Safety and aesthetic outcomes of SERASYNTHⓇ MESH BR for direct-to-implant breast reconstruction: A retrospective single center analysis of 32 consecutive cases.

Background: Bilateral mastectomy for both therapeutic and prophylactic reasons is becoming increasingly important. To achieve good results after mastectomy, synthetic meshes are often used as an alternative to acellular dermal matrices (ADMs). The aim of this study is to analyze the results of subcutaneous mastectomies and direct-to-implant breast reconstruction using SERASYNTHⓇ MESH BR. Methods: In this work, data from mastectomies (n = 32) in 22 patients without prior radiation after breast reconstruction with SERASYNTHⓇ MESH BR from a single center were retrospectively analyzed with 1 year follow-up. Complications were categorized as serious (need for revision surgery) and minor events. Statistical analysis was performed using the t-test in SPSS. Data were compared with the existing literature. Results: Major complications occurred in 15.6% (n = 5). Two out of five revisions were due to hematoma. In three cases, a seroma followed by other complications (e.g., infections, necrosis) necessitated revision. Minor complications occurred in 12.5% of cases. Due to the safety aspect, implants were replaced in each revision. There was no significant difference in complication rates between prophylactic and therapeutic mastectomies (p = 0.3815, SE = 0.171). There was no statistically significant difference in esthetic outcomes (p = 0.3846). Conclusion: The application of the absorbable polymer poly-p-dioxanone SERASYNTHⓇ MESH BR has complication rates comparable to those reported in the existing literature. Careful patient selection is paramount in order to limit the complication rate. SERASYNTHⓇ MESH BR can be considered a safe tool to achieve esthetic results in combination with direct-to-implant breast reconstruction.

Microsurgical Reconstruction in Orthopedic Tumor Resections as Part of a Multidisciplinary Surgical Approach for Sarcomas of the Extremities.

A central element of modern sarcoma therapy is complete surgical tumor resection with an adequate safety margin, embedded in an interdisciplinary multimodal therapy concept. Along with ensuring patient survival, functional limb preservation is an important goal for sarcomas of the extremities. This review provides an overview of the relevant literature on indications and goals of reconstructive options, the scope and contribution of microsurgical reconstructive procedures, and the associated interdisciplinary decision making and workup. Furthermore, the impact of (neo)-adjuvant therapy on reconstructive decisions will be highlighted. These aspects will be illustrated by four comprehensive case studies that demonstrate both useful strategies and the need for individually tailored therapies. Nowadays, extremity-preserving therapy is possible in more than 90% of sarcomas. Technical and procedural innovations such as microsurgery and microsurgical reconstructive procedures have significantly contributed to this evolution of therapy.

Comorbidities rather than older age define outcome in adult patients with tumors of the Ewing sarcoma family.

BACKGROUND: Ewing family of tumors (EFT) is rarely diagnosed in patients (pts) over the age of 18 years (years), and data on the clinical course and the outcome of adult EFT pts is sparse. METHODS: In this retrospective analysis, we summarize our experience with adult EFT pts. From 2002 to 2020, we identified 71 pts of whom 58 were evaluable for the final analysis. RESULTS: Median age was 31 years (18-90 years). Pts presented with skeletal (n = 26), and extra-skeletal primary disease (n =32). Tumor size was ≥8 cm in 20 pts and 19 pts were metastasized at first diagnosis. Between the age groups (≤25 vs. 26-40 vs. ≥41 years) we observed differences of Charlson comorbidity index (CCI), tumor origin, as well as type and number of therapy cycles. Overall, median overall survival (OS) was 79 months (95% confidence interval, CI; 28.5-131.4 months), and median progression-free survival (PFS) 34 months (95% CI; 21.4-45.8 months). We observed a poorer outcome (OS, PFS) in older pts. This could be in part due to differences in treatment intensity and the CCI (<3 vs. ≥3; hazard ratio, HR 0.334, 95% CI 0.15-0.72, p = 0.006). In addition, tumor stage had a significant impact on PFS (localized vs. metastasized stage: HR 0.403, 95% CI 0.18-0.87, p = 0.021). CONCLUSIONS: Our data confirms the feasibility of intensive treatment regimens in adult EFT pts. While in our cohort outcome was influenced by age, due to differences in treatment intensity, CCI, and tumor stage, larger studies are warranted to further explore optimized treatment protocols in adult EFT pts.

