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In bone regenerative medicine there is a need for suitable bone substitutes. Hydrogels have excellent biocompatible and biodegradable characteristics, but their visco-elastic properties limit their applicability, especially with respect to 3D bioprinting. In this study, we modified the naturally occurring extracellular matrix glycosaminoglycan hyaluronic acid (HA), in order to yield photo-crosslinkable hydrogels with increased mechanical stiffness and long-term stability, and with minimal decrease in cytocompatibility. Application of these tailor-made methacrylated hyaluronic acid (MeHA) gels for bone tissue engineering and 3D bioprinting was the subject of investigation. Visco-elastic properties of MeHA gels, measured by rheology and dynamic mechanical analysis, showed that irradiation of the hydrogels with UV light led to increased storage moduli and elastic moduli, indicating increasing gel rigidity. Subsequently, human bone marrow derived mesenchymal stromal cells (MSCs) were incorporated into MeHA hydrogels, and cell viability remained 64.4% after 21 days of culture. Osteogenic differentiation of MSCs occurred spontaneously in hydrogels with high concentrations of MeHA polymer, in absence of additional osteogenic stimuli. Addition of bone morphogenetic protein-2 (BMP-2) to the culture medium further increased osteogenic differentiation, as evidenced by increased matrix mineralisation. MeHA hydrogels demonstrated to be suitable for 3D bioprinting, and were printed into porous and anatomically shaped scaffolds. Taken together, photosensitive MeHA-based hydrogels fulfilled our criteria for cellular bioprinted bone constructs within a narrow window of concentration.

Etoricoxib is a selective inhibitor of COX-2 enzyme. It is proposed as a potent anti-inflammatory drug intended for the control of irritable bowel syndrome. The current work aimed at developing etoricoxib-loaded nanoparticles for colon- targeting. PLGA nanoparticles were developed via nano-spray drying technique. The D-optimal design was adopted for the investigation of the influence of i) DL-lactide-coglycolide (PLGA) concentration, ii) polyvinylpyrrolidone K30 (PVP K30) concentration and iii) lactide:glycolide ratio in the copolymer chain on the yield%, the encapsulation efficiency (EE%), particle size (PS) and percentage of drug release after 2h (P ), 4h (P ) and 12h (P ). To promote colon targeting of the systems, the best achieved system (M14) was either directly coated with poly(methacrylic acid-co-methyl methacrylate) [Eudragit -S100] or loaded into hard gelatin capsules and the capsules were coated with poly(methacrylic acid-co-methyl methacrylate) (E-M14C). The pharmacokinetic parameters of etoricoxib following oral administration of E-M14C in healthy volunteers were assessed relative to commercial etoricoxib tablets. M14 system was prepared using PLGA (0.5% w/v) at a lactide:glycolide ratio of 100:0, in the presence of PVP K30 (2% w/v). M14 system was nano-spherical particles of 488 nm size possessing promising yield% (63.5%) and EE% (91.2%). The percentage drug released after 2, 4 and 12 hours were 43.41%, 47.34 and 64.96%, respectively. Following M14-loading into hard gelatin capsules and coating with poly(methacrylic acid-co-methyl methacrylate) [Eudragit-S100], the respective P , P and P were 10.1%, 28.60% and 65.45%. Significant ( < 0.05) differences between the pharmacokinetic parameter of E-M14C in comparison with the commercial product were revealed with a delay in T (from 2.5h to 6h), a prolongation in MRT (from 24.4h to 34.7h) and an increase in the relative oral bioavailability (4.23 folds). E-M14C is a potential system for possible colon targeting of etoricoxib.

Despite advanced sterilization and aseptic techniques, infections associated with medical implants have not been eradicated. Most present coatings cannot simultaneously fulfil the requirements of antibacterial and antifungal activity as well as biocompatibility and reusability. Here, we report an antimicrobial hydrogel based on dimethyldecylammonium chitosan (with high quaternization)- graft -poly(ethylene glycol) methacrylate (DMDC-Q- g -EM) and poly(ethylene glycol) diacrylate, which has excellent antimicrobial efficacy against Pseudomonas aeruginosa , Escherichia coli , Staphylococcus aureus and Fusarium solani . The proposed mechanism of the antimicrobial activity of the polycationic hydrogel is by attraction of sections of anionic microbial membrane into the internal nanopores of the hydrogel, like an ‘anion sponge’, leading to microbial membrane disruption and then microbe death. We have also demonstrated a thin uniform adherent coating of the hydrogel by simple ultraviolet immobilization. An animal study shows that DMDC-Q- g -EM hydrogel coating is biocompatible with rabbit conjunctiva and has no toxicity to the epithelial cells or the underlying stroma. A polymeric hydrogel coating shows impressive antimicrobial activity against both bacteria and fungi. The biocompatible and reusable coating, formed of a polycationic nanoporous hydrogel, is thought to act by drawing anionic sections of phospholipids on bacterial cell membranes into its pores, causing membrane disruption and cell death.

