pK50─A Rigorous Indicator of Individual Functional Group Acidity/Basicity in Multiprotic Compounds.

In this work, we show that the apparent pKa measured by standard titration experiments is an insufficient measure of acidity or basicity of organic functional groups in multiprotic compounds─a frequent aspect of lead optimization in pharmaceutical research. We show that the use of the apparent pKa in this context may result in costly mistakes. To properly represent the group's true acidity/basicity, we propose pK50─a single-proton midpoint measure derived from a statistical thermodynamics treatment of multiprotic ionization. We show that pK50, which may be directly measured in specialized NMR titration experiments, is superior in tracking the functional group's acidity/basicity across congeneric series of related compounds and converges to the well familiar ionization constant in the monoprotic case.

Low-shrinkage-stress nanocomposite: An insight into shrinkage stress, antibacterial, and ion release properties.

The aims are: (a) To develop the first low-shrinkage-stress nanocomposite with antibacterial and remineralization capabilities through the incorporation of dimethylaminododecyl methacrylate (DMAHDM) and nanoparticles of amorphous calcium phosphate (NACP); (b) to investigate the effects of the new composite on biofilm inhibition, mechanical properties, shrinkage stress, and calcium (Ca) and phosphate (P) ion releases. The low-shrinkage-stress resin consisted of urethane dimethacrylate and triethylene glycol divinylbenzyl ether. Composite was formulated with 3% DMAHDM and 20% NACP. Mechanical properties, shrinkage stress, and degree of conversion were evaluated. Streptococcus mutans biofilm growth on composites was assessed. Ca and P ion releases were measured. The shrinkage stress of the low-shrinkage-stress composite containing 3% DMAHDM and 20% NACP was 36% lower than that of traditional composite control (p < 0.05), with similar degrees of conversion of 73.9%. The new composite decreased the biofilm colony-forming unit by 4 log orders and substantially reduced biofilm lactic acid production compared to control composite (p < 0.05). Incorporating DMAHDM to the low-shrinkage-stress composite did not adversely affect the Ca and P ion release. A novel bioactive nanocomposite was developed with low shrinkage stress, strong antibiofilm activity, and high levels of ion release for remineralization, without undermining the mechanical properties and degree of conversion.

Temperature dependence of nickel ion release from nitinol medical devices.

Nitinol exhibits unique (thermo)mechanical properties that make it central to the design of many medical devices. However, nitinol nominally contains 50 atomic percent nickel, which if released in sufficient quantities, can lead to adverse health effects. While nickel release from nitinol devices is typically characterized using in vitro immersion tests, these evaluations require lengthy time periods. We have explored elevated temperature as a potential method to expedite this testing. Nickel release was characterized in nitinol materials with surface oxide thickness ranging from 12 to 1564 nm at four different temperatures from 310 to 360 K. We found that for three of the materials with relatively thin oxide layers, ≤ 87 nm nickel release exhibited Arrhenius behavior over the entire temperature range with activation energies of 80 to 85 kJ/mol. Conversely, the fourth ''black-oxide'' material, with a much thicker, complex oxide layer, was not well characterized by an Arrhenius relationship. Power law release profiles were observed in all four materials; however, the exponent from the thin oxide materials was approximately 1/4 compared with 3/4 for the black-oxide material. To illustrate the potential benefit of using elevated temperature to abbreviate nickel release testing, we demonstrated that a > 50 day 310 K release profile could be accurately recovered by testing for less than 1 week at 340 K. However, because the materials explored in this study were limited, additional testing and mechanistic insight are needed to establish a protective temperature scaling that can be applied to all nitinol medical device components.

The synergistic effects of SrF2 nanoparticles, YSZ nanoparticles, and poly-ε-l-lysin on physicomechanical, ion release, and antibacterial-cellular behavior of the flowable dental composites.

