Preparation and characterization of microfiltration flat polymeric membranes for biomedical applications

Dissertation presented to Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa for obtaining the master degree in Membrane EngineeringThe optimal methodology for flat supported hydrophobic microporous poly(vinylidene) fluoride (PVDF) industrial membranes (Fortex 0.1, Fortex 0.2, Fortex 1.2 and Fortex 3.0) production were developed with implementation of wet phase-inversion technique. The effect of different indicators of the production conditions, such as composition of polymer solution, quantity and type of additives, dissolving temperature, composition and temperature of the coagulation bath were studied. All the comparisons were performed in the narrow range of values in order to have better understanding of how slight deviation of each parameter can influence the performance of the industrially manufactured membrane. During the development process it was observed that the increase of dissolving temperature results in formation of membrane with more open structure, justified by higher values of air flow (AF) and lower critical water entry pressure (water break through (WBT)). Moreover, the low molecular weight inorganic lithium salt has stronger effect on membrane performance than organic pore former applied. After the optimization of production parameters for each type of membranes at the laboratory scale, the implementation of these conditions was realized at industrial scale. The good reproducibility of membrane characteristics prepared at laboratory and industrial scale was observed for three membrane types. The industrial trial for Fortex 0.2 membrane was not successful and this result was hypothetically related to the high viscosity of the casting solution. Additionally, it was demonstrated that absorbance of air moisture by polymer solution may significantly influence properties of manufactured membranes. Moreover, the industrially manufactured membranes as well as laboratory samples of Fortex 0.2 were characterized by means of scanning electron microscope, permporometry and Fourier Transform Infrared Spectroscopy. It was shown that usage of different solvent/non-solvent pairs (DMAc/water and DMAc/alcohol) was leading to the different membrane morphologies. Basing on permporometry test results, the largest active pores inside membranes were identified. Finally, it was shown that all the developed membranes possess β and γ crystalline phases and only Fortex 0.1 exhibited presence of α structure.The EM3E Master is an Education Programme supported by the European Commission, the European Membrane Society (EMS), the European Membrane House (EMH), and a large international network of industrial companies, research centres and universitie

Medium sized molecules clearance through artificial kidneys

Malgré une longue histoire de développement, l'hémodialyse (rein artificiel) possède encore quelques limitations, telles que la perte des propriétés initiales de la membrane en cours de traitement à cause du colmatage et la mauvaise élimination des toxines urémiques de taille moyenne. La présente étude fait partie d'un projet européen nommé BioArt dont le but est d'apporter des solutions à ces limites. Dans cet objectif, l'un des partenaires du projet a proposé le développement d'un nouveau concept de membrane double couche au sein de laquelle sont incorporées des particules adsorbantes. Une caractérisation complète de cette nouvelle membrane était alors nécessaire, plus précisément l'impact de la matrice mixte sur l'élimination des toxines urémiques de divers groupes devait être évalué, ainsi que la propension du matériau membranaire à se colmater. Les études des phénomènes de colmatage sont classiquement menées à l'échelle macroscopique (faisceau de fibres creuses) sans analyse à l'échelle d'une fibre isolée. Le but premier de la présente thèse a alors été de proposer un dispositif permettant une étude du colmatage membranaire induit par la protéine à l'échelle microscopique. Un dispositif microfluidique transparent dans lequel la membrane polymère est insérée a été élaboré et mis en œuvre pour la filtration des protéines modèles : l'albumine de sérum bovin (BSA) et l'a-lactalbumine. Grâce au couplage avec la microscopie de fluorescence, différents modes d'adsorption des protéines sur la surface de la membrane ont été observés et liés aux variations des conditions hydrodynamiques à l'intérieur de la puce. Il a été constaté, sous certaines conditions, une différence dans l'accumulation de protéines entre l'entrée, le centre et la sortie du canal tandis que dans d'autres conditions cet effet s'annule. En outre, un phénomène inattendu, l'agrégation de l'a-lactalbumine, a été observé au cours de la filtration. La localisation dans le canal et la forme des agrégats dépendent également des conditions hydrodynamiques et de la pression transmembranaire appliquée. Dans le but d'optimiser la conception de la membrane vis à vis de son aptitude à éliminer des molécules de taille moyenne de la circulation sanguine, un modèle mathématique a été proposé. L'objectif du modèle était, en prenant en compte la présence de particules adsorbantes à l'intérieur de la membrane double couche, de rendre compte de la combinaison des trois mécanismes d'élimination du soluté : la convection, la diffusion et l'adsorption. Le modèle permet de prédire l'influence de divers paramètres tels que la diffusivité de la molécule, l'épaisseur de la membrane, la présence de la convection, la charge en particules adsorbantes, sur l'intensification des flux à travers la membrane. Le modèle semble être un outil utile pouvant être appliqué à l'optimisation de membranes pour l'élimination des toxines.Despite a long history of development, the hemodialysis procedure (artificial kidney) still possesses some limitations, such as loss of the initial properties of the membrane due to fouling and poor removal of the middle sized uremic toxins. The present study is part of an European project named BioArt the aim of which was to overcome these limitations. In that objective, one of the partners of BioArt project reported on the development of the novel promising concept of double layer membrane with embedded adsorptive particles. A thorough characterization of the new membrane was then necessary, more precisely the extent to which mixed matrix layer can improve the removal of the uremic toxins from various groups needed to be evaluated, as well as the propensity of the membrane material to become fouled. The studies of the fouling phenomena are conventionally performed at the macro scale (bundle of hollow fibers) without insights of what is happening at the scale of an isolated fiber. Therefore, the primary aim of the present Thesis was to transfer the research of the protein-induced membrane fouling from the macro to the micro scale. A novel transparent microfluidics device with the polymeric membrane inside has been developed and applied for the filtration of model proteins: bovine serum albumin (BSA) and a-lactalbumin. Thanks to the coupling of the microchip with the fluorescent microscopy, different patterns of protein deposition on the membrane surface were observed and related to the variations in the hydrodynamic conditions inside the microchip. It was found that at certain conditions one may observe the difference in protein accumulation in the inlet, the middle, and the outlet of the channel while at other conditions this effect vanishes. Additionally, the unexpected phenomena of a-lactalbumin aggregation was observed over the course of filtration. The location and shape of the aggregates were also dependent on the hydrodynamic conditions and the applied transmembrane pressure. Aiming to address the problem of membrane design optimization for the enhancement of the middle molecules elimination from the bloodstream, a mathematical model, which accounts for the presence of adsorptive particles inside the complex double-layer membrane, has been proposed. The objective of the model was to understand the interplay of three solute removal mechanisms: convection, diffusion, and adsorption. The model allows predicting the influence of various parameters such as molecule diffusivity, membrane thickness, the presence of convection, content of adsorptive particles on the flux intensification across the membrane. The developed model seems to be a useful tool, which may be applied to design optimized membranes for the removal of toxins

