Macro and Microfluidic Flows for Skeletal Regenerative Medicine

Abstract

Fluid flow has a great potential as a cell stimulatory tool for skeletal regenerative medicine, because fluid flow-induced bone cell mechanotransduction in vivo plays a critical role in maintaining healthy bone homeostasis. Applications of fluid flow for skeletal regenerative medicine are reviewed at macro and microscale. Macroflow in two dimensions (2D), in which flow velocity varies along the normal direction to the flow, has explored molecular mechanisms of bone forming cell mechanotransduction responsible for flow-regulated differentiation, mineralized matrix deposition, and stem cell osteogenesis. Though 2D flow set-ups are useful for mechanistic studies due to easiness in in situ and post-flow assays, engineering skeletal tissue constructs should involve three dimensional (3D) flows, e.g., flow through porous