Hepatic artery reconstruction using an operating microscope in pediatric liver transplantation-Is it worth the effort?

INTRODUCTION: In pediatric liver transplantation (pLT), hepatic artery thrombosis (HAT) is associated with inferior transplant outcome. Hepatic artery reconstruction (HAR) using an operating microscope (OM) is considered to reduce the incidence of HAT. METHODS: HAR using an OM was compared to a historic cohort using surgical loupes (SL) in pLT performed between 2009 and 2020. Primary endpoint was the occurrence of HAT. Secondary endpoints were 1-year patient and graft survival determined by Kaplan-Meier analysis and complications. Multivariate analysis was used to identify independent risk factors for HAT and adverse events. RESULTS: A total of 79 pLTs were performed [30 (38.0%) living donations; 49 (62.0%) postmortem donations] divided into 23 (29.1%) segment 2/3, 32 (40.5%) left lobe, 4 (5.1%) extended right lobe, and 20 (25.3%) full-size grafts. One-year patient and graft survival were both 95.2% in the OM group versus 86.2% and 77.8% in the SL group (p = .276 and p = .077). HAT rate was 0% in the OM group versus 24.1% in the SL group (p = .013). One-year patient and graft survival were 64.3% and 35.7% in patient with HAT, compared to 93.9% and 92.8% in patients with no HAT (both p < .001). Multivariate analysis revealed HAR with SL (p = .022) and deceased donor liver transplantation (DDLT) (p = .014) as independent risk factors for HAT. The occurrence of HAT was independently associated with the need for retransplantation (p < .001) and biliary leakage (p = .045). CONCLUSION: In pLT, the use of an OM is significantly associated to reduce HAT rate, biliary complications, and graft loss and outweighs the disadvantages of delayed arterial perfusion and prolonged warm ischemia time (WIT).

Combination therapy with Olaratumab/doxorubicin in advanced or metastatic soft tissue sarcoma -a single-Centre experience.

BACKGROUND: The antibody targeting platelet-derived growth factor receptor alpha (PDGFRA), olaratumab, was approved in 2016 for metastatic soft tissue sarcoma (STS) in combination with doxorubicin based on promising results of a phase Ib/II trial by the Food and Drug Administration (FDA). However, recently the phase III ANNOUNCE trial could not confirm the additional value of olaratumab in this context. METHODS: Here, in a retrospective analysis we share our single-centre experience with olaratumab/doxorubicin in STS by including n = 32 patients treated with olaratumab/doxorubicin between 2016 and 2019. RESULTS: Median progression-free survival (PFS) in the overall cohort was 3.1 months (range 0.6-16.2). A response [complete remission (CR), partial remission (PR) or stable disease (SD)] was seen in n = 11 (34%) cases, whereas n = 21 (66%) patients showed progressive disease (PD). In n = 9 patients surgery was performed subsequently in an individual therapeutic approach. Out of n = 5 patients receiving additional regional hyperthermia, n = 3 achieved PR or SD. CONCLUSIONS: This single-centre experience does also not support the promising phase Ib/II results for olaratumab/doxorubicin in STS. However, our findings do not preclude that olaratumab combination therapy could be valuable in a neoadjuvant setting. This warrants further exploration also taking into account the heterogeneous nature of STS.

Sequential robotic-assisted lung resection with a subxiphoid utility incision.

For the past two years, the authors have used a subxiphoid utility incision for robot-assisted lobectomies. This approach prevents unnecessary rib pressure, offers a good angle of approach to the hilum, and allows specimen retrieval with minimal resistance. Robot-assisted lung resection is an established technique that facilitates postoperative recovery by minimizing operative trauma and postoperative pain. We believe the subxiphoid utility incision further enhances recovery and facilitates early repeat surgery. We present two cases of staged sequential robot-assisted anatomical lung resection using the same subxiphoid utility incision on each occasion.

