the conduct of the subcutaneous implantation model in Wistar rats were applied. Moreover, established methods combining histological, immunohistochemical, and histomorphometrical procedures were applied to analyze the tissue reactions to the vessel graft materials, including the induction of pro- and anti-inflammatory macrophages to test the immune response. (3) Results: The results showed that the PAP implants induced a special cellular infiltration and host tissue integration based on its three different parts based on the different layers of the donor tissue. Thereby, these material parts induced a vascularization pattern that branches to all parts of the graft and altogether a balanced immune tissue reaction in contrast to the control material. (4) Conclusions: PAP implants seemed to be advantageous in many aspects: (i) cellular infiltration and host tissue integration, (ii) vascularization pattern that branches to all parts of the graft, and (iii) balanced immune tissue reaction that can result in less scar tissue and enhanced integrative healing patterns. Moreover, the unique trans-implant vascularization can provide unprecedented anti-infection properties that can avoid material-related bacterial infections.

Cleft lip and palate (CL/P) is the most prevalent craniofacial birth defect in humans. None of the surgical procedures currently used for CL/P repair lead to definitive correction of hard palate bone interruption. Advances in tissue engineering and regenerative medicine aim to develop new strategies to restore palatal bone interruption by using tissue or organ-decellularized bioscaffolds seeded with host cells. Aim of this study was to set up a new natural scaffold deriving from a decellularized porcine mucoperiosteum, engineered by an innovative micro-perforation procedure based on Quantum Molecular Resonance (QMR) and then subjected to in vitro recellularization with human bone marrow-derived mesenchymal stem cells (hBM-MSCs). Our results demonstrated the efficiency of decellularization treatment gaining a natural, non-immunogenic scaffold with preserved collagen microenvironment that displays a favorable support to hMSC engraftment, spreading and differentiation. Ultrastructural analysis showed that the micro-perforation procedure preserved the collagen mesh, increasing the osteoinductive potential for mesenchymal precursor cells. In conclusion, we developed a novel tissue engineering protocol to obtain a non-immunogenic mucoperiosteal scaffold suitable for allogenic transplantation and CL/P repair. The innovative micro-perforation procedure improving hMSC osteogenic differentiation potentially impacts for enhanced palatal bone regeneration leading to future clinical applications in humans., (© 2021. The Author(s).)

Mutations in microglia may cause brain disorders. Replacement of dysfunctional microglia by allogeneic wild-type microglia from bone marrow transplantation (Mr BMT) or peripheral blood can correct the gene deficiency at the brain-wide scale but cannot achieve precise replacement at specific brain regions. Here, we introduce a strategy with potential clinical relevance-microglia replacement by microglia transplantation (Mr MT), combining tamoxifen-induced ablation of Mr BMT cells and intracranial injection of microglia to mouse brain, to achieve region-sepcific microglia replacement. The original abbreviation of this microglia replacement strategy is mrMT. We hereby change the name to Mr MT. For complete details on the use and execution of this protocol, please refer to Xu et al. (2020)., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

Invariant natural killer T (iNKT) cells are a conserved population of innate T lymphocytes that interact with key antigen-presenting cells to modulate adaptive T-cell responses in ways that can either promote protective immunity, or limit pathological immune activation. Understanding the immunological networks engaged by iNKT cells to mediate these opposing functions is a key pre-requisite to effectively using iNKT cells for therapeutic applications. Using a human umbilical cord blood xenotransplantation model, we show here that co-transplanted allogeneic CD4 + iNKT cells interact with monocytes and T cells in the graft to coordinate pro-hematopoietic and immunoregulatory pathways. The nexus of iNKT cells, monocytes, and cord blood T cells led to the release of cytokines (IL-3, GM-CSF) that enhance hematopoietic stem and progenitor cell activity, and concurrently induced PGE 2 -mediated suppression of T-cell inflammatory responses that limit hematopoietic stem and progenitor cell engraftment. This resulted in successful long-term hematopoietic engraftment without pretransplant conditioning, including multi-lineage human chimerism and colonization of the spleen by antibody-producing human B cells. These results highlight the potential for using iNKT cellular immunotherapy to improve rates of hematopoietic engraftment independently of pretransplant conditioning., (© 2021 Hess et al.)

Background: Incidental or intentional durotomy in spine surgery is associated with a risk of cerebrospinal fluid (CSF) leakage and reoperation. Several strategies have been introduced, but the incomplete closure is still relatively frequent and troublesome. In this study, we review current evidence on spinal dural repair strategies and evaluate their efficacy., Methods: PubMed, Web of Science, and Scopus were used to search primary studies about the repair of the spinal dura with different techniques. Of 265 articles found, 11 studies, which specified repair techniques and postoperative outcomes, were included for qualitative and quantitative analysis. The primary outcomes were CSF leakage and postoperative infection., Results: The outcomes of different dural repair techniques were available in 776 cases. Pooled analysis of 11 studies demonstrated that the most commonly used technique was a combination of primary closure, patch or graft, and sealant (22.7%, 176/776). A combination of primary closure and patch or graft resulted in the lowest rate of CSF leakage (5.5%, 7/128). In this study, sealants as an adjunct to primary closure (13.7%, 18/131) did not significantly reduce the rate of CSF leakage compared with primary closure alone (17.6%, 18/102). The rates of infection and postoperative neurologic deficit were similar regardless of the repair techniques., Conclusions: Although the use of sealants has become prevalent, available sealants as an adjunct to primary closure did not reduce the rate of CSF leakage compared with primary closure. The combination of primary closure and patches or grafts could be effective in decreasing postoperative CSF leakage., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Free nipple grafting indications in breast reduction surgery are outdated. Safety of inferior pedicle technique for large resections and long pedicles has not been clearly defined. We evaluated patients who underwent inferior pedicle reduction mammoplasty to define the safety constraints of the inferior pedicle., Methods: A retrospective review of patients who underwent inferior pedicle reduction mammoplasty due to symptomatic macromastia at Mayo Clinic over a six-year period was conducted. Patients with prior breast surgeries were excluded. Demographics, breast measurements, and surgical outcomes were collected. Univariate and multivariate analyses were performed to assess for predictors of necrosis., Results: Overall, 288 patients (576 breasts) underwent inferior pedicle breast reduction from 2014 to 2019. The mean sternal notch-to-nipple (SNN) distance was 31.5 cm (standard deviation[SD]:4.2; range[r]:16-48), and the mean nipple-to-inframammary fold (N-IMF) distance was 14.8 cm (SD:4.0; r:7.5-27). The mean resection weight was 699.6 g (SD:310.4; r:125-2,385). The median follow-up was 3.9 months (interquartile range[IQR]:2.8-9.0). The overall skin or nipple areolar complex necrosis rate was 2.1%; the overall complication rate was 14.8%. On multivariate analysis, overall necrosis was not found to be associated with the N-IMF distance (adjusted odds ratio[aOR]:1.05, 95%-CI 0.88-1.16). Resection weight was statistically associated with an increased risk of overall necrosis (aOR:1.003, 95%-CI 1.001-1.005), adjusting for N-IMF and SNN distances., Conclusion: Inferior pedicle breast reduction offers low risk of necrosis and can be safely performed in patients regardless of the N-IMF distance. No association was found between N-IMF distance and overall necrosis in our cohort, including lengths >15 cm. However, large resections could increase the risk of necrosis., Competing Interests: Declaration of Competing Interest All authors declare that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript., (Copyright © 2020 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

