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Background: Pasteurized bone autograft is a recycling biological reconstruction method for limb-sparing surgery when an allograft or other reconstruction technique is unavailable. Since the application of a local bisphosphonate to morselized allografts can reduce graft resorption and enhance bone formation without systemic complications, adding the local bisphosphonate to pasteurized bone autografts should reduce the graft resorption and improve the graft incorporation to host bone. However, no study that we know of has described the outcomes of local bisphosphonate application to massive allografts or pasteurized bone autografts. Thus, this study compared the outcomes of pasteurized bone autografts with and without local zoledronate., Questions/purposes: (1) What is the survival of pasteurized bone autografts and what complications lead to graft removal? (2) Does treatment of pasteurized bone autografts with zoledronate alter the survival of pasteurized bone autografts compared with grafts without treatment? (3) Does the local application of zoledronate reduce the proportion of patients with fractures because of metaphyseal graft resorption? (4) Does local application of zoledronate improve union at the graft-host bone junction compared with untreated grafts?, Methods: Between July 2011 and December 2019, we performed 538 musculoskeletal bone tumor resections. Of these, 101 patients underwent reconstruction with pasteurized bone autografts. Other reconstructions included tumor prostheses (150 patients), allografts (70 patients), reconstruction using a bone cement-plate construct (62 patients), and resection only (155 patients). We generally used pasteurized bone autograft when tumors showed an osteoblastic pattern, had less than one-third cortical destruction, and less than half of metaphyseal bone destruction. Six percent (6 of 101) were lost to follow-up, 6% (6 of 101) had incomplete clinical data, and 16% (16 of 101) had a follow-up period less than 2 years without an event, leaving 73 patients for evaluation. The median (interquartile range) age of the patients was 18 years (15 to 26). Ninety-seven percent (71 of 73) had a diagnosis of bone sarcoma. The median follow-up time was 46 months (33 to 75). From 2011 to 2014, 21 pasteurized bone autografts were prepared without local zoledronate, and from 2014 to 2019, 52 pasteurized bone autografts were prepared with local zoledronate because we thought it might improve union and reduce resorption of the graft. From our tumor registry database, we obtained age, sex, use of chemotherapy, graft length and location, pasteurized bone graft type, fixation methods, the use of local zoledronate, osteotomy gap, complications, proportion of grafts that united by 2 years, and local recurrences. Curves for graft survival were determined using the Kaplan-Meier method with the endpoint of autograft removal and metaphyseal fracture from graft resorption. The probabilities of graft removal were estimated by cumulative incidences using the competing risk analysis, where death was considered as the competing event. Intergroup differences in survival and multivariable analyses were performed using the log-rank test and a Cox regression analysis. A logistic regression model was used to evaluate the association between graft-host osseous union by 2 years and other baseline factors. Union was defined when a callus was seen to bridge the osteotomy line for at least three cortices in both the AP and mediolateral planes., Results: The 5-year survival rate of all 73 pasteurized grafts was 85% (95% confidence interval 74% to 92%). With the numbers available, we found no difference in the 5-year survival rates between grafts with and without local zoledronate (90% [95% CI 78% to 96%] versus 74% [95% CI 48% to 89%]; p = 0.30). Eleven percent (8 of 73) of patients had metaphyseal fractures because of graft resorption, primarily associated with osteoarticular grafts (5-year fracture-free survival 56% [95% CI 20 to 80]) rather than pasteurized graft-prosthesis composites (94% [95% CI 78% to 98%]) and intercalary grafts (91% [95% CI 50 to 99]; p = 0.001); there was no association with the use of local zoledronate (13%; 7 of 52) compared with those without local zoledronate (5%; 1 of 21) (odds ratio 3.1 [95% CI 0.4 to 27]; p = 0.43). Of the 84 graft-host bone junctions, 85% (71) of the grafts unified within 2 years, 7% (6) unified after 2 years, and 8% (7) of grafts showed nonunion. Union within 2 years was associated with fixation using plate compared with those with stem and with both stem and plate (odds ratio 6.6 [95% CI 1.4 to 31]; p = 0.02) and grafts treated with local zoledronate compared with those without treatment (OR 5.9 [95% CI 1.3 to 28]; p = 0.02)., Conclusion: The application of local zoledronate to pasteurized bone autografts for limb-sparing surgery improved the likelihood of graft union compared with untreated grafts, especially when the osteotomy junctions were fixed using plate osteosynthesis, but it did not appear to alter the proportion of patients who experience metaphyseal fracture of the grafts because of graft resorption. Although this is a small study, it suggests that the treatment of pasteurized bone autografts and perhaps bone allografts should be studied further to determine whether bisphosphonates or other adjuncts can improve the union time and return to function in patients undergoing bone tumor resections using these reconstruction types., 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.)