Pedicled and free flaps for intrathoracic fistula management.

OBJECTIVES: Intrathoracic fistulae are among the potential sequelae of radiation therapy, empyema and abscess clearance and surgical tumour resections. Interdisciplinary plastic-reconstructive flap surgery is a helpful tool for the successful treatment of intrathoracic fistulae. METHODS: From February 2006 to April 2016, 13 patients (3 females and 10 males) underwent flap surgery for bronchial (n = 5), tracheal (n = 2), oesophageal (n = 2), post-pneumonectomy bronchopleural fistula (n = 2), tracheo-oesophageal (n = 1), gastrobronchial (n = 1) and oesophagobronchial (n = 1) fistulae. Patient characteristics, identified pathogenic micro-organisms, treatment and decision criteria, long-term outcome and postoperative complications were evaluated by analysing patient charts and surgical reports. RESULTS: The mean age of the 13 patients who underwent reconstructive surgery was 55.5 years (range: 42-66 years). The median follow-up time was 31.4 months (range: 2-96 months). American Society of Anaesthesiologists classification was II for 1 patient, III for 8 patients and IV for 4 patients. In total, 18 flaps were performed (7 latissimus dorsi pedicled flaps, 7 pectoralis major pedicled flaps, 2 rectus abdominis myocutaneous flaps, 1 free temporo-parietal fascia flap and 1 intercostal muscle flap). A second flap was indicated in 5 cases (38.5%) due to fistula recurrence; of these, 1 patient developed a bronchial fistula after successful reconstruction of a gastrobronchial fistula. Eight of the 13 patients (61.5%) were evaluated postoperatively at regular intervals for at least 1 year and showed no signs of fistula recurrence. CONCLUSIONS: Our study showed that plastic-reconstructive flap surgery, although associated with significant morbidity and mortality, can be a life-saving tool for intrathoracic fistula reconstruction. CLINICAL TRIAL REGISTRATION: DRKS00010447.

Does the addition of postoperative radiotherapy to adjuvant chemotherapy offer any benefit in patients with non-small cell lung cancer and mediastinal lymphadenopathy?

A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was whether the addition of postoperative radiotherapy (PORT) to adjuvant chemotherapy offers any benefit in patients undergoing curative resection for non-small cell lung cancer found to harbour mediastinal lymphadenopathy. A total of 77 papers were identified using the reported search, of which 11 represented the best evidence to answer the clinical question. Only studies reporting on survival data of patients receiving adjuvant chemotherapy with and without PORT were included in this analysis. The authors, date, journal, country, study type, population, outcomes and key results are tabulated. Six studies reported a statistically significant positive impact of PORT on long-term or disease-free survival (DFS) (P = 0.048-0.0001). Five more studies found no difference in terms of survival between patients receiving and not receiving PORT. Among the 11 studies, only two were randomized controlled, with one of them reporting improved disease-free (P = 0.041) but not overall survival (P = 0.073), while the other finding no difference in survival. Furthermore, three more studies reported on DFS and/or locoregional recurrence of the disease. One of these studies reported a significantly improved DFS among patients receiving PORT (P = 0.003), while two of them reported a reduced rate of locoregional recurrence in this group (P = 0.032-0.009). Many studies report a positive effect of PORT when combined in parallel or sequentially with adjuvant chemotherapy in terms of long-term, disease free survival or locoregional control of the disease in patients who have undergone surgical resection of NSCLC and are found to harbour N2 disease. However, these reports are counterbalanced by an almost equal number of studies which show no difference between PORT and no PORT. Only one study reported significantly increased radiation related adverse effects in patients undergoing chemotherapy and PORT.

A self-made, low-cost infrared system for evaluating the sciatic functional index in mice.

