Cutting-Edge Technologies for Inflamed Joints on Chip: How Close Are We?

Abstract

Osteoarthritis (OA) is a painful and disabling musculoskeletal disorder, with a large impact on the global population, resulting in several limitations on daily activities. In OA, inflammation is frequent and mainly controlled through inflammatory cytokines released by immune cells. These outbalanced inflammatory cytokines cause cartilage extracellular matrix (ECM) degradation and possible growth of neuronal fibers into subchondral bone triggering pain. Even though pain is the major symptom of musculoskeletal diseases, there are still no effective treatments to counteract it and the mechanisms behind these pathologies are not fully understood. Thus, there is an urgent need to establish reliable models for assessing the molecular mechanisms and consequently new therapeutic targets. Models have been established to support this research field by providing reliable tools to replicate the joint tissue in vitro. Studies firstly started with simple 2D culture setups, followed by 3D culture focusing mainly on cell-cell interactions to mimic healthy and inflamed cartilage. Cellular approaches were improved by scaffold-based strategies to enhance cell-matrix interactions as well as contribute to developing mechanically more stable in vitro models. The progression of the cartilage tissue engineering would then profit from the integration of 3D bioprinting technologies as these provide 3D constructs with versatile structural arrangements of the 3D constructs. The upgrade of the available tools with dynamic conditions was then achieved using bioreactors and fluid systems. Finally, the organ-on-a-chip encloses all the state of the art on cartilage tissue engineering by incorporation of different microenvironments, cells and stimuli and pave the way to potentially simulate crucial biological, chemical, and mechanical features of arthritic joint. In this review, we describe the several available tools ranging from simple cartilage pellets to complex organ-on-a-chip platforms, including 3D tissue-engineered constructs and bioprinting tools. Moreover, we provide a fruitful discussion on the possible upgrades to enhance the in vitro systems making them more robust regarding the physiological and pathological modeling of the joint tissue/OA.

Anti-chondrogenic role of nerve growth factor in osteoarthritis and human induced pluripotent stem cells-derived chondrogenesis model

“…The use of tanezumab has received attention as a promising treatment for reducing pain in patients with OA after blocking NGF; however, its use is currently being discontinued owing to various side effects (35,36). NGF is involved in nerve growth and survival, and it has recently been reported to be associated with OA pain (37,38). However, the mechanisms underlying the effects of NGF on OA are yet to be elucidated.…”

Progress of Microfluidic Hydrogel‐Based Scaffolds and Organ‐on‐Chips for the Cartilage Tissue Engineering

“…Apart from merely employing microfluidic technology in designing scaffolds, it can be utilized in creating leading-edge devices named OoCs. [313,314] In essence, OoC refers to a single-channel or multichannel 3D chip of a microfluidic cell culture simulating organ-level or tissue-level physiology, categorized into hydrogelbased OoCs (as one of the most promising microfluidic platforms) and those without embedding hydrogels. [315][316][317][318] The difference between these devices and other traditional cell platforms is that they can be used for biochemical, mechanical, and electrical stimulations.…”

“…[373,374] Nonetheless, since the mechanisms of these phenomena are not clearly understood, there is a dire need to produce reliable models for evaluating them. [313] Concerning this subject, Rothbauer and co-workers [375] decided to develop the first synovium-on-a-chip with non-invasive sensors in 2020 to better realize the initiation as well as the progression of inflammatory RA in response to stimulation with a proinflammatory cytokine, TNF-𝛼 in particular. The designed chip included time-resolved biosensing based upon light scatter measurements and microchambers containing synovium organoids formed by a mixture of non-induced or TNF-𝛼-induced RA-derived human fibroblast-like synoviocytes (3000 cells μL −1 ) and the Matrigel or commercial Tisseel fibrin hydrogel.…”

Inflammatory Synovial Fibroblast Culture in 3D Systems: A Comparative Transcriptomic and Functional Study

“…Alternatively, scaffold-based 3D techniques include protein-based structures, such as the extensively used Matrigel ® , but also natural and synthetic hydrogels and hard polymer scaffolds (7)(8)(9)(10)(11)(12). In these systems, cells are seeded on an acellular matrix, polymeric materials or dispersed 4 in a liquid matrix followed by polymerization.…”