Characterization of nanochannel delivery membrane systems for the sustained release of resveratrol and atorvastatin: new perspectives on promoting heart health

Novel drug delivery systems capable of continuous sustained release of therapeutics have been studied extensively for use in the prevention and management of chronic diseases. The use of these systems holds promise as a means to achieve higher patient compliance while improving therapeutic index and reducing systemic toxicity. In this work, an implantable nanochannel drug delivery system (nDS) is characterized and evaluated for the long-term sustained release of atorvastatin (ATS) and trans-resveratrol (t-RES), compounds with a proven role in managing atherogenic dyslipidemia and promoting cardioprotection. The primary mediators of drug release in the nDS are nanofluidic membranes with hundreds of thousands of nanochannels (up to 100,000/mm²) that attain zero-order release kinetics by exploiting nanoconfinement and molecule-to-surface interactions that dominate diffusive transport at the nanoscale. These membranes were characterized using gas flow analysis, acetone diffusion, and scanning and transmission electron microscopy (SEM, TEM). The surface properties of the dielectric materials lining the nanochannels, SiO₂ and low-stress silicon nitride, were further investigated using surface charge analysis. Continuous, sustained in vitro release for both ATS and t-RES was established for durations exceeding 1 month. Finally, the influence of the membranes on cell viability was assessed using human microvascular endothelial cells. Morphology changes and adhesion to the surface were analyzed using SEM, while an MTT proliferation assay was used to determine the cell viability. The nanochannel delivery approach, here demonstrated in vitro, not only possesses all requirements for large-scale high-yield industrial fabrication, but also presents the key components for a rapid clinical translation as an implantable delivery system for the sustained administration of cardioprotectants.     

Evolution of porosity in geotechnical composites

Nuclear magnetic resonance (NMR) (H1) transverse relaxation measurements were carried out on 37x70-mm cylindrical mineral/organic composites to determine and monitor the porosity evolution. Porosity is related, in principle, to the stability of such materials in geotechnical applications, for example, engineering foundations. The specimens represented novel formulations of mixed "wastes" containing coarse screened mineral, digested sewage sludge, quicklime, and pulverized fuel ash mixed and compacted together to form mechanically competent material. The measurements on a selected formulation indicated initially low porosity (<12%) that becomes lower over 6 months ( approximately 8%) due to pozzolanic reactions occurring. A relaxation time cutoff of 1.5 ms between "bound" and 'mobile' pore water much lower than sandstones (33 ms) was observed. The results confirmed that the NMR method allows a more reliable assessment of porosity and pore-size evolution.     

A low-voltage electrokinetic nanochannel drug delivery system

Recent work has elucidated the potential of important new therapeutic paradigms, including metronomic delivery and chronotherapy, in which the precise timing and location of therapeutic administration has a significant impact on efficacy and toxicity. New drug delivery architectures are needed to not only release drug continuously at precise rates, but also synchronize their release with circadian cycles. We present an actively controlled nanofluidic membrane that exploits electrophoresis to control the magnitude, duration, and timing of drug release. The membrane, produced using high precision silicon fabrication techniques, has platinum electrodes integrated at the inlet and outlet that allow both amplification and reversal of analyte delivery with low applied voltage (at or below 2 VDC). Device operation was demonstrated with solutions of both fluorescein isothiocyanate conjugated bovine serum albumin and lysozyme using fluorescence spectroscopy, fluorescence microscopy, and a lysozyme specific bio-assay and has been characterized for long-term molecular release and release reversibility. Through a combination of theoretical and experimental analysis, the relative contributions of electrophoresis and electroosmosis have been investigated. The membrane's clinically relevant electrophoretic release rate at 2 VDC exceeds the passive release by nearly one order of magnitude, demonstrating the potential to realize the therapeutic paradigm goal.     

Immiscible Displacement in Cross-Bedded Heterogeneous Porous Media

Direct insight into the mechanisms of flow and displacements within small-scale (cm) systems having permeability heterogeneities that are not parallel to the flow direction (cross-bedding and fault zones) have been carried out. In our experiments, we have used visual models with unconsolidated glass bead packs having carefully controlled permeability contrasts to observe the processes with coloured fluids and streamlines. The displacements were followed visually and by video recording for later analysis. The experiments show the significance that heterogeneities have on residual saturations and recovery, as well as the displacement patterns themselves. During a waterflood, high permeability regions can be by-passed due to capillary pressure differences, giving rise to high residual oil saturations in these regions. This study demonstrates the importance of incorporating reservoir heterogeneity into core displacement analysis, but of course the nature of the heterogeneity has to be known. In general, the effects created by the heterogeneities and their unknown boundaries hamper interpretation of flood experiments in heterogeneous real sandstone cores. Our experiments, therefore, offer clear visual information to provide a firmer understanding of the displacement processes during immiscible displacement, to present benchmark data for input to numerical simulators, and to validate the simulator through a comparison with our experimental results for these difficult flow problems.     