The sciatic functional index (SFI) is a popular parameter for peripheral nerve evaluation that relies on footprints obtained with ink and paper. Drawbacks include smearing artefacts and a lack of dynamic information during measurement. Modern applications use digitized systems that can deliver results with less analytical effort and fewer mice. However, the systems are expensive (€40,000). This study aimed to evaluate the applicability and precision of a self-made, low-cost infrared system for evaluating SFI in mice. Mice were subjected to unilateral sciatic nerve crush injury (crush group; n = 7) and sham operation (sham group; n = 4). They were evaluated on the day before surgery, the 2(nd), 4(th) and 6(th) days after injury, and then every day up to the 23(rd) day after injury. We compared two SFI evaluation methods, i.e., conventional ink-and-paper SFI (C-SFI) and our infrared system (I-SFI). Our apparatus visualized footprints with totally internally reflected infrared light (950 nm) and a camera that can only detect this wavelength. Additionally we performed an analysis with the ladder beam walking test (LBWT) as a reference test. I-SFI assessment reduced the standard deviation by about 33 percent, from 11.6 to 7.8, and cut the variance around the baseline to 21 percent. The system thus requires fewer measurement repetitions and fewer animals, and cuts the cost of keeping the animals. The apparatus cost €321 to build. Our results show that the process of obtaining the SFI can be made more precise via digitization with a self-made, low-cost infrared system.

Electrical Nerve Stimulation Enhances Perilesional Branching after Nerve Grafting but Fails to Increase Regeneration Speed in a Murine Model.

Background Electrical stimulation immediately following nerve lesion helps regenerating axons cross the subsequently grafted nerve repair site. However, the results and the mechanisms remain open to debate. Some findings show that stimulation after crush injury increases axonal crossing of the repair site without affecting regeneration speed. Others show that stimulation after transection and fibrin glue repair doubles regeneration distance. Methods Using a sciatic-nerve-transection-graft in vivo model, we investigated the morphological behavior of regenerating axons around the repair site after unilateral nerve stimulation (20 Hz, 1 hour). With mice expressing axonal fluorescent proteins (thy1-YFP), we were able to calculate the following at 5 and 7 days: percentage of regenerating axons and arborizing axons, branches per axon, and regeneration distance and speed. Results Brief stimulation significantly increases the percentage of regenerating axons (5 days: 35.5 vs. 27.3% nonstimulated, p < 0.05; 7 days: 43.3 vs. 33.9% nonstimulated, p < 0.05), mainly by increasing arborizing axons (5 days: 49.3 [4.4] vs. 33.9 [4.1]% [p < 0.001]; 7 days: 42.2 [5.6] vs. 33.2 [3.1]% [p < 0.001]). Neither branches per arborizing axon nor regeneration speed were affected. Conclusion Our morphological data analysis revealed that electrical stimulation in this model increases axonal crossing of the repair site and promotes homogeneous perilesional branching, but does not affect regeneration speed.

Soft Tissue Sarcomas of the Arm - Oncosurgical and Reconstructive Principles within a Multimodal, Interdisciplinary Setting.

Soft tissue sarcomas of the upper extremity represent a severe threat for the patient and a difficult task for the treatment team. Due to the complex anatomy of the arm, most sarcomas involve valuable functional structures. Nonetheless, a large portion of the patients can be treated in a limb-sparing manner, and surgery is the mainstay of local tumor control. This review gives an overview of the disease entities and their epidemiology, on necessary patient work-up, staging, and imaging modalities, as well as the importance of interdisciplinary decision-making. The surgical therapies and principles of tumor excision are outlined, as well as reconstructive options. Furthermore, adjuvant treatments are discussed with a special focus on the various application techniques for radiation therapy. In spite of established treatment algorithms, each case is an individual challenge and individually tailored therapy is required. This aspect is illustrated by presenting three comprehensive cases demonstrating useful strategies. A summary of the relevant literature is given.

An Integrative Therapeutic Concept for Surgical Treatment of Severe Cases of Lymphedema of the Lower Extremity.

