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Background: Neutrophils, the most abundant leukocytes circulating in blood, contribute to host defense and play a significant role in chronic inflammatory disorders. They can release their DNA in the form of extracellular traps (NETs), which serve as scaffolds for capturing bacteria and various blood cells. However, uncontrolled formation of NETs (NETosis) can lead to excessive activation of coagulation pathways and thrombosis. Once neutrophils are migrated to infected or injured tissues, they become exposed to mechanical forces from their surrounding environment. However, the impact of transient changes in tissue mechanics due to the natural process of aging, infection, tissue injury, and cancer on neutrophils remains unknown. To address this gap, we explored the interactive effects of changes in substrate stiffness and cyclic stretch on NETosis. Primary neutrophils were cultured on a silicon-based substrate with stiffness levels of 30 and 300 kPa for at least 3 h under static conditions or cyclic stretch levels of 5% and 10%, mirroring the biomechanics of aged and young arteries., Results: Using this approach, we found that neutrophils are sensitive to cyclic stretch and that increases in stretch intensity and substrate stiffness enhance nuclei decondensation and histone H3 citrullination (CitH3). In addition, stretch intensity and substrate stiffness promote the response of neutrophils to the NET-inducing agents phorbol 12-myristate 13-acetate (PMA), adenosine triphosphate (ATP), and lipopolysaccharides (LPS). Stretch-induced activation of neutrophils was dependent on calpain activity, the phosphatidylinositol 3-kinase (PI3K)/focal adhesion kinase (FAK) signalling and actin polymerization., Conclusions: In summary, these results demonstrate that the mechanical forces originating from the surrounding tissue influence NETosis, an important neutrophil function, and thus identify a potential novel therapeutic target., (© 2024. The Author(s).)

Foam cell formation is a complex blood vessel pathology, which is characterized by a series of events, including endothelium dysfunction, inflammation, and accumulation of immune cells underneath the blood vessel walls. Novel bioengineered models capable of recapitulating these events are required to better understand the complex pathological processes underlying the development of foam cell formation and, consequently, advanced bioengineered platforms for screening drugs. Here, we generated a microfluidic blood vessel model, incorporating a three-dimensional (3D) extracellular matrix coated with an endothelial layer. This system enables us to perform experiments under a dynamic microenvironment that recapitulates the complexities of the native vascular regions. Using this model, we studied the effectors that regulate monocyte adhesion and migration, as well as foam cell formation inside vessel walls. We found that monocyte adhesion and migration are regulated by both the endothelium and monocytes themselves. Monocytes migrated into the extracellular matrix only when endothelial cells were cultured in the vessel model. In addition, the exposure of an endothelial layer to tumor necrosis factor α (TNF-α) and low shear stress both increased monocyte migration into the subendothelial space toward the matrix. Furthermore, we demonstrated the process of foam cell formation, 3 days after transmigration of peripheral blood mononuclear cells (PBMCs) into the vessel wall. We showed that pre-exposure of PBMCs to high shear rates increases their adhesion and migration through the TNF-α-treated endothelium but does not affect their capacity to form foam cells. The versatility of our model allows for mechanistic studies on foam cell formation under customized pathological conditions.

Here, we describe a motorized cam-driven system for the cyclic stretch of aortic endothelial cells. Our modular design allows for generating customized spatiotemporal stretch profiles by varying the profile and size of 3D printed cam and follower elements. The system is controllable, compact, inexpensive, and amenable for parallelization and long-term experiments. Experiments using human aortic endothelial cells show significant changes in the cytoskeletal structure and morphology of cells following exposure to 5 and 10% cyclic stretch over 9 and 16 h. The system provides upportunities for exploring the complex molecular and cellular processes governing the response of mechanosensitive cells under cyclic stretch., Competing Interests: Author SN is employed by Leading Technology Group. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Aguilera Suarez, Sekar, Nguyen, Lai, Thurgood, Zhou, Needham, Pirogova, Khoshmanesh and Baratchi.)

The human circulatory system is a marvelous fluidic system, which is very sensitive to biophysical and biochemical cues. The current animal and cell culture models do not recapitulate the functional properties of the human circulatory system, limiting our ability to fully understand the complex biological processes underlying the dysfunction of this multifaceted system. In this review, we discuss the unique ability of microfluidic systems to recapitulate the biophysical, biochemical, and functional properties of the human circulatory system. We also describe the remarkable capacity of microfluidic technologies for exploring the complex mechanobiology of the cardiovascular system, mechanistic studying of cardiovascular diseases, and screening cardiovascular drugs with the additional benefit of reducing the need for animal models. We also discuss opportunities for further advancement in this exciting field., Competing Interests: Conflict of interestThe authors declare no competing interests., (© International Union for Pure and Applied Biophysics (IUPAB) and Springer-Verlag GmbH Germany, part of Springer Nature 2021.)