The inferior alveolar nerve (IAN) is a sensitive branch of the mandibular nerve innervating the lower lip, the chin, the buccal mucosa and the teeths. Lesions of the IAN are reported to occur in the 64,4% of maxillo-facial procedures, leading to anesthesia, hypoestesia and/or neurogenic discomfort. An extensive segment of the nerve can be moreover removed during mandibular resection for benign or malignant pathologies. Nervous grafts can be used in these cases to restore the nerve continuity. In order to optimize the procedure and to allow a concomitant mandibular osseous reconstruction, the Authors identified several standardized steps. The technique described allows to perform confortable and safe nervous anastomoses and to reduce the risk of damage and tension during the flap insetting phases., (Copyright © 2020. Published by Elsevier Ltd.)

Introduction: The gold standard reconstruction for facial reanimation is the functional muscle transfer. The reinnervation of a muscle is never complete, and clinical results are variable with 20% not achieving a satisfactory outcome. We hypothesise that this may be due to a mismatch between the characteristics of the donor nerve and transferred muscle., Method: 81 YFP-16 and 14 YFP-H mice were studied in three intervention groups over three time periods. Two parameters were investigated: the number and surface area of reinnervated neuromuscular junctions and regenerating axons. An assessment was made of motor unit proportions., Results: All cases of nerve repair and nerve graft, the neuromuscular junctions (NMJ) were completely reinnervated by regenerating axons. The number and calibre of the regenerating axons were significantly different from controls for both intervention groups. The motor units were smaller in both intervention groups., Discussion: Reinnervation occurs after nerve repair or graft; however, the arbour was reinnervated by large numbers of much smaller axons. These axons showed some evidence of remodelling in the repair group, but not in the graft group. Neither group achieved the parameters of the control group. There were persistent qualitative changes to the morphology of both axons and junctions. Imaging documented both synkinesis and alterations that resemble those seen in ageing., Conclusion: Overall, the efficacy of reinnervation is very high with all NMJ reoccupied by regenerating axons. The way small axons are remodelled is different in the nerve repairs compared with the nerve grafts., Competing Interests: Declaration of Competing Interest None declared., (Crown Copyright © 2020. Published by Elsevier Ltd. All rights reserved.)

Background: The treatment of defects on the volar surface of the finger has been scarcely reported, and its utility for digital resurfacing remains unclear. This study compared the outcomes of free medial plantar artery flap (MPAF) and dorsal digital-metacarpal flap (DDMF) in finger reconstruction., Methods: This retrospective cohort study included 24 patients with soft-tissue defects on the volar surface of the finger from March 2014 to March 2017. The patients were divided into two groups: the MPAF group and the DDMF group. The operation time, complications, such as flap necrosis, graft loss, infection, paresthesia, and donor-site morbidity, as well as two-point discrimination (2-PD) were carefully recorded. The Michigan Hand Outcomes Questionnaire was used for conduct follow-up assessment., Results: After more than 12 months of follow-up, the MPAF group had a longer operative time compared with DDMF group, but there was no significant difference between postoperative complications and 2-PD test result in patients without nerve injury. And in terms of overall function, Modified VSS score and 2-PD test (the patients with nerve injury), There were relatively obvious statistical differences, MPAF was superior to DDMF (p < 0.005)., Conclusion: MPAF and DDMF are reliable for reconstruction of the volar surface of the finger; however, MPAF offers better functional outcomes and is associated with a lower incidence of postoperative complications.

Aim: To review current techniques used in fat grafting to optimise graft persistence and achieve optimal cosmetic outcomes., Background: Fat transplantation has been used extensively in the reconstruction and cosmetic industry for many years. However, there is significant adipocyte loss and reabsorption rates, leading to the loss of external cosmetic volume and the need for repeat procedures. Adipocyte loss can occur at all four stages of transplantation and this review discusses each of these methods with the aim being to optimise graft outcome., Results: Several new techniques have been discussed including liposuction techniques, fat processing, and assisted fat grafting which show an improvement in adipocyte survival, revasculisation and graft outcomes., Conclusion: There have been many improvements in fat grafting and the implementation of these will optimise surgical outcomes but there are still strategies to improve further. However, there is still a lack of standardised techniques and training. More research is needed in the areas of fat processing and the use of additives to the fat graft. More clinical research is needed in the fat placement technique, which has very little published evidence and current techniques are mostly anecdotal by cosmetic surgeons., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Due to the increasing number of studies performed in the field of regenerative medicine during the last two decades, more analytic studies are still needed to clarify the future prospect of this area of science. The main aim of this research was to review the clinical applications of human Amniotic membrane in the field of regenerative medicine critically. Furthermore, in the light of increasing numbers of available products derived from amniotic membrane, we aimed look in depth to see whether regenerative medicine research strategies have a place in the clinical setting. More specifically, in the present study, we attempted to provide insight on developing the new indication for more research and in the next step, for market leaders companies to expand cost-effectiveness of new derived AM products. 20 companies or distributers have offered some commercial products in this field. Survey on more than 90 clinical trials in last five years showed dermatology (and more specific wound healing), orthopedic, and ophthalmology are heavily biased toward multibillion dollar industry. Moreover, urology and dentistry with fewer numbers of clinical data in comparison with the above-mentioned areas, currently are in the path of translation (especially dentistry). In addition, otolaryngology and oncology with the lowest number showed more potential of research thorough understanding the properties that will help guiding the use of AM-derived products in these two areas in future. More than 50% of clinical studies were done or are developing in USA, which have the biggest share in market products. Subsequently, China, Egypt, India, Iran, and Germany with the ongoing clinical trials in different phases may have more approved products in near future., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

We report a technique to reconstruct cardiovascular tissue using multiscale scaffolds incorporating polycaprolactone fibers with double-layered hydrogels comprising fibrin hydrogel surrounded by secondary alginate hydrogel. The scaffolds compartmentalized cells into the core region of cardiac tissue and the peripheral region of blood vessels to construct cardiovascular tissue, which was accomplished by a triple culture system of adipose-derived mesenchymal stem cells (ADSCs) with C2C12 myoblasts on polycaprolactone (PCL) fibers along with human umbilical vein endothelial cells (HUVECs) in fibrin hydrogel. The secondary alginate hydrogel prevented encapsulated cells from migrating outside scaffold and maintained the scaffold structure without distortion after subcutaneous implantation. According to in vitro studies, resultant scaffolds promoted new blood vessel formation as well as cardiomyogenic phenotype expression of ADSCs. Cardiac muscle-specific genes were expressed from stem cells and peripheral blood vessels from HUVECs were also successfully developed in subcutaneously implanted cell-laden multiscale scaffolds. Furthermore, the encapsulated stem cells modulated the immune response of scaffolds by secreting anti-inflammatory cytokines for successful tissue construction. Our study reveals that multiscale scaffolds can be promising for the remodeling and transplantation of cardiovascular tissue.

