A bi-functional pH-responsive chip with a soft hydrogel-supported 3D-like renal tumor model for sustained drug delivery.

Abstract

Renal cell carcinoma (RCC) remains a major therapeutic challenge due to its limited responsiveness to systemic chemotherapy and the toxicity associated with high drug dosages. In this study, a pH-responsive sodium carboxymethyl cellulose/poly(vinyl alcohol)/agarose (CPA) hydrogel microphysiological platform was developed to enable localized and sustained delivery of 5-fluorouracil (5-FU) under physiologically relevant conditions. The hydrogel network, formed through the physical crosslinking of hydrophilic polymers, exhibited strong hydrogen bonding, enhanced thermal stability, and a highly interconnected porous architecture, as confirmed by FTIR, TGA, and FESEM analyses. Rheological evaluation revealed viscoelastic profile suitable for injectable or <i>in situ</i> applications. Among all formulations, CPA5% demonstrated the greatest structural stability and was integrated into a PMMA-based microfluidic chip to mimic a dynamic soft hydrogel-supported 3D-like renal tumor model. The CPA5%-5-FU hydrogel showed a high drug-loading efficiency of 61.67% ± 0.59 at pH 7.4 and 59% ± 0.40 at pH 5.0, and a pH-dependent, diffusion-controlled release behavior, enabling prolonged therapeutic exposure at acidic tumor pH. <i>In vitro</i> assays on A498 RCC cells confirmed the biocompatibility of the blank hydrogel and the potent, sustained cytotoxicity of the drug-loaded construct across 2D, soft hydrogel-supported 3D-like, and on-chip models. Mechanistic analyses linked diffusion-convection kinetics to the regulation of apoptosis, demonstrating spatially confined and physiologically relevant chemotherapeutic effects. This CPA hydrogel-on-chip system thus offers a promising biomimetic platform for localized cancer therapy and mechanistic drug screening.