Resin-based pit-and-fissure sealants (flowable resin composites) were formulated using bisphenol-A-glycerolatedimethacrylate (Bis-GMA)-triethylene glycol dimethacrylate-(TEGDMA)-diurethanedimethacrylate (UDMA) mixed monomers and multiple fillers, including synthetic strontium fluoride (SrF2) nanoparticles as a fluoride-releasing and antibacterial agent, yttria-stabilized zirconia (YSZ) nanoparticles as an auxiliary filler, and poly-ε-l-lysin (ε-PL) as an auxiliary antibacterial agent. Based on the physical, mechanical and initial antibacterial properties, the formulated nano-sealant containing 5 wt% SrF2, 5 wt% YSZ and 0.5 wt% ε-PL was selected as the optimal specimen and examined for ion release and cytotoxicity. The results showed an average release rate of 0.87 µg·cm-2·day-1 in the aqueous medium (pH 6.9) and 1.58 µg·cm-2·day-1 in acidic medium (pH 4.0). The maximum cytotoxicity of 20% toward human bone marrow mesenchymal stem cells (hMSCs) was observed according to the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) cytotoxicity assay and acridine orange staining test. A synergy between SrF2 nanoparticles and ε-PL exhibited a better antibacterial activity in terms of colony reduction compared to the other samples. However, the inclusion of SrF2 and ε-PL caused mechanically weakening of the sealants that was partly compensated by incorporation of YSZ nanoparticles (up to 10 wt%).

Effect of TiO2 doping on degradation rate, microstructure and strength of borate bioactive glass scaffolds.

A titanium-containing borate glass series based on the system (52-X) B2O3-12CaO-6P2O5-14Na2O-16ZnO-XTiO2 with X varying from 0, 5 and 15 mol% of TiO2 incorporated, identified as BRT0, BRT1 and BRT3, respectively, were used in this study. Scaffolds (pore sizes, 165-230 µm and porosity, 53.51-69.51%) were prepared using a polymer foam replication technique. BRT3 scaffolds exhibited higher compressive strength (7.16 ±â€¯0.22 MPa) when compared to BRT0 (6.02 ±â€¯0.47 MPa) and BRT1 (5.65 ±â€¯0.28 MPa) scaffolds with lower, or no, TiO2 content. The solubility of the scaffolds decreased as the TiO2 content increased up to 15 mol% when samples of each scaffold were immersed in DI water and the pH of all these extracts went up from 7.0 to 8.5 in 30 days. The cumulative ion release from the scaffolds showed significant difference with respect to TiO2 content; addition of 5 mol% TiO2 at the expense of borate (B2O3) decreased the ion release remarkably. Furthermore, it was found that for all three scaffolds, cumulative ion release increased with incubation time. The results indicate that the degradation rates and compressive strengths of borate bioactive glass scaffolds could be controlled by varying the amount of TiO2 incorporated, confirming their potential as scaffolds in TKA and rTKA.

Probing the molecular toxic mechanism of lead (II) ions with glutathione peroxidase 6 from Arabidopsis thaliana.

Along with non-biodegradability and accumulation in agricultural soil, lead (II) ions exert considerable harmful effects on plants even at trace amount, especially for the oxidative damages elicited by the lead ions-induced excessive reactive oxygen species (ROS). The glutathione peroxidases were reported to be correspondent with the oxidative stress induced by heavy metals. However, limited data are available about the potential hazardous mechanisms of the lead ions-induced oxidative damage to plants at molecular level. In this study, the harmful impacts of lead ions on Arabidopsis thaliana glutathione peroxidase 6 (AtGPX6) were assessed based on multi-spectroscopic measurements and molecular docking study. The characteristic fluorescence of AtGPX6 was quenched by lead ions with static mechanism at different temperatures. AtGPX6 exhibits a single binding site with lead ions, and then the complex formation was mainly driven by hydrogen bonding interaction and van der Waals forces on account of the negative ΔH and ΔS. The secondary structural changes were observed from the synchronous fluorescence, UV-visible absorption and Circular dichroism spectra, which led to loosen and unfold of the protein framework accompanied by the incremental hydrophobicity around the vicinity of the tryptophan residues. Therefore, this work illustrates the detailed binding mode between lead (II) ions and glutathione peroxidase 6 from Arabidopsis thaliana and the toxic effects on antioxidative defense system induced by lead ions at molecular level.

ISI-mitigating modulation scheme using ion reaction for molecular communications.

