Multiscale Regulation of the Intervertebral Disc: Achievements in Experimental, In Silico, and Regenerative Research

Abstract

Intervertebral disc (IVD) degeneration is a major risk factor of low back pain. It is defined by a progressive loss of the IVD structure and functionality, leading to severe impairments with restricted treatment options due to the highly demanding mechanical exposure of the IVD. Degenerative changes in the IVD usually increase with age but at an accelerated rate in some individuals. To understand the initiation and progression of this disease, it is crucial to identify key top-down and bottom-up regulations’ processes, across the cell, tissue, and organ levels, in health and disease. Owing to unremitting investigation of experimental research, the comprehension of detailed cell signaling pathways and their effect on matrix turnover significantly rose. Likewise, in silico research substantially contributed to a holistic understanding of spatiotemporal effects and complex, multifactorial interactions within the IVD. Together with important achievements in the research of biomaterials, manifold promising approaches for regenerative treatment options were presented over the last years. This review provides an integrative analysis of the current knowledge about (1) the multiscale function and regulation of the IVD in health and disease, (2) the possible regenerative strategies, and (3) the in silico models that shall eventually support the development of advanced therapies.

The nucleus pulposus microenvironment in the intervertebral disc: the fountain of youth?

“…In human lumbar, thoracic, and cervical discs, oxygen levels vary considerably and do not appear to correlate with ageing or the degree of severity of pathological disease such as disc degeneration. Oxygen concentrations decrease from the AF across the disc inner structure (between 19.5 % and 0.65 %) with average normoxic levels in the central part of the NP being between 0.5 % and 10 % of oxygen www.ecmjournal.org (Bartels et al, 1998;Buckley et al, 2018). These levels are mainly determined by the transport through the CEP, but also by the cellular density within the tissue, and the cellular consumption rates.…”

“…Another important parameter in the NP tissue microenvironment is the pH. The pH ranges from 2 to 6, which is mainly due to the local production of lactic acid, as a result of glycolysis by the IVD cells (Bartels et al, 1998). Several in vivo measurements revealed pH ranges from 5.7 to 7.5 (with a median at 7.0) (Bez et al, 2018;Gilbert et al, 2016;Nachemson, 1969).…”

“…The microenvironment of the native and, by extension, of degenerated IVD remains an important factor in the development of effective regenerative therapies (Baumgartner et al, 2021), presenting a challenge not only for the application of cell therapies but also for interventions based on growth factors, or other biologicals such as drugs, and biomaterials.…”

“…The VAST clinical trial aimed to safely supplement tissue loss to degenerate IVDs. By injection of a supplemental viable disc matrix, improved pain, and function at one-year was achieved (Beall et al, 2020).…”

Development of a standardized histopathology scoring system for human intervertebral disc degeneration: an Orthopaedic Research Society Spine Section Initiative

“…17 Likewise, elevated levels of pro-inflammatory cytokines measured in these IVD and endplate tissues, 32,80 in particular associated with cellular clusters, 81 suggest these cytokines may play an important role in promoting degeneration and pain. 82,83 When interpreting the histologic features described here, it is also important to distinguish between prevalence vs pathogenesis and between an association vs causation. Indeed, some features may be highly prevalent, although their role in IVD degeneration pathophysiology remains unclear.…”