Lost in Translation: Why Biologic Therapies for Intervertebral Disc Degeneration and Low Back Pain Have Not Reached the Clinic (Yet): Bridging Biology, Pain Phenotyping, and Trial Design.

From preclinical promise to clinical translation in intervertebral disc degeneration (IDD). Robust preclinical evidence supports a range of biologic therapies, with consistent improvements in imaging, extracellular matrix composition, inflammation, and behavior. However, a substantial translational gap persists, driven by key challenges including the discordance between IDD and pain, patient heterogeneity, inadequate phenotyping, placebo effects, limitations of preclinical models, hostile disc microenvironment, and practical/clinical trial barriers. A precision medicine framework is crucial to overcome these limitations, based on improved patient stratification, definition of molecular and clinical endotypes linked to targeted therapies, integration of advanced biomarkers, development of more sensitive outcome measures, and optimization of clinical trial design, ultimately aiming to enable successful clinical translation.