Introduction: Snus availability has been claimed to have contributed to the low rates of smoking among Swedish men and made possible the transfer to a less harmful form of nicotine dependence. Methods: Fourteen cigarette smokers were randomly assigned to 2 types of 1 g Swedish portion snus and 4 mg nicotine polacrilex (NP) chewing gum in open-label, single-dose crossover study. Nicotine delivery and pharmacokinetics were estimated, and self-reports of subjective effects were obtained using Visual Analogue Scales (VASs). Results: Extracted dose from the NP gum averaged 2.56 mg compared with 2.12 and 2.18 mg, respectively, for Swedish portion snus. This resulted in a slightly larger area under the curve (AUC) for the NP chewing gum. The rise of the nicotine plasma concentration was faster for Swedish snus. Median T max was shorter, 30 min for snus compared with 45 min for the NP gum. The lower C max of NP gum compared with the snus products in spite of larger AUC may be explained by slower absorption from the chewing gum. The faster absorption of nicotine from Swedish portion snus was mirrored in a higher VAS score for \"head rush.\" Craving/urges to smoke decreased similarly for all treatments. Salivation and throat burn were rated higher for the 4 mg NP gum compared with both types of snus. Conclusions: Swedish snus produced higher maximum blood nicotine concentration in shorter time and with a quicker onset of \"head rush\" compared with 4 mg NP chewing gum in spite of a smaller extracted dose. The quicker onset of \"head rush\" and supposedly higher satisfaction from snus may partly explain the widespread use of snus for stopping smoking in Sweden.

Coffee, the most popular beverage in the 21st century society, was tested as a reaction environment for activators regenerated by electron transfer atom transfer radical polymerization (ARGET ATRP) without an additional reducing agent. Two blends were selected: pure Arabica beans and a proportional blend of Arabica and Robusta beans. The use of the solution received from the mixture with Robusta obtained a high molecular weight polymer product in a short time while maintaining a controlled structure of the synthesized product. Various monomers with hydrophilic characteristics, i.e., 2-(dimethylamino)ethyl methacrylate (DMAEMA), oligo(ethylene glycol) methyl ether methacrylate (OEGMA500), and glycidyl methacrylate (GMA), were polymerized. The proposed concept was carried out at different concentrations of coffee grounds, followed by the determination of the molar concentration of caffeine in applied beverages using DPV and HPLC techniques.

Unreacted monomers eluted from resin-based restorative materials have been considered a reason of local and systemic adverse reactions. This study was designed to determine the effect of finishing and polishing procedures on the elution of Bis-GMA, TEGDMA, UDMA, and HEMA monomers from compomer and bulk-fill composite resins. Bulk-fill composite (3M ESPE GmbH, Seefeld, Germany) and compomer (Dentsply DeTrey GmbH, Konstanz, Germany) specimens with 3×4 mm diameters were prepared. The specimens were randomly divided into two groups, and finishing-polishing procedures were applied only to the experimental groups. Release of residual monomers was analyzed by using High-Performance Liquid Chromatography (HPLC) after 24, 48, and 72 hours. Repeated measures ANOVA and Tukey post hoc tests were used for comparisons. Finishing and polishing procedures had a significant effect on reducing the quantity of UDMA release in the Filtek™ Bulk Fill composite and Bis-GMA, HEMA, and TEGDMA in the Dyract XP compomer (p<0.05). The restorative materials investigated here are not chemically stable after polymerization, and concentrations of eluted monomers may reach critical toxicity levels even after one restoration placement. Finishing and polishing procedures are mandatory to reduce residual monomers.

Purpose The stabilization mechanism of a supersaturated solution of mefenamic acid (MFA) from a solid dispersion with EUDRAGIT ® EPO (EPO) was investigated. Methods The solid dispersions were prepared by cryogenic grinding method. Powder X-ray diffractometry, in vitro dissolution test, in vivo oral absorption study, infrared spectroscopy, and solid- and solution-state NMR spectroscopies were used to characterize the solid dispersions. Results Dissolution tests in acetate buffer (pH 5.5) revealed that solid dispersion showed > 200-fold higher concentration of MFA. Supersaturated solution was stable over 1 month and exhibited improved oral bioavailability of MFA in rats, with a 7.8-fold higher area under the plasma concentration- versus -time curve. Solid-state 1 H spin–lattice relaxation time (T 1 ) measurement showed that MFA was almost monomolecularly dispersed in the EPO polymer matrix. Intermolecular interaction between MFA and EPO was indicated by solid-state infrared and 13 C-T 1 measurements. Solution-state 1 H-NMR measurement demonstrated that MFA existed in monomolecular state in supersaturated solution. 1 H-T 1 and difference nuclear Overhauser effect measurements indicated that cross relaxation occurred between MFA and EPO due to the small distance between them. Conclusions The formation and high stability of the supersaturated solution were attributable to the specifically formed intermolecular interactions between MFA and EPO.