We evaluated the abscopal effect of re-implantation of liquid nitrogen-treated tumor-bearing bone grafts and the synergistic effect of anti-PD-1 (programmed death-1) therapy using a bone metastasis model, created by injecting MMT-060562 cells into the bilateral tibiae of 6-8-week-old female C3H mice. After 2 weeks, the lateral tumors were treated by excision, cryotreatment using liquid nitrogen, excision with anti-PD-1 treatment, and cryotreatment with anti-PD-1 treatment. Anti-mouse PD-1 4H2 was injected on days 1, 6, 12, and 18 post-treatment. The mice were euthanized after 3 weeks; the abscopal effect was evaluated by focusing on growth inhibition of the abscopal tumor. The re-implantation of frozen autografts significantly inhibited the growth of the remaining abscopal tumors. However, a more potent abscopal effect was observed in the anti-PD-1 antibody group. The number of CD8+ T cells infiltrating the abscopal tumor and tumor-specific interferon-γ (IFN-γ)-producing spleen cells increased in the liquid nitrogen-treated group compared with those in the excision group, with no significant difference. The number was significantly higher in the anti-PD-1 antibody-treated group than in the non-treated group. Overall, re-implantation of tumor-bearing frozen autograft has an abscopal effect on abscopal tumor growth, although re-implantation of liquid nitrogen-treated bone grafts did not induce a strong T-cell response or tumor-suppressive effect.

Purpose: To determine and compare the incidence of postoperative septic arthritis following revision anterior cruciate ligament reconstruction (R-ACLR) with and without soaking of the graft in vancomycin solution prior to implantation in a large single-centre series., Methods: A total of 2155 isolated R-ACLR with autologous tendons were performed from 2004 to 2019 and were reviewed with regard to the occurrence of postoperative septic arthritis. From February 2017 onwards, all grafts were wrapped in a vancomycin-soaked (5 mg/ml) gauze swab between harvest and implantation (517 patients, treatment group (2), prospectively followed). These were compared to 1638 patients before that date (control group (1), retrospectively evaluated). The technique of R-ACLR did not significantly change during the years of the study. Hamstring tendons were used in 1310 patients (60.8%) and quadriceps tendons with patellar bone block were used in 845 patients (39.2%), respectively, with no difference between the groups (n.s.). Routine follow-up examination was performed 6 weeks postoperatively (follow-up rate 96.5%), and patients with no treatment for septic arthritis until that time were classified as non-infected., Results: There were 14 cases of postoperative septic arthritis in group 1 (incidence 0.9%), and none in group 2 (incidence 0.0%), respectively. The difference was significant (p = 0.029)., Conclusion: Soaking of the graft in vancomycin solution prior to implantation dramatically reduces the incidence of postoperative septic arthritis in R-ACLR., Level of Evidence: III.

Background:  The treatment of peripheral nerve defects requires bridging materials. Skeletal muscle grafts have been studied as an alternative to nerve autografts because they contain longitudinally aligned basal laminar tubes that are similar to axons. Several pretreatment methods for muscle grafts have promoted axonal regeneration. Here, a new method of doxorubicin pretreatment was used, and the efficacy of the pretreated muscle graft was evaluated in a rat model of a sciatic nerve defect., Methods:  A rat model of a 10-mm sciatic nerve defect was analyzed in three settings: muscle grafts with and without doxorubicin pretreatment (M-graft-w-Dox and M-graft-w/o-Dox groups, respectively) and a nerve autograft group (N-graft) ( n  = 6/group). The M-graft-w-Dox group was immersed in a doxorubicin solution for 10 minutes and rinsed with saline. Analyses of target muscle atrophy, electrophysiology, and histology were performed 8 weeks after grafting., Results:  Electrophysiological parameters and target muscle atrophy were significantly superior in the M-graft-w-Dox group compared with the M-graft-w/o-Dox group. Histological assessment revealed the presence of a significantly greater number of regenerated axons in the M-graft-w-Dox group versus the M-graft-w/o-Dox group, while there were no significant differences between the M-graft-w-Dox and N-graft groups. The diameter of myelinated axons of the regenerated nerve in the M-graft-w-Dox group was significantly larger than that in the M-graft-w/o-Dox group, while it was not significantly different compared with the N-graft group., Conclusion:  Pretreatment of muscle grafts with doxorubicin promoted significant peripheral nerve regeneration. This method may represent a new option for the treatment of peripheral nerve defects., Competing Interests: None declared., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Lenalidomide (LEN) is commonly used as part of induction therapy in transplant-eligible patients with multiple myeloma. However, LEN use is associated with increased chance of peripheral blood stem cell (PBSC) collection failure. This has led to early collection in patients receiving induction with LEN-containing regimens, and the use of mobilization agents such as plerixafor. Despite potential significant clinical implications, the impact of LEN on autograft composition is unclear. We examined the effect of LEN exposure on hematopoietic progenitors in collected grafts of 94 patients who underwent autologous stem cell transplantation (HSCT) at our institution. LEN exposure resulted in lower myeloid and erythroid progenitors in collected grafts, but this effect was not seen in patients who received plerixafor-based mobilization. Exposure to LEN did not affect PBSC collection, possibly due to high plerixafor use in our cohort (70%). LEN changes the composition of PBSC grafts; the clinical implication of this finding is unknown.

