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 in situ 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. In vitro 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.