Gefitinib is an anticancer agent which acts by inhibiting epidermal growth factor receptor tyrosine kinase receptors. The aim of the present study was to prepare gefitinib nanosuspension. Gefitinib was encapsulated in Eudragit RL100 and then dispersed in stabilizer solution, polyvinyl alcohol, and polyvinylpyrrolidone K30. Nanosuspension was prepared by using homogenization and ultrasonication techniques. The quality by design approach was also used in the study to understand the effect of critical material attributes (CMAs) and critical processing parameters (CPPs) on critical quality attributes and to improve the quality and safety of formulation. To study the effect of CMAs and CPPs, 2 full factorial design was applied. The particle size, polydispersity index, and zeta potential of the optimized solution were 248.20 nm, 0.391, and -5.62 mV, respectively. Drug content of the optimized nanoformulation was found to be 87.74%±1.19%. Atomic force microscopy studies of the optimized formulation confirmed that the prepared nanoparticles are smooth and spherical in nature. In vitro cytotoxicity studies of the nanosuspension on Vero cell line revealed that the formulation is nontoxic. The gefitinib nanosuspension released 60.03%±4.09% drug over a period of 84 h, whereas standard drug dispersion released only 10.39%±3.37% drug in the same duration. From the pharmacokinetic studies, half-life, C , and T of the drug of an optimized nanosuspension were found to be 8.65±1.99 h, 46,211.04±5,805.97 ng/mL, and 6.67±1.77 h, respectively. A 1.812-fold increase in relative bioavailability of nanosuspension was found, which confirmed that the present formulation is suitable to enhance the oral bioavailability of gefitinib.

Monomers are released from dental resin materials, and thus cause adverse biological effects in mammalian cells. Cytotoxicity and genotoxicity of some of these methacrylates have been identified in a vast number of investigations during the last decade. It has been well-established that the co-monomer triethylene glycol dimethacrylate (TEGDMA) causes gene mutations in vitro. The formation of micronuclei is indicative of chromosomal damage and the induction of DNA strand breaks detected with monomers like TEGDMA and 2-hydroxyethyl methacrylate (HEMA). As a consequence of DNA damage, the mammalian cell cycle was delayed in both G1 and G2/M phases, depending on the concentrations of the monomers. Yet, the mechanisms underlying the genetic and cellular toxicology of resin monomers have remained obscure until recently. New findings indicate that increased oxidative stress results in an impairment of the cellular pro- and anti-oxidant redox balance caused by monomers. It has been demonstrated that monomers reduced the levels of the natural radical scavenger glutathione (GSH), which protects cell structures from damage caused by reactive oxygen species (ROS). Depletion of the intracellular GSH pool may then significantly contribute to cytotoxicity, because a related increase in ROS levels can activate pathways leading to apoptosis. Complementary, cytotoxic, and genotoxic effects of TEGDMA and HEMA are inhibited in the presence of ROS scavengers like N-acetylcysteine (NAC), ascorbate, and Trolox (vitamin E). Elevated intracellular levels of ROS can also activate a complex network of redox-responsive macromolecules, including redox-sensitive transcription factors like nuclear factor kappaB (NF-κB). It has been shown that NF-κB is activated probably to counteract HEMA-induced apoptosis. The induction of apoptosis by TEGDMA in human pulp cells has been associated with an inhibition of the phosphatidylinositol 3-kinase (PI3-K) cell-survival signaling pathway. Although the details of the mechanisms leading to cell death, genotoxicity, and cell-cycle delay are not completely understood, resin monomers may be able to alter the functions of the cells of the oral cavity. Pathways regulating cellular homeostasis, dentinogenesis, or tissue repair may be modified by monomers at concentrations well below those which cause acute cytotoxicity.

Controlling superstructure of binary nanoparticle mixtures in three dimensions from self-assembly opens enormous opportunities for the design of materials with unique properties. Here we report on how the intimate coupling of synthesis, in-depth electron tomographic characterization and theory enables exquisite control of superstructure in highly ordered porous three-dimensional continuous networks from single and binary mixtures of metal nanoparticles with a triblock terpolymer. Poly(isoprene- block -styrene- block -( N,N -dimethylamino)ethyl methacrylate) is synthesized and used as structure-directing agent for ligand-stabilized platinum and gold nanoparticles. Quantitative analysis provides insights into short- and long-range nanoparticle–nanoparticle correlations, and local and global contributions to structural chirality in the networks. Results provide synthesis criteria for next-generation mesoporous network superstructures from binary nanoparticle mixtures for potential applications in areas including catalysis. Three-dimensional superstructures of binary nanoparticles offer a flexible design approach towards materials with designable properties. Here, Li et al. study metal nanoparticle–triblock terpolymer superstructures, where an experimental and theoretical understanding can lead to their application in fields such as catalysis.