Theranostics 2021; 11(1):27-47. doi:10.7150/thno.48987


Small molecule-based treatment approaches for intervertebral disc degeneration: Current options and future directions

Amir Kamali1, Reihane Ziadlou1,3, Gernot Lang2, Judith Pfannkuche1, Shangbin Cui1,4, Zhen Li1, R. Geoff Richards1, Mauro Alini1, Sibylle Grad1✉

1. AO Research Institute Davos, Davos, Switzerland.
2. Department of Orthopaedic and Trauma Surgery, University Medical Center Freiburg, Albert-Ludwigs University of Freiburg, Freiburg, Germany.
3. Department of Biomedical Engineering, Medical Faculty of the University of Basel, Basel, CH.
4. The first affiliated hospital of Sun Yat-sen University, Guangzhou, China.

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Kamali A, Ziadlou R, Lang G, Pfannkuche J, Cui S, Li Z, Richards RG, Alini M, Grad S. Small molecule-based treatment approaches for intervertebral disc degeneration: Current options and future directions. Theranostics 2021; 11(1):27-47. doi:10.7150/thno.48987. Available from

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Low back pain (LBP) is a major reason for disability, and symptomatic intervertebral disc (IVD) degeneration (IDD) contributes to roughly 40% of all LBP cases. Current treatment modalities for IDD include conservative and surgical strategies. Unfortunately, there is a significant number of patients in which conventional therapies fail with the result that these patients remain suffering from chronic pain and disability. Furthermore, none of the current therapies successfully address the underlying biological problem - the symptomatic degenerated disc. Both spinal fusion as well as total disc replacement devices reduce spinal motion and are associated with adjacent segment disease. Thus, there is an unmet need for novel and stage-adjusted therapies to combat IDD. Several new treatment options aiming to regenerate the IVD are currently under investigation. The most common approaches include tissue engineering, growth factor therapy, gene therapy, and cell-based treatments according to the stage of degeneration. Recently, the regenerative activity of small molecules (low molecular weight organic compounds with less than 900 daltons) on IDD was demonstrated. However, small molecule-based therapy in IDD is still in its infancy due to limited knowledge about the mechanisms that control different cell signaling pathways of IVD homeostasis. Small molecules can act as anti-inflammatory, anti-apoptotic, anti-oxidative, and anabolic agents, which can prevent further degeneration of disc cells and enhance their regeneration. This review pursues to give a comprehensive overview of small molecules, focusing on low molecular weight organic compounds, and their potential utilization in patients with IDD based on recent in vitro, in vivo, and pre-clinical studies.

Keywords: small molecules, discogenic pain, intervertebral disc, degeneration, inflammation