Impact Statement: The development of autograft extenders is a significant clinical need in bone tissue engineering. We report new settable poly(thioketal urethane)-based autograft extenders that have bone-like mechanical properties and handling properties comparable to calcium phosphate bone cements. These settable autograft extenders remodeled to form new bone in a biologically stringent intertransverse process model of bone formation that does not heal when treated with calcium phosphate bone void fillers or cements alone. This is the first study to report settable autograft extenders with bone-like strength and handling properties comparable to ceramic bone cements, which have the potential to improve treatment of bone fractures and other orthopedic conditions.

Background: Salvia miltiorrhiza (SM) is an herb used in Chinese medicine formulations for promoting blood circulation and minimizing vascular stasis. It has been successfully utilized in treating cardiovascular diseases, such as atherosclerosis, thromboembolism, and angina., Objectives: The authors sought to study the effect of SM injections in autologous fat grafting to the breast., Methods: Fifteen women who elected to undergo breast augmentation with autologous fat grafting were included in this study. Of these, 10 were given intravenous infusions of SM for 4 weeks perioperatively, and the remaining 5 did not receive herbal infusion. The increase in breast volume after fat grafting was measured in both the groups using a three-dimensional scanner. Breast tissue specimens were harvested just before the second fat injection procedure and were analyzed by the immunofluorescence staining test., Results: All of the patients showed improvement in breast volume after fat grafting. The fat graft retention rate in the SM group was 60.06 ± 16.12%, whereas that in the non-SM group was 34.04 ± 11.15%. In addition, the SMG showed good breast morphology and absence of cyst formation., Conclusions: SM has the potential to increase the retention rate of fat grafts in breast augmentation., (© 2019 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: journals.permissions@oup.com.)

Study Question: How efficacious is transplantation of ovarian cortex previously exposed to chemotherapy?, Summary Answer: Prior exposure to chemotherapy did not disrupt the function of cryopreserved ovarian tissue after transplantation., What Is Known Already: Ovarian tissue cryopreservation (OTC) followed by ovarian tissue transplantation (OTT) is an efficacious technique for restoration of female fertility. At least 130 children have been born following this procedure. To date, little is known about the efficacy of OTT in patients exposed to cancer chemotherapy prior to OTC., Study Design, Size, Duration: This study evaluates the recovery of ovarian function and fertility in 31 consecutive patients who had received OTT, between 2005 and 2015., Participants/materials, Setting, Methods: Thirty one patients, wanting children, were transplanted with autologous ovarian cortex, among which 22 patients (71%) had been exposed to chemotherapy before OTC. Recovery of ovarian function was considered total once menstruation occurred. Ovarian function recovery (OFR), ovarian graft survival, and incidence of pregnancy were related to previous chemotherapy exposure, type of chemotherapy and graft characteristics (number of grafted fragments and follicular density)., Main Results and Role of Chance: The amount of ovarian tissue collected was the only parameter to show any significant change between patients with versus without previous chemotherapy. At 1 year after OTT, the cumulative incidence of OFR was 83% (93% in patients exposed to chemotherapy and 67% in others (P = 0.14)). A low follicular density (<0.3 foll/mm2) in the transplant and a low number of grafted fragments (<16) were significantly associated with a delayed OFR. Graft survival at 2 years after OTT was 77%. It was significantly lower in patients exposed to bifunctional alkylating agents before ovarian cryopreservation and in patients with a low follicular density. The proportion of women who succeeded in having at least one live birth was 23% in the total population, 0% (0/9) in the group 'no previous chemotherapy', and 32% (7/22) in the group 'previous chemotherapy'. The cumulative incidence of pregnancy (Kaplan-Meier) at 3 years after OTT was 36% overall and 49% in case of previous chemotherapy, with no difference related to previous chemotherapy exposure. In total there were 13 pregnancies and 8 births in 7 patients., Limitations, Reasons for Caution: The pathology in the two groups of patients was not comparable. In the group of patients who had chemotherapy before OTC, there were 95% of hematological malignancies. In the group of patients who did not have chemotherapy before OTC only 1 out of 9 patients had a malignant hematological disease while 44% had some pathology affecting the ovaries. Few women are available for study and only large changes are likely to have statistical significance., Wider Implications of the Findings: These results suggest that prior cancer chemotherapy should no longer be considered a limitation to cryopreservation of ovarian tissue and current recommendations in this regard should be revised., Study Funding/competing Interest(s): This study was supported by the Agence de la Biomédecine (France's biomedical office). There are no competing interests to report., Trial Registration Number: NCT02184806., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Three randomized controlled trials and a meta-analysis reported lenalidomide given after high-dose therapy and an autologous hemopoietic cell transplantation is associated with increase in progression-free survival (PFS) and survival in persons with plasma cell myeloma (PCM). Based on these data, posttransplant lenalidomide is considered by many a standard-of-care in this setting. However, decisions on the use of new therapies should consider not only results of such trials and meta-analyses but also other factors including quality-of-evidence, anticipated desired and undesired effects of the drug, costs and feasibility of the therapy option. In this review, we critically analyzed evidence on posttransplant lenalidomide in PCM, and we identified criteria which should be considered in designating posttransplant lenalidomide the standard-of-care. Using Grading of Evidence, Assessment, Development and Evaluation (GRADE) approach we judged posttransplant lenalidomide improves PFS with high-quality evidence. However, we identified inconsistency and imprecision as limitations in the conclusions regarding a survival benefit rating the quality-of-evidence for a survival benefit moderate. We also highlighted inconsistency in claims of an increased risk of new cancers associated with posttransplant lenalidomide. We emphasize the need for a value-based reasoning which considers PFS and survival as well as health-related quality-of-life and costs. We conclude the decision to use posttransplant lenalidomide should be individualized based on pre- and posttransplant variables such as remission state, risk category and/or posttransplant measurable residual disease (MRD)-test results. Validity of these variables in estimating benefits and risks of posttransplant lenalidomide should be tested in randomized clinical trials.

