Entropy-Regulated Swelling as the Mechanistic Driver of Drug Diffusion in a Mechanically Robust Hydroxyapatite/PVA Hybrid Hydrogel

Hydrogels exhibit excellent permeability for solute transport, with their degree of swelling directly modulating drug diffusion through their polymer network. This dynamic hinders the quantitative prediction of the swelling mechanisms of these materials, owing to a decrease in configurational entropy resulting from the extension of polymer chains during water absorption. This study provides important insights into transport phenomena in a hydroxyapatite (HAp)-poly-(vinyl alcohol) (PVA) hydrogel by considering the thermodynamic principles governing molecular diffusion up to equilibrium and elucidating mechanisms relevant to drug delivery. HAp shows a hexagonal phase, and its unit cell volume increases by ∼2% after vinyl functionalization (HAp-π). PVA was converted to a chemically cross-linkable polymer and subsequently reacted with HAp-π to form a hybrid hydrogel network. The resulting system exhibits mechanical robustness resulting not only from chemical cross-links but also from noncovalent network constraints, which cooperatively give rise to a high density of effective cross-linking points. The hydrogel absorbs water and releases the drug slowly due to strong constraints imposed by the polymer structure. Despite these restrictions, molecular diffusion remains thermodynamically spontaneous (Δ<i>G</i> < 0), driven by a low, positive entropy change (Δ<i>S</i>), while enthalpic contributions (Δ<i>H</i>) are unfavorable. During swelling, water penetrates the hydrogel, driven by its higher chemical potential in the initially pure surrounding liquid, migrating into the polymer matrix and inducing network expansion, in a direction opposite to that of drug diffusion out of the hydrogel which further hinders the release dynamics because the solute is already in a high-entropy environment. Mass transport through a water-swellable release system constitutes an entropically driven process, dominated by diffusion within a constrained network. This work provides insight into entropy-regulated drug release, demonstrating that spontaneity is achieved at physiological temperature (∼37 °C) without altering the thermal energy so as to compromise long-term practical applications.