Water Diffusion and Uptake in Injectable ETTMP/PEGDA Hydrogels.

Differential scanning calorimetry (DSC) and pulsed field gradient spin echo nuclear magnetic resonance (PFGSE NMR) were used to characterize water in hydrogels of ethoxylated trimethylolpropane tri-3-mercaptopropionate (ETTMP) and poly(ethylene glycol) diacrylate (PEGDA). Freezable and nonfreezable water were quantified using DSC; water diffusion coefficients were measured using PFGSE NMR. No freezable water (free or intermediate) was detected from DSC for hydrogels of 0.68 and greater polymer mass fractions. Water diffusion coefficients, from NMR, decreased with increasing polymer content and were assumed to be weighted averages of free and bound water contributions. Both techniques showed decreasing ratios of bound or nonfreezable water mass per polymer mass with increasing polymer content. Swelling studies were used to quantify the equilibrium water content (EWC) to determine which compositions would swell or deswell when placed in the body. At 30 and 37 °C, fully cured, non-degraded ETTMP/PEGDA hydrogels at polymer mass fractions of 0.25 and 0.375, respectively, were shown to be at EWC.

A two-region transport model for interpreting T1-T2 measurements in complex systems.

A 1D two region coupled pore model with discrete pore coupling is developed to elucidate the eigenmode interactions in regions with different surface relaxivity. Numerical solution of the model and simulation of the correlation experiment for varying surface relaxivity, pore connectivity and pore size ratio indicate the role of negative eigenmodes and overlap of T1 and T2 eigenmodes in generating a time domain signal increase with inversion recovery time, t1. The eigenmodes and eigenfunctions are considered in detail providing connection between the mathematical model and the diffusion dynamics and spin physics of the system. Physical systems, i.e. a microporous glass bead pack, a cyclopentane/water hydrate former, and beeswax, showing experimentally measured T1-T2 time domain signal rise are considered within the limitations of the model.

Flow velocity maps measured by nuclear magnetic resonance in medical intravenous catheter needleless connectors.

This work explains the motivation, advantages, and novel approach of using velocity magnetic resonance imaging (MRI) for studying the hydrodynamics in a complicated structural biomedical device such as an intravenous catheter needleless connector (NC). MRI was applied as a non-invasive and non-destructive technique to evaluate the fluid dynamics associated with various internal designs of the NC. Spatial velocity maps of fluid flow at specific locations within these medical devices were acquired. Dynamic MRI is demonstrated as an effective method to quantify flow patterns and fluid dynamic dependence on structural features of NCs. These spatial velocity maps could be used as a basis for groundtruthing computational fluid dynamics (CFD) methods that could impact the design of NCs.

Quantifying NMR relaxation correlation and exchange in articular cartilage with time domain analysis.

Measured nuclear magnetic resonance (NMR) transverse relaxation data in articular cartilage has been shown to be multi-exponential and correlated to the health of the tissue. The observed relaxation rates are dependent on experimental parameters such as solvent, data acquisition methods, data analysis methods, and alignment to the magnetic field. In this study, we show that diffusive exchange occurs in porcine articular cartilage and impacts the observed relaxation rates in T1-T2 correlation experiments. By using time domain analysis of T2-T2 exchange spectroscopy, the diffusive exchange time can be quantified by measurements that use a single mixing time. Measured characteristic times for exchange are commensurate with T1 in this material and so impacts the observed T1 behavior. The approach used here allows for reliable quantification of NMR relaxation behavior in cartilage in the presence of diffusive fluid exchange between two environments.

Unused medications and disposal patterns at home: Findings from a Medicare patient survey and claims data.

OBJECTIVE: To examine what medications are most frequently left unused by patients, how much is left unused, and how these medications are disposed of among Medicare beneficiaries. DESIGN: Secondary data analysis combining insurance claims and telephone survey data of Medicare Advantage members. SETTING: Regional health plan in Central Pennsylvania. PARTICIPANTS: Seven hundred twenty-one Medicare Advantage members who had Part D coverage through the plan as of December 31, 2013, and completed the telephone survey in May 2014. INTERVENTION: Telephone survey conducted by a survey research center. MAIN OUTCOME MEASURE: Member survey response. RESULTS: Of the 2,994 medications in the dataset, 247 (8%) were reported being left unused by patients. Of the 247, the most common medications were those for pain (15%), hypertension (14%), antibiotics (11%), and psychiatric disorders (9%). Approximately 15% of unused medications were controlled substances. The reasons for being unused varied by drug type. For example, for pain medications, adverse effects and overprescribing were the most commonly cited reasons; for hypertension medications, "dosage changed by doctor" was the most common reason. Most commonly, unused portions accounted for approximately 25% to 50% of the unused medications identified by patients. Approximately 11% of unused medication was disposed of via drug take-back programs, whereas the majority was kept in a cabinet (55%), thrown in the trash (14%), or flushed down the toilet (9%). CONCLUSION: A lack of patient adherence alone does not explain unused medications and their improper disposal. Community-level interventions designed to improve prescription efficiency and patient awareness of appropriate disposal methods-particularly of controlled substances-are necessary to reduce the potentially harmful effects of improper disposal of unused medications.

