Smart responsive hydrogels for intervertebral disc regeneration

Intervertebral disc degeneration (IVDD) is the leading cause of chronic low back pain (LBP), driven by a pathological microenvironment marked by acidic pH, increased reactive oxygen species (ROS), and elevated matrix metalloproteinase (MMP) activity, which hinder tissue regeneration. Conventional hydrogels, while replicating the hydrophilic environment of the nucleus pulposus and enabling minimally invasive delivery, fail to dynamically adapt to the evolving pathological signals during degeneration due to their static structure. Smart responsive hydrogels overcome this limitation by integrating “sensing-response-output” functionality, achieved through molecular elements such as dynamic covalent/non-covalent bonds, enzyme-substrate peptides, and external field-responsive units, or gene circuits responsive to specific pathological cues, including pH changes, ROS levels, MMP concentrations, and mechanical stress. Recent developments highlight that these materials provide timely mechanical support (e.g., in situ modulus enhancement to mitigate fibrosis) and enable microenvironment-driven sequential therapies, including targeted delivery of anti-inflammatory/pro-regenerative factors, ROS scavenging, inhibition of enzymatic activity, immune microenvironment remodeling, and precise regulation of cell fate via endogenous stem cell recruitment/differentiation and ferroptosis suppression. Advanced fabrication techniques such as microfluidics, 3D bioprinting, and in situ self-assembly further enhance biomimetic structural and functional integration. Despite promising regenerative outcomes in animal models—such as achieving NP cell survival rates reaching 85%, a 3.3-fold increase in COL2 synthesis, and 87% recovery of disc height through spatiotemporally controlled release, ROS scavenging, and immune modulation—significant challenges remain for clinical translation. These include the need for long-term biosafety validation, the stability of delivery systems under physiological conditions, and their adaptability to the complex mechanical environment of the spine. This review systematically explores the design principles, response mechanisms, fabrication innovations, therapeutic applications, and translational challenges of smart responsive hydrogels for IVDD regeneration, providing a roadmap for future development.