BACKGROUND: Lymphedema results from insufficient lymphatic drainage and typically affects the extremities. Recent studies revealed obesity as another cause of extremity lymphedema. Conservative treatment of patients with elephantiastic lymphedema of the lower extremity is limited and often inadequate. Resecting surgery plays an important role in these cases. Here, we investigated the effects of an integrated therapy concept on outcome and complication rates. METHODS: We retrospectively analyzed the clinical outcome of 26 patients with elephantiastic lymphedema of the lower limb who underwent a complex decongestive physical therapy (CDP) perioperatively and reduction surgery in our clinic between 1998 and 2011. We subsequently compared these patients (group A) with a control group of 30 patients (group B) who received medial thigh lift due to post-bariatric or aesthetic issues between 2011 and 2013. The incidence of complications, reoperations, blood transfusion, and duration of hospital stay was analyzed. All patients in group A received CDP perioperatively in a specialized lymphological clinic. RESULTS: Both groups are comparable in terms of age and sex. Patients significantly differ in terms of BMI (p < 0.001). Thirty-six reductive procedures were performed in group A and 30 in group B. We did not see any significant difference in the incidence of complications (p = 1.000) and the rate of postoperative blood transfusions (p = 0.116). CONCLUSIONS: We were able to show that an integrative concept including surgery is a good additional option for the treatment of severe cases of lymphedema in appropriate candidates. Furthermore, an adequate perioperative conservative setting helps to minimize possible complications.

Is revisional surgery mandatory when an unexpected sarcoma diagnosis is made following primary surgery?

BACKGROUND: Soft tissue sarcomas (STS) are often diagnosed unexpectedly after surgery, and many excisions are incomplete. As histopathological assessments are challenging, patients later referred to comprehensive cancer centers (CCC) often come with an unclear status. This can make treatment planning problematic. We investigated the reliability of primary histopathological assessments, whether revisional surgery improved resection status, and the prognostic value of residual tumor at re-excision. METHODS: We analyzed the demographic and clinical characteristics of all patients referred to our CCC between 2003 and 2013. We compared patients treated exclusively at our CCC with those who had primary surgery elsewhere, and focused on resection margins, re-excision type, residual tumor, resection status after re-excision, and oncological outcome. RESULTS: Over half (n = 110) of all patients (n = 204) were referred from elsewhere. Seventy-one had undergone an excision without suspicion of malignancy. Resection status in referred patients was significantly inferior to the CCC group (p < 0.0001), although the latter had significantly more serious tumors and advanced disease stages (p < 0.05). The residual tumor rate was 53.13%, with a significantly higher probability in an upper extremity (p = 0.001). Initial histopathological classification was misleading in 46.9% of cases. Re-excision improved resection status in 69% of cases. Residual tumor presumably leads to higher rates of local recurrence (p = 0.057) and significantly shorter times to recurrence (p < 0.05). CONCLUSIONS: Re-excision should always follow unplanned STS excisions. Resection margins and histopathological assessments from referring institutions are often unreliable and unsuitable for treatment planning. Residual tumor is a risk factor for earlier and more likely local recurrence.

Fibrin glue repair leads to enhanced axonal elongation during early peripheral nerve regeneration in an in vivo mouse model.

Microsurgical suturing is the gold standard of nerve coaptation. Although literature on the usefulness of fibrin glue as an alternative is becoming increasingly available, it remains contradictory. Furthermore, no data exist on how both repair methods might influence the morphological aspects (arborization; branching) of early peripheral nerve regeneration. We used the sciatic nerve transplantation model in thy-1 yellow fluorescent protein mice (YFP; n = 10). Pieces of nerve (1cm) were grafted from YFP-negative mice (n = 10) into those expressing YFP. We performed microsuture coaptations on one side and used fibrin glue for repair on the contralateral side. Seven days after grafting, the regeneration distance, the percentage of regenerating and arborizing axons, the number of branches per axon, the coaptation failure rate, the gap size at the repair site and the time needed for surgical repair were all investigated. Fibrin glue repair resulted in regenerating axons travelling further into the distal nerve. It also increased the percentage of arborizing axons. No coaptation failure was detected. Gap sizes were comparable in both groups. Fibrin glue significantly reduced surgical repair time. The increase in regeneration distance, even after the short period of time, is in line with the results of others that showed faster axonal regeneration after fibrin glue repair. The increase in arborizing axons could be another explanation for better functional and electrophysiological results after fibrin glue repair. Fibrin glue nerve coaptation seems to be a promising alternative to microsuture repair.

