A Nucleobase-Driven Self-Gelled Hyaluronic Acid-Based Injectable Adhesive Hydrogel Enhances Intervertebral Disc Repair

Cell therapy strategies hold great promise for nucleus pulposus (NP) regeneration and intervertebral disc degeneration (IVDD) treatment. However, their therapeutic efficiency is compromised by the anoikis of administered cells and the harsh environment in degenerated intervertebral discs (IVD). Inspired by the ability of nucleobases to form multiple H-bonds, a nucleobase-driven self-gelling strategy is proposed for the incorporation of nucleobases (e.g., thymine) into hyaluronic acid (HA) chains to trigger gel formation through enhanced intermolecular H-bond interactions. An aqueous solution of a thymine-modified HA (HAT) supramolecular polymer is shown to exhibit self-gelation behavior, injectability, tissue adhesion, and hydration capacity (comparable to that observed in the NP tissue of a 25-year-old adult). These characteristics enable the injection and filling of the HAT hydrogel system in the IVD, integration of the separated NP tissues, restoration of the biomechanical functions of the degenerated IVD, and securing of the encapsulated cells in the NP site. Manganese dioxide (MnO2) nanoparticles incorporated into the HAT system (HATMn) regulate oxidative stress and the hypoxic microenvironment in degenerated IVD, ensuring the viability of the encapsulated cells. The 12-week in vivo study results demonstrate that the administration of the MSCs-laden HATMn system (HATMn-MSCs) effectively restores the structure and function of degenerated IVD. Inspired by the inherent ability of nucleobases to form multiple H-bonds, thymine is coupled to hyaluronic acid derivative to trigger self-gelation through intermolecular H-bond interactions. The injectable MnO2-doped thymine-hyaluronic acid hydrogel can securely adhere to tissue, serving as a cell delivery system to augment intervertebral disc repair by restoring biomechanical functionality and modulating the local harsh physiological conditions. image