The role of biomechanical factors in models of intervertebral disc degeneration across multiple length scales

Abstract

Low back pain is the leading cause of disability, producing a substantial socio-economic burden on healthcare systems worldwide. Intervertebral disc (IVD) degeneration is a primary cause of lower back pain, and while regenerative therapies aimed at full functional recovery of the disc have been developed in recent years, no commercially available, approved devices or therapies for the regeneration of the IVD currently exist. In the development of these new approaches, numerous models for mechanical stimulation and preclinical assessment, including in vitro cell studies using microfluidics, ex vivo organ studies coupled with bioreactors and mechanical testing rigs, and in vivo testing in a variety of large and small animals, have emerged. These approaches have provided different capabilities, certainly improving the preclinical evaluation of these regenerative therapies, but challenges within the research environment, and compromises relating to non-representative mechanical stimulation and unrealistic test conditions, remain to be resolved. In this review, insights into the ideal characteristics of a disc model for the testing of IVD regenerative approaches are first assessed. Key learnings from in vivo, ex vivo, and in vitro IVD models under mechanical loading stimulation to date are presented alongside the merits and limitations of each model based on the physiological resemblance to the human IVD environment (biological and mechanical) as well as the possible feedback and output measurements for each approach. When moving from simplified in vitro models to ex vivo and in vivo approaches, the complexity increases resulting in less controllable models but providing a better representation of the physiological environment. Although cost, time, and ethical constraints are dependent on each approach, they escalate with the model complexity. These constraints are discussed and weighted as part of the characteristics of each model.