Attenuation of the secondary injury of spinal cord injury (SCI) can suppress the spread of spinal cord tissue damage, possibly resulting in spinal cord sparing that can improve functional prognoses. Granulocyte colony-stimulating factor (G-CSF) is a haematological cytokine commonly used to treat neutropenia. Previous reports have shown that G-CSF promotes functional recovery in rodent models of SCI. Based on preclinical results, we conducted early phase clinical trials, showing safety/feasibility and suggestive efficacy. These lines of evidence demonstrate that G-CSF might have therapeutic benefits for acute SCI in humans. To confirm this efficacy and to obtain strong evidence for pharmaceutical approval of G-CSF therapy for SCI, we conducted a phase 3 clinical trial designed as a prospective, randomized, double-blinded and placebo-controlled comparative trial. The current trial included cervical SCI [severity of American Spinal Injury Association (ASIA) Impairment Scale (AIS) B or C] within 48 h after injury. Patients are randomly assigned to G-CSF and placebo groups. The G-CSF group was administered 400 μg/m2/day × 5 days of G-CSF in normal saline via intravenous infusion for five consecutive days. The placebo group was similarly administered a placebo. Allocation was concealed between blinded evaluators of efficacy/safety and those for laboratory data, as G-CSF markedly increases white blood cell counts that can reveal patient treatment. Efficacy and safety were evaluated by blinded observer. Our primary end point was changes in ASIA motor scores from baseline to 3 months after drug administration. Each group includes 44 patients (88 total patients). Our protocol was approved by the Pharmaceuticals and Medical Device Agency in Japan and this trial is funded by the Center for Clinical Trials, Japan Medical Association. There was no significant difference in the primary end point between the G-CSF and the placebo control groups. In contrast, one of the secondary end points showed that the ASIA motor score 6 months (P = 0.062) and 1 year (P = 0.073) after drug administration tend to be higher in the G-CSF group compared with the placebo control group. Moreover, in patients aged over 65 years old, motor recovery 6 months after drug administration showed a strong trend towards a better recovery in the G-CSF treated group (P = 0.056) compared with the control group. The present trial failed to show a significant effect of G-CSF in primary end point although the subanalyses of the present trial suggested potential G-CSF benefits for specific population.
Peri-implant infection is a serious complication in surgical procedures involving implants. We conducted an in vitro study to determine whether the use of a fluorinated diamond-like carbon (F-DLC) coating on a titanium alloy surface can prevent peri-implant infection. After applying the F-DLC, we evaluated its antibacterial and cytotoxic properties. The coating groups, containing controlled fluorine concentrations of 5.44%, 17.43%, 24.09%, and 30%, were examined for the presence of Staphylococcus aureus and Escherichia coli according to ISO 22196 for the measurement of antibacterial activity on plastics and other nonporous surfaces. Biological toxicity was evaluated using Chinese hamster V79 cells according to ISO 10993-5 for the biological evaluation of medical devices. In the control group, populations of S. aureus and E. coli substantially increased from 2.4 × 104 to (1.45 ± 1.11) × 106 colony-forming units (CFUs) and from 2.54 × 104 to (4.04 ± 0.44) × 106 CFUs, respectively. However, no bacteria colonies were detected in any F-DLC group with a fluorine concentration of ≥ 17.43%. In the biological toxicity study, an F-DLC coating with a fluorine concentration of 30% showed a colony formation rate of 105.8 ± 24.1%, which did not differ significantly from the colony formation rate of 107.5 ± 31.1% in the nontoxic control group. An F-DLC coating on titanium alloy discs showed excellent in vitro antibacterial activity with no biological toxicity.
IntroductionGranulocyte colony-stimulating factor (G-CSF) is generally used for neutropaenia. Previous experimental studies revealed that G-CSF promoted neurological recovery after spinal cord injury (SCI). Next, we moved to early phase of clinical trials. In a phase I/IIa trial, no adverse events were observed. Next, we conducted a non-randomised, non-blinded, comparative trial, which suggested the efficacy of G-CSF for promoting neurological recovery. Based on those results, we are now performing a phase III trial.Methods and analysisThe objective of this study is to evaluate the efficacy of G-CSF for acute SCI. The study design is a prospective, multicentre, randomised, double-blinded, placebo-controlled comparative study. The current trial includes cervical SCI (severity of American Spinal Injury Association (ASIA) Impairment Scale B/C) within 48 hours after injury. Patients are randomly assigned to G-CSF and placebo groups. The G-CSF group is administered 400 µg/m2/day×5 days of G-CSF in normal saline via intravenous infusion for 5 consecutive days. The placebo group is similarly administered a placebo. Our primary endpoint is changes in ASIA motor scores from baseline to 3 months. Each group includes 44 patients (88 total patients).Ethics and disseminationThe study will be conducted according to the principles of the World Medical Association Declaration of Helsinki and in accordance with the Japanese Medical Research Involving Human Subjects Act and other guidelines, regulations and Acts. Results of the clinical study will be submitted to the head of the respective clinical study site as a report after conclusion of the clinical study by the sponsor-investigator. Even if the results are not favourable despite conducting the clinical study properly, the data will be published as a paper.Trial registration numberUMIN000018752.
We fabricated Ti-6Al-7Nb bone scaffolds with 5 mm diameter and 20 mm length comprise of a three-dimensional (3D) honeycomb frame structure of truncated octahedra created by selective laser sintering 3D printing. The honeycomb frame was then coated with 0.1 μm thick diamond-like carbon (DLC) to increase biocompatibility. A round rod of Ti-6Al-7Nb alloy (ASTM F1295) was as a control material. They were implanted into the femur bones of beagles to evaluate bone morphometrics and to investigate changes in the transcriptome of the new bone tissue using DNA microarray analysis and real-time polymerase chain reaction (PCR). In the present report, the 3D honeycomb material with and without DLC film consisting of a-C:H is referred to as 3D_a-C: H and 3D_non, respectively. At 3 weeks after implantation, the 3D_non had more contact between the new and artificial bones compared with the control, and the 3D_a-C: H had more contact between the new and artificial bones compared with the control and 3D_non. Furthermore, 3D_a-C:H showed even more new bone compared with the control and 3D_non. At 8 weeks after implantation, more appeared lamellar bone with the 3D_a-C:H implant than those with the control and 3D_non. The real-time PCR results at 1 week of implantation revealed higher expression levels of VEGF, RANKL, and NOTCH2 expression with 3D_a-C:H than with 3D_non and control. As a result of real-time PCR at 2 weeks of implantation, OPN and CTSK expressions were found to be higher with 3D_a-C:H and 3D_non than that with the control. K E Y W O R D S artificial bone scaffolds, diamond-like carbon coating, osteoconduction, transcriptome analysis 1 | INTRODUCTION Data from the World Population Prospects (2019 Revision) show a significant increase in the number of persons aged 65 years or over in most countries and regions. 1 It is known that motor function disorders caused by aging such as degenerative lumbar spondylolisthesis, degenerative hip osteoarthritis and vertebral compression fractures have been consideredto reduce the quality of life (QOL). 2 Clinically, implants were applied to these conditions and functional restorations were made. [3][4][5][6] In these reports, autogenous bone grafts were used in conjunction with implants to improve the initial fixation of the implants and bone fusion. However, as bone grafting is associated with the sectioning of healthy portions for
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