Here, according to the type-based modulation technique, the authors develop a novel modulation scheme by utilising ion collision and reaction to mitigate inter-symbol interference (ISI) in diffusive molecular communication (MC) systems. Two types of ions are employed as messenger molecules that cause a chemical reaction in the medium. According to the residual molecules and chemical reaction, the proposed modulation scheme adaptively adjusts the number of emitted molecules, thereby guaranteeing that the number of molecules that arrived at the receiver remains at a stable level. The authors evaluate the performance of the proposed scheme by comparing it with the conventional binary molecule shift keying (BMoSK), BMoSK with power adjustment (BMoSK-PA), and ideal BMoSK (without ISI) modulation techniques via diffusion. Numerical results show that the bit error probability and channel capacity of the proposed modulation scheme are much closer to the ideal BMoSK modulation scheme compared to the conventional BMoSK and the BMoSK-PA modulation schemes.

Date pits activated carbon for divalent lead ions removal.

Phosphoric acid impregnated activated carbon from date pits (DPAC) was prepared through single step activation. Prepared DPAC was studied for its structural, elemental, chemical, surface and crystal nature. Adsorption ability of the DPAC was assessed through divalent lead ions separation studies. Effect of adsorbent dosage, contact time, pH, operating temperature and initial feed concentration on lead removal by DPAC was studied. Maximum Pb(II) adsorption capacity of 101.35 mg/g was attained for a contact time of 30 min and pH of 6 at 30°C. Increase in initial feed concentration enhanced the adsorption ability of DPAC and the rise in adsorbent dosage resulted in improved Pb(II) removal efficiency. Thermodynamic studies revealed that the lead adsorption on DPAC was exothermic and instantaneous in nature. Kinetic and equilibrium studies confirmed the suitability of pseudo-second order and Langmuir isotherm for divalent lead ions binding on DPAC. Reusability studies showed that HCl was the effective regeneration medium and the DPAC could be reused for a maximum of 4 times with slight reduction in Pb(II) removal efficiency (<10%). Results indicated the promising use of date pits biomass as a low cost and efficient starting material to prepare activated carbon for divalent lead ions removal.

A multi-method analysis of the interaction between humic acids and heavy metal ions.

Understanding of the interaction between humic acids (HAs) and heavy metal ions (HMIs) is essential for the assessment of environmental and health risks of HMIs. Multiple analyses, including fluorescence quenching of HAs; solution pH, zeta potential, and hydrodynamic size changes; and coprecipitation of HAs and HMIs, were carried out to investigate the interaction between two HAs and four HMIs (Ag+, Pb2+, Cd2+, and Cr3+). The HA-HMI interaction mainly included chemical complexation, H+-HMI exchange, electrostatic attraction, and flocculation. The chemical complexation between HAs and HMIs revealed by the Stern-Volmer quenching constant was ordered as Ag < Cd < Pb < Cr. HMIs replaced protons in the acidic functional groups of HAs and thus lowered the pH of the solution. The electrostatic interaction between the negatively charged HAs and HMIs reduced the electronegativity of HAs. Interaction with HMIs, especially the high-valent ions, induced aggregation of HAs, causing precipitation of both HAs and HMIs in the sorptive solution. Cr3+ flocculated and precipitated HAs, but at high concentrations, it reversed the surface charge of HAs and resuspended them. The HA-HMI interaction increased as the HA acidity and solution pH increased.

Surface changes of nanotopography by carbon ion implantation to enhance the biocompatibility of silicone rubber: an in vitro study of the optimum ion fluence and adsorbed protein.

Lower cellular adhesion and dense fibrous capsule formation around silicone breast implants caused by lower biocompatibility is a serious clinical problem. Preliminary work has shown that ion implantation enhances cell adhesion. Whether the biocompatibility is further enhanced by higher doses of carbon ion implantation and the mechanism by which ion implantation enhances biocompatibility remain unclear. In this study, five doses of carbon ions, which gradually increase, were implanted on the surface of silicone rubber and then the surface characteristics were surveyed. Then, cell adhesion, proliferation and migration were investigated. Furthermore, the vitronectin (VN) protein was used as a model protein to investigate whether the ion implantation affected the adsorbed protein on the surface. The obtained results indicate that enhanced cytocompatibility is dose dependent when the doses of ion implantation are less than 1 × 1016 ions/cm2. However, when the doses of ion implantation are more than 1 × 1016 ions/cm2, enhanced cytocompatibility is not significant. In addition, surface physicochemical changes by ion implantation induced a conformational change of the adsorbed vitronectin protein that enhanced cytocompatibility. Together, these results suggest that the optimum value of carbon ion implantation in silicone rubber to enhance biocompatibility is 1 × 1016 ions/cm2, and ion implantation regulates conformational changes of adsorbed ECM proteins, such as VN, and mediates the expression of intracellular signals that enhance the biocompatibility of silicone rubber. The results herein provide new insights into the surface modification of implant polymer materials to enhance biocompatibility. It has potentially broad applications in the biomedical field.

