Modeling Thixotropic Hydrogel Carriers to Limit Healthy-Tissue Exposure via Localized Drug Retention in Chemotherapy.

In this work, we develop a coupled multiphysics model that integrates polymer carriers exhibiting time-dependent thixotropic structural recovery with Darcy flow, linear Biot poroelasticity and advection-diffusion transport in a spherically symmetric, isotropic and homogeneous tissue domain. The formulation explicitly links rheological evolution to pressure-driven flow, interstitial deformation and solute transport through a unified framework, enabling systematic prediction of post-injection behavior. Unlike conventional approaches that assume constant carrier properties, the present model incorporates a time-dependent viscosity evolution, capturing the transition from an initially shear-thinned state to a recovered, highly viscous structure. Numerical simulations using hydroxypropyl methylcellulose and methotrexate parameters as representative components demonstrate that rapid post-injection viscosity recovery suppresses pressure-driven transport and diffusion, thereby enhancing local drug retention near the injection site. A systematic sensitivity analysis identifies the equilibrium viscosity as the dominant parameter controlling spatial localization, whereas tissue mechanical properties exert a comparatively minor influence. An effectiveness metric based on the Kullback-Leibler divergence reveals a tumor-size-dependent trade-off between spatial coverage and retention. The proposed framework thus introduces a predictive tool for analyzing coupled rheological-transport interactions and for the rational design and optimization of thixotropy-enhanced local chemotherapy strategies.