Decoupling Mechanical Reinforcement and Therapeutic Transport through Asymmetric Network Architecture in Single-Component GelMA Double-Network Hydrogels

Abstract

Double-network (DN) hydrogels have emerged as promising biomaterials for tissue engineering and therapeutic delivery because of their superior mechanical performance. However, independently regulating mechanical reinforcement and molecular transport remains challenging, as modifications to network architecture are often accompanied by changes in polymer chemistry or composition. Here, we present a network engineering strategy to decouple these functions by developing a single-component gelatin methacryloyl (GelMA) DN hydrogel through sequential photo-cross-linking of GelMA macromers with distinct degrees of substitution (DoS). This asymmetric network architecture enables systematic tuning of network structure while maintaining the same polymer chemistry. The highly cross-linked primary network provided mechanical reinforcement, whereas the loosely cross-linked secondary network regulated network density and transport pathways. By tailoring the secondary network architecture, the hydrogels exhibited controllable physical and physicochemical properties without compromising the intrinsic biocompatibility of GelMA. Furthermore, engineering the network architecture regulated curcumin loading and sustained release by modulating water uptake and molecular diffusion, resulting in enhanced fibroblast migration. Collectively, these findings establish asymmetric network engineering as a versatile strategy for independently tuning mechanical reinforcement and therapeutic transport within homopolymer hydrogels, providing a broadly applicable framework for the rational design of multifunctional biomaterials for drug delivery and tissue engineering.