Variable absorption rate is one of the biggest problems of fat grafting and one of the most important causes of fat graft volume loss is apoptosis. Minocycline is a tetracycline derivative and besides its antibacterial capacity, it has been widely using for anti-apoptotic effects. This study was designed to investigate the effect of minocycline on fat graft survival and adipocyte apoptosis. A total of two main and eight subgroups were designed and a total of 48 experimental animals, 6 in each group, were used. Fat grafts are obtained from Wistar albino rats and implanted to dorsal area of rats. Local and systemic minocycline was applied in the study groups. On the 9th day, apoptotic cells were detected by the terminal deoxynucleotidyl transferase dUTP nick end labeling method and on the 90th day morphologic characteristics and viability of adipocytes were evaluated using histologic and immunohistochemical methods and statistically compared. This study revealed that the fat grafts were bigger, and they kept their structures better and they were more vascular in the minocycline groups and apoptosis was significantly lower in the minocycline groups. The authors demonstrated that minocycline increases fat graft survival and statistical improvement in apoptosis inhibition via using minocycline therapy has been shown., Competing Interests: None., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Neuroactive steroids such as progesterone, testosterone, and their derivatives have been widely studied for their neuroprotective roles in the nervous system. Autologous nerve transplantation is considered as the gold standard repair technique when primary suture is impossible; nevertheless, this method is far from ideal. In this study, we aimed to explore the impact of dihydrotestosterone (DHT), a 5α-reduced derivative of testosterone, on the recovery of peripheral nerve injury treated with autologous nerve transplantation. Sprague-Dawley rats were subjected to a 10-mm right side sciatic nerve reversed autologous nerve transplantation and randomly divided into groups that received DHT or DHT + flutamide (an androgen receptor blocker) daily for 8 weeks after operation. Our results demonstrated that DHT could speed up the rate of axonal regeneration and increase the expression of myelin protein zero (P0) in autograft reversal sciatic nerves. Thus, our study provided new insights into improving the prognosis of patients with long gap peripheral nerve defects.

Among the many graft materials that have been used for the treatment of bone defects in oral and maxillofacial regions is xenograft. To improve osteoconductive effects of xenografts, they have been combined with various biocompatible materials, such as hyaluronic acid and bone morphogenetic protein. To determine bone-healing capacity of high molecular weight hyaluronic acid (HA) combined with xenograft in rabbit calvarial bone defects. Ten adult male New Zealand rabbits (mean weight 3 kg) were included in the study. Three 6-mm-diameter bicortical cranial defects were created on calvarial bone of all rabbits. These defects were filled as follows: a) xenograft; b) HA+xenograft; c) autograft. One month after the first operation, rabbits were sacrificed. Specimens were evaluated histomorphometrically. Considering multiple comparisons, differences regarding new bone were statistically significant between all groups (p<0.05). The volume of residual graft was significantly decreased in HA group compared to xenograft group (p=0.035). Marrow space, trabecular thickness (TbTh), trabecular width (TbWi), trabecular separation (TbSp), and number of node: number of terminus (NNd:NTm) in the autograft group were significantly better than xenograft and HA groups (p<0.05). However, regarding marrow space, TbTh, TbWi, TbSp, and NNd:NTm values, xenograft and HA groups showed similar results and the difference were not significant (p>0.05). These results support that high molecular weight hyaluronic acid could contribute to the healing of xenograft by improving the percentage of new bone formation and reducing the percentage of residual graft. However, HA did not significantly affect the quality of newly formed bone assessed by microarchitectural parameters.

Background: Replantation of the avulsed nerve root has been proposed for the treatment of severe brachial plexus injury for several decades. However, due to the complexity of the technique and limited functional improvement, practical applications are yet to be implemented., Objective: In the present study, we investigated the effect of pretreatment with resveratrol on nerve autografts used for replantation surgery in a rat model of nerve root avulsion., Methods: Resveratrol pretreatment was performed using an explant culture technique. Two surgical procedures were performed. During the first surgery, Sprague-Dawley rats were subjected to left C6 nerve root avulsion, and nerves were harvested for autografting. The harvested grafts were explant-cultured for 1 week. A second procedure was performed to replant the C6 nerve root using the explant-cultured nerve graft 1 week after the first procedure. Histological and immunohistochemical analyses were performed 8 weeks after the second procedure. We first compared findings between explant-cultured nerve grafts and fresh nerve grafts, following which we compared findings between explant-cultured grafts pretreated with and without resveratrol. Changes induced within nerve grafts by 1 week of explant culture with or without resveratrol were investigated in vitro., Results: There was no significant difference in outcomes between 1 week-explant-cultured and fresh nerve grafts. Addition of resveratrol to the explant culture medium resulted in a significant increase in the number and myelin thickness of regenerated axons, and in the number of regenerating motor neurons in the C6 spinal cord segment. In vitro analyses revealed that nerve grafts pretreated with resveratrol exhibited significant increases in glial cell line-derived neurotrophic factor (GDNF) expression and the number of dedifferentiated Schwann cells., Conclusions: Resveratrol may promote axonal regeneration following replantation surgery for the treatment of nerve root avulsion injury; however, further studies are required to verify these findings in humans.

