Stem cell therapy for degenerative disc disease: A systematic review of preclinical evidence, clinical translation, and future directions.

Background: Degenerative disc disease (DDD) is a leading contributor to chronic low back pain and global disability. Existing therapies, from conservative management to spinal fusion, do not reverse the underlying molecular degeneration, leaving a critical treatment gap. Given its regenerative capabilities the advent of stem-cell therapy may constitute an ideal solution to fulfill such a therapeutic gap. Methods: This PRISMA-compliant systematic review evaluates stem cell-based strategies for intervertebral disc regeneration by examining preclinical evidence, clinical translation, and future directions. Searches of PubMed, Scopus, Web of Science, and related databases (from January 2000-May 2025) identified studies reporting on pain (Visual Analogue Scale), function (Oswestry Disability Index), and structural outcomes (MRI). Results: Preclinical models uniformly demonstrate meaningful regeneration, including restoration of disc height and extracellular matrix. Clinical evidence, however, is limited: thirteen low to moderate-quality trials show modest, albeit statistically significant, improvements in pain and disability, without compelling imaging proof of biological repair. Short to mid-term safety appears acceptable. Conclusions: The use of stem-cell therapy for treatment of degenerative disc disease is constrained by the somewhat hostile and avascular microenvironment of the intervertebral disc. Existing trials exhibit significant methodological weaknesses which substantially impair their application to the daily clinical practice. Future progress will likely depend on incorporating biomaterial-assisted delivery systems, cell-free exosome approaches, biological scaffolds and gene-editing technologies aimed at engineering the disc niche rather than simply focusing on cell replacement.