Inter-laboratory study for extraction testing of medical devices.

Biocompatibility evaluation of medical devices often relies on chemical testing according to ISO 10993-18 as a critical component for consideration. However, the precision associated with these non-targeted chemical characterization assessments has not been well established. Therefore, we have conducted a study to characterize intra-laboratory (repeatability) and inter-laboratory (reproducibility) variability associated with chemical testing of extractables from polymeric materials. To accomplish this, this study focused on two polymers, each with nine chemicals that were intentionally compounded into the materials. Eight different laboratories performed extraction testing in two solvents and subsequently characterized the extracts using gas chromatography and liquid chromatography methods. Analysis of the resulting data revealed the central 90 % range for the repeatability and reproducibility relative standard deviations are (0.09, 0.22) and (0.30, 0.85), respectively, for the participating laboratory methods. This finding implies that if the same sample was tested by two different laboratories using the same extraction conditions, there is 95 % confidence for 95 % of systems that the test results could exhibit differences up to 240 %. While the study was not designed to evaluate the relative impact of specific underlying factors that may contribute to variability in quantitation, the data obtained suggest the variability associated with analytical method alone is a substantial contribution to the overall variability. The relatively large reproducibility limits we observed may have significant implications where variability in extraction measurements can impact aspects of biocompatibility risk evaluation, such as exposure dose estimation and chemical equivalence assessments.

Separation of C18 Fatty Acid Esters and Fatty Acids Derived from Vegetable Oils Using Nanometer-Sized Covalent Organic Frameworks Incorporated in Polyepoxy Membranes.

Fatty acids (FAs) and FA methyl esters (FAMEs) are easily isolated from vegetable oil and are important starting materials for the chemical industry to produce commercial products that are green, biorenewable, and nontoxic. A challenge in these applications is that mixtures of five or more FAs and FAMEs are isolated from a vegetable oil source, and methods to separate these mixtures are decades old and have increasingly high costs associated with the production of high-purity single-component FAs or FAMEs. We developed a method to separate these mixtures using mixed matrix membranes containing nanometer-sized covalent organic frameworks. The 2D, crystalline COFs possessed narrow distributions of pore sizes of 1.3, 1.8, 2.3, and 3.4 nm that separated FAs and FAMEs based on their degrees of unsaturation. The COFs were synthesized, characterized, and then encapsulated at 10 or 20% by weight into a prepolymer of epoxy that was then fully cured. For all mixed matrix membranes, as the degree of unsaturation increased, the FAs or FAMEs had a slower flux. The largest difference in flux was obtained for a COF/epoxy membrane with a pore size of 1.8 nm, and methyl stearate had a 5.9× faster flux than methyl linolenate. These are the first membranes that can separate the important C18 FAs and FAMEs found in vegetable oil.

Synthesis of Sulfur-35-Labeled Trisulfides and GYY-4137 as Donors of Radioactive Hydrogen Sulfide.

Hydrogen sulfide has emerged as a key gasotransmitter in humans and in plants, and the addition of exogenous hydrogen sulfide has many beneficial effects in vivo and in vitro. A challenge in investigating the effect of exogenous hydrogen sulfide is tracking the location of exogenous hydrogen sulfide on an organism and cellular level. In this article, we report the synthesis of three key chemicals (cysteine trisulfide, glutathione trisulfide, and GYY-4137) that release radiolabeled 35S as hydrogen sulfide. The synthesis started with the reduction of Na235SO4 mixed with Na2SO4 to generate hydrogen sulfide gas that was trapped with aq NaOH to yield radiolabeled Na2S. The Na2S was converted in one step to GYY-4137 at 65% yield. It was also converted to bis(tributyltin) sulfide that readily reacted with N-bromophthalimide to yield a monosulfur transfer reagent. Trisulfides were synthesized by reaction with the monosulfur transfer reagent and the corresponding thiols. The levels of radioactivity of the final products could be varied on a per gram basis to alter the radioactivity for applications that require different loadings of hydrogen sulfide donors.

Sustained Release of Hydrogen Sulfide from Di(t-butanol)dithiophosphate Phenethylamine Salt Encapsulated into Poly(lactic acid) Microparticles to Enhance the Growth of Radish Plants.

The slow release of hydrogen sulfide has been shown to be beneficial to plants by protecting them from environmental stressors, increasing germination, and extending the lifetime of harvested fruits. A major challenge in this field is controlling the amount and location of release of hydrogen sulfide so that it is available for use by plants at optimal amounts. This article reports a dual method to release hydrogen sulfide near the roots of plants by controlling its release using the hydrolysis of a dithiophosphate and the degradation of poly(lactic acid) [PLA]. Di(t-butanol)dithiophosphate phenylethylamine (tBDPA) was dissolved in a solution of PLA, and the solvent was allowed to evaporate. The resulting solid was crushed in a blender and separated into microparticles with two different size distributions of 250-500 or 500-2000 µm. The microparticles were characterized by powder X-ray diffraction to measure the presence of microcrystals of tBDPA within PLA, and images obtained using scanning electron microscopy with energy dispersive X-ray analysis confirmed the presence of these crystals. Microparticles of tBDPA loaded within PLA were characterized for their release of phosphorus and hydrogen sulfide, which both showed a burst release within 3 days, followed by a steady release. Radish plants grown with microparticles of PLA loaded with tBDPA had up to a 141% increase in harvest yield compared to plants grown in the presence of free tBDPA not loaded into PLA, PLA microparticles without tBDPA, and control plants grown without PLA or tBDPA. These experiments showed that loading hydrogen sulfide-releasing chemicals into PLA is a promising method to improve the effect of hydrogen sulfide on plants.

Synthesis, Stability, and Kinetics of Hydrogen Sulfide Release of Dithiophosphates.

The development of chemicals to slowly release hydrogen sulfide would aid the survival of plants under environmental stressors as well as increase harvest yields. We report a series of dialkyldithiophosphates and disulfidedithiophosphates that slowly degrade to release hydrogen sulfide in the presence of water. Kinetics of the degradation of these chemicals were obtained at 85 °C and room temperature, and it was shown that the identity of the alkyl or sulfide group had a large impact on the rate of hydrolysis, and the rate constant varied by more than 104×. For example, using tert-butanol as the nucleophile yielded a dithiophosphate (8) that hydrolyzed 13,750× faster than the dithiophosphate synthesized from n-butanol (1), indicating that the rate of hydrolysis is structure-dependent. The rates of hydrolysis at 85 °C varied from a low value of 6.9 × 10-4 h-1 to a high value of 14.1 h-1. Hydrogen sulfide release in water was also quantified using a hydrogen sulfide-sensitive electrode. Corn was grown on an industrial scale and dosed with dibutyldithiophosphate to show that these dithiophosphates have potential applications in agriculture. At a loading of 2 kg per acre, a 6.4% increase in the harvest yield of corn was observed.