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Dental resins represent an important family of biomaterials that have been evolving in response to the needs in biocompatibility and mechanical properties. They are composite materials consisting of mostly inorganic fillers and additives bound together with a polymer matrix. A large number of fillers in a variety of forms (spheroidal, fibrous, porous, etc.) along with other additives have been studied to enhance the performance of the composites. Silane derivatives are attached as coupling agents to the fillers to improve their interfacial properties. A review of the literature on dental composite fillers seems to suggest that each of the fillers tested presents its own strengths and weaknesses, and often combinations of these yield resin composites with the desired balance of properties. Additives such as nanotubes, whiskers, fibers, and nanoclusters have been shown to enhance the properties of these hybrid materials, and their use in small fractions may enhance the overall performance of the dental resin materials.

Objectives The aim of this study is to evaluate the packing properties of uniform silica particles and their mixture with secondary particles yielding maximally loaded dental composites. We intend to verify the difference between the idealized models (the close-packed structures and the random-packed structures) and the actual experimental results, in order to provide guidance for the preparation of dental composites. The influence of secondary particle size and the resin composition on the physical–mechanical properties and the rheological properties of the experimental dental composites was also investigated. Methods Silica particles (S-920, S-360, and S-195) with average diameters of 920, 360, and 195 nm were synthesized via the Stober process. Their morphology and size distribution were determined by field-emission scanning electron microscopy and laser particle sizer. A series of silica fillers, S-920, S-920+195, S-920+360, and S-920+360+195, were then formulated with two Bis-GMA/TEGDMA resins (weight ratios of 70:30 and 50:50). For these experimental dental composites, their maximum filler loadings were assessed and compared to the theory. The mechanical properties, degree of conversion, depth of cure, and polymerization shrinkage of these composites were then evaluated. Their rheological behaviors were measured with a rheometer. Results Unimodal S-920 had the maximally filler loading of 70.80 wt% with the 5B5T resin, close to the theoretical estimation of the random loose packing (71.92 wt%). The maximum loading of the S-920+360+195 filled composite was 72.92 wt% for the same resin, compared to the theoretical estimation of 89.29 wt% obtained for the close-packed structures. These findings indicate that random loose packing matches more closely to the real packing state for the filler formulations used. When maximally loaded, the composite with S-920+360+195 produced the best mechanical properties and the lowest polymerization shrinkage. The degree of conversion and depth of cure were higher with secondary particles added, and the viscosity of all unpolymerized pastes exhibited shear thinning behavior. Significance Theoretical estimations of filler packing structures provide a useful guidance in the design of multimodal filler formulations and the preparation of dental composites with higher filler loading, improved physical–mechanical properties.

The properties of the dental resin composites have been studied extensively with several different methods including infrared and Raman spectroscopy, volume dilatometry, and mechanical analyses. Photo-calorimetry has also been used to measure the kinetics and extent of polymerization, but many of the variables associated with this technique remain to be fully defined and tested to enable quick and reproducible measurements under clinically relevant conditions. We have systematically varied the sample mass, light intensity, temperature, nitrogen purge time, and examined their effects on the monomer conversion and polymerization kinetics with the aim to optimize and standardize the photo-DSC method for the study of dental resins. A post-cure isothermal baseline at 37 °C yielded reproducible results. This systematic study detailing the effects of several variables of photo-calorimetry allows its direct use as a standard method to study polymerization kinetics and monomer conversion of dental resins and other photo-curable materials.

Objective The aim of this work is to explore the reinforcing effect of wrinkled mesoporous silica (WMS), which should allow micromechanical resin matrix/filler interlocking in dental resin composites, and to investigate the effect of silica morphology, loading, and compositions on their mechanical properties. Methods WMS (average diameter of 496 nm) was prepared through the self-assembly method and characterized by the use of the electron microscopy, dynamic light scattering, and the N2 adsorption–desorption measurements. The mechanical properties of resin composites containing silanized WMS and nonporous smaller silica were evaluated with a universal mechanical testing machine. Field-emission scanning electron microscopy was used to study the fracture morphology of dental composites. Resin composites including silanized silica particles (average diameter of 507 nm) served as the control group. Results Higher filler loading of silanized WMS substantially improved the mechanical properties of the neat resin matrix, over the composites loaded with regular silanized silica particles similar in size. The impregnation of smaller secondary silica particles with diameters of 90 and 190 nm, denoted respectively as Si90 and Si190, increased the filler loading of the bimodal WMS filler (WMS-Si90 or WMS-Si190) to 60 wt%, and the corresponding composites exhibited better mechanical properties than the control fillers made with regular silica particles. Among all composites, the optimal WMS-Si190- filled composite (mass ratio WMS:Si190 = 10:90, total filler loading 60 wt%) exhibited the best mechanical performance including flexural strength, flexural modulus, compressive strength and Vickers microhardness. Significance The incorporation of WMS and its mixed bimodal fillers with smaller silica particles led to the design and formulation of dental resin composites with superior mechanical properties.