Experimental displacement patterns in a 2 × 2 quadrant block with permeability and wettability heterogeneities—problems for numerical modelling

The effect of heterogeneities on miscible and immiscible flood displacements in 2D bead packs in quadrant form, 2 × 2 block heterogeneity, with either a permeability or a wettability contrast is the subject of this paper. The physical processes occurring during miscible and immiscible flow and displacement within permeability and wettability quadrant bead pack models have been studied experimentally. This geometry occurs in a number of situations relevant to hydrocarbon production: particularly faults where adjacent rocks have large permeability contrasts with rapid changes, in the laboratory with core butting, in reservoir simulation where grid blocks have different permeability and in reservoirs having near-wellbore damage problems. The model quadrants 1–4, had 1 and 4 and 2 and 3 with identical properties, either in permeability or wettability. Reported are complete unit mobility miscible displacements, then the effects of viscosity differences (mobility modifiers) and finally immiscible displacements on displacement patterns for initial linear injection. The experiments demonstrate that nodal flow occurs for both miscible and immiscible flow, but for immiscible flow there are boundary effects due to capillary pressure differences created by water saturation changes or wettability contrasts which can leave patches of isolated fluid within a quadrant. The displacement patterns for the different models and fluids change significantly with the viscosity and wettability changes, particularly for the immiscible displacements. This is due to the changing capillary pressure between the quadrant blocks as the water saturation change. These are difficult to address in numerical modelling but should be accounted for. Other effects include coupling of all physical processes governing the flow through the node and creations of microzones of trapped residual oil. Our displacement patterns can therefore be a valuable verification benchmark tool for numerical modelling and a calibration data source for those wishing to simulate the effects of capillary pressure under differing wettability conditions and for those investigating upscaling modelling procedures. However, the possible loss of physical reality when averaging must always be considered.     

Osmotic pressure beyond concentration restrictions

Osmosis is a fundamental physical process that involves the transit of solvent molecules across a membrane separating two liquid solutions. Osmosis plays a role in many biological processes such as fluid exchange in animal cells (Cell Biochem. Biophys. 2005, 42, 277-345;1 J. Periodontol. 2007, 78, 757-7632) and water transport in plants. It is also involved in many technological applications such as drug delivery systems (Crit. Rev. Ther. Drug. 2004, 21, 477-520;3 J. Micro-Electromech. Syst. 2004, 13, 75-824) and water purification. Extensive attention has been dedicated in the past to the modeling of osmosis, starting with the classical theories of van't Hoff and Morse. These are predictive, in the sense that they do not involve adjustable parameters; however, they are directly applicable only to limited regimes of dilute solute concentrations. Extensions beyond the domains of validity of these classical theories have required recourse to fitting parameters, transitioning therefore to semiempirical, or nonpredictive models. A novel approach was presented by Granik et al., which is not a priori restricted in concentration domains, presents no adjustable parameters, and is mechanistic, in the sense that it is based on a coupled diffusion model. In this work, we examine the validity of predictive theories of osmosis, by comparison with our new experimental results, and a meta-analysis of literature data.     

Microscale Visual Study of End Effects at Permeability Discontinuities

The physical effect of multiphase fluid distribution and flow at permeability boundaries has not been fully investigated, particularly at the pore scale (1–100 μm), although such behaviour can significantly affect the overall scaled-up reservoir trapping capacity and production performance. In this article, microscale physical models have been used to qualitatively study the pore scale flow events at permeability boundaries, both high to low and vice versa, to gain a better understanding of the role of these boundaries and water saturation on multiphase displacement behaviour at the pore scale. We have used etched glass models of stripes of large and small (a factor of two) pores with circular matrix. Capillary pressure, which is the controlling parameter is itself dependant on pore size and its spatial distribution, the magnitude of the interfacial tensions and the wettability between the fluids and the solid surface of the models. Sometimes, the only way the non-wetting fluid can penetrate the boundary is through a fortuitous leakage, whereby the presence of an initial saturation reduces the controlling capillary pressure. Examples are demonstrated including mechanisms of end-effects and how capillary boundary resistance (due to capillary forces) can be broken down and fluid movement across the boundary can develop. These micromodel experiments show vividly that connate water can assist in these processes, particularly oil trapping and leakage of water across a permeability boundary.     

Flow of water through channels filled with deformable polymer gels

A mathematical model is developed for the flow of water through a channel impregnated with a polymer gel that is treated as an elastic and deformable porous medium. The model uses a Brinkman equation along with an experimentally observed velocity-dependent permeability. Numerical and approximate analytical solutions are given. These results show that the gel intrinsic properties, i.e., gel reference permeability and elastic index, control the water flow. First, the permeability of water flow through the gel increases with an increase of gel reference permeability. Second, the velocity of water decreases when the gel velocity exponent increases. Our theoretical results show that the velocity-dependent permeability of water flow through polymer gels is in fact an intrinsic property of the gel rather than a property of the channel or some interaction between the gel and the pore walls.     

Rheology and Permeability of Crosslinked Polyacrylamide Gel

Gels produced by crosslinking polyacrylamide solutions with chromium (III) have been characterized by dynamic rheology studies. To vary the gel strength, different polymer concentrations were used, while keeping the temperature, salinity, and crosslinker concentration constant. Both the loss and storage moduli increased with the polymer concentration for this gel system. The storage modulus at the end of the gelation was used to characterize the gel strength. Steady-state water flow experiments through gel-filled capillary tubes were performed, with the aim of linking the gel strength and flow behavior. The permeability was found to be a function of the water flow rate (velocity) and polymer concentration. Two parameters were used to characterize the flow behavior, intrinsic gel permeability and elasticity index, which are each functions of the polymer concentration. However, only one parameter is needed to fully identify the flow and rheological gel properties, as the elasticity index and storage modulus are linked by a power-law relationship. The loss modulus and intrinsic permeability are correlated with the storage modulus and elasticity index, respectively. A theoretical model for this behavior linking both gel properties based on the dual domain structure was used to demonstrate that the flow and rheological behavior of the gel are indeed related and that the gel strength controls the water permeability. Implications for prediction of flow of water through gels emplaced in a porous medium are discussed.