N-Propionylmannosamine stimulates axonal elongation in a murine model of sciatic nerve injury.

Increasing evidence indicates that sialic acid plays an important role during nerve regeneration. Sialic acids can be modified in vitro as well as in vivo using metabolic oligosaccharide engineering of the N-acyl side chain. N-Propionylmannosamine (ManNProp) increases neurite outgrowth and accelerates the reestablishment of functional synapses in vitro. We investigated the influence of systemic ManNProp application using a specific in vivo mouse model. Using mice expressing axonal fluorescent proteins, we quantified the extension of regenerating axons, the number of regenerating axons, the number of arborising axons and the number of branches per axon 5 days after injury. Sciatic nerves from non-expressing mice were grafted into those expressing yellow fluorescent protein. We began a twice-daily intraperitoneal application of either peracetylated ManNProp (200 mg/kg) or saline solution 5 days before injury, and continued it until nerve harvest (5 days after transection). ManNProp significantly increased the mean distance of axonal regeneration (2.49 mm vs. 1.53 mm; P < 0.005) and the number of arborizing axons (21% vs. 16%; P = 0.008) 5 days after sciatic nerve grafting. ManNProp did not affect the number of regenerating axons or the number of branches per arborizing axon. The biochemical glycoengineering of the N-acyl side chain of sialic acid might be a promising approach for improving peripheral nerve regeneration.

In Situ Deactivation of Interleukin-6 Enhances Early Peripheral Nerve Regeneration in a Murine Injury Model.

BACKGROUND: Systemic alteration of interleukin-6 (IL-6) influences peripheral nerve regeneration. We investigated the potential influences of in situ (at the coaptation site) IL-6 modulation in a peripheral-nerve-transection/sciatic-nerve-graft in vivo model. METHODS: We quantified the elongation of regenerating axons, the number of arborizing axons, and the number of branches per arborizing axon 7 days after the injury in mice expressing axonal fluorescent proteins (thy-1-YFP mice). Sciatic nerves from nonexpressing mice (C57Bl6 or IL-6(-/-) mice) were grafted into those expressing yellow fluorescent protein. We altered the in situ IL-6 concentration by loading a topical gelatin sponge with an inhibiting IL-6 receptor antibody or IL-6 combined with a soluble IL-6 receptor. Sciatic nerves from IL-6(-/-) mice were grafted into an additional group. The contralateral sham-operated side served as control in all the groups. RESULTS: Axonal elongation increased significantly with the in situ application of the IL-6 receptor antibody, while topical IL-6 significantly reduced the regeneration distance. The number of arborizing axons increased significantly in nerves grafted from IL-6(-/-) mice, whereas branches per arborizing axons remained stable. CONCLUSION: In situ IL-6 receptor inhibition and IL-6(-/-) nerve grafting enhance early peripheral nerve regeneration in an acute murine injury model.

Second intercostal internal mammary artery perforator (IMAP) fasciocutaneous flap as an alternative choice for the treatment of deep sternal wound infections (DSWI).

