Mechanism-guided biomaterial strategies for intervertebral disc degeneration: Pathological heterogeneity, functional...

Intervertebral disc degeneration (IVDD) is a multifactorial and clinically heterogeneous condition involving disturbances in oxidative balance, mitochondrial homeostasis, inflammatory signaling, susceptibility to regulated cell death, extracellular matrix integrity, and biomechanical function. Although biomaterial-based strategies have shown significant promise in preclinical studies, their clinical translation remains hindered by pathological heterogeneity, insufficient mechanistic validation, and frequent reliance on simplified experimental models. These models often fail to fully replicate the chronic, mechanically complex, and clinically diverse nature of human disc degeneration. In addition, current biomaterial strategies are commonly classified according to material composition or isolated molecular targets, potentially obscuring their functional objectives and limiting mechanistic comparisons across therapeutic platforms. This review presents a mechanism-guided framework for interpreting biomaterial interventions in IVDD. Biomaterial strategies are discussed based on their primary pathological targets and therapeutic intentions, including inflammatory regulation, restoration of redox homeostasis, mitochondrial protection, ferroptosis modulation, extracellular matrix preservation, and multifunctional microenvironment-responsive interventions. This framework acknowledges that these pathological processes are interconnected and vary in their relative dominance across clinical and pathological contexts and patient populations. We further analyze current biomaterial strategies according to mechanistic intervention layers, including upstream sensing and initiation-level control, restraint of intracellular amplification, organelle stabilization, regulation of execution checkpoints, and integration with higher-order structural organization. This layered perspective emphasizes that the efficacy of biomaterials depends not only on their composition but also on the pathological context, depth of regulatory influence, mechanistic specificity, and compatibility across intervention layers. Collectively, this review provides an integrated, mechanism-oriented framework for biomaterial design, preclinical evaluation, and translational development in IVDD therapy.