Morphology and microtopology of cation-exchange polymers and the origin of the overlimiting current.

In electrodialysis desalination processes, the operating current density is limited by concentration polarization. In contrast to other membrane processes such as ultrafiltration, in electrodialysis, current transport above the limiting current is possible. In this work, the origin of the overlimiting current at cation-exchange polymers is investigated. We show that, under certain experimental conditions, electroconvection is the origin of the overlimiting conductance. The theory concerning electroconvection predicts a shortening of the plateau length of membranes with increased conductive or geometrical heterogeneity. We investigate the influence of these two parameters and show that the creation of line undulations on the membrane surface normal to the flow direction, having distances in the range of approximately 50-200% of the boundary-layer thickness, lead to an earlier onset of the overlimiting current. The plateau length of the undulated membranes is reduced by up to 60% compared to that of a flat membrane. These results verify the existence of electroconvection as a mechanism destabilizing the laminar boundary layer at the liquid-membrane interface and causing ionic transport above the limiting current density.

Controlled transport of timolol maleate through artificial membranes under passive and iontophoretic conditions.

The passive and iontophoretic permeability of timolol maleate (TM) through porous and dense artificial membranes was investigated in order to select the most optimal membrane for a transdermal drug delivery system. For the meso-porous membranes (pore diameter 2-50 nm), the TM permeability for passive diffusion and iontophoresis was practically the same. For the micro-porous membranes (pore diameter<2 nm), a significant transport contribution of iontophoresis was observed, which was more pronounced when higher current densities were applied. The electrical resistance of all the porous membranes was lower than the electrical resistance of human skin. For dense membranes, passive and iontophoretic TM permeability was significantly lower than for porous membranes and in most cases their electrical resistance was comparable or even higher than the resistance of human skin. For most of the membranes studied the average adsorption of TM at 37 degrees C was low (0.02-0.33 mg/cm(2)) and independent of the TM concentration. For the meso-porous mixed cellulose acetate-cellulose nitrate membrane the TM adsorption was significantly higher and increased with the TM concentration. Based on our results, the optimum membrane for an iontophoretic transdermal TM delivery system is the LFC 1 micro-porous membrane because it mainly controls the TM delivery (TM iontophoretic permeability: 0.86 x 10(-6) cm/s), has very low electrical resistance (0.9-1.5 komega cm(2)) and the TM adsorption to it is low (0.15 mg/cm(2)). The therapeutic plasma TM concentration is achievable by application of this membrane in realistic sizes (5-64 cm(2)) and by application of current densities between 0.13 and 0.5 mA/cm(2).

Delivery of timolol through artificial membranes and pig stratum corneum.

The in vitro passive and iontophoretic (applied current density: 0.5 mA/cm(2)) timolol (TM) permeability from a liquid solution through pig stratum corneum (SC) is found to be 0.9 +/- 0.5 x 10(-6) and 3.9 +/- 0.9 x 10(-6) cm/s, respectively. The in vitro iontophoretic TM delivery through the combination of artificial porous membranes with pig SC is investigated as well. When the meso-porous PES-30 membrane is applied, the SC mainly controls the TM delivery. When the microporous NF-PES-10 membrane is applied, both the membrane and the SC contribute to controlling the delivery of TM. When the microporous LFC 1 membrane is applied, the TM delivery is membrane controlled. In all cases, however, the efficiency of the TM delivery is low and would need to be improved for the development of a commercially viable product.

Passive and iontophoretic controlled delivery of salmon calcitonin through artificial membranes.

The development of a transdermal delivery system for drug molecules of high molecular weight (peptides or proteins) is nowadays a great scientific and commercial challenge. For these molecules, the passive transport through the skin is generally very low and should be enhanced by the application of the electrical current (a method called iontophoresis). A very important component of a transdermal iontophoretic system is the artificial membrane, which acts as the interface between the drug reservoir and the skin. The optimum membrane should (i) provide an effective drug delivery; (ii) have low electrical resistance and (ii) have low drug adsorption. In this work, the selection of membrane(s) for a transdermal iontophoretic salmon calcitonin (sCT, MW approximately 3500) system is performed. The passive and iontophoretic transport of sCT through porous artificial membranes, the sCT adsorption to them and the electrical resistance of all porous membranes in iontophoretic experiments is studied. The sCT transport through the membranes is compared with that through human skin, and based on the above three criteria the optimum membranes are selected for the sCT transdermal system.

In vitro evaluation of a hydroxypropyl cellulose gel system for transdermal delivery of timolol.