A microfluidic method to measure small molecule diffusion in hydrogels.

Drug release from a fluid-contacting biomaterial is simulated using a microfluidic device with a channel defined by solute-loaded hydrogel; as water is pumped through the channel, solute transfers from the hydrogel into the water. Optical analysis of in-situ hydrogels, characterization of the microfluidic device effluent, and NMR methods were used to find diffusion coefficients of several dyes (model drugs) in poly(ethylene glycol) diacrylate (PEG-DA) hydrogels. Diffusion coefficients for methylene blue and sulforhodamine 101 in PEG-DA calculated using the three methods are in good agreement; both dyes are mobile in the hydrogel and elute from the hydrogel at the aqueous channel interface. However, the dye acid blue 22 deviates from typical diffusion behavior and does not release as expected from the hydrogel. Importantly, only the microfluidic method is capable of detecting this behavior. Characterizing solute diffusion with a combination of NMR, optical and effluent methods offer greater insight into molecular diffusion in hydrogels than employing each technique individually. The NMR method made precise measurements for solute diffusion in all cases. The microfluidic optical method was effective for visualizing diffusion of the optically active solutes. The optical and effluent methods show potential to be used to screen solutes to determine if they elute from a hydrogel in contact with flowing fluid. Our data suggest that when designing a drug delivery device, analyzing the diffusion from the molecular level to the device level is important to establish a complete picture of drug elution, and microfluidic methods to study such diffusion can play a key role.

Critical review of coupled flux formulations for clay membranes based on nonequilibrium thermodynamics.

Extensive research conducted over the past several decades has indicated that semipermeable membrane behavior (i.e., the ability of a porous medium to restrict the passage of solutes) may have a significant influence on solute migration through a wide variety of clay-rich soils, including both natural clay formations (aquitards, aquicludes) and engineered clay barriers (e.g., landfill liners and vertical cutoff walls). Restricted solute migration through clay membranes generally has been described using coupled flux formulations based on nonequilibrium (irreversible) thermodynamics. However, these formulations have differed depending on the assumptions inherent in the theoretical development, resulting in some confusion regarding the applicability of the formulations. Accordingly, a critical review of coupled flux formulations for liquid, current, and solutes through a semipermeable clay membrane under isothermal conditions is undertaken with the goals of explicitly resolving differences among the formulations and illustrating the significance of the differences from theoretical and practical perspectives. Formulations based on single-solute systems (i.e., uncharged solute), single-salt systems, and general systems containing multiple cations or anions are presented. Also, expressions relating the phenomenological coefficients in the coupled flux equations to relevant soil properties (e.g., hydraulic conductivity and effective diffusion coefficient) are summarized for each system. A major difference in the formulations is shown to exist depending on whether counter diffusion or salt diffusion is assumed. This difference between counter and salt diffusion is shown to affect the interpretation of values for the effective diffusion coefficient in a clay membrane based on previously published experimental data. Solute transport theories based on both counter and salt diffusion then are used to re-evaluate previously published column test data for the same clay membrane. The results indicate that, despite the theoretical inconsistency between the counter-diffusion assumption and the salt-diffusion conditions of the experiments, the predictive ability of solute transport theory based on the assumption of counter diffusion is not significantly different from that based on the assumption of salt diffusion, provided that the input parameters used in each theory are derived under the same assumption inherent in the theory. Nonetheless, salt-diffusion theory is fundamentally correct and, therefore, is more appropriate for problems involving salt diffusion in clay membranes. Finally, the fact that solute diffusion cannot occur in an ideal or perfect membrane is not explicitly captured in any of the theoretical expressions for total solute flux in clay membranes, but rather is generally accounted for via inclusion of an effective porosity, n(e), or a restrictive tortuosity factor, τ(r), in the formulation of Fick's first law for diffusion. Both n(e) and τ(r) have been correlated as a linear function of membrane efficiency. This linear correlation is supported theoretically by pore-scale modeling of solid-liquid interactions, but experimental support is limited. Additional data are needed to bolster the validity of the linear correlation for clay membranes.

Magnetic resonance analysis of capillary formation reaction front dynamics in alginate gels.

The formation of heterogeneous structures in biopolymer gels is of current interest for biomedical applications and is of fundamental interest to understanding the molecular level origins of structures generated from disordered solutions by reactions. The cation-mediated physical gelation of alginate by calcium and copper is analyzed using magnetic resonance measurements of spatially resolved molecular dynamics during gel front propagation. Relaxation time and pulse-field gradient methods are applied to determine the impact of ion front motion on molecular translational dynamics. The formation of capillaries in alginate copper gels is correlated to changes in translational dynamics.