Objective: The decision-making in neonatal brachial plexus palsy (NBPP) treatment continues to have many areas in need of clarification. Graft repair was the gold standard until the introduction of nerve transfer strategies. Currently, there is conflicting evidence regarding outcomes in patients with nerve grafts versus nerve transfers in relation to shoulder function. The objective of this study was to further define the outcomes for reconstruction strategies in NBPP with a specific focus on the shoulder., Methods: A cohort of patients with NBPP and surgical repairs from a single center were reviewed. Demographic and standard clinical data, including imaging and electrodiagnostics, were gathered from a clinical database. Clinical data from physical therapy evaluations, including active and passive range of motion, were examined. Statistical analysis was performed on the available data., Results: Forty-five patients met the inclusion criteria for this study, 19 with graft repair and 26 with nerve transfers. There were no significant differences in demographics between the two groups. Understandably, there were no patients in the nerve grafting group with preganglionic lesions, resulting in a difference in lesion type between the cohorts. There were no differences in preoperative shoulder function between the cohorts. Both groups reached statistically significant improvements in shoulder flexion and shoulder abduction. The nerve transfer group experienced a significant improvement in shoulder external rotation, from -78° to -28° (p = 0.0001), whereas a significant difference was not reached in the graft group. When compared between groups, there appeared to be a trend favoring nerve transfer in shoulder external rotation, with the graft patients improving by 17° and the transfer patients improving by 49° (p = 0.07)., Conclusions: In NBPP, patients with shoulder weakness experience statistically significant improvements in shoulder flexion and abduction after graft repair or nerve transfer, and patients with nerve transfers additionally experience significant improvement in external rotation. With regard to shoulder external rotation, there appear to be some data supporting the use of nerve transfers.

Transplantation of retinal pigment epithelial (RPE) sheets derived from human induced pluripotent cells (hiPSC) is a promising cell therapy for RPE degeneration, such as in age-related macular degeneration. Current RPE replacement therapies, however, face major challenges. They require a tedious manual process of selecting differentiated RPE from hiPSC-derived cells, and despite wide variation in quality of RPE sheets, there exists no efficient process for distinguishing functional RPE sheets from those unsuitable for transplantation. To overcome these issues, we developed methods for the generation of RPE sheets from hiPSC, and image-based evaluation. We found that stepwise treatment with six signaling pathway inhibitors along with nicotinamide increased RPE differentiation efficiency (RPE6iN), enabling the RPE sheet generation at high purity without manual selection. Machine learning models were developed based on cellular morphological features of F-actin-labeled RPE images for predicting transepithelial electrical resistance values, an indicator of RPE sheet function. Our model was effective at identifying low-quality RPE sheets for elimination, even when using label-free images. The RPE6iN-based RPE sheet generation combined with the non-destructive image-based prediction offers a comprehensive new solution for the large-scale production of pure RPE sheets with lot-to-lot variations and should facilitate the further development of RPE replacement therapies.

Control of patterning and the specification of body axes are fundamental aspects of animal development involving complex interactions between chemical, physical, and genetic signals. The freshwater polyp Hydra has long been recognized as a useful model system to address these questions due to its simple anatomy, optical transparency, and strong regenerative abilities, which enabled clever grafting experiments to alter and probe patterning. Reliable methods exist for the transplantation of small tissue pieces into the body column or the combination of sections cut perpendicular to the body axis, which can be used to examine oral-aboral gradients and axis induction potential of tissue fragments. However, existing methods do not allow researchers to probe questions of axis alignment and lateral information exchange. We therefore developed a technique to produce chimeric animals split longitudinally along the body axis of the animal by anesthetizing the animals with the terpene linalool and threading the donor pieces onto pairs of fine glass needles. Our novel approach can be applied to study questions in Hydra research that have thus far been inaccessible, including patterning processes acting perpendicular to the oral-aboral axis and the extent of lateral cell migration., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Wound complications after total ankle arthroplasty (TAA) are a common postoperative complication occurring in 14% to 66% of all surgeries. Soft tissue breakdown along the anterior incision can cause exposure of anterior tendons and implant, and adhesions of the extensor tendons of the foot. Recent publications have advocated for the implantation of dehydrated human amniotic membrane (DHAM) allograft during closure of anterior ankle incisions during TAA. The goal of this study was to determine whether implantation of DHAM allograft in TAAs decreased overall postoperative wound complications., Methods: One hundred seventy patients with end-stage ankle arthritis refractory to conservative management underwent TAA with a standard anterior approach by 1 of 3 board-certified foot and ankle orthopedic surgeons. Ninety-one patients underwent closure of the anterior incision with addition of DHAM, whereas 79 patients served as the control (no addition of DHAM). The primary endpoints considered were postoperative complications and reoperation. Included in the postoperative complications was return to the operating room, postoperative plastic surgery intervention, wound communication with the implant, removal of the implant, neurolysis, tendon debridement, and extensor hallucis longus contracture/adhesions., Results: In the analysis of our demographically homogenous cohorts, there was no statistically significant difference in any postoperative complications between patients closed with DHAM and controls. Return to the operating room occurred in 8.9% of controls and 15.4% of the DHAM group ( P = .291). Similarly, there was no statistically significant difference in postoperative plastic surgery, wound communication with the implant, implant removal, neurolysis, and tendon debridement between the control and DHAM groups., Conclusion: The application of DHAM theoretically acts to decrease overall wound complications in TAA. The use of DHAM preceding wound closure in TAA did not show a statistically significant reduction in overall wound complications in our retrospective analysis. Further study, including prospective randomized studies, is needed to further investigate the effectiveness of DHAM in reducing wound complications in TAAs., Level of Evidence: Level III, retrospective cohort study.

We aimed to compare the performance of acellular nerves prepared by different decellularization methods, screening out the optimal decellularization protocol, repairing the sciatic nerve defects in rats by the allogeneic transplantation, and evaluating the effect of regenerative nerve on the function reconstruction. The Sondell, SB-SDS, TnBP, and the high/low permeation methods were used to decellularize donor nerves. Nerves without any treatment were as the control group. The histological results were evaluated by HE staining and toluidine blue (TB) staining. The proliferation activity of L929 cells was detected by CCK-8 assay. The adhesion of Schwann cells was observed and quantified by SEM. Balb/c mice were used to evaluate the cellular and humoral immunogenicity of the nerve scaffolds. The rat sciatic nerve defect model was applied to observe the repair effect of acellular nerve scaffold in vivo. To SB-SDS group, it remained the original state of the nerves, with no observed nucleus and axons, the neurotoxicity grade detected by CCK-8 being almost 0, and it kept the largest number of Schwann cells adhered to the acellular nerve and the better morphology. Further, it showed that the selected SB-SDS rats acellular nerve scaffold could promote the nerve repair of the rats by HE staining and TB staining. We could conclude that the acellular nerve matrix prepared by the SB-SDS method effectively removes the cellular components in the nerve tissue and retains the main components of the extracellular matrix of the nerve tissue, whose rats decellularized nerve scaffold could promote the sciatic nerve repair better., (© 2019 Wiley Periodicals, Inc.)