Permeation of topically applied Magnesium ions through human skin is facilitated by hair follicles.

Magnesium is an important micronutrient essential for various biological processes and its deficiency has been linked to several inflammatory disorders in humans. Topical magnesium delivery is one of the oldest forms of therapy for skin diseases, for example Dead Sea therapy and Epsom salt baths. Some anecdotal evidence and a few published reports have attributed amelioration of inflammatory skin conditions to the topical application of magnesium. On the other hand, transport of magnesium ions across the protective barrier of skin, the stratum corneum, is contentious. Our primary aim in this study was to estimate the extent of magnesium ion permeation through human skin and the role of hair follicles in facilitating the permeation. Upon topical application of magnesium solution, we found that magnesium penetrates through human stratum corneum and it depends on concentration and time of exposure. We also found that hair follicles make a significant contribution to magnesium penetration.

Biodynamics of copper oxide nanoparticles and copper ions in an oligochaete - Part II: Subcellular distribution following sediment exposure.

The use and likely incidental release of metal nanoparticles (NPs) is steadily increasing. Despite the increasing amount of published literature on metal NP toxicity in the aquatic environment, very little is known about the biological fate of NPs after sediment exposures. Here, we compare the bioavailability and subcellular distribution of copper oxide (CuO) NPs and aqueous Cu (Cu-Aq) in the sediment-dwelling worm Lumbriculus variegatus. Ten days (d) sediment exposure resulted in marginal Cu bioaccumulation in L. variegatus for both forms of Cu. Bioaccumulation was detected because isotopically enriched 65Cu was used as a tracer. Neither burrowing behavior or survival was affected by the exposure. Once incorporated into tissue, Cu loss was negligible over 10 d of elimination in clean sediment (Cu elimination rate constants were not different from zero). With the exception of day 10, differences in bioaccumulation and subcellular distribution between Cu forms were either not detectable or marginal. After 10 d of exposure to Cu-Aq, the accumulated Cu was primarily partitioned in the subcellular fraction containing metallothionein-like proteins (MTLP, ≈40%) and cellular debris (CD, ≈30%). Cu concentrations in these fractions were significantly higher than in controls. For worms exposed to CuO NPs for 10 d, most of the accumulated Cu was partitioned in the CD fraction (≈40%), which was the only subcellular fraction where the Cu concentration was significantly higher than for the control group. Our results indicate that L. variegatus handle the two Cu forms differently. However, longer-term exposures are suggested in order to clearly highlight differences in the subcellular distribution of these two Cu forms.

Silver ions eluted from partially protected silver nanoparticles.

The most prominent character of a new type of antibacterial urological catheters is the zebra-stripe pattern of a silver film, which is plated electroless on their interior wall and capped by a very thin semipermeable layer of parylene. This design effectively controls the release rate of Ag(+) ions in artificial urine, which has been measured as function of time with optical emission spectroscopy. By evaluating the minimum inhibitory concentration against certain strains of bacteria with solutions of AgNO3 of known concentration with the method of optical density and applying this analysis to the silver-eluting catheters, it was shown that this moderation prolongs the period of their application significantly. But to act as antibacterial agent in chlorine-containing solutions, as in urine, the presence of urea is required to avoid precipitation of AgCl and to meet or even exceed the minimum inhibitory concentration of Ag(+). The quality of the silver depot layer was further determined by the deposition rate and its morphology, which revealed that the film consisted of grains with a mean size of 150 nm.

Systemic cobalt toxicity from total hip arthroplasties: review of a rare condition Part 1 - history, mechanism, measurements, and pathophysiology.

