In Situ Stress‐Dispersing Hydrogel Millispheres via Load Redistribution to Restore Nucleus Pulposus Metabolic Homeostasis

ABSTRACT Abnormal mechanical stress can disrupt the metab homeostasis of the nucleus pulposus (NP) and induce inflammatory reactions and matrix degradation, thereby driving the progression of intervertebral disc degeneration (IDD). Owing to their small particle size, traditional micron hydrogel microspheres exhibit insufficient load dispersion, and it is difficult to effectively restore the stable environment of NP metabolism destroyed by local stress concentration. This study developed a bionic hydrogel millimeter sphere, approximately 1 mm in diameter, using a dual network design (HAMA/ChSMA, HA:ChS = 1:4) (ChS@HM) to realize the synergistic effect of mechanical dispersion and long‐term hydration lubrication. Finite element analysis showed that millimeter spheres can reduce the maximum stress on the spherical surface by approximately 50% compared to microspheres and reduce the stress concentration at the bottom by nearly 86%. In vitro experiments showed that continuous ChS@HM release of ChS alleviated the inflammatory microenvironment. Animal experiments have verified that it can promote matrix reconstruction. RNA sequencing revealed that ChS@HM regulates the Hippo/YAP signaling pathway, alleviates the inflammatory response and cell apoptosis induced by mechanical stress. This study innovatively developed an HA/ChS hydrogel millimeter sphere, which provides a new treatment strategy for IDD through an in situ stress dispersion mechanism.