Sternal wound infections after sternotomy are associated with high morbidity, high mortality and escalating treatment costs. Repeated radical debridement - with the removal of any hardware - and wound conditioning are the prerequisites for reconstruction. Muscle and, less frequently, omentum flaps are usually used for reconstruction. However, these flaps are associated with considerable donor-site morbidity, long operation times and aesthetic impairment. Fasciocutaneous flaps seem to be an alternative. This study presents our experience of using the second intercostal mammary artery fasciocutaneous perforator flap for defect closure in nine patients (mean age: 70.2 years). Following a retrospective chart review, we assessed data on patient demographics, the type of cardiac surgery, the prevalence of deep sternal wound infection (DSWI) risk factors, identified pathogens, surgery duration, hospitalization tim patients had undergone coronary artery bypass surgery, and two had valve replacements. The mean duration of surgery (121.4 ± 39 min) was short. The patients had a mean body mass index (BMI) of 32.8 ± 4.9 kg/m(2). An average flap size of 124 ± 22 cm(2) sufficiently covered and obliterated each defect. One mediastinal haematoma required revision surgery. One wound dehiscence at the flap and two at the donor site were managed conservatively. Our experience reveals that a fasciocutaneous flap based on the second intercostal perforator of the internal mammary artery can be an alternative, quick-to-prepare flap for covering sternal defects. In adipose patients, it has sufficient bulk, and it is large enough to cover common sternal wounds. It also has low complication and morbidity rates, and it achieves an aesthetically pleasing result.

Utilization of a genetically modified muscle flap for local BMP-2 production and its effects on bone healing: a histomorphometric and radiological study in a rat model.

AIM OF THE STUDY: We developed an experimental rat model to explore the possibility of enhancing the healing of critical-size bone defects. The aim of this study was to demonstrate the feasibility of this concept by achieving high local BMP-2 expression via a transduced muscle flap that would facilitate bony union while minimizing systemic sequelae. METHODS: The transduction potential of the adenoviral vector encoding for BMP-2 was tested in different cell lines in vitro. In vivo experiments consisted of harvesting a pedicled quadriceps femoris muscle flap with subsequent creation of a critical-size defect in the left femur in Sprague-Dawley rats. Next, the pedicled muscle flap was perfused with high titers of Ad.BMP-2 and Ad.GFP virus, respectively. Twelve animals were divided into three groups comparing the effects of Ad.BMP-2 transduction to Ad.GFP and placebo. Bone healing was monitored radiologically with subsequent histological analysis post-mortem. RESULTS: The feasibility of this concept was demonstrated by successful transduction in vitro and in vivo as evidenced by a marked increase of BMP-2 expression. The three examined groups only showed minor difference regarding bone regeneration; however, one complete bridging of the defect was observed in the Ad.BMP-2 group. No evidence of systemic viral contamination was noted. CONCLUSIONS: A marked increase of local BMP-2 expression (without untoward systemic sequelae) was detected. However, bone healing was not found to be significantly enhanced, possibly due to the small sample size of the study.

In vivo stimulation of early peripheral axon regeneration by N-propionylmannosamine in the presence of polysialyltransferase ST8SIA2.

The key enzyme of sialic acid (Sia) biosynthesis is the bifunctional UDP-N-acetylglucosamine 2-epimerase/ManNAc kinase (GNE/MNK). It metabolizes the physiological precursor ManNAc and N-acyl modified analogues such as N-propionylmannosamine (ManNProp) to the respective modified sialic acid. Polysialic acid (polySia) is a crucial compound for several functions in the nervous system and is synthesized by the polysialyltransferases ST8SIA2 and ST8SIA4. PolySia can be modified in vitro and in vivo by metabolic glycoengineering of the N-acyl side chain of Sia. In vitro studies show that the application of ManNProp increases neurite outgrowth and accelerates the re-establishment of functional synapses. In this study, we investigate in vivo how ManNProp application might benefit peripheral nerve regeneration. In mice expressing axonal fluorescent proteins (thy-1-YFP), we transected the sciatic nerve and then replaced part of it with a sciatic nerve graft from non-expressing mice (wild-type mice or St8sia2(-/-) mice). Analyses conducted 5 days after grafting showed that systemic application of ManNProp (200 mg/kg, twice a day, i.p.), but not of physiological ManNAc (1 g/kg, twice a day, i.p.), significantly increased the extent of axonal elongation, the number of arborizing axons and the number of branches per regenerating axon within the grafts from wild-type mice, but not in those from St8sia2(-/-) mice. The results demonstrate that the application of ManNProp has beneficial effects on early peripheral nerve regeneration and indicate that the stimulation of axon growth depends on ST8SIA2 activity in the nerve graft.