Objective: This case report explores an effective treatment modality in a medically complicated patient, with considerable wound dehiscence refractory to treatment with negative pressure wound therapy (NPWT)., Case Report: A 35-year-old woman with a past medical history of hypothyroidism, osteoporosis, and rheumatoid arthritis treated with tumor necrosis factor (TNF) alpha inhibitors and disease-modifying antirheumatic drugs presented to the clinic following right great toe arthrodesis, metatarsal neck osteotomies, extensor tendon lengthening, and capsulotomy of the second, third, fourth, and fifth toes 2 weeks prior, with wound dehiscence of the right great toe and subsequent exposure of surgical hardware, complicated by infection. At the 2-week postop, a urinary bladder matrix was placed on the wound following failed NPWT, which was in place for 10 days. At the 3-month follow-up, the wound was closed and without any drainage. Patient reported a significant reduction in pain (visual analogue scale: 3) with adherence to weight-bearing restrictions., Conclusions: Wound healing was accomplished without removal of the exposed deep hardware in a patient with comorbidities and post-surgical wound dehiscence.

Background: Small cardiac tissue engineering constructs show promise for limiting post-infarct sequelae in animal models. This study sought to scale-up a 2-cm 2 preclinical construct into a human-size advanced therapy medicinal product (ATMP; PeriCord), and to test it in a first-in-human implantation., Methods: The PeriCord is a clinical-size (12-16 cm 2 ) decellularised pericardial matrix colonised with human viable Wharton's jelly-derived mesenchymal stromal cells (WJ-MSCs). WJ-MSCs expanded following good manufacturing practices (GMP) met safety and quality standards regarding the number of cumulative population doublings, genomic stability, and sterility. Human decellularised pericardial scaffolds were tested for DNA content, matrix stiffness, pore size, and absence of microbiological growth., Findings: PeriCord implantation was surgically performed on a large non-revascularisable scar in the inferior wall of a 63-year-old male patient. Coronary artery bypass grafting was concomitantly performed in the non-infarcted area. At implantation, the 16-cm 2 pericardial scaffold contained 12·5 × 10 6 viable WJ-MSCs (85·4% cell viability; <0·51 endotoxin units (EU)/mL). Intraoperative PeriCord delivery was expeditious, and secured with surgical glue. The post-operative course showed non-adverse reaction to the PeriCord, without requiring host immunosuppression. The three-month clinical follow-up was uneventful, and three-month cardiac magnetic resonance imaging showed ~9% reduction in scar mass in the treated area., Interpretation: This preliminary report describes the development of a scalable clinical-size allogeneic PeriCord cardiac bioimplant, and its first-in-human implantation., Funding: La Marató de TV3 Foundation, Government of Catalonia, Catalan Society of Cardiology, "La Caixa" Banking Foundation, Spanish Ministry of Science, Innovation and Universities, Institute of Health Carlos III, and the European Regional Development Fund., Competing Interests: Declarations of Competing Interest There are no conflicts of interest., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: This study aimed to compare two different tendon grafting techniques for coracoclavicular ligament reconstruction from the data obtained using finite element analysis., Methods: Three different finite element models of the shoulder girdle were formulated using computerized tomography images: the reference model, coracoid loop technique (CLT), and drilling technique (DT) model. In all these models, forces were applied to the clavicle along three axes (x, y, and z) of the trapezius and sternocleidomastoid muscles. Thereafter, data regarding the loading values of the tendon grafts, loads on the coracoid base, and coracoclavicular vertical distance were measured., Results: While the reference model yielded the lowest values for all the loading conditions as well as the shortest coracoclavicular distance, the DT model demonstrated the highest values for all the loading conditions and the largest coracoclavicular distance., Conclusion: Different tendon grafting techniques may offer different loading values on both bone surface and tendon graft during coracoclavicular ligament reconstruction. The drilling technique may be associated with increased loading on the tendon graft and bone surface, causing further loss of reduction and consequent complications.

Sterile and decellularized allograft tendons are viable biomaterials used in reconstructive surgeries for dense connective tissue injuries. Established allograft processing techniques including gamma irradiation and sodium dodecyl sulfate (SDS) can affect tissue integrity. Supercritical carbon dioxide (SCCO 2 ) represents a novel alternative that has the potential to decellularize and sterilize tendons with minimized exposure to denaturants, shortened treatment time, lack of toxic residues, and superior tissue penetration, and thus efficacy. This study attempted to develop a single-step hybrid decellularization and sterilization protocol for tendons that involved SCCO 2 treatment with various chemical additives. The processed tendons were evaluated with mechanical testing, histology, scanning electron microscopy (SEM), and Fourier-transform infrared (FTIR) spectroscopy. Uniaxial mechanical testing showed that tendons treated with SCCO 2 and additive NovaKill TM Gen2 and 0.1% SDS had significantly higher ( p < 0.05) ultimate tensile stress (UTS) and Young's modulus compared to gamma-irradiated and standard-SDS-treated tendons. This was corroborated by the ultrastructural intactness of SCCO 2 -treated tendons as examined by SEM and FTIR spectroscopy, which was not preserved in gamma-irradiated and standard SDS-treated tendons. However, complete decellularization was not achieved by the experimented SCCO 2 -SDS protocols used in this study. The present study therefore serves as a concrete starting point for development of an SCCO 2 -based combined sterilization and decellularization protocol for allograft tendons, where additive choice is to be optimized., Competing Interests: The authors declare no conflicts of interest.

Objective: Free flap reconstruction in elderly patients is one of the most challenging surgeries in the treatment of head and neck cancers. The aim of this study was to examine the oncological and functional outcomes of free flap reconstruction for elderly patients with head and neck cancer., Methods: We retrospectively reviewed elderly patients who underwent free flap reconstruction for the treatment of head and neck cancers. All patients were 80 years or older. Clinicopathologic features, surgical procedures, oncological and functional outcomes were obtained from medical records., Results: Free flap reconstructions were performed in 13 patients (3 female, 10 male). The mean age was 82.6 ± 3.4 years (range: 80-91). The mean follow-up period was 23.3 months (range 4-41 months). The mean disease-free survival was 49 ± 6 months (range 4-60 months). All patients had been alive more than one year after surgery. Reconstruction was performed using free jejunum in 10 patients and radial forearm flap in 3 patients. Graft necrosis occurred in 2 patients. Other two patients experienced major postoperative medical complications., Conclusion: Free flap reconstruction in well-selected older adults is safe and effective. Advanced age should not preclude consideration of free flap reconstruction in those patients., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Tissue transplantation is an important approach in developmental neurobiology to determine cell fate, to uncover inductive interactions required for tissue specification and patterning as well as to establish tissue competence and commitment. Combined with state-of-the-art molecular approaches, transplantation assays have been instrumental for the discovery of gene regulatory networks controlling cell fate choices and how such networks change over time. Avian species are among the favorite model systems for these approaches because of their accessibility and relatively large size. Here we describe two culture techniques used to generate quail-chick chimeras at different embryonic stages and methods to distinguish graft and donor tissue.