UNLABELLED: Recently, the use of metal-on-metal articulations in total hip arthroplasty (THA) has led to an increase in adverse events owing to local soft-tissue reactions from metal ions and wear debris. While the majority of these implants perform well, it has been increasingly recognised that a small proportion of patients may develop complications secondary to systemic cobalt toxicity when these implants fail. However, distinguishing true toxicity from benign elevations in cobalt ion levels can be challenging. The purpose of this two part series is to review the use of cobalt alloys in THA and to highlight the following related topics of interest: mechanisms of cobalt ion release and their measurement, definitions of pathological cobalt ion levels, and the pathophysiology, risk factors and treatment of cobalt toxicity. Historically, these metal-on-metal arthroplasties are composed of a chromium-cobalt articulation. The release of cobalt is due to the mechanical and oxidative stresses placed on the prosthetic joint. It exerts its pathological effects through direct cellular toxicity. This manuscript will highlight the pathophysiology of cobalt toxicity in patients with metal-on-metal hip arthroplasties. TAKE HOME MESSAGE: Patients with new or evolving hip symptoms with a prior history of THA warrant orthopaedic surgical evaluation. Increased awareness of the range of systemic symptoms associated with cobalt toxicity, coupled with prompt orthopaedic intervention, may forestall the development of further complications.

Evaluation of selected properties of a new root repair cement containing surface pre-reacted glass ionomer fillers.

OBJECTIVE: This study evaluated selected properties of a prototype root repair cement containing surface pre-reacted glass ionomer fillers (S-PRG) in comparison to mineral trioxide aggregate (MTA) and intermediate restorative material (IRM). MATERIALS AND METHODS: The antibacterial effect of S-PRG, MTA, and IRM cements was tested against Porphyromonas gingivalis and Enterococcus faecalis after 1 and 3 days of aging of the cements. The set cements were immersed in distilled water for 4 h to 28 days, and ion-releasing ability was evaluated. Initial and final setting times of all cements were evaluated using Gilmore needles. The push-out bond strength between radicular dentin and all cements was tested at different levels of the roots. RESULTS: S-PRG and IRM cements, but not MTA cement, demonstrated significant antibacterial effect against P. gingivalis. All types of cements exhibited significant antibacterial effect against E. faecalis without being able to eliminate the bacterium. S-PRG cement provided continuous release of fluoride, strontium, boron, sodium, aluminum, and zinc throughout all tested time points. Both initial and final setting times were significantly shorter for S-PRG and IRM cements in comparison to MTA. The push-out bond strength was significantly lower for S-PRG cement in comparison to MTA and IRM at coronal and middle levels of the roots. CONCLUSIONS: S-PRG cement demonstrated significant antibacterial effects against endodontic pathogens, multiple ion-releasing ability, relatively short setting time, and low bonding strength. CLINICAL RELEVANCE: S-PRG cement can be used as a one-visit root repair material with promising antibacterial properties and ion-releasing capacity.

Nanoparticle surface charge impacts distribution, uptake and lymph node trafficking by pulmonary antigen-presenting cells.

Engineered nanoparticles have the potential to expand the breadth of pulmonary therapeutics, especially as respiratory vaccines. Notably, cationic nanoparticles have been demonstrated to produce superior local immune responses following pulmonary delivery; however, the cellular mechanisms of this increased response remain unknown. To this end, we investigated the cellular response of lung APCs following pulmonary instillation of anionic and cationic charged nanoparticles. While nanoparticles of both surface charges were capable of trafficking to the draining lymph node and were readily internalized by alveolar macrophages, both CD11b and CD103 lung dendritic cell (DC) subtypes preferentially associated with cationic nanoparticles. Instillation of cationic nanoparticles resulted in the upregulation of Ccl2 and Cxc10, which likely contributes to the recruitment of CD11b DCs to the lung. In total, these cellular mechanisms explain the increased efficacy of cationic formulations as a pulmonary vaccine carrier and provide critical benchmarks in the design of pulmonary vaccine nanoparticles. FROM THE CLINICAL EDITOR: Advance in nanotechnology has allowed the production of precise nanoparticles as vaccines. In this regard, pulmonary delivery has the most potential. In this article, the authors investigated the interaction of nanoparticles with various types of lung antigen presenting cells in an attempt to understand the cellular mechanisms. The findings would further help the future design of much improved vaccines for clinical use.

