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.

Recent Advances in Managing Spinal Intervertebral Discs Degeneration

“…The minimally invasive transplantation of different cells (e.g., MSCs, induced pluripotent stem cells (iPSCs), embryonic stem cells (ESCs), NP-derived cells, chondrocyte-like cells) has the potential to support the IVD by differentiating into IVD-like cells and/or by secreting trophic and anti-inflammatory factors. Thus, cell-based therapies can be used to regenerate or at least slow down degeneration, whereas combining cells with a biocompatible material can additionally provide initial mechanical stability and protection after implantation [ 3 , 7 , 90 ].…”

“…Spinal disorders cover many pathologies (e.g., osteoporotic fractures, disc degeneration, spondylolisthesis, tumors, and large deformations), being among the most prevalent and costly medical conditions in Western societies [ 1 ]. Particularly, the degeneration of intervertebral discs (IVDs) has been considered the major cause of low back pain [ 2 , 3 , 4 , 5 ]. Mostly correlated with age, but not exclusively, IVD degeneration (IDD) can further aggravate into connected diseases, such as disc herniation, spinal canal stenosis, and spinal deformities [ 3 , 6 , 7 ].…”

“…Particularly, the degeneration of intervertebral discs (IVDs) has been considered the major cause of low back pain [ 2 , 3 , 4 , 5 ]. Mostly correlated with age, but not exclusively, IVD degeneration (IDD) can further aggravate into connected diseases, such as disc herniation, spinal canal stenosis, and spinal deformities [ 3 , 6 , 7 ]. Thus, proper and prompt treatment should be given to IDD patients to avoid the condition worsening ( Figure 1 ).…”

Mechanical Stretch Induced Osteogenesis on Human Annulus Fibrosus Cells through Upregulation of BMP-2/6 Heterodimer and Activation of P38 and SMAD1/5/8 Signaling Pathways

“…Abnormal mechanical loading also affects the metabolism of AF cells, resulting in structural damage leading to IVD degeneration [ 21 , 22 ]. Thus, mechanical force may play a critical role in the homeostasis of AF cellular structure and function [ 12 , 23 , 24 ]. Excessive mechanical stretching has also been shown to enhance the inflammatory responses in IVDs [ 20 ], thereby inducing the expression of matrix-degrading enzymes and inhibiting extracellular matrix synthesis [ 25 , 26 ], ultimately accelerating IVD degeneration [ 12 , 23 , 24 ].…”

“…Thus, mechanical force may play a critical role in the homeostasis of AF cellular structure and function [ 12 , 23 , 24 ]. Excessive mechanical stretching has also been shown to enhance the inflammatory responses in IVDs [ 20 ], thereby inducing the expression of matrix-degrading enzymes and inhibiting extracellular matrix synthesis [ 25 , 26 ], ultimately accelerating IVD degeneration [ 12 , 23 , 24 ]. It is well known that stem or progenitor cells reside inside IVDs and their endplates [ 27 , 28 ].…”