In this work, the development of a gel reservoir for a timolol (TM) transdermal iontophoretic delivery system is investigated. TM gel is prepared using hydroxypropyl cellulose (HPC) and the permeability of TM from the gel through an artificial membrane (Polyflux) and pig stratum corneum (SC) is studied. For a constant TM donor concentration, the TM transport across the Polyflux membrane alone decreases when the concentration of the gel increases due to increase of the gel viscosity. For constant gel concentration, however, the TM permeation across the membrane increases when the TM donor concentration increases. In addition, no effect of the electrical current (iontophoresis, current density 0.5 mA cm-2) on the TM permeation is found. For the combination of the Polyflux membrane with pig SC, the TM transport is much lower than for the membrane alone and the SC fully controls the TM delivery. In this case, the application of electrical current enhances the TM delivery 13-15 times in comparison to passive (no current) transport. According to our estimation, the daily TM dose (10-60 mg) can be delivered by an iontophoretic patch with Polyflux membrane area of 6-36 cm2 containing 20% (w/w) HPC gel and 15 mg cm-3 of TM.

A modular versatile chip carrier for high-throughput screening of cell-biomaterial interactions.

The field of biomaterials research is witnessing a steady rise in high-throughput screening approaches, comprising arrays of materials of different physico-chemical composition in a chip format. Even though the cell arrays provide many benefits in terms of throughput, they also bring new challenges. One of them is the establishment of robust homogeneous cell seeding techniques and strong control over cell culture, especially for long time periods. To meet these demands, seeding cells with low variation per tester area is required, in addition to robust cell culture parameters. In this study, we describe the development of a modular chip carrier which represents an important step in standardizing cell seeding and cell culture conditions in array formats. Our carrier allows flexible and controlled cell seeding and subsequent cell culture using dynamic perfusion. To demonstrate the application of our device, we successfully cultured and evaluated C2C12 premyoblast cell viability under dynamic conditions for a period of 5 days using an automated pipeline for image acquisition and analysis. In addition, using computational fluid dynamics, lactate and BMP-2 as model molecules, we estimated that there is good exchange of nutrients and metabolites with the flowing medium, whereas no cross-talk between adjacent TestUnits should be expected. Moreover, the shear stresses to the cells can be tailored uniformly over the entire chip area. Based on these findings, we believe our chip carrier may be a versatile tool for high-throughput cell experiments in biomaterials sciences.

Integration of hollow fiber membranes improves nutrient supply in three-dimensional tissue constructs.

Sufficient nutrient and oxygen transport is a potent modulator of cell proliferation in in vitro tissue-engineered constructs. The lack of oxygen and culture medium can create a potentially lethal environment and limit cellular metabolic activity and growth. Diffusion through scaffold and multi-cellular tissue typically limits transport in vitro, leading to potential hypoxic regions and reduction in the viable tissue thickness. For the in vitro generation of clinically relevant tissue-engineered grafts, current nutrient diffusion limitations should be addressed. Major approaches to overcoming these include culture with bioreactors, scaffolds with artificial microvasculature, oxygen carriers and pre-vascularization of the engineered tissues. This study focuses on the development and utilization of a new perfusion culture system to provide adequate nutrient delivery to cells within large three-dimensional (3D) scaffolds. Perfusion of oxygenated culture medium through porous hollow fiber (HF) integrated within 3D free form fabricated (FFF) scaffolds is proposed. Mouse pre-myoblast (C2C12) cells cultured on scaffolds of poly(ethylene-oxide-terephthalate)-poly(butylene-terephthalate) block copolymer (300PEOT55PBT45) integrated with porous HF membranes of modified poly(ether-sulfone) (mPES, Gambro GmbH) is used as a model system. Various parameters such as fiber transport properties, fiber spacing within a scaffold and medium flow conditions are optimized. The results show that four HF membranes integrated with the scaffold significantly improve the cell density and cell distribution. This study provides a basis for the development of a new HF perfusion culture methodology to overcome the limitations of nutrient diffusion in the culture of large 3D tissue constructs.

Structure and permeation properties of cellulose esters asymmetric membranes.

The permeation properties of a series of membranes of cellulose esters, presenting a wide range of characteristics, were studied and correlated to the structure of water in the pores, to the polymer hydrophilicity/hydrophobicity, and to the morphology of the surface of the active layer. Asymmetric membranes of cellulose acetate, cellulose acetate propionate, and cellulose acetate butyrate were prepared by the phase inversion method and their preferential permeation performance tested. The surface morphology and the structure of the water in the pores of the active layer were studied by atomic force microscopy (AFM) and attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy, respectively. Results show that higher rejection to NaCl and low fluxes are generally associated with smaller clusters of water in the pores. On the other hand, the surface of the membranes presenting smaller clusters of water in the active layer show generally surfaces with lower roughness as measured by AFM.