To address these limitations, we present a systematic methodology to investigate solute partitioning and diffusion in both amorphous and semicrystalline hydrogels. Specifically, we study hydrodynamic transport behavior in a comprehensive library of 73 multi-arm poly(ethylene glycol) (PEG) hydrogels, synthesized via full-factorial modulation of four independent structural parameters: initial polymer volume fraction, degree of polymerization between junctions, junction functionality, and chain-end defect frequency. High-throughput fluorescence recovery after photobleaching (FRAP) and confocal microscopy enabled quantification of size-dependent solute diffusivity and partitioning using fluorescein and dextrans of multiple molecular weights. Our results reveal that solute transport is not solely determined by classical metrics like mesh size but is significantly impacted by network geometry, particularly junction functionality. These findings validate the use of a geometry-responsive mesh radius, which more accurately captures hydrodynamic constraints than traditional models. The Richbourg-Peppas swollen polymer network (SPN) model demonstrated superior predictive power over the large pore effective medium (LPEM) model, especially in accounting for the effects of solute size and structural heterogeneity. Additionally, chain-end defect frequency displayed a size-dependent influence on solute partitioning, reflecting a nuanced coupling between network imperfections and hydrodynamic resistance. We further expand on this work for there application in 3D cell culture, wherein we report that by incorporating a degradable crosslinker, the trends are somewhat conserved, but solute diffusion is actually decreased. This is perhaps converse to what would be expected, as the degradable crosslinker is much longer of a crosslinker than DTT.
In parallel, we investigate transport behaviour in semicrystalline hydrogels generated through salting out of freeze–thawed poly(vinyl alcohol) (PVA) gels—materials with microstructural heterogeneity. These systems require distinguishing between global and region-specific diffusion coefficients to accurately characterize solute mobility while also accounting for the degree of crystallinity. This added structural complexity emphasizes the need for spatially resolved transport analysis in semicrystalline systems, where standard bulk diffusion models may fail to capture localized barriers or enhanced pathways.
Together, these findings offer a structure-informed framework for the rational design of hydrogel-based drug delivery systems, providing both modeling tools and experimental validation to guide the control of solute transport across diverse hydrogel architectures.