Synthesis of multifunctional chlorhexidine-doped thin films for titanium-based implant materials
MATERIALS SCIENCE & ENGINEERING C-MATERIALS FOR BIOLOGICAL APPLICATIONS
Authors: Matos, Adaias Oliveira; de Almeida, Amanda Bandeira; Beline, Thamara; Tonon, Caroline C.; Viana Casarin, Renato Correa; Windsor, Lester Jack; Duarte, Simone; Nociti Jr, Francisco Humberto; Rangel, Elidiane Cipriano; Gregory, Richard L.; Ricardo Barao, Valentim Adelino
Abstract
Our goal was to create bio-functional chlorhexidine (CHX)-doped thin films on commercially pure titanium (cpTi) discs using the glow discharge plasma approach. Different plasma deposition times (50, 35 and 20 min) were used to create bio-functional surfaces based on silicon films with CHX that were compared to the control groups [no CHX and bulk cpTi surface (machined)]. Physico-chemical and biological characterizations included: 1. Morphology, roughness, elemental chemical composition, film thickness, contact angle and surface free energy; 2. CHX-release rate; 3. Antibacterial effect on Streptococcus sanguinis biofilms at 24, 48 and 72 h; 4. Cytotoxicity and metabolic activity using fibroblasts cell culture (NIH-F3T3 cells) at 1, 2, 3 and 4 days; 5. Protein expression by NIH-F3T3 cells at 1, 2, 3 and 4 days; and 6. Co-culture assay of fibroblasts cells and S. sanguinis to assess live and dead cells on the confocal laser scanning microscopy, mitochondrial activity (XTT), membrane leakage (LDH release), and metabolic activity (WST-1 assay) at 1, 2 and 3 days of co-incubation. Data analysis showed that silicon films, with or without CHX coated cpTi discs, increased surface wettability and free energy (p < 0.05) without affecting surface roughness. CHX release was maintained over a 22-day period and resulted in a significant inhibition of biofilm growth (p < 0.05) at 48 and 72 h of biofilm formation for 50 min and 20 min of plasma deposition time groups, respectively. In general, CHX treatment did not significantly affect NIH-F3T3 cell viability (p > 0.05), whereas cell metabolism (MTT assay) was affected by CHX, with the 35 min of plasma deposition time group displaying the lowest values as compared to bulk cpTi (p < 0.05). Moreover, data analysis showed that films, with or without CHX, significantly affected the expression profile of inflammatory cytokines, including IL-4, IL-6, IL-17, IFN-y and TNF-alpha by NIH-F3T3 cells (p < 0.05). Co-culture demonstrated that CHX-doped film did not affect the metabolic activity, cytotoxicity and viability of fibroblasts cells (p > 0.05). Altogether, the findings of the current study support the conclusion that silicon films added with CHX can be successfully created on titanium discs and have the potential to affect bacterial growth and inflammatory markers without affecting cell viability/proliferation rates.
Data Mining for Adverse Events of Tumor Necrosis Factor-Alpha Inhibitors in Pediatric Patients: Tree-Based Scan Statistic Analyses of Danish Nationwide Health Data
CLINICAL DRUG INVESTIGATION
Authors: Wintzell, Viktor; Svanstrom, Henrik; Melbye, Mads; Ludvigsson, Jonas F.; Pasternak, Bjorn; Kulldorff, Martin
Abstract
Background and Objectives Tumor necrosis factor-alpha (TNF-alpha) inhibitors are efficacious and considered generally safe in adults. However, pediatric-specific safety evidence is scarce. The aim of this study was to screen for signals of previously unknown adverse events of TNF-alpha inhibitors in pediatric patients. Methods We conducted a data-mining study based on routinely collected, nationwide Danish healthcare data for 2004-2016. Using tree-based scan statistics to identify events with unexpectedly high incidence during TNF-alpha inhibitor use among patients with inflammatory bowel disease or juvenile idiopathic arthritis, two analyses were performed: comparison with episodes of no use and with other time periods from the same patient. Based on incident physician-assigned diagnosis codes from outpatient and inpatient visits in specialist care, we screened thousands of potential adverse events while adjusting for multiple testing. Results We identified 1310 episodes of new TNF-alpha inhibitor use that met the eligibility criteria. Two signals of adverse events of TNF-alpha inhibitors, as compared with no use, were detected. First, there were excess events of dermatologic complications (ICD-10: L00-L99, 87 vs. 44 events, risk difference [RD] 3.3%), which have been described previously in adults and children. Second, there were excess events of psychiatric diagnosis adjustment disorders (ICD-10: F432, 33 vs. 7 events, RD 2.0%), which was likely associated with the underlying disease and its severity, rather than with the treatment. The self-controlled analysis generated no signal. Conclusions No signals of previously unknown adverse events of TNF-alpha inhibitors in pediatric patients were detected. The study showed that real-world data and newly developed methods for adverse events data mining can play a particularly important role in pediatrics where pre-approval drug safety data are scarce.