Background: Tendon injuries are common musculoskeletal injuries that heal with scar tissue formation, often achieving reduced biomechanical and functional properties. The murine patellar tendon is a research tool that holds potential for investigating tendon healing and can be useful for exploring therapeutic strategies. Since healing is a complex process that results from the collaboration between the systemic and local tissue environment, a murine tendon transplantation model that can be applied to transgenic mice and genetic mutants would allow isolation of systemic versus local tendon factors in driving effective tendon healing. Preliminary studies have shown that transplantation with simple tendon sutures results in a proximalization of the patellar bone due to the involuntary quadriceps muscle force leading to tearing of the graft and failure of the knee extensor mechanism. To avoid this elongation of the graft, two cerclage techniques for murine patellar tendon transplantation were introduced and validated., Methods: Three developed surgical techniques (no-cerclage-augmentation (NCA)), transfascial suture cerclage with encirclement of the patellar tendon (TFSC), and dual-cerclage-augmentation with a transosseous bone-to-bone cerclage through the patella bone and an additional musculotendinous cerclage (DCA)) were compared at 4 and 8 weeks macroscopically in regards to graft continuity, cerclage integrity, gap formation, and radiologically by measuring the patello-tibial distance and using a patella bone position grading system., Results: The NCA group showed complete failure at 5-7 days after surgery. The TFSC has led to 69% functional failure of the cerclage. In contrast, the DCA with a has led to 78% success with improvement in patellar bone position and a similar patello-tibial distance to the naïve contralateral murine knees over the time period of 8 weeks., Conclusions: This study shows that a bone-to-bone cerclage is necessary to maintain a desired graft length in murine patellar tendon models. This surgery technique can serve for future graft trans- and implantations in the murine patellar tendon.

The patient was a 40-year-old female who had been treated at our hospital for left peroneal tendonitis due to an ankle sprain 2 years earlier. She re-injured that ankle while dancing. The pain in the lateral left foot soon improved, but she had difficulty standing with the left foot in equinus. Complete peroneus longus and brevis tendon ruptures were diagnosed. The ipsilateral semitendinosus and gracilis tendons were harvested and used to reconstruct the tendons. Three months after surgery, the patient was able to stand in equinus, and at 5 months after surgery she resumed her original level of sports activities., Competing Interests: No potential conflict of interest relevant to this article was reported.

The skin is the first protective barrier of our body. Wound healing is therefore an essential mechanism. However, this phenomenon can be impaired when wounds are too large or chronic, for example, in diabetes. Interestingly, adult skin heals with scars, whereas foetuses present scarless regeneration. The objective of this review is to highlight the difference in healing pathways between foetal and adult skin and to present the recent therapeutic strategies envisaged using foetal properties in the clinic. The main features that distinguish foetal wound healing from adult wound healing are less tissue inflammation, faster reepithelialisation, and less contraction of the neodermis, allowing foetal tissues to regenerate. Recently, new therapies in regenerative medicine have been introduced using these foetal properties. For the first time, our team has developed CICAFAST, an innovative dressing composed of foetal keratinocytes and fibroblasts, which has been tested on a skin graft donor site in a clinical Phase 1/2 trial.

Objective: The purpose of this study was to investigate and summarize the characteristics of spontaneous cerebrospinal fluid rhinorrhea cases and the efficacy of transnasal endoscopic repair of spontaneous cerebrospinal fluid rhinorrhea with the assistance of computer-assisted navigation system., Methods: This is a retrospective study including 21 adult patients with spontaneous cerebrospinal fluid rhinorrhea who underwent transnasal endoscopic repair with the assistance of computer-assisted navigation system between January 2007 and December 2017. Data collected included patient demographics, body mass index, patient symptoms, biochemical findings, radiographic findings, location of defect, type and size of defect, type of repair, follow-up time, reoccurrence, and complications., Results: Spontaneous cerebrospinal fluid rhinorrhea was more commonly seen in females who were middle-aged and overweight in our series. The effluent was determined as cerebrospinal fluid by testing of glucose concentration and β 2 -transferrin. The location of the lesion was determined by rigid nasal endoscopy combined with radiologic study. Intraoperatively, the skull base defects were found most frequently on the ethmoid roof in 12 cases (57.1%), followed by the cribriform plate in seven cases (33.3%), and sphenoid sinus in two cases (9.5%). The size of the skull base defect was < 5 mm in 13 cases, 5 mm ~ 10 mm in six cases and two cases involved defects of ≥ 10 mm. The graft materials were chosen based on the size of the defect. In small leaks, the thigh muscle was dumbbell-shaped herniated into the bony defect, reinforced by fascia lata. Larger defects were packed with the anterior part of middle turbinate with an overlay of fascia lata. All 21 patients had no recurrence of cerebrospinal fluid rhinorrhea during the follow-up period, which ranged from 11 to 24 months., Conclusion: The transnasal endoscopic approach with assistance of computer-assisted navigation system is a safe and effective procedure for the repair of spontaneous cerebrospinal fluid rhinorrhea.

Purpose: The best surgical method for the management of adhesive otitis media is controversial. The aim of the study was to explore the feasibility and effectiveness of tympanoplasty combined with fascia grafting catheterization in the treatment of adhesive otitis media., Methods: This was a retrospective study of patients with adhesive otitis media and who underwent tympanoplasty combined with fascia grafting and catheterization between April 2015 and December 2016 at the Eye-Ear-Nose-Throat Hospital Affiliated to Fudan University. All injured ears were examined by pure tone audiometry at 0.5, 1 and 2 kHz before and at 3 months after operation., Results: Thirty-five patients (35 ears) were followed for 12-44 months. The air-conduction pure tone average was 31.7 ± 12.3 dBnHL. Hearing of 28 patients (80%) was improved to a practical level within 40 dBnHL, but 2 patients (6%) had no change in postoperative hearing. Numbers of patients with spontaneous prolapse, artificial removal of tympanic membrane ventilation tube, and unobstructed in place were 15, 12, and 8, respectively. Twenty-seven patients had perforations left after the prolapse and removal of tympanic membrane ventilation tubes, of which 22 (81%) had perforations healing by themselves. All patients had dry ears after operation, without recurrence. Thirty-three patients (94%) had dry ears within 3 months and only 2 patients (6%) for more than 6 months., Conclusion: Tympanoplasty combined with fascia grafting catheterization is effective in the treatment of adhesive otitis media.