Insight into the transport mechanism of solute removed in dialysis by a membrane with double functionality

The present study aims at shedding light on the transport mechanisms involved in a functionalized membrane designed for improving hemodialysis. This membrane is prepared by embedding absorptive micro particles within its porous structure. To understand the transport mechanism through the membrane and make suggestions for its optimization, a mathematical model coupling convection, diffusion and adsorption is developed and validated by comparison of experimental and theoretical results. In fact, the model provides a description of the concentration profile from the donor (feed) compartment across the several layers with different properties to the acceptor (dialysate) compartment. In addition, the model allows to predict the influence of various parameters such as molecule diffusivity, membrane thickness, presence of convection, content of adsorptive particles on the flux intensification across the membrane. Comparison with experimental measurements demonstrates that the model is able to describe the transmembrane mass flux variation over time as a function of hydrodynamic conditions and membrane/module geometric parameters. The model also illustrates how the proposed double-layer membrane concept offers significant benefits in terms of toxin removal in comparison to conventional dialysis. As so, the main achievement of the developed model is that it may serve as tool for the further improvement of functionalized membrane in terms of toxin removal and optimization of process condition

Combining fluorescence and permeability measurements in a membrane microfluidic device to study protein sorption mechanisms

Membrane fouling by proteins is an important problem in hemodialysis or hemofiltration (artificial kidney). The mechanisms leading to fouling are still not fully understood and then predictable. In this paper we describe a microfluidic chip fitted with a filtration membrane which allows the real time in situ fluorescent analysis of labelled proteins and the measurement of the membrane permeability. The apparent kinetics rates of adsorption derived from the changes in fluorescence signal are combined with permeability measurements. This allows to discriminate two clearly distinct fouling mechanism by Bovine Serum Albumin (BSA) and α-lactalbumin (LALBA). The fouling kinetics of BSA is very rapid, independent of the flow conditions and can then be viewed as a protein monolayer adsorption controlled by protein-membrane interactions. In contrast, the fouling kinetics by LALBA is slower and very sensitive to flow conditions. We also describe a fluorescence quenching induced by protein aggregation and compression at high permeation rate. The fouling mechanism can then be viewed as a flow induced aggregation followed by a deposition of aggregates on the membrane. The complexity of sorption mechanisms on membrane during cross-flow filtration can be unraveled with this experimental set-up

New membranes based on polyethersulfone – SlipSkin™ polymer blends with low fouling and high blood compatibility

Hemodialysis is an important therapy for treating patients with End Stage Renal Disease (ESRD). These patients visit the hospital 3 times a week and each time their blood is cleansed during 4-hour dialysis sessions using a hollow fiber membrane module; also called artificial kidney. This device mainly achieves removal of small water-soluble toxins and a limited number of middle molecules. To improve the clearance of toxins, especially middle molecules and protein bound toxins, longer treatment via nocturnal dialysis and/or the application of portable/wearable artificial kidney is required. Such therapies require application of membranes with very low fouling and very good blood compatibility. Current membranes often contain hydrophilic additives which could elute during sterilization processes and/or during long-term filtration. In this study, we propose a simple method for developing low fouling blood compatible membranes by blending of polyethersulfone (PES), a material already used for fabrication of dialysis membranes, with small amounts of SlipSkin™ (SS), a blood compatible random copolymer of hydrophilic N-vinylpyrrolidone (NVP) and hydrophobic N-butylmethacrylate (BMA). Our results show that membranes with 2 wt% of SS have high fouling resistance to proteins and middle-size molecules and very good blood compatibility, making these membranes promising for application in dialysis therapy

