Abstract
Discogenic back pain is one of the most diffused musculoskeletal pathologies and a hurdle to a good quality of life for millions of people. Existing therapeutic options are exclusively directed at reducing symptoms, not at targeting the underlying, still poorly understood, degenerative processes. Common intervertebral disc (IVD) disease models still do not fully replicate the course of degenerative IVD disease. Advanced disease models that incorporate mechanical loading are needed to investigate pathological causes and processes, as well as to identify therapeutic targets. Organs-on-chip (OoC) are microfluidic-based devices that aim at recapitulating tissue functions in vitro by introducing key features of the tissue microenvironment (e.g., 3D architecture, soluble signals and mechanical conditioning). In this review we analyze and depict existing OoC platforms used to investigate pathological alterations of IVD cells/tissues and discuss their benefits and limitations. Starting from the consideration that mechanobiology plays a pivotal role in both IVD homeostasis and degeneration, we then focus on OoC settings enabling to recapitulate physiological or aberrant mechanical loading, in conjunction with other relevant features (such as inflammation). Finally, we propose our view on design criteria for IVD-on-a-chip systems, offering a future perspective to model IVD mechanobiology.
Highlights
Low back pain (LBP) is a prevalent health problem, with 80% of people suffering from it at least once in their lifetime (Wieser et al, 2011; Vlaeyen et al, 2018)
Cyclic stretching of intervertebral disc (IVD) cells at a high strain of 8–20% and at either hypo-physiological (0.001 and 0.01 Hz) or physiological frequencies (0.1–1 Hz) was shown to induce downregulation of anabolic markers (Wang et al, 2018) and upregulation of catabolic (MMP 1, 3, 9, 13, A Disintegrin And Metalloproteinase with ThromboSpondin motifs (ADAMTSs) 4, 5) (Sowa et al, 2011a; Wang et al, 2018) and pro-inflammatory mediators (cyclooxygenase-2 (COX2), prostaglandin E2 (PGE2), interleukins (IL) 1β, 6, 8, 15, toll-like receptors (TLR) 2, 4, nerve growth factor (NGF), tumur necrosis factor alpha (TNF-α), monocyte chemoattractant protein (MCP) 1, 3, and monokine induced by gamma interferon (MIG)) (Miyamoto et al, 2006; Gawri et al, 2014; Pratsinis et al, 2016; Wang et al, 2018)
The transient receptor potential (TRP) vanilloid 4 (TRPV4) ion channel was recently identified as a mediator of stretchinduced inflammation and compression-induced cell damage and degeneration in IVD cells and tissues in the context of hyperphysiological mechanical loading (Cambria et al, 2020a; Cambria et al, 2021)
Summary
Low back pain (LBP) is a prevalent health problem, with 80% of people suffering from it at least once in their lifetime (Wieser et al, 2011; Vlaeyen et al, 2018). Despite large advances in macroscale in vitro and ex vivo IVD models, it is still challenging to use such systems to investigate fundamental questions on specific cell functions and molecular mechanisms involved in the conversion of mechanical loading to biochemical responses such as inflammation and pain. To improve the understanding of mechanotransduction and predict the success of new therapeutic approaches under loading, new in vitro models that enable both 1) recapitulation of the IVD native-like mechanically active environment at a cellular relevant scale and 2) compatibility with high-throughput setups, are warranted. This comprehensive review is intended for readers with different backgrounds ranging from medical and biological scientists to engineers
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