Background: The meniscus is critical for the normal functioning of the knee joint. The specific aim of this study was to validate an in vitro culture model of meniscus explants for testing the impact of culture conditions on meniscus biomechanical properties. We hypothesized that culturing menisci in the presence of intermediate and high concentration of serum would have a positive effect on the compressive stiffness of the meniscus., Methods: Unconstrained microindentation testing was performed on porcine meniscus explants cultured with varying concentrations 1%, 5%, or 10% of fetal bovine serum media. Meniscus explants that were not cultured were used as a control. These tests quantified the Young's Modulus of the listed groups of cultured and uncultured explant tissues., Findings: The Young's modulus for 10% cultured explants were significantly higher compared to the control, 1%, and 5% cultured meniscus explants. There was no statistical significance when the Young's modulus between control, 1%, and 5% cultured explants were compared., Interpretation: These results suggest that low concentrations of serum do not impart an anabolic effect on meniscus tissue explant biomechanical properties., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The columellar strut graft is one of the most commonly used invisible grafts in tip plasty techniques for nasal tip projection. However, the columellar strut graft induces cephalic rotation of the dome with nasal tip projection. This is an effective change in Western people with a long nose; however, this change should be avoided in Asians who have a relatively short nose and visible nostrils. We designed a more convenient and effective technique using a rein-shaped columellar strut graft that can prevent cephalic rotation of the dome., Methods: A total of 32 patients underwent surgery with a rein-shaped columellar strut graft with a septal cartilage. The projection and location of the nasal tip, nasal length, and nasolabial angle were measured after taking a photograph of the lateral view, and the preoperative and postoperative results were compared., Results: There were statistically significant differences between the preoperative and postoperative values of the nasal tip projection ratio and nasal tip location ratio. There were no revision surgeries and no direct complications associated with the use of the columellar strut graft., Conclusion: We performed tip plasty with a modified columellar strut graft-the rein-shaped columellar strut graft. In most cases of using this method, the tip projection was increased and the cephalic rotation of the tip was prevented. This surgical procedure can also be used for lengthening (rotating caudally) of the nose in some cases, as well as for the purpose of preventing the cephalic rotation of the tip., Level of Evidence Iv: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Background: Tympanoplasty is regularly performed in various ages but data about the procedure in elderly is insufficient. Objectives: To compare the success rates and hearing outcomes of fascia and perichondrium grafts used for tympanoplasty in patients >65 years and to evaluate the prognostic factors affecting the success of tympanoplasty. Methods: Reviewing records of 49 elderly patients underwent tympanoplasty, two groups were constituted: perichondrium (25 patients) and fascia (24 patients) groups. Ages, genders, perforation sides, type and location of perforation, graft success rates, functional success rates and air-bone gap (ABG) gains were compared. Results: Overall graft success rate was 85.7%. After a mean follow-up of 23.3 ± 8.32 months, overall mean ABG gain was 11.33 ± 8.42 dB. Overall median postoperative ABG value (9 dB) was significantly lower compared to the median preoperative value (24 dB) ( p  < .001). Graft success rate was higher in perichondrium group (96%) compared to fascia group (75%) ( p  = .04). Functional success rate did not significantly differ between perichondrium (68%) and fascia groups (62.5%) ( p  = .68). Conclusion and significance: Tympanoplasty is an effective procedure with a graft success rate of 85.7% in elderly. Both fascia and perichondrium are suitable materials; however, perichondrium had higher success rate.

Background: The use of tendon tissue for transfer and grafting is a common practice in hand surgery. Many local tendons are usually used, mainly that of the palmaris longus muscle. However, this tendon could be absent in up to 46%. Extra slips of the extensor digitorum communis (EDC) and extra tendons such as the extensor indicis (EI) and the extensor digiti minimi (EDM) could be valuable sources for tendon tissue. Methods: A systematic review was conducted to quantify the proportion of extra slips in relation to each tendon and extra tendons in relation to each long finger. The aim is to better predict the location of tendon tissue sources on the dorsum of the hand in reconstructive surgery. Results: Based on 39 studies including 7847 hands, the cumulative frequencies of extra slips and extra tendons and the association between double-slip frequency and ancestry were as follows: (1) the little finger showed the highest cumulative frequency of extra slips (96.54%), followed by the ring (37.5%), long (30.6%), and index (9.5%) fingers; (2) the index with its EI and its variants and the little finger with its EDM bear by far the highest cumulative frequency of extra tendons (≈100%); and (3) double slips are found to be rare in Indian populations, most prevalent in Japanese populations, more prevalent in the index and little fingers of Caucasians, and more prevalent in the ring fingers of Middle Eastern populations. Conclusions: Knowledge of the frequencies of extra slips for each long extensor tendon and extra tendons for each long finger along with their prevalence in different populations would improve: (1) location prevision of tendon source for tendon grafting; and (2) surgical planning while supporting a patient-centered approach. Evidence-based hand anatomy would have a major potential to contribute to the practice of an evidence-based hand surgery. Predicting the possible tendon sources that could be present on the dorsum of the hand is thought to be very valuable for hand surgeons. In addition and from an evolutionary perspective, we hypothesized that the observed significantly higher frequency values of the double-slip and triple-slip types of the EDC of the ring finger, EDC of the little finger, and EDM might indicate a natural selection tendency for a higher independence of the former digits in the future evolution of the human hand.

Background: Fat grafting has been described as an option to repair frontotemporal contour deformities (volumetric deficiency of bone and/or soft tissues) after neurosurgical/craniofacial surgical interventions. However, technical surgical descriptions have varied, with reports describing the bolus fat injection or the classical multilayer injection, but with no detailed descriptions concerning how and where the fat should be grafted. The purpose of this study was to assess the frontotemporal symmetry outcomes after a single fat-grafting procedure for postoperative frontotemporal contour deformity reconstructions using the anatomical fat-grafting approach., Methods: A prospective analysis was conducted of consecutive patients (n = 106) who underwent anatomical fat grafting (Coleman's structural fat grafting technique using anatomical facial subunit and fat compartment principles) to reconstruct frontotemporal contour deformities after neurosurgical/craniofacial surgical interventions. A subjective assessment by a panel of external surgical professionals and laypersons was obtained to grade the frontotemporal symmetry. Objective ultrasound symmetry assessment was blindly performed preoperatively and at 3- and 12-month follow-up., Results: There were significant (all P  <  0.05) postoperative subjective and objective frontotemporal symmetry enhancements (preoperative < postoperative) after anatomical fat grafting, with no differences (all P > 0.05) between the 3- and 12-month postoperative comparisons. Thirty-seven percent of patients required an additional fat grafting session for residual asymmetry after 12 months of follow-up., Conclusions: Patients with frontotemporal contour deformities presented improved subjective and objective frontotemporal symmetry after an anatomical fat grafting session., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The derivation of induced pluripotent stem cells (iPSCs) over a decade ago sparked widespread enthusiasm for the development of new models of human disease, enhanced platforms for drug discovery and more widespread use of autologous cell-based therapy. Early studies using directed differentiation of iPSCs frequently uncovered cell-level phenotypes in monogenic diseases, but translation to tissue-level and organ-level diseases has required development of more complex, 3D, multicellular systems. Organoids and human-rodent chimaeras more accurately mirror the diverse cellular ecosystems of complex tissues and are being applied to iPSC disease models to recapitulate the pathobiology of a broad spectrum of human maladies, including infectious diseases, genetic disorders and cancer.

