Osseointegrative effect of rhBMP-2 covalently bound on a titan-plasma-spray-surface after modification with chromosulfuric acid in a large animal bone gap-healing model with the Göttingen minipig

Background: Bone morphogenetic proteins play an important role as osseointegrative factors. It is used widely in orthopedic research and surgery to enhance the osseointegrative potential of implants, e.g., in spinal fusion or alveolar socket augmentation. The aim of the present study was to investigate the benefit of rhBMP-2 on a titan plasma spray (TPS) layer after a special modification with chromosulfuric acid (CSA) at different postoperative times, regarding osseoconduction and osseoinduction. Methods: We allocated 27 Göttinger minipigs into three groups consisting of nine animals each. They received four dumbbell-shaped implants in the metaphyseal parts of the femora. The implants had a TPS surface with (CSA group) and without a CSA treatment (TPS group). The former received an additional layer of BMP-2 (BMP-2 group). For the assessment of osseointegration after healing periods of 4, 8, and 12 weeks, histomorphometry was applied to undecalcified specimens after staining according to Masson-Goldner. An intravital labeling with different fluorochromes was used in the gap model. A multivariable analysis with repeated measurement design was performed for statistical evaluation. Results: We observed several statistical differences in a three-way ANOVA. The comparison between the BMP-2 and the TPS group (two-way ANOVA) showed statistically significant differences in terms of the osseoinduction (osteoid volume), and pronounced for the osseoconduction (bone and osteoid ongrowth), in favor of the BMP-2 group. In the pairwise comparison between BMP-2 and CSA (two-way ANOVA), no statistical significance occurred. The intravital staining with tetracycline, calcein green, and xylenol orange revealed no considerable differences between the groups. Conclusion: BMP-2, covalently bound on a CSA-treated TPS surface, has positive effects on the osseointegration in the large animal bone gap-healing model over the observation period of 12 weeks

Analysis of the osseointegrative force of a hyperhydrophilic and nanostructured surface refinement for TPS surfaces in a gap healing model with the Göttingen minipig

Background: A lot of advantages can result in a high wettability as well as a nanostructure at a titanium surface on bone implants. Thus, the aim of this study was to evaluate the osseointegrative potential of a titan plasma-sprayed (TPS) surface refinement by acid-etching with chromosulfuric acid. This results in a hyperhydrophilic surface with a nanostructure and an extreme high wetting rate. Methods: In total, 72 dumbbell shape titan implants were inserted in the spongy bone of the femora of 18 Göttingen minipigs in a conservative gap model. Thirty-six titan implants were coated with a standard TPS surface and 36 with the hyperhydrophilic chromosulfuric acid (CSA) surface. After a healing period of 4, 8, and 12 weeks, the animals were killed. The chronological healing process was histomorphometrically analyzed. Results: The de novo bone formation, represented by the bone area (BA), is increased by approximately 1.5 times after 12 weeks with little additional benefit by use of the CSA surface. The bone-to-implant contact (BIC), which represents osseoconductive forces, shows results with a highly increased osteoid production in the CSA implants beginning at 8 and 12 weeks compared to TPS. This culminates in a 17-fold increase in BIC after a healing period of 12 weeks. After 4 weeks, significantly more osteoid was seen in the gap as de novo formation in the CSA group (p = 0.0062). Osteoid was also found more frequently after 12 weeks at the CSA-treated surface (p = 0.0355). The site of implantation, intertrochanteric or intercondylar, may influence on the de novo bone formation in the gap. Conclusions: There is a benefit by the CSA surface treatment of the TPS layer for osseointegration over an observation time up to 12 weeks. Significant differences were able to be shown in two direct comparisons between the CSA and the TPS surface for osteoid formation in the gap model. Further trials may reveal the benefit of the CSA treatment of the TPS layer involving mechanical tests if possible

Kypho-IORT - a novel approach of intraoperative radiotherapy during kyphoplasty for vertebral metastases

<p>Abstract</p> <p>Background</p> <p>Instable and painful vertebral metastases in patients with progressive visceral metastases present a common therapeutic dilemma. We developed a novel approach to deliver intraoperative radiotherapy (IORT) during kyphoplasty and report the first treated case.</p> <p>Methods/Results</p> <p>60 year old patient with metastasizing breast cancer under chemotherapy presented with a newly diagnosed painful metastasis in the 12^ththoracic vertebra. Under general anaesthesia, a bipedicular approach into the vertebra was chosen with insertion of specially designed metallic sleeves to guide the electron drift tube of the miniature X-ray generator (INTRABEAM, Carl Zeiss Surgical, Oberkochen, Germany). This was inserted with a novel sheet designed for this approach protecting the drift tube. A radiation dose of 8 Gy in 5 mm distance (50 kV X-rays) was delivered. The kyphoplasty balloons (KyphX, Kyphon Inc, Sunnyvale) were inflated after IORT and polymethylmethacrylate cement was injected. The whole procedure lasted less than 90 minutes.</p> <p>Conclusion</p> <p>In conclusion, this novel, minimally invasive procedure can be performed in standard operating rooms and may become a valuable option for patients with vertebral metastases providing immediate stability and local control. A phase I/II study is under way to establish the optimal dose prescription.</p

