Nanoporous anodic aluminum oxide (AAO) structures have received considerable attention in the research community for a range of uses. The self-ordering and straight channel porous structure has been exploited primarily as a template structure for producing nanorods/nanofibers of Au, Pt, Cu and Ag, as well as several polymers.^1-4 More recently, nanoporous AAO has also been used to develop nanoporous membranes for a variety of medical devices.^5-7 Here, the development of AAO membranes has been concentrated on applications for biological fluid separation. Proteins, toxins and viruses on the molecular level are capable of being separated from human blood using synthetic polymer membranes.

AAO Membranes and Hemodialysis

Enlarge this picture Figure 1. A nanoporous AAO membrane (surface view, a; cross-section, b).

Hemodialysis, one of the applications that uses polymer membranes, refers to the extracorporeal filtering of blood through an artificial kidney for the purpose of maintaining or supplementing kidney function. In this process, a blood circuit is formed when blood is drawn from a patient and circulated continuously past a synthetic polymer membrane to remove small- and middle-molecular-weight (MW) solutes normally passed by the kidney. As the primary treatment modality for chronic kidney disease (CKD) and end-stage renal disease (ESRD) patients, hemodialysis is the limiting step in determining the performance of a dialysis session.

A uremic toxin is characterized by different molecular weight, degree of protein binding, volume of distribution and charge. Low-MW nitrogenous waste products are the most extensively studied group of these toxins.⁸ These toxins feature a high diffusivity of mass transfer characteristics due to their low molecular weight and lack of protein binding.⁹

Improving the efficiency of maintenance dialysis can be accomplished in part through the development of new dialysis membranes, whereby the survival rate of the patient may be improved. The non-uniformity of pore distribution, irregularities in pore shapes and size, and the limited reusability of current dialysis membranes has led to extensive research in the area of membranes for hemodialysis.

Nanoporous AAO membranes have a self-ordering pore arrangement with high pore densities that are essential to maximize permeation and molecular flux across the membrane in a fluid separation application (see Figure 1). AAO membranes with this highly uniform and self-organized nanoporous structure are an ideal choice over the contemporary cellulose-based and synthetic polymer membranes in the hemodialysis application. AAO membrane advantages include high porosity while maintaining uniform pore size between 5 and 300 nm, high hydraulic conductivity (water permeability), uniform distribution of pores, straight pore structure, and high resistance to chemical and temperature degradation (sterilization).

Nanoporous AAO is created as a thin-film oxide during the electrochemical process of anodization of an aluminum substrate. The aluminum substrate is placed in an acid electrolyte as the anode in an electrochemical cell setup. As the electrical potential is raised, a nanoporous array of aluminum oxide is grown at a specified rate. Membrane characteristics, such as pore size, interpore spacing and thickness, are highly dependent on the anodization parameters, the details of which are shown elsewhere.^10-12 AAO membranes have been successfully manufactured in both sheet and tube form.

High Porosity and Uniform Pore Size

Figure 2. A state-of-the-art PES membrane (surface view, a; cross-section, b).

High-resolution scanning electron microscope (SEM) images of the morphology of an AAO membrane are shown in Figure 1. In comparison, a polyethersulfone (PES) membrane currently used as a dialysis membrane is shown in Figure 2. The pore sizes on the surface of the PES dialysis membrane are not uniform, and the regularity of pore shapes is also unsatisfactory. Some pores appear oval in shape while some appear as slits. In contrast, the pore shape on the AAO membrane surface is uniformly circular. In addition, the cross-section of the AAO membrane reveals straight channels of nanometer scale, whereas the polymer membrane exhibits a tortuous structure.

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The primary determinants of convective solute removal are the sieving properties of the membrane used and the ultrafiltration rate.¹³ The mechanism by which convection occurs is termed solvent drag. If the molecular dimensions of a solute are such that transmembrane passage occurs, the solute is swept (“dragged”) across the membrane in association with ultrafiltered plasma water. Thus, the rate of convective solute removal can be modified by changing either the rate of solvent (plasma water) flow or the mean effective pore size of the membrane. If a straight cylindrical pore model is considered (such as the case in this ceramic membrane), the fluid flow along the length of a cylinder is governed by the Hagen-Poiseuille equation:¹⁴ where DP is the pressure gradient across the membrane (transmembrane pressure), Q is the flow rate or ultrafiltration rate across the membrane, L is the length of pore channel, and r is the radius of pore. So, the rate of ultrafiltration is directly related to the fourth-power of the pore radius at a constant transmembrane pressure. In other words, the convective transfer of solute is determined by the fourth-power of the pore radius.