Background: Fat grafting is a common procedure in plastic surgery. A major limitation is unpredictable graft retention, in part caused by inadequate oxygen delivery during the early posttransfer period., Methods: The authors present a bioengineered approach to the design of a fat graft based on mathematical theory, which can estimate the limitations of oxygen delivery. To simplify the problem, four variables were defined: (1) recipient-site oxygen partial pressure; (2) adipose tissue oxygen permeability; (3) adipose tissue oxygen consumption rate; and (4) fat graft size. Recipient-site oxygen partial pressure and adipose tissue oxygen permeability were estimated from literature, whereas adipose tissue oxygen consumption rate was measured using stirred microchamber technology. Calculations were performed in both spherical and planar geometry to calculate the maximum allowable fat graft size from an oxygen delivery standpoint., Results: As expected, planar geometry is less favorable for oxygenation but represents a realistic configuration for a fat graft. Maximum allowable fat graft thickness is only approximately 1 to 2 mm at external oxygen partial pressures of 10 to 40 mm Hg; any thicker and an anoxic or necrotic core likely develops. Given a reasonably large surface area and assuming several planes of injection, the maximum allowable fat graft volume is tens of milliliters., Conclusions: A systematic bioengineered approach may help better design a fat graft. Applying principles of mass transfer theory can predict whether a fat graft has a favorable chance of surviving from an oxygen delivery standpoint and can direct the development of strategies for improved fat graft oxygenation.

Subepithelial connective tissue graft (SCTG) is an essential therapeutic tool in periodontal plastic surgery and implantology. The aim of this preliminary study was to observe and make a histological and histomorphometric comparison of the composition of subepithelial connective tissue grafts (SCTGs) harvested from the palatal mucosa by two different harvesting techniques: mucoperiosteal (lamina propria and complete submucosa including periosteum) and mucosal (lamina propria and a portion of the submucosa). The main hypothesis proposes that SCTG harvested with the mucosal technique contains a greater proportion of connective tissue proper (CTP) and a lower proportion of adipose tissue (AT) than the mucoperiosteal technique. Twenty healthy patients who required SCTG for different purposes were selected and assigned to one of the two following groups: group A (n=10; mucoperiosteal harvesting technique) and group B (n=10, mucosal harvesting technique). The histological sample was obtained by removing a 2 mm thick slice from the most distal portion of the graft. The proportions of adipose tissue (AT), connective tissue proper (CTP) and vascular tissue (VT) were evaluated. In group A, histomorphometric analysis showed that CTP accounted for 58.2% of the graft while AT accounted for 32.64%. In group B, the proportions of CTP and AT were 79.86% and 11.93%, respectively. The differences between groups were statistically significant for both tissues (p< .05). In contrast, no statistically significant difference was observed in the proportion of VT. Within the limitations of this study, the results show that the SCTGs harvested by the mucosal technique contain a greater proportion of CTP and a lower proportion of AT than those obtained by the mucoperiosteal technique, whereas the proportion of VT does not differ. Further long-term clinical and histological studies with more samples are needed to evaluate the clinical implications of SCTG composition., (Sociedad Argentina de Investigación Odontológica.)

Background: Correction of the hump nose entails more than just simple elimination of the dorsal hump. Recent trend is toward conservative reduction of the hump and appropriate adjustment of the radix height. East Asians often present with pseudo-hump due to underprojected radix or tip, which accentuates the height of the hump. This study introduces our method of pseudo-hump correction and achieving a balanced nasal profile with minimal reduction of the hump and augmentation of the dorsum and tip with a modified augmentation spreader graft., Methods: A retrospective review was conducted of 97 consecutive cases of Korean patients undergoing hump reduction with simultaneous augmentation of the radix with resected hump fragments and augmentation of the nasal dorsum with augmentation spreader graft. No implants were used in any of the patients. Anthropometric analysis was performed, and patient satisfaction was evaluated at postoperative 1 year., Results: Postoperatively, hump was eliminated, and the dorsum and tip were successfully elevated using only autologous septal cartilage. The radix was augmented without surface irregularity or graft visibility. Nasal dorsum, tip, and radix projection increased significantly after surgery. Subjective evaluation revealed a high level of satisfaction in 84%., Conclusions: Our multipurpose bilateral augmentation spreader graft positioned above the septal plane was effective in dorsal and tip augmentation without the need for alloplastic material. Conservative hump reduction combined with augmentation of the relatively deficient areas of the nose produces a balanced nasal profile.

Objective: Combining vascular bypass surgery with free flap coverage is one of the treatment methods for complex soft tissue defects in the ischaemic lower limb. Endovascular revascularisation has become the first line treatment for limb ischaemia in many centres. Surgeons now perform free tissue transfer after angioplasty. The early and long-term limb salvage rate in diabetic patients who had undergone infrapopliteal endovascular revascularisation and free flap reconstruction are assessed., Methods: This was retrospective study of all consecutive diabetic patients who had undergone endovascular revascularisation with free flap reconstruction for lower limb salvage between 2008 and 2014. They were followed up for at least 2 years or to death (mean follow up 39 ± 17 months). Cox regression analysis was used to analyse variables influencing outcome., Results: There were 55 patients who had undergone 60 procedures. Five patients had undergone the procedure to the contralateral leg. All tissue lesions were Wagner-Meggit classification Grades 3 or 4. Thirty-six patients had TASC C lesions and 24 patients with TASC D lesions. Combined below knee triple vessel disease was seen in 30% of the cases, 28% involved both the anterior and posterior tibial artery, 7% and 2% involved the anterior tibial or the posterior tibial and the peroneal arteries. The free flap success rate was 95%. The peri-operative mortality was 1.7%. Twenty-one cases required surgical re-intervention. Mean length of hospital admission was 32 ± 9 days. One and five year amputation free survival rates were 94% and 68%, patient survival rates were 95% and 67%, limb salvage rates were 93% and 91% and respectively., Conclusions: The results show that excellent early and late limb salvage can be achieved with free tissue transfer based on endovascular revascularisation of infrapopliteal arteries. This can be a further treatment option in diabetic patients with complex soft tissue defects., (Copyright © 2018 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.)

