ABSTRACT
Bone diseases, such as osteoporosis and bone defects, often lead to structural and functional deformities of the patient's body. Understanding the complicated pathophysiology and finding new drugs for bone diseases are in dire need but challenging with the conventional cell and animal models. Bone-on-a-chip (BoC) models recapitulate key features of bone at an unprecedented level and can potentially shift the paradigm of future bone research and therapeutic development. Nevertheless, current BoC models predominantly rely on off-chip analysis which provides only endpoint measurements. To this end, integrating biosensors within the BoC can provide non-invasive, continuous monitoring of the experiment progression, significantly facilitating bone research. This review aims to summarize research progress in BoC and biosensor integrations and share perspectives on this exciting but rudimentary research area. We first introduce the research progress of BoC models in the study of bone remodeling and bone diseases, respectively. We then summarize the need for BoC characterization and reported works on biosensor integration in organ chips. Finally, we discuss the limitations and future directions of BoC models and biosensor integrations as next-generation technologies for bone research.
ABSTRACT
It is well-recognized that the matrix stiffness as an important stem cell niche can mediate stem cell behavior such as attachment, proliferation and differentiation, but how matrix stiffness affects the immunomodulatory efficacy of stem cells has been little explored, which, however, is of significant importance in determining the outcomes of stem cell-based therapies and engineered tissue mimics. We herein studied the immunomodulatory efficacy of mesenchymal stem cells (MSCs) in response to matrix stiffness by the evaluation of macrophage polarization in vitro and inflammatory response in vivo by subcutaneous implantation of MSC-laden hydrogels. Remarkably, we found that soft matrix enabled MSCs to produce significantly higher levels of immunomodulatory factors compared to stiff matrix, and induced the presence of more anti-inflammatory macrophages in vitro and attenuated macrophages-mediated inflammatory response in vivo. More importantly, we revealed stiffness-mediated immunoregulatory effect of MSCs was mainly attributed to tumor necrosis factor-α-stimulated protein 6 (TSG-6), which was mechanosensitively regulated by the MAPK and Hippo signaling pathway and downstream AP1 complex, and which in turn exerted an effect on macrophages through CD44 receptor to inhibit NF-κB pathway. To conclude, our results for the first time identify TSG-6 as the key factor in regulating immunomodulatory efficacy of MSCs in mechanical response, and can be potentially utilized to empower stem cell-based therapy and tissue engineering strategy in regenerative medicine. STATEMENT OF SIGNIFICANCE: Matrix stiffness as an important stem cell niche can mediate stem cell behavior such as attachment and differentiation, but how matrix stiffness affects the immunomodulatory efficacy of stem cells has been little explored, which, however, is of significant importance in determining the outcomes of stem cell-based therapies and engineered tissue mimics. Our results for the first time identify TSG-6 as the key factor in regulating the immunomodulatory efficacy of MSCs in mechanical response, which was regulated by the MAPK and Hippo signaling pathways and downstream AP1 complex, and which in turn exerted an effect on macrophages through CD44 receptor to inhibit NF-κB pathway, and can be potentially utilized to empower stem cell-based therapy and tissue engineering strategy in regenerative medicine.