Improving lithium therapeutics by crystal engineering of novel ionic cocrystals.

Current United States Food and Drug Administration (FDA)-approved lithium salts are plagued with a narrow therapeutic window. Recent attempts to find alternative drugs have identified new chemical entities, but lithium's polypharmacological mechanisms for treating neuropsychiatric disorders are highly debated and are not yet matched. Thus, re-engineering current lithium solid forms in order to optimize performance represents a low cost and low risk approach to the desired therapeutic outcome. In this contribution, we employed a crystal engineering strategy to synthesize the first ionic cocrystals (ICCs) of lithium salts with organic anions. We are unaware of any previous studies that have assessed the biological efficacy of any ICCs, and encouragingly we found that the new speciation did not negatively affect established bioactivities of lithium. We also observed that lithium ICCs exhibit modulated pharmacokinetics compared to lithium carbonate. Indeed, the studies detailed herein represent an important advancement in a crystal engineering approach to a new generation of lithium therapeutics.

A physiologically based pharmacokinetic model for ionic silver and silver nanoparticles.

Silver is a strong antibiotic that is increasingly incorporated into consumer products as a bulk, salt, or nanosilver, thus potentially causing side-effects related to human exposure. However, the fate and behavior of (nano)silver in the human body is presently not well understood. In order to aggregate the existing experimental information, a physiologically based pharmacokinetic model (PBPK) was developed in this study for ionic silver and nanosilver. The structure of the model was established on the basis of toxicokinetic data from intravenous studies. The number of calibrated parameters was minimized in order to enhance the predictive capability of the model. We validated the model structure for both silver forms by reproducing exposure conditions (dermal, oral, and inhalation) of in vivo experiments and comparing simulated and experimentally assessed organ concentrations. Therefore, the percutaneous, intestinal, or pulmonary absorption fraction was estimated based on the blood silver concentration of the respective experimental data set. In all of the cases examined, the model could successfully predict the biodistribution of ionic silver and 15-150 nm silver nanoparticles, which were not coated with substances designed to prolong the circulatory time (eg, polyethylene glycol). Furthermore, the results of our model indicate that: (1) within the application domain of our model, the particle size and coating had a minor influence on the biodistribution; (2) in vivo, it is more likely that silver nanoparticles are directly stored as insoluble salt particles than dissolve into Ag⁺; and (3) compartments of the mononuclear phagocytic system play a minor role in exposure levels that are relevant for human consumers. We also give an example of how the model can be used in exposure and risk assessments based on five different exposure scenarios, namely dietary intake, use of three separate consumer products, and occupational exposure.

Transepithelial transport of a natural cholinesterase inhibitor, huperzine A, along the gastrointestinal tract: the role of ionization on absorption mechanism.

During recent years there has been increasing interest in the Lycopodium alkaloid huperzine A as a potential therapeutic agent for neurodegenerative diseases. This study aimed to characterize huperzine A's permeability across the enterocyte barrier along the gastrointestinal tract with an emphasis on the effect of ionization on the drug absorption. Intestinal permeability of huperzine A was evaluated by in vitro Caco-2 and parallel artificial membrane permeation assay models and by the ex vivo Ussing chamber model. The permeability rate was strongly dependent on the degree of ionization and increased with elevation of the donor medium pH in all studied models. The transport of the unionized fraction was similar to the permeability of the markers for passive transcellular diffusion. Addition of the paracellular permeability modulator palmitoylcarnitine in the Caco-2 model led to significant enhancement in the permeability of the ionized huperzine A fraction. No evidence of active transport of huperzine A was detected in this study. The Ussing chamber model experiments showed similar drug permeability along the entire rat intestine. In conclusion, huperzine A permeates the intestinal border mainly by passive transcellular diffusion whereas some fraction, dependent on the degree of huperzine A ionization, is absorbed by the paracellular route. Huperzine A's permeability characteristics pave the way to the development of its oral extended release dosage form. The specific population of the potential users of huperzine A and the high potency of this molecule support the rationale for such a delivery.