Emergent approaches in regenerative medicine look toward the use of extracellular vesicles (EVs) as a next-generation treatment strategy for intervertebral disc (IVD) degeneration (IVDD) because of their ability to attenuate chronic inflammation, reduce apoptosis, and stimulate proliferation in a number of tissue systems. Yet, there are no Food and Drug Administration (FDA)-approved EV therapeutics in the market with an indication for IVDD, which motivates this article to review the current state of the field and provide an IVD-specific framework to assess its efficacy. In this systematic review, 29 preclinical studies that investigate EVs in relation to the IVD are identified, and additionally, the regulatory approval process is reviewed in an effort to accelerate emerging EV-based therapeutics toward FDA submission and timeline-to-market. The majority of studies focus on nucleus pulposus responses to EV treatment, where the main findings show that stem cell-derived EVs can decelerate the progression of IVDD on the molecular, cellular, and organ level. The findings also highlight the importance of the EV parent cell's pathophysiological and differentiation state, which affects downstream treatment responses and therapeutic outcomes. This systematic review substantiates the use of EVs as a promising cell-free strategy to treat IVDD and enhance endogenous repair.

Objective Intervertebral disk degeneration is a prevalent postoperative complication after discectomy, underscoring the need to develop preventative and bioactive treatment strategies that decelerate degeneration and seal annulus fibrosus (AF) defects. Human mesenchymal stem cell–derived exosomes (MSC-Exos) hold promise for cell-free bioactive repair; however, their ability to promote AF repair is poorly understood. The objective of this study was to evaluate the ability of MSC-Exos to promote endogenous AF repair processes and integrate MSC-Exos within a biomaterial delivery system. Design We characterize biophysical and biochemical properties of normoxic (Nx) and hypoxic (Hx) preconditioned MSC-Exos from young, healthy donors and examine their effects on AF cell proliferation, migration, and gene expression. We then integrate a poly(lactic- co-glycolic acid) microsphere (PLGA µSphere) delivery platform within an interpenetrating network hydrogel to facilitate sustained MSC-Exo delivery. Results Hx MSC-Exos led to a more robust response in AF cell proliferation and migration than Nx MSC-Exos and was selected for a downstream protection experiment. Hx MSC-Exos maintained a healthy AF cell phenotype under a TNFα challenge in vitro and attenuated catabolic responses. In all functional assays, AF cell responses were more sensitive to Hx MSC-Exos than Nx MSC-Exos. PLGA µSpheres released MSC-Exos over a clinically relevant timescale without affecting hydrogel modulus or pH upon initial embedment and µSphere degradation. Conclusions This MSC-Exo treatment strategy may offer benefits of stem cell therapy without the need for exogenous stem cell transplantation by stimulating cell proliferation, promoting cell migration, and protecting cells from the degenerative proinflammatory microenvironment.