Objectives The aim of this study was to formulate resin-based composites using spherical silica particulate fillers with graded size (75, 150, 350, 500, and 1000 nm), and to evaluate the influence of their size and loading on the mechanical and light transmission properties of the resulting material. Methods A series of five spherical silica fillers were synthesized, and then formulated with BisGMA/TEGDMA or UDMA/TEGDMA resins. These were then tested for maximum filler loading, flexural strength and modulus, as well as transparency and depth of cure. Results Low dispersity spherical silica particles of 75, 150, 350, 500, and 1000 nm were synthesized. Maximum loading was 70 wt% for the three largest particle, and decreased for the smaller sizes, where UDMA-based resins allowed slightly higher loading. When maximally loaded, the largest particle sizes produced the highest flexural properties. However, when using the same loading, all filler sized produced similar flexural strengths and moduli. The optical properties and depth of cure were increased as the filler size decreased. Significance While hybrid filler particles are the norm in commercial materials, by studying and understanding the influence of individual components on the material properties, we can finely tune the properties of the materials as desired.

Objective The inorganic filler particles in dental resin composites serve to improve their mechanical properties and reduce polymerization shrinkage during their use. Efforts have been made in academia and industry to increase the filler particle content, but, few studies examine the theoretical basis for the maximum particle loading. Methods This work evaluates the packing of spherical particles in a close-packed state for highly loaded composites. Results Calculations show that for low dispersity particles, the maximum amount of particles is 74.05 vol%, regardless of the particle size. This can be further improved by using a mix of large and small particles or by the use of non-spherical particles. For representative spherical particles with a diameter of 1000 nm, two types of secondary particles with respective sizes of 414 nm (dI) and 225 nm (dII) are selected. The results show that after embedding secondary particles I & II into primary spherical particles, the packing factor is increased to 81.19% for the close-packed structures, which shows an improvement of 9.64%, compared to the 74.05% obtained only with primary spherical particles. This packing factor is also higher than either structure with the embedded secondary particles I or II. Significance Examples of these mixtures with different spherical particle sizes are shown as a theoretical estimation, serving as a guideline for the design and formulation of new dental resin composites with better properties and improved performance.

Objective The viscosity of dental resin composites is important in their formulation and clinical use; it depends on the filler particle size and loading. We intend to study the viscosity and conversion of composites made of low dispersity spherical silica fillers. Methods Experimental dental resin composites were formulated using low dispersity spherical silica particles of graded sizes (75, 150, 500, 350, 500, 1000 nm) at several loading levels with resins based on Bis-GMA and UDMA. Their rheological properties and double bond conversion were measured with a rheometer and differential scanning calorimeter, respectively. Results The complex viscosity of the unpolymerized pastes can be fit to an extended Krieger–Dougherty equation that includes an adjustment factor to account for filler particle surface area. This relationship is also extended to estimate the degree of conversion, where the calculated or experimental viscosity is used to predict the resulting conversion. Significance The enhanced understanding of the relationship of filler size, composite viscosity, and monomer conversion will allow improved accuracy in the prediction of the properties of dental resin composite formulations to obtain ideal viscosity for their clinical use and a high degree of conversion.

In this study, quartz fibres (QFs) surface modification using a sol-gel method was proposed and dental posts reinforced with modified QFs were produced. A silica sol (SS) was prepared using tetraethoxysilane (TEOS) and 3-methacryloxypropyltrimethoxysilane (γ-MPS) as precursors. The amount of γ-MPS in the sol-gel system was varied from 0 to 24 wt.% with a constant molar ratio of TEOS, ethanol, deionized water, and HCl. Thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FT-IR), and contact angle (CA) measurements were used to characterize the modified QFs, which confirmed that SS had successfully coated the surface of QFs. SEM images showed good interfacial bonding between the modified QFs and the resin matrix. The results of three-point bending tests of the fibre reinforced composite (FRC) posts showed that the QFs modified by SS with 12 wt.% γ-MPS presented the best mechanical properties, demonstrating improvements of 108.3% and 89.6% for the flexural strength and flexural modulus, respectively, compared with untreated QFs. Furthermore, the sorption and solubility of the prepared dental posts were also studied by immersing the posts in artificial saliva (AS) for 4 weeks, and yielded favourable results. This sol-gel surface modification method promises to resolve interfacial bonding issues of fibres with the resin matrix, and produce FRC posts with excellent properties.

