Cell Shock Absorption via Stress Relaxation Hydrogel Microspheres for Alleviating Endoplasmic Reticulum Stress in Chondrocytes

Chronic mechanical vibrations and endoplasmic reticulum (ER) stress are major contributors to osteoarthritis (OA) progression. This study proposes a novel "cellular shock absorption" approach by developing viscoelastic hydrogel microspheres with tunable stress relaxation properties. By modulating the chemical bonds in the hydrogel network through oxidation and hydrazine coupling reaction, hydrogel microspheres capable of absorbing shock and reducing mechanical stimulus-induced ER stress in chondrocytes are created. Cationic liposomes, modified with the cartilage-targeting peptide Wyrgrl and loaded with tauroursodeoxycholic acid (TUDCA), are encapsulated within these hydrogel microspheres. The microspheres not only dissipate intra-articular impact forces, reducing vibration and pressure transmission, but also provide sustained release of TUDCA, alleviating ER stress and slowing OA progression. In vitro studies showed that the stress relaxation time constant (τ) of the microspheres was tuned to 23.81 s, closely resembling the mechanical properties of the cartilage matrix. This property, combined with targeted TUDCA delivery, reduced Grp78 and CHOP expression, alleviating ER stress and inhibiting chondrocyte apoptosis. In vivo, the microspheres preserved joint cartilage structure, suppressed ER stress responses, and substantially delayed OA progression. This strategy presents a promising approach to mitigating cartilage damage and delaying OA by reducing mechanical stress and alleviating ER stress.