Manipulation of Oxygen Tension in Damaged Regions via Hypoxia‐Induced IPN Hydrogel Microspheres for Intervertebral Disc Regeneration

Abstract Disruption of low oxygen tension homeostasis during intervertebral disc degeneration inhibits endogenous stem cell viability and function, posing a challenge for endogenous regeneration. Here, to achieve sustained hypoxia manipulation, constructed hypoxia‐inducible interpenetrating polymer network (IPN) hydrogel microspheres (HIMS) are constructed by microfluidics to integrate the hypoxic system with a stabilizing network. The IPN is synthesized through a two‐step polymerization process, consisting of rapid photo‐crosslinked gelatin methacrylate anhydride (GM) polymer I and slow enzyme‐crosslinked vanillin‐grafted gelatin (GV) polymer II. The enzymatic reaction between GV and laccase is able to create a hypoxic microenvironment to modulate oxygen tension in situ within the injured region. HIMS can reduce microenvironmental oxygen tension by 1/3 and maintain a hypoxic microenvironment for up to 5 days, thereby activating the PI3K/AKT/HIF‐1α signaling pathway in endogenous stem cells to promote differentiation into nucleus pulposus‐like cells. Additionally, NSC‐Exos are loaded onto HIMS to trigger endogenous progenitor/stem cell recruitment and migration. Both in vitro and in vivo assays demonstrate that NSC‐Exos@HIMS facilitates stem cell recruitment, targets differentiation, and stimulates extracellular matrix synthesis. Overall, the microspheres established herein provide a novel strategy for manipulating oxygen tension and enhancing endogenous tissue regeneration in injured regions during intervertebral disc degeneration.