Background: Although columellar strut grafts (CSGs) are considered among the fundamental steps for providing nasal tip support, a downward rotation of the nasal tip in patients with strut grafts can still be encountered. Patient-related factors such as nasal skin thickness can allow the plastic surgeon to anticipate certain drawbacks that can be encountered in the healing phase, but patient-based differences of nasal cartilage and the resulting impact have yet to be investigated. The purpose of this study was to evaluate the effect of the biomechanical properties of CSGs on late postoperative nasal tip position and support., Methods: The study was undertaken with the participation of 20 patients undergoing closed-technique primary rhinoplasty with CSGs. Each cartilage specimen was biomechanically analyzed to calculate the modulus of elasticity. Preoperative and postoperative images were obtained to determine nasal tip position and rotation with quantitative measurements. Postoperative 3- and 12-month measurements were evaluated according to their relationship with the elasticity modulus of the utilized cartilages., Results: The evaluation demonstrated that the elasticity modulus can impact the long-term support of the nasolabial angle in which an increase in the coefficient of elasticity can result in a decrease in long-term nasal tip support., Conclusion: The results of the study reveal a new objective variable that can impact nasal tip dynamics and patient-related differences following rhinoplasty. This study not only brings forth a different perspective in the evaluation of nasal tip dynamics but can also provide data for determining ideal values for cartilage prefabrication.

Background: The objective of the study was to compare the results of a primary anterior cruciate ligament reconstruction (ACLR) using the press-fit fixation technique for a quadriceps tendon (QT) graft to a standard quadrupled hamstring (HT) graft with interference screw fixation., Methods: A retrospective cohort study with a 12-month follow up provided data for 92 patients. Exclusion criteria were accompanying ligament injuries and contralateral ACL injury. Patients who suffered a graft failure, which was defined as a side-to-side difference of > 3 mm, or infection were rated 'D' according to the IKDC and excluded from further evaluation. Forty-six patients underwent primary ACLR using the press-fit fixation technique for autologous bone QT graft. These patients were matched in terms of age, gender, accompanying meniscus tear and cartilage injury to 46 patients who underwent standard HT graft with interference screw fixation. Patients were evaluated according to the Lachman test, Pivot-Shift test, IKDC score, Tegner score, Rolimeter measurements, one-leg hop test, thigh circumference and donor side morbidity., Results: No significant differences in Tegner score (p = 0.9), subjective or objective IKDC score (p = 0.9;p = 0.6), knee stability (Lachman Test p = 0.6; Pivot-Shift Test p = 0.4; Side-to-Side Difference p = 0.4), functioning testing (One-Leg Hop Test p = 0.6; Thigh Circumference p = 0.4) or donor side morbidity (p = 0.4) were observed at the follow up. The Lachman test was negative for 85% of the QT group and 83% of the HT group. The Pivot Shift Test was negative for 80% of the QT group and 85% of the HT group. The mean side-to-side difference was 1.6 ± 0 .2mm in both groups. The one-leg hop test revealed a collateral-side jumping distance of 96.2 ± 8.5% for the QT group and 95.5 ± 8.5% for the HT group. The thigh circumference of the injured leg was 98.3 ± 3.0% on the uninjured side in the QT group and 99.7 ± 3.0% in the HT group. A knee walking test resulted in no discomfort for 90% of the QT group and 85% of the HT group. The graft failure rate was 7.3% in the QT group and 9.8% in the HT group., Conclusion: QT grafts fixated using the press-fit technique are a reliable alternative for primary ACL surgery.

Objective: To demonstrate the technical advances since the time we reported the first successful case in 2000 and our modern approach to autologous transplantation of frozen-thawed human ovarian tissue., Design: A step-by-step video demonstration of three surgical approaches was created by editing the surgical footage obtained during ovarian transplantation procedures., Setting: Academic., Patient(s): Three patients who previously underwent ovarian tissue harvesting and cryopreservation before gonadotoxic cancer treatments or radical cancer surgery are presented., Intervention(s): The illustrated techniques include robot-assisted orthotopic (technique 1) and heterotopic (technique 2) approaches using the da Vinci Xi (Intuitive Surgical) robotic system and a decellularized human extracellular tissue matrix (Alloderm; LifeCell Corp.) as a tissue scaffold, as well as a percutaneous autotransplantation approach (technique 3)., Main Outcome Measure(s): Successful completion of procedures without complications and ovarian graft function with demonstration of E 2 production and follicle development., Result(s): All cases were completed without complications. Ovarian graft function was confirmed by E 2 production, follicle growth by 10-14 weeks after transplantation, and later embryo development., Conclusion(s): Since our first report of successful restoration of ovarian function after orthotopic transplantation of frozen-banked ovarian tissue in 2000 (1), followed by our first reports of subcutaneous heterotopic transplantation techniques (2, 3), ovarian tissue cryopreservation followed by subsequent transplantation has become a promising fertility preservation option for young women with cancer who do not have sufficient time to undergo oocyte or embryo cryopreservation and for prepubertal girls (4, 5). The same approach also has the advantage of restoring ovarian endocrine function and fertility without a need for assisted reproduction (6, 7). In the very first successful procedure that we reported in 2000, we used conventional laparoscopy, and the tissues were reconstructed and mounted on a polycellulose scaffold (Surgicel) (1, 7). Since then, we have made significant modifications in our surgical approach with potential improvements in outcomes. Here we illustrate three main techniques of ovarian tissue transplantation resulting in the restoration of ovarian function in all cases. In the first two cases, we illustrated the robot-assisted orthotopic and heterotopic approaches using Alloderm. Robotic ovarian transplantation may increase precision, provide more delicate graft handling, and reduce the time from tissue thawing to transplantation (6, 8). Alloderm is regenerated de-epithelized human cadaver skin, which consists of several extracellular matrix components. It has been safely used in the surgery and dentistry fields for enhancing tissue regeneration and vascularization (9, 10). Furthermore, our earlier laboratory work indicated the critical role of extracellular matrix in primordial follicle growth initiation and preantral follicle growth (11, 12). Prior to our use of Alloderm as part of ovarian transplant procedures, we tested it in human ovarian xenograft models and found Alloderm to incorporate well with ovarian tissue (8). Only after that test did we adopt it for use in ovarian transplants. The utility of the extracellular tissue matrix may thus enhance our ovarian autotransplantation techniques by facilitating ovarian reconstruction and potentially improving neovascularization. In fact, we have seen improved follicle growth and response to ovarian stimulation with the use of Alloderm in our first cases (8). We use heterotopic ovarian transplantation when the pelvis is not suitable for autotransplantation due to past radiation or scarring or when there are other medical contraindications for transplantation in the pelvis. The third technique we illustrated was percutaneous heterotopic ovarian autotransplantation. This is a simple approach that can be used in surgically high-risk patients, as it is done with local anesthesia or IV sedation and without entering abdominal cavity. Additionally, same approach can be utilized when there is heightened concern that the ovarian tissue may harbor a disease that can recur, requiring close surveillance and easier removal of the ovarian graft. While ovarian endocrine function and follicle growth are restored with efficiency using the percutaneous ovarian transplants, our initial experience suggests that oocyte quality may be impaired in SC locations (2, 3, 13). Hence that technique may be more suitable when the only purpose is restoration of ovarian endocrine function. However, we have encountered recurrent live births from spontaneous conceptions following SC ovarian transplants, prompting the question of whether the grafted tissue can augment the function of in situ menopausal ovary (13, 14). While ovarian cryopreservation and transplantation may no longer be considered experimental, there are many exciting questions remaining to be answered on the full potential of this procedure., (Copyright © 2018 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)