Clairance de molécules de taille moyenne à travers un rein artificiel

Despite a long history of development, the hemodialysis procedure (artificial kidney) still possesses some limitations, such as loss of the initial properties of the membrane due to fouling and poor removal of the middle sized uremic toxins. The present study is part of an European project named BioArt the aim of which was to overcome these limitations. In that objective, one of the partners of BioArt project reported on the development of the novel promising concept of double layer membrane with embedded adsorptive particles. A thorough characterization of the new membrane was then necessary, more precisely the extent to which mixed matrix layer can improve the removal of the uremic toxins from various groups needed to be evaluated, as well as the propensity of the membrane material to become fouled. The studies of the fouling phenomena are conventionally performed at the macro scale (bundle of hollow fibers) without insights of what is happening at the scale of an isolated fiber. Therefore, the primary aim of the present Thesis was to transfer the research of the protein-induced membrane fouling from the macro to the micro scale. A novel transparent microfluidics device with the polymeric membrane inside has been developed and applied for the filtration of model proteins: bovine serum albumin (BSA) and a-lactalbumin. Thanks to the coupling of the microchip with the fluorescent microscopy, different patterns of protein deposition on the membrane surface were observed and related to the variations in the hydrodynamic conditions inside the microchip. It was found that at certain conditions one may observe the difference in protein accumulation in the inlet, the middle, and the outlet of the channel while at other conditions this effect vanishes. Additionally, the unexpected phenomena of a-lactalbumin aggregation was observed over the course of filtration. The location and shape of the aggregates were also dependent on the hydrodynamic conditions and the applied transmembrane pressure. Aiming to address the problem of membrane design optimization for the enhancement of the middle molecules elimination from the bloodstream, a mathematical model, which accounts for the presence of adsorptive particles inside the complex double-layer membrane, has been proposed. The objective of the model was to understand the interplay of three solute removal mechanisms: convection, diffusion, and adsorption. The model allows predicting the influence of various parameters such as molecule diffusivity, membrane thickness, the presence of convection, content of adsorptive particles on the flux intensification across the membrane. The developed model seems to be a useful tool, which may be applied to design optimized membranes for the removal of toxins.Malgré une longue histoire de développement, l'hémodialyse (rein artificiel) possède encore quelques limitations, telles que la perte des propriétés initiales de la membrane en cours de traitement à cause du colmatage et la mauvaise élimination des toxines urémiques de taille moyenne. La présente étude fait partie d'un projet européen nommé BioArt dont le but est d'apporter des solutions à ces limites. Dans cet objectif, l'un des partenaires du projet a proposé le développement d'un nouveau concept de membrane double couche au sein de laquelle sont incorporées des particules adsorbantes. Une caractérisation complète de cette nouvelle membrane était alors nécessaire, plus précisément l'impact de la matrice mixte sur l'élimination des toxines urémiques de divers groupes devait être évalué, ainsi que la propension du matériau membranaire à se colmater. Les études des phénomènes de colmatage sont classiquement menées à l'échelle macroscopique (faisceau de fibres creuses) sans analyse à l'échelle d'une fibre isolée. Le but premier de la présente thèse a alors été de proposer un dispositif permettant une étude du colmatage membranaire induit par la protéine à l'échelle microscopique. Un dispositif microfluidique transparent dans lequel la membrane polymère est insérée a été élaboré et mis en œuvre pour la filtration des protéines modèles : l'albumine de sérum bovin (BSA) et l'a-lactalbumine. Grâce au couplage avec la microscopie de fluorescence, différents modes d'adsorption des protéines sur la surface de la membrane ont été observés et liés aux variations des conditions hydrodynamiques à l'intérieur de la puce. Il a été constaté, sous certaines conditions, une différence dans l'accumulation de protéines entre l'entrée, le centre et la sortie du canal tandis que dans d'autres conditions cet effet s'annule. En outre, un phénomène inattendu, l'agrégation de l'a-lactalbumine, a été observé au cours de la filtration. La localisation dans le canal et la forme des agrégats dépendent également des conditions hydrodynamiques et de la pression transmembranaire appliquée. Dans le but d'optimiser la conception de la membrane vis à vis de son aptitude à éliminer des molécules de taille moyenne de la circulation sanguine, un modèle mathématique a été proposé. L'objectif du modèle était, en prenant en compte la présence de particules adsorbantes à l'intérieur de la membrane double couche, de rendre compte de la combinaison des trois mécanismes d'élimination du soluté : la convection, la diffusion et l'adsorption. Le modèle permet de prédire l'influence de divers paramètres tels que la diffusivité de la molécule, l'épaisseur de la membrane, la présence de la convection, la charge en particules adsorbantes, sur l'intensification des flux à travers la membrane. Le modèle semble être un outil utile pouvant être appliqué à l'optimisation de membranes pour l'élimination des toxines