The aim of this study was to evaluate the safety and clinical effectiveness of rhBMP-7 (or osteogenic protein-1) versus that of autogenous iliac crest bone graft (ICBG) in single-level posterolateral fusion (PLF) of the lumbar spine. A systematic search of all articles published through July 1, 2016 was conducted in databases such as PubMed, EMBASE, Scopus, and the Cochrane Collaboration Library. Randomized controlled trials (RCTs) that compared rhBMP-7 with ICBG for the treatment of single-level degenerative spondylolisthesis, provided the fusion rate, clinical success rate, safety and adverse events report, operation time, and hospital stay durations as the outcome were assessed. As a result, a total of five RCTs involving 539 patients met the inclusion criteria. The outcomes of subgroup analysis demonstrated that when compared with autogenous ICBG, rhBMP-7 appear to yield lower fusion rates in instrumented posterolateral fusion patients (RR = 0.76, 95% CI [0.60, 0.98], P = 0.03), despite the test for overall fusion rates suggested that there was no significant difference between the two groups (RR = 0.89, 95% CI [0.78, 1.02], P = 0.09). Patients treated with OP-1 had shorter operation times versus those treated with ICBG (WMD = -16.70,95% CI [-25.83, -7.57], P = 0.0003). Additionally, the outcomes demonstrated a lack of significant differences between rhBMP-7 and ICBG in terms of clinical success of ODI, overall adverse events, revision rates and duration of hospitalization. In conclusion, with the exception of reducing the operation time, our review suggests that the use of the rhBMP-7 instead of ICBG produce no any additional beneficial effect on the fusion rates, clinical success of ODI, overall adverse events, revision rates and duration of hospitalization in single level PLF. On the contrary, it appeared to yield lower fusion rate in the instrumented posterolateral fusion patients and cannot be recommended as an effective tool for this set of patients.

Background/aim: Ovarian transplantation can preserve fertility in cancer patients. The aim of this study was to compare ovarian transplantation into granulation tissue (GT) versus back muscle (BM) sites and also to investigate the effects of N-acetylcysteine (NAC) as an antioxidant on ovarian survival in a rat autograft model.Materials and methods: Twenty-eight adult female rats were divided into four equal groups (n = 7 each) as follows: Group 1, ovarian tissue grafted into GT + saline (GT + saline); Group 2, ovarian tissue grafted into GT + NAC (GT + NAC); Group 3, ovarian tissue grafted into BM + saline (BM + saline); and Group 4, ovarian tissue grafted into BM + NAC (BM + NAC). After 28 days, serum concentrations of malondialdehyde (MDA), progesterone, and estradiol (E2) were measured. Ovarian follicle counts were performed from hematoxylin and eosin-stained slides. Furthermore, apoptosis was assessed by terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL). Results: There were no significant differences found in levels of MDA, progesterone, and E2 among the groups. The percentage of apoptotic granulosa cells was significantly (P < 0.05) lower in the ovarian tissue autografted in the GT + NAC group compared to the GT + saline and BM + NAC groups. In addition, the number of blood vessels formed in the ovarian tissue in the GT + NAC group was significantly higher than in the GT + saline and BM + NAC groups (P < 0.05 and P < 0.001 respectively).Conclusion: The granulation tissue site is a suitable candidate for ovarian graft in rats. Furthermore, NAC could not restore autografted ovarian functions.

To investigate the antioxidant and anti-inflammatory effects of alpha-lipoic acid (ALA) in the treatment of endometriosis in an experimental rat model by evaluating biochemical and histopathologic parameters. Experimental endometriosis was induced by the peritoneal implantation of autologous endometrial tissue. The rats were randomly divided into two groups with eight rats each. Group I was intraperitoneally administered ALA 100 mg/kg/day for 14 days. Group II was intraperitoneally administered saline solution at the same dosage and over the same period. Endometrial implant volume was measured in both groups both pre- and post-treatment. Tumor necrosis factor alpha (TNF-α) was measured in peritoneal fluid. Total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI) were assessed in serum. The implants were histopathologically evaluated. In the ALA group, the serum TOS and OSI levels, the endometrial implant volumes, the TNF-α levels in serum and peritoneal fluid, and the histopathologic scores were significantly lower compared to the control group (P < 0.05). Alpha-lipoic acid may have a therapeutic potential in the treatment of endometriosis due to its antioxidant and anti-inflammatory effects., (© 2017 Société Française de Pharmacologie et de Thérapeutique.)