Influence of adsorption on phenol transport through soil-bentonite vertical barriers amended with activated carbon.

The potential for enhanced containment of phenol by soil-bentonite (SB) vertical barriers amended with activated carbon (AC) was investigated. Results of batch equilibrium adsorption tests on model SB backfills amended with 0-10 wt.% granular AC (GAC) or powdered AC (PAC) illustrate that the backfills exhibited nonlinear adsorption behavior that was described well by both the Freundlich and Tóth adsorption models. The AC amended backfills exhibited enhanced phenol adsorption relative to unamended backfill due to hydrophobic partitioning to the AC. Adsorption capacity increased with increasing AC content but was insensitive to AC type (GAC versus PAC). Results of numerical transport simulations based on the measured adsorption behavior show that the Tóth model yielded similar or lower phenol breakthrough times than the Freundlich model for the range of source concentrations (C(o)) considered in the simulations (0.1-10 mg/L). Breakthrough time decreased with increasing C(o) but increased with increasing AC content. Predicted breakthrough times for an SB vertical barrier amended with 2-10 wt.% AC increased by several orders of magnitude relative to the theoretical case of a nonreactive (non-adsorbing) barrier. The findings suggest that AC may be a highly effective adsorption amendment for sustaining the containment performance of SB vertical barriers.

Advancement in the modeling of pressure-flow for the guidance of development and scale-up of commercial-scale biopharmaceutical chromatography.

This paper details the advancements made in the modeling of open column and packed bed pressure-flow. The theoretical description is a one-dimensional elasticity model. By accounting for the loss of intra-particle porosity through empiricism, and by systematically selecting the functional form of the elastic modulus from stress-strain data, this model can accurately predict several kinds of large-scale behavior from small-scale data: packed pressure-flow, open column pressure-flow, and critical velocity. The robustness of the model has been demonstrated for MabSelect, SP 650M, Butyl Sepharose 4 FF and several other agarose-based and polymethacrylate-based resins. The predicted critical velocities are on average within +/-5% of observations. A simple modification to the Blake-Kozeny permeability expression allows accurate prediction of packed bed pressure-flow explicitly from compression factor, packed bed height, and settled bed inter-particle porosity. The model provides limits on mobile phase velocity and on operating pressure-flow as a function of bed height, particle size, and resin rigidity, and allows exploration of commercial manufacturing scenarios to identify scalable process time and cycle number.

Toward a robust model of packing and scale-up for chromatographic beds. 1. Mechanical compression.

The packing of compressible biochromatographic resins at large scale suffers from a poor understanding of how column packing method, resin properties, and column geometry impact column performance. To improve understanding, we develop and evaluate a one-dimensional, continuum mechanics model of column packing by mechanical compression. We show that the model can quantitatively predict the change in bed height, applied stress, and internal axial porosity profile without adjustable parameters when the modulus and wall friction coefficients are determined independently. The model possesses theoretical relationships for wall support and resin rigidity that should enable it to describe the mechanical compression of any biochromatographic resin for any column diameter. Moreover, this framework could provide a path to analogous models for flow packing and dynamic axial compression.

Toward a robust model of packing and scale-up for chromatographic beds. 2. Flow packing.

We developed and evaluated a model for predicting the flow packing of nonrigid chromatographic resins. The model is based on elasticity theory and accounts for resin rigidity and column diameter. When a modulus determined from a standard mechanical compression (consolidation) test is used, the model captures the primary phenomena of the scale-up process. However, moduli determined from flow-packing experiments improve the accuracy of the predictions and show that the apparent rigidity of chromatographic resins is lower for flow packing than for mechanical compression. Using a modulus from flow-packing experiments provided quantitative scale-up predictions of flow packing carried out in columns with diameters between 200 and 450 mm at different locations and by different operators.

Analysis of bacterial random motility in a porous medium using magnetic resonance imaging and immunomagnetic labeling.

In this study, we demonstrate the application of immunomagnetic labeling and magnetic resonance imaging (MRI) for the noninvasive visualization of changes in bacterial density distributions as a function of time in a water-saturated porous medium. Magnetite particles (50-60 nm diameter) were attached via a monoclonal antibody to the surface' of Escherichia coli K12 NR50 cells. The cells maintained their motility after labeling, and the presence of the magnetite did not significantly alter cell swimming speed. Diffusive migration for both motile and nonmotile E. coli through a porous medium with a particle-diameter distribution of 250-300 microm was compared. The movement of the nonmotile cells was described by an effective random motility coefficient consistent with Brownian diffusion of a nonmotile colloid. An effective coefficient determined a priori from bacterial motility in an aqueous medium and properties of the porous medium adequately described the movement of the motile cells. The ability to noninvasively visualize bacterial concentrations within an opaque porous medium in real time provides researchers with a powerful tool for studying bacterial transport in porous media. This is important for understanding the impact of bacterial transport on remediation strategies for environmental cleanup of polluted groundwater.