Pantothenamides are N-substituted pantothenate derivatives which are known to exert antimicrobial activity through interference with coenzyme A (CoA) biosynthesis or downstream CoA-utilizing proteins. A previous report has shown that replacement of the ProR methyl group of the benchmark N-pentylpantothenamide with an allyl group (R-anti configuration) yielded one of the most potent antibacterial pantothenamides reported so far (MIC of 3.2 μM for both sensitive and resistant Staphylococcus aureus). We describe herein a synthetic route for accessing the corresponding R-syn diastereomer using a key diastereoselective reduction with Baker’s yeast, and report on the scope of this reaction for modified systems. Interestingly, whilst the R-anti diastereomer is the only one to show antibacterial activity, the R-syn isomer proved to be significantly more potent against the malaria parasite (IC50 of 2.4 ± 0.2 μM). Our research underlines the striking influence that stereochemistry has on the biological activity of pantothenamides, and may find utility in the study of various CoA-utilizing systems.

The coenzyme A (CoA) biosynthetic enzymes have been used to produce various CoA analogues, including mechanistic probes of CoA-dependent enzymes such as those involved in fatty acid biosynthesis. These enzymes are also important for the activation of the pantothenamide class of antibacterial agents, and of a recently reported family of antibiotic resistance inhibitors. Herein we report a study on the selectivity of pantothenate kinase, the first and rate limiting step of CoA biosynthesis. A robust synthetic route was developed to allow rapid access to a small library of pantothenate analogs diversified at the β-alanine moiety, the carboxylate or the geminal dimethyl group. All derivatives were tested as substrates of Escherichia coli pantothenate kinase (EcPanK). Four derivatives, all N-aromatic pantothenamides, proved to be equivalent to the benchmark N-pentylpantothenamide (N5-pan) as substrates of EcPanK, while two others, also with N-aromatic groups, were some of the best substrates reported for this enzyme. This collection of data provides insight for the future design of PanK substrates in the production of useful CoA analogues.

Cancer cells adapt to high levels of oxidative stress in order to survive and proliferate, making the transcription factors involved in antioxidant defense regulation targets of interest. The transcription factor NF E2 Related Factor 2 (NRF-2) regulates cellular defense genes including those encoding intracellular redox-balancing proteins such as enzymes involved in glutathione metabolism. Glutathione in particular is an important intracellular antioxidant molecule. NRF-2 binds to the Antioxidant Response Element (ARE) in the promoter of its target genes. Under basal conditions, KEAP1 acts as an inhibitor that targets NRF-2 for ubiquitination. During oxidative stress, NRF-2 dissociates from KEAP1 and enters the nucleus to bind to the ARE sequence. It is hypothesized that the elevated Reactive Oxygen Species may be depleting the glutathione levels within the cancer cell. System xc- is a cysteine/glutamate antiporter that exports glutamate while importing cysteine to synthesize glutathione. In response to oxidative stress the cells increase system xc- activity in order to provide cysteine for glutathione synthesis. There is evidence that expression of xCT the specific subunit of System X is regulated by NRF-2. However this has not yet been demonstrated in human cancer cells, which is the focus of this project. Basal expression of NRF-2, Keap1 and xCT was characterized in two breast cancer cell lines (MDA MB 231 and MCF-7) compared to normal human breast epithelial 184B5 cells. Compared to 184B5 cells, Keap-1, NRF-2 and xCT were upregulated in MDA MB 231 cells, but down regulated in MCF-7 cells. MCF-7 cells were treated with H202 resulting in NRF-2 protein accumulation in the nucleus and decreased levels in the cytosol. Under the same treatment conditions, Keap-1 protein decreased in the nucleus and increased in the cytosol. With H202 treatment, xCT mRNA levels increased in MCF-7 cells. We have cloned approximately 2.6 kilobase (-2329 to +278 bp) of the human xCT promoter region from genomic DNA isolated from MDA MB 231 breast cancer cells. We found that the xCT promoter was responsive to treatment with H2O2, which increased transcriptional activity. This is consistent with results described for the mouse promoter, which is known to contain an antioxidant response element that can be bound by NRF-2 during oxidative stress. Co transfection of MDA MB 231 with the xCT promoter and an NRF-2 expression vector also increased promoter activity. This data suggests that under oxidative stress, NRF-2 is localized to the nucleus and transcriptionally upregulates xCT. This is the first study in which the regulation of xCT has been linked to oxidative stress via NRF-2 in human breast cancer cells. This work was supported by the Canadian Institutes for Health Research. Citation Format: Eric Habib, Katja Linher-Melville, Gurmit Singh. H2O2 upregulates xCT in human breast cancer cells via NRF-2. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 506. doi:10.1158/1538-7445.AM2014-506