Mechanical strain-regulated hydrogel biodegradation for biological scaffolds with programmable lifetime

Precise control over hydrogel biodegradation kinetics is of importance for drug delivery and tissue engineering. However, existing strategies usually rely on fixed material chemistries and offer limited tunability once implanted. Here, we introduce mechanical strain as a programmable cue to regulate hydrogel degradation <i>in situ</i>. Using peptide-crosslinked tetra-PEG hydrogels and proteinase K as a model system, we developed a real-time stress-monitoring platform to quantitatively study strain-dependent enzymatic degradation. Time-resolved measurements reveal that mechanical strain significantly accelerates degradation by simultaneously enhancing diffusion and reaction rates. For thick hydrogel samples, uniaxial stretching significantly reduces the degradation time by four-fold from 7.6 hours (undeformed) to 1.9 hours (stretched), shifting the process from slow, surface-limited to rapid, volumetric degradation. A multiscale theoretical model that we developed identifies three synergistic effects of mechanical strain: reduced diffusion path due to geometric thinning, increased network mesh size for enhanced enzyme penetration, and elevated chain tension that promotes bond cleavage. These findings establish mechanical loading as a universal tool in biological systems to dynamically modulate hydrogel lifetimes, offering new opportunities for programmable drug release and scaffold-guided tissue remodeling.