Experiments concerning peripheral nerve regeneration have been reported since the end of the 19 th century. The need to implement an effective surgical procedure in terms of functional recovery has resulted in the appearance of several approaches to solve this problem. Nerve autograft was the first approach studied and is still considered the gold standard. Since autografts require donor harvesting, other strategies involving the use of natural materials have also been studied. Nevertheless, the results were not very encouraging and attention has moved towards the use of nerve conduits made from polymers, whose properties can be easily tailored and which allow the nerve conduit to be easily processed into a variety of shapes and forms. Some of these materials are already approved by the US Food and Drug Administration (FDA), as is presented here. Furthermore, polymers with conductive properties have very recently been subject to intensive study in this field, since it is believed that such properties have a positive influence in the regeneration of the new axons. This manuscript intends to give a global view of the mechanisms involved in peripheral nerve regeneration and the main strategies used to recover motor and sensorial function of injured nerves., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Unlabelled: Scarcity of donor tissue to treat corneal blindness and the need to deliver stem cells or pharmacologic agents to ensure corneal graft survival are major challenges. Here, new composite collagen-based hydrogels are developed as implants to restore corneal transparency while serving as a possible reservoir for cells and drugs. The composite hydrogels have a centrally transparent core and embedded peripheral skirt of adjustable transparency and degradability, with the skirt exhibiting faster degradation in vitro. Both core and skirt supported human epithelial cell populations in vitro and the skirt merged homogeneously with the core material to smoothly distribute a mechanical load in vitro. After in vivo transplantation in rabbit corneas over three months, composites maintained overall corneal shape and integrity, while skirt degradation could be tracked in vivo and non-invasively due to partial opacity. Skirt degradation was associated with partial collagen breakdown, thinning, and migration of host stromal cells and macrophages, while the central core maintained integrity and transparency as host cells migrated and nerves regenerated., Impact: This study indicates the feasibility of a collagen-based composite hydrogel to maintain corneal stability and transparency while providing a degradable peripheral reservoir for cell or substance release., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objective: This study aimed to explore the influence of traditional Chinese medicines: Salvia miltiorrhiza on the survival of auto-transplantation of adipose tissue in a rabbit model., Methods: Minced adipose tissue harvested from the scapular region was transplanted into the dorsum of the ears of New Zealand rabbits. The experimental groups were intra-peritoneally injected with S. miltiorrhiza for a total 4 weeks. The rabbits in control group were intra-peritoneally injected with normal saline. Plasma VEGF levels were assayed at week 1, 2, 4, 6, and 8 after fat tissue auto-transplantation in the dorsum of rabbit ears. Graft samples were collected and measured at week 2, 4, and 12. Survival rates were calculated, and histologic morphology was evaluated. The expression of CD31 was detected by means of immune-histochemical staining to observe neo-vascularization of the auto-transplanted fat tissue. Perilipin was detected by means of immune-histochemical staining to observe the survival of fat cells., Results: At 12 weeks, the survival rates in the experimental group were statistically greater than that in the control group, respectively (p < 0.05). Plasma levels of VEGF in the experimental group at different time points were significantly higher than that in the control group (p < 0.05). Histologically, grafts in the experimental group showed better survival of adipocytes and neo-vascularization. By perilipin immuno-histochemical staining, the experimental group demonstrated better adipocyte survival., Conclusions: In the rabbit model, S. miltiorrhiza can promote the neo-vascularization of adipose tissue grafts and significantly improves the survival rate of auto-transplanted adipose tissue., No Level Assigned: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. 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.

No clinically applicable drug is currently available to enhance neurite elongation after nerve injury. To identify a clinically applicable drug, we screened pre-approved drugs for neurite elongation in the motor neuron-like NSC34 cells. We found that zonisamide, an anti-epileptic and anti-Parkinson's disease drug, promoted neurite elongation in cultured primary motor neurons and NSC34 cells in a concentration-dependent manner. The neurite-scratch assay revealed that zonisamide enhanced neurite regeneration. Zonisamide was also protective against oxidative stress-induced cell death of primary motor neurons. Zonisamide induced mRNA expression of nerve growth factors (BDNF, NGF, and neurotrophin-4/5), and their receptors (tropomyosin receptor kinase A and B). In a mouse model of sciatic nerve autograft, intragastric administration of zonisamide for 1 week increased the size of axons distal to the transected site 3.9-fold. Zonisamide also improved the sciatic function index, a marker for motor function of hindlimbs after sciatic nerve autograft, from 6 weeks after surgery. At 8 weeks after surgery, zonisamide was protective against denervation-induced muscle degeneration in tibialis anterior, and increased gene expression of Chrne, Colq, and Rapsn, which are specifically expressed at the neuromuscular junction. We propose that zonisamide is a potential therapeutic agent for peripheral nerve injuries as well as for neuropathies due to other etiologies.

