Solute Partitioning and Hindered Diffusion in Hydrogels

Author(s): Liu, David Ezra | Advisor(s): Radke, Clayton J | Abstract: Solute uptake and release govern the efficacy of hydrogels in controlled drug delivery, tissue engineering, and chromatographic separations. In soft contact lenses, uptake and release of wetting, packaging, and care-solution agents is extensively employed to improve on-eye lens performance. Key physical parameters are the equilibrium solute partition coefficient and the solute diffusion coefficient in the gel that dictate the amounts and rates of uptake/release, respectively. To investigate the mechanisms of solute uptake and release in hydrogels, this work experimentally and theoretically determines equilibrium partition and diffusion coefficients of prototypical macromolecules and drugs in hydrogels over a wide range of water contents. A hydrogel is a crosslinked polymer network with water-filled voids arranged in an unstructured three-dimensional mesh. Solutes (e.g., drugs, sugars, proteins, polymers) typically partition into and diffuse through the water-filled mesh but are excluded from mesh voids smaller than solute size. Consequently, solute size and the distribution of mesh sizes in the hydrogel-polymer network are vital to understand solute uptake and release. Solutes may also exhibit specific interactions with and, accordingly, adsorb to hydrogel polymer chains by hydrogen bonding or counterion binding. Specific solute adsorption to hydrogel-polymer strands results in larger partition coefficients and diminished effective diffusion rates. To elucidate size effects on aqueous-solute transport rates, diffusion coefficients of large macromolecules in hydrogels with relatively small mesh sizes are investigated experimentally and theoretically. Two photon-confocal microscopy measures transient uptake and release concentration profiles of fluorescently labeled dextrans of varying molecular weight, and fluorescently labeled cationic avidin protein. Dextrans are highly water-soluble polysaccharides. Consequently, they exhibit negligible specific interactions with the hydrogel polymer network. Hydrogel uptake and release follow Fick’s second law with almost identical diffusion coefficients in the uptake and release directions. To interpret our data, we implement a Large Pore Effective Medium (LPEM) model taking into account hydrodynamic drag, steric obstruction, and the distribution of mesh sizes available for solute transport. All necessary parameters are measured independently. In all cases, a priori- predicted diffusion coefficients by LPEM theory display excellent agreement with experiment. In contrast to the nonspecific interacting dextrans, cationic avidin protein exhibits near irreversible adsorption with incomplete loading even after 6 days and incomplete release even after two weeks. Avidin protein uptake and release rates clearly highlight the significance of solute-specific adsorption in understanding solute transport rates in hydrogels. Despite its importance, little attention has been given to how solute-specific interactions affect solute uptake in and release from hydrogels. We measure and theoretically predict partition and diffusion coefficients for prototypical water-soluble drugs in hydrogels where solute-specific binding is pronounced. Hydrogel composition is varied by adjusting the ratio of monomer constituents, 2-hydroxyethyl methacrylate (HEMA) and methacrylic acid (MAA). Partition and diffusion coefficients are obtained through two-photon confocal microscopy and UV/Vis-absorption spectrophotometry upon back extraction. The studied prototypical drugs all exhibit specific adsorption to nonionic MAA and HEMA moieties characterized by greater-than-unity partition coefficients and smaller effective diffusion rates. Conversely, none of the prototypical drugs displayed specific interactions with anionic MAA moieties. To predict equilibrium partition coefficients, we express the partition coefficient as a product of the hydrogel water content and individual enhancement factors for size-exclusion, nonspecific electrostatic interactions, and specific adsorption. Again, all necessary parameters are obtained independently. To predict effective diffusion coefficients, we extend LPEM for specific-solute adsorption and impose local equilibrium. As with the non-interacting dextran solutes, predicted partition and diffusion coefficients are in good agreement with experiment. A framework is now available to predict solute partitioning and diffusion in solute-hydrogel systems that exhibit specific interactions. The developed theories for solute partitioning are further extended for direct application to silicone-hydrogel contact-lens materials. Silicone hydrogels (SiHy) are microphase-separated materials with silicone domains for oxygen transport and hydrophilic-polymer domains for aqueous-solute transport. Equilibrium silicone-hydrogel water and solute uptake are measured and predicted with an extended partitioning theory assuming that water and aqueous solutes reside only in the hydrophilic-polymer phase, whereas oleophilic solutes partition primarily into the silicone microphase. Excellent agreement is found between theory and experiment. Significantly, our development provides estimation of partitioning properties in silicone hydrogels based solely on synthesis formulation chemistry. Finally, we deduce compositional properties of a laminated soft contact lens, DAILIES TOTAL 1® (delefilcon A) through measurement of fluorescent solute partition coefficients. Measured partition coefficients and solute-partitioning theory establish (1) the silicone-hydrogel core of the laminated lens is structurally similar to that of a non-laminated commercial SiHy soft contact lens, O2OPTIXTM, (2) the laminated-lens surface-gel layers are ~10 µm in thickness, (3) the laminated-lens surface-gel layers are of higher water content than the core, and (4) the surface-gel layers of the laminated lens are anionic, whereas the core is nonionic. Importantly, with solute-uptake properties known, our proposed solute-partitioning theory provides a means to elucidate hydrogel physico-chemical properties.