Combined kyphoplasty and intraoperative radiotherapy (Kypho-IORT) versus external beam radiotherapy (EBRT) for painful vertebral metastases - a randomized phase III study

Background: The spine is the most frequent location of bone metastases. Local treatment aims at palliation of pain and, given the increased likelihood of long-term cancer survival, at local control. Kyphoplasty and intraoperative radiotherapy (Kypho-IORT) provided instantaneous pain relief in 70% of patients at the first day after the intervention and resulted in local control rates of &gt; 93% at 1 year in a recently conducted phase I/II trial. To assess its clinical value, we designed a phase III trial which tests Kypho-IORT against the most widespread standard-of-care, external beam radiotherapy (EBRT), in patients with painful vertebral metastases. Methods: This phase III study includes patients ≥50 years of age with up to 4 vertebral metastases and a pain score of at least 3/10 points on the visual/numeric analogy scale (VAS). Patients randomized into the experimental arm (A) will undergo Kypho-IORT (Kyphoplasty plus IORT with 8 Gy prescribed to 13 mm depth). Patients randomized into the control arm (B) will receive EBRT with either 30 Gy in 10 fractions or 8 Gy as a single dose. The primary end point is pain reduction defined as at least − 3 points on the VAS compared to baseline at day 1. Assuming that 40% of patients in the Kypho-IORT arm and 5% of patients in the control arm will achieve this reduction and 20% will drop out, a total of 54 patients will have to be included to reach a power of 0.817 with a two-sided alpha of 0.05. Secondary endpoints are evaluation of the percentage of patients with a pain reduction of at least 3 points at 2 and 6 weeks, local tumor control, frequency of re-intervention, secondary fractures/sintering, complication rates, skin toxicity/wound healing, progression-free survival (PFS), overall survival (OS) and quality of life. Discussion: This trial will generate level 1 evidence on the clinical value of a one-stop procedure which may provide instantaneous pain relief, long-term control and shortened intervals to further adjuvant (systemic) therapies in patients with spinal metastases. Trial registration Registered with ClinicalTrials.gov, number: NCT02773966. Registration date: 05/16/2016

The IceCube Neutrino Observatory, the Pierre Auger Observatory and the Telescope Array: Joint Contribution to the 34th International Cosmic Ray Conference (ICRC 2015)

We have conducted three searches for correlations between ultra-high energy cosmic rays detected by the Telescope Array and the Pierre Auger Observatory, and high-energy neutrino candidate events from IceCube. Two cross-correlation analyses with UHECRs are done: one with 39 cascades from the IceCube `high-energy starting events' sample and the other with 16 high-energy `track events'. The angular separation between the arrival directions of neutrinos and UHECRs is scanned over. The same events are also used in a separate search using a maximum likelihood approach, after the neutrino arrival directions are stacked. To estimate the significance we assume UHECR magnetic deflections to be inversely proportional to their energy, with values $3^\circ$, $6^\circ$ and $9^\circ$ at 100 EeV to allow for the uncertainties on the magnetic field strength and UHECR charge. A similar analysis is performed on stacked UHECR arrival directions and the IceCube sample of through-going muon track events which were optimized for neutrino point-source searches.Comment: one proceeding, the 34th International Cosmic Ray Conference, 30 July - 6 August 2015, The Hague, The Netherlands; will appear in PoS(ICRC2015

Update on the Combined Analysis of Muon Measurements from Nine Air Shower Experiments

Over the last two decades, various experiments have measured muon densities in extensive air showers over several orders of magnitude in primary energy. While some experiments observed differences in the muon densities between simulated and experimentally measured air showers, others reported no discrepancies. We will present an update of the meta-analysis of muon measurements from nine air shower experiments, covering shower energies between a few PeV and tens of EeV and muon threshold energies from a few 100 MeV to about 10GeV. In order to compare measurements from different experiments, their energy scale was cross-calibrated and the experimental data has been compared using a universal reference scale based on air shower simulations. Above 10 PeV, we find a muon excess with respect to simulations for all hadronic interaction models, which is increasing with shower energy. For EPOS-LHC and QGSJet-II.04 the significance of the slope of the increase is analyzed in detail under different assumptions of the individual experimental uncertainties

The IceCube Neutrino Observatory, the Pierre Auger Observatory and the Telescope Array:Joint Contribution to the 34th International Cosmic Ray Conference (ICRC 2015)

We have conducted three searches for correlations between ultra-high energy cosmic rays detected by the Telescope Array and the Pierre Auger Observatory, and high-energy neutrino candidate events from IceCube. Two cross-correlation analyses with UHECRs are done: one with 39 cascades from the IceCube `high-energy starting events' sample and the other with 16 high-energy `track events'. The angular separation between the arrival directions of neutrinos and UHECRs is scanned over. The same events are also used in a separate search using a maximum likelihood approach, after the neutrino arrival directions are stacked. To estimate the significance we assume UHECR magnetic deflections to be inversely proportional to their energy, with values $3^\circ$, $6^\circ$ and $9^\circ$ at 100 EeV to allow for the uncertainties on the magnetic field strength and UHECR charge. A similar analysis is performed on stacked UHECR arrival directions and the IceCube sample of through-going muon track events which were optimized for neutrino point-source searches