The diffusive properties of a dialysis membrane are determined mainly by the porosity and pore size.¹⁵ Based on a cylindrical pore model,¹⁶ membrane porosity is directly proportional to both the number of pores and the fourth power of the pore radius (r⁴). Therefore, diffusive permeability is strongly dependent on pore size. Studies over the past 15 years suggest a direct relationship between delivered urea-based hemodialysis doses and patient outcome.^17-21 Since the elimination of low-MW nitrogenous waste products is mainly obtained by diffusion through a dialysis membrane, higher porosity will achieve better elimination of these uremic toxins. In other words, AAO membranes with higher porosity can deliver a higher urea-based hemodialysis dose than polymer membranes, given the same timeframe.

High Hydraulic Conductivity

A previous study by Huang et al. showed that hydraulic conductivity (water permeability) of a sheet AAO membrane was approximately twice that of a PES dialysis membrane.²² As stated previously, PES dialysis membranes have an irregular pore structure (both inner and outer surfaces) and a wide pore size distribution, whereas AAO membranes have a highly monodisperse pore size distribution. The more uniform the pore size of the membrane, the higher its hydraulic conductivity. Enhanced convective transfer of middle- and large-molecular-weight solutes can therefore be achieved by using nanoporous AAO membranes with these properties.

When comparing the cross-section of the two membrane types, large differences in their structures are evident (see Figures 1 and 2). The channel or path from the interior to the exterior surface of the PES dialysis membrane is not straight. It is unclear if there are true channels or paths from one side to the other. Instead, the cross-section of the polymer membrane resembles a sponge-like material.

Accordingly, in practice, some blood or blood fragments might be left inside this structure even after a thorough cleaning with chemical reagents. In contrast, the channel or path connecting both surfaces of an AAO membrane is straight and smooth. In addition to the above structure limitation, heat disinfecting methods cannot be used on cellulose or synthetic polymer dialyzers due to their inadequate temperature resistance. The high temperature resistance of AAO membranes makes them better for heat disinfecting processes, thereby significantly increasing the reusability.

Uniform Pore Size Distribution

Figure 3. Equivalent diffusion coefficient vs. molecular weight of AAO and PES membranes.

Hemodialysis membranes currently used in dialysis equipment do not have a cylindrical pore structure with monodispersed pore sizes; rather, they exhibit a wide pore size distribution and a tortuous structure.

Experimental studies have been conducted on mini-module hemodialyzers to measure the hydraulic conductivity, diffusive permeability, rejection coefficient/sieving coefficient and clearance of solutes (urea, creatinine, vancomycin and inulin) of nanoporous AAO tube membranes.^23-25 For the nanoporous alumina membrane, the measured hydraulic permeability was: Lp = 8.7 × 10^-9 m•s^-1•Pa^-1 (K = 30.3 × 10^-15 m²•s^-1•Pa^-1), while for a PES membrane, it has been reported as: Lp = 5.02 × 10^-15 m•s^-1•Pa^-1 (K = 15.06 × 10^-15 M²•s^-1•Pa^-1).²⁶ The hydraulic conductivity of the AAO tube membrane is therefore approximately twice that of the PES membrane.

The solutes’ diffusive permeability results are shown in Figure 3. The diffusive permeability for three investigated solutes passing through the alumina membrane is approximately 140% higher than for the PES membrane.²⁶ The difference is most likely due to the pore structure that allows easier passage of solutes through the straight channels on the AAO membrane.

Future Work

While the methodology of manufacturing nanoporous AAO templates and membranes has been studied and the effect of processing parameters on membrane properties has been established, the extent of biocompatibility (cytotoxicity, genetotoxicity, biofouling, complement activation, etc.) still needs to be more closely scrutinized before it sees widespread use in biological environments. In addition, the incorporation of ion-sensing coatings or a drug could still be explored to further add value to AAO structures in a very competitive medical device market.

For more information regarding AAO membranes, contact EMV Technologies, LLC, 205 Webster St., Bethlehem, PA 18025; (610) 419-4952; fax (610) 419-2568; e-mail info@emvtechnologies.com; or visit www.emvtechnologies.com.