Spheroid-Based Tissue Engineering Strategies for Regeneration of the Intervertebral Disc

Abstract

Degenerative disc disease, a painful pathology of the intervertebral disc (IVD), often causes disability and reduces quality of life. Although regenerative cell-based strategies have shown promise in clinical trials, none have been widely adopted clinically. Recent developments demonstrated that spheroid-based approaches might help overcome challenges associated with cell-based IVD therapies. Spheroids are three-dimensional multicellular aggregates with architecture that enables the cells to differentiate and synthesize endogenous ECM, promotes cell-ECM interactions, enhances adhesion, and protects cells from harsh conditions. Spheroids could be applied in the IVD both in scaffold-free and scaffold-based configurations, possibly providing advantages over cell suspensions. This review highlights areas of future research in spheroid-based regeneration of nucleus pulposus (NP) and annulus fibrosus (AF). We also discuss cell sources and methods for spheroid fabrication and characterization, mechanisms related to spheroid fusion, as well as enhancement of spheroid performance in the context of the IVD microenvironment.

Keywords: annulus fibrosus; cell therapy; intervertebral disc degeneration; nucleus pulposus; regenerative medicine.

Figure 1

Spheroid-based regeneration of the intervertebral disc (IVD). (A) Several cell sources have been proposed for IVD repair. (B) While a variety of spheroid fabrication methods are suitable for research purposes, low adherence plates facilitating large-scale standardized spheroid production might be the first-choice technology for clinical application. (C) The systematic characterization of the produced spheroids (e.g., cell viability, spheroid geometry, extracellular matrix (ECM) composition, and biomechanical properties) is essential to ensure their applicability for IVD repair. (D) Spheroids can exhibit several modes of action to support the IVD, including rapid fusion with target tissue and mechanical support, differentiation of the constituent cells into IVD-like cells, and by secretion of biomolecules (cytokines, growth factors, extracellular vesicles (EVs), ECM proteins, etc.). (E) Both scaffold-based and scaffold-free approaches demonstrate the potential for the regeneration of the IVD. IVD = intervertebral disc, ECM = extracellular matrix, GAG = glycosaminoglycans, NP = nucleus pulposus, AF = annulus fibrosus, EVs = extracellular vesicles. Created with BioRender.com.