The aim of this study was to evaluate the effects of low-level laser therapy (LLLT) on the bone repair of critical size defects (CSDs) filled with autogenous bone in the calvaria of immunosuppressed rats. A 5 mm-diameter CSD was created in the calvaria of 30 rats. The animals were divided into 5 groups (n = 6): Control (C)--the defect was filled with a blood clot; Dexamethasone (D)--dexamethasone treatment, and the defect was filled with a blood clot; Autogenous bone (AB)--dexamethasone treatment, and the defect was filled with autogenous bone; LLLT--dexamethasone treatment, and the defect received LLLT (660 nm; 35 mW; 24.7 J/cm(2)); and AB + LLLT--dexamethasone treatment, and the defect was filled with autogenous bone and received LLLT. All animals were euthanized at 30 postoperative days. Histometric and histological analyses were performed. The new bone area (NBA) was calculated as the percentage of the total area of the original defect. Data were analysed statistically (an analysis of variance and Tukey's test; P < 0.05). The AB + LLLT group showed the largest NBA of all groups (P < 0.05). The use of LLLT with AB effectively stimulated bone formation in CSDs in the calvaria of immunosuppressed rats., (Copyright © 2014 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Aim: The aim of this study was to assess the enamel matrix derivative (EMD) as biomaterial used in autogenous tooth transplantation., Material and Methods: The study consisted of 3 beagle dogs, 5 months old, in which six incisors and six premolars were transplanted to mechanically prepared recipient alveolar sockets. One group of teeth was transplanted to a recipient bed, with EMD in the root surface. The second groups of teeth were transplanted using saline solution in the root surface. Every week, clinical examinations were done. Nine weeks later, the animals were killed and the specimens decalcified and prepared for histological and imunohistochemical analysis. Periodontal healing was evaluated by undertaking histomorphometric investigation and analyzed using the Mann- Whitney test (P = 0.05)., Results: In both groups, all the transplanted teeth survived. Between the experimental groups, there was statistically significant difference in the complete healing (P = 0.004). There was statistically significant difference between the treatment group in the occurrence of inflammatory root resorption (P = 0.015) and the occurrence of replacement root resorption (P = 0.041)., Conclusions: Emdogain gel used on the surface of transplanted teeth improves the occurrence of complete healing and reduces root resorption.

Background: Autologous bone grafts are usually well consolidated after 4 to 5 months but can be incompletely interlocked with the native bone. This study investigated the effect of acid demineralization of the graft-bed interface on graft consolidation., Methods: Onlay bone grafts were performed on the calvaria of 36 guinea pigs. Half of the animals had the graft-bed contacting surfaces demineralized with 50% citric acid (pH 1.0) for 3 minutes (test group). The other half received no demineralization (control group). The bone grafts were immobilized by a resorbable membrane glued to the recipient bed with cyanoacrylate. After 7, 30, and 90 days, specimens (n = 6) were obtained for light microscopy. Data from qualitative analysis and computerized histomorphometry were statistically processed at a significance level of 5%., Results: Osteogenesis was not seen at the interface after 7 days. After 30 days, the test group showed 34.39% ± 13.4% of the interface area filled with mineralized tissue, compared to 17.14% ± 8.6% in the control group (P = 0.026). After 90 days, the mean percentages of mineralized tissue at the interface in the test and control specimens were 54.00% ± 11.23% and 38.65% ± 7.76% (P = 0.041), respectively. Within groups, a higher percentage of the area filled with mineralized tissue was seen at 90 days compared to 30 days (P = 0.004 for control and 0.041 for test)., Conclusions: Demineralization of the contacting surfaces between autologous bone graft and bone bed improved new bone formation and bone consolidation. These data need to be confirmed in humans.

Autologous transplantation of the submandibular gland is an effective treatment for severe dry eye syndrome. However, more than 40% of patients experience epiphora 3 to 6 months after transplantation. The underlying mechanism of epiphora remains to be elucidated. To investigate the potential roles of muscarinic acetylcholine receptors (mAChRs) in the induction of epiphora in transplanted glands, we assessed and found elevated mRNA and protein expression of M1- and M3-mAChR in transplanted glands from epiphora patients. The content of inositol 1, 4, 5-trisphosphate was also elevated. Moreover, carbachol (5 and 10 µM) induced greater increase of [Ca(2+)]i in isolated epiphora submandibular cells than in controls. Although aquaporin-5 (AQP5) content and distribution in the apical and lateral plasma of epiphora glands did not change, AQP5 content was reduced in lipid microdomains (lipid rafts and caveolae) but increased in non-lipid microdomains compared with controls. Carbachol (10 µM) increased the ratio of non-lipid microdomain to total AQP5 in the cultured control submandibular gland tissue. Taken together, these results indicated that hypersensitive mAChRs might be involved in the epiphora of transplanted submandibular glands by modulating AQP5 trafficking.

Aim: To evaluate clinical outcomes in patients who underwent alcohol-inactivated autograft replantation with joint preservation for the treatment of osteosarcoma of the distal femur., Patients and Methods: 10 patients (7 men, 3 women; mean age: 20.1 years) were treated. 9 patients had Enneking stage IIb tumors and 1 patient had stage III. The mean follow-up time was 34 months. All patients obtained first-stage healing., Results: 1 patient died of local recurrence and multiple metastases 13 months after surgery; 3 patients died of multiple metastases 9, 12, and 24 months after surgery, respectively. 3 patients required second surgery because of fracture of the inactivated autograft, 1 patient died 6 months later, 1 patient experienced bony healing 4 months later with no further complications, and 1 patient required subsequent open reduction and bone implantation with internal fixation (bony healing was evident 6 months later; however, joint instability and limited knee flexion were apparent). At final follow-up, the mean International Society of Limb Salvage (ISOLS) graft score was 31 (87%), whereas the mean Musculoskeletal Tumour Society (MSTS) function score was 23 (77%)., Conclusions: These preliminary findings indicate that alcohol-inactivated autograft replantation with joint preservation may be effective in treating osteosarcoma of the distal femur in some patients. Larger-scale studies are needed to fully evaluate the efficacy/safety of this approach., (© 2014 S. Karger GmbH, Freiburg.)

Aim: The purpose of this study was to analyze histologically the effect of ozone therapy in combination with autogenous bone graft on bone healing in rat calvaria., Methods: Critical size defects were created in calvaria of 27 male Wistar rats. The animals were divided into three groups of nine animals each: autogenous bone graft group (n = 9); autogenous bone graft with ozone therapy group (80%, 30 s 3 d for 2 wk, n = 9); non-treatment (control) group (n = 9). Animals were killed after 8 wk. Histomorphometric assessments, using image analysis software, and histological analyses were performed. Primary outcome was total bone area. Secondary outcomes (osteoblast number, new bone formation) were also measured., Results: Histomorphometrically, the total bone area in the autogenous bone graft with ozone therapy group (9.3 ± 2.2) were significantly higher than that of the autogenous bone graft group (5.1 ± 1.8) (p < 0.05). Also, the ozone therapy group significantly increased the percentage of total bone area compared to the autogenous bone graft group (p < 0.05). The osteoblast number significantly increased in the autogenous bone graft with the ozone therapy group (58 ± 12.3) compared to the autogenous bone graft group (9.3 ± 3.5) (p < 0.05). Also, it was observed that autogenous bone graft with ozone therapy group showed significant new bone formation when compared to the autogenous bone graft group (p < 0.05)., Conclusion: Ozone therapy enhances new bone formation by autogenous bone graft in the rat calvarial defect model., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The most common application of bone grafts is spinal fusion surgery, in which the use of iliac crest autograft is the gold standard. Harvesting of autograft, however, requires an extra surgical procedure, which is associated with additional morbidity. Allograft is the well-known alternative, but it is generally considered less effective in posterior fusions. Therefore, the need for an effective alternative remains. Recently, it was shown that ceramics can be endowed with biologically instructive properties by changing the basic parameters of the material. In this study, we compared a novel tricalcium phosphate ceramic (TCP) to iliac crest autograft and allograft, in instrumented posterolateral fusions in a goat model. A total of nine goats were included, who underwent a two-level lumbar fusion. Each side of the spine was randomized into one type of graft: iliac crest autograft; fresh-frozen allograft; TCP alone; or TCP combined with local autograft (50:50). The fusion rates after 16 weeks were comparable between the groups (autograft 3/8, allograft 4/8, TCP 4/8, and TCP/local autograft 5/8). Calculation of the fusion volume on computed tomography images, showed significantly greater volume in the control groups (autograft 7.8 mL and allograft 8.9 mL) compared with the groups with TCP (TCP 6.1 mL and TCP/local autograft 6.0 mL). No adverse tissue response was seen on histological analysis and TCP was almost completely resorbed. The results demonstrate that TCP is capable of achieving fusion at a similar rate to iliac crest autograft in posterolateral fusions, while almost completely resorbing within 16 weeks. Despite the lower fusion volume, the TCP is a promising alternative circumventing the disadvantages of autograft and allograft.

This study proposes a biodegradable nerve conduit comprising 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) cross-linked gelatin annexed with β-tricalcium phosphate (β-TCP) ceramic particles (EDC-gelatin-TCP, EGT). For this study, the EGT-implant site in rats was irradiated using 660-nm GaAlAsP laser diodes (50 mW) for trigger point therapy to investigate the use of low-level laser (LLL) stimulation in the regeneration of a 15-mm transected sciatic nerve. Animals were divided into three groups: a control group undergoing autologous nerve graft (autograft); a sham-irradiated group (EGT), and an experimental group undergoing laser stimulation (EGT/LS). Two trigger points on the surgical incision along the sciatic nerve were irradiated transcutaneously for 2 min daily for 10 consecutive days. Twelve weeks after implantation, walking track analysis showed a significantly higher sciatic functional index (SFI; p < 0.05) and improved toe spreading development in the autograft and EGT/LS groups, compared to the EGT group. In the electrophysiological measurement, the mean recovery index (peak amplitude and area) of the compound muscle action potential curves in the autograft and EGT/LS groups showed significantly improved functional recovery than in the EGT group (p < 0.05). Compared with the EGT group, the autograft and EGT/LS groups showed a reduction in muscular atrophy. Histomorphometric assessments showed that the EGT/LS group had undergone more rapid nerve regeneration than the EGT group. Therefore, motor function, electrophysiological reaction, muscular reinnervation, and histomorphometric assessments demonstrate that LLL therapy can accelerate the repair of a 15-mm transected peripheral nerve in rats after being bridged with the EGT nerve conduit., (Copyright © 2013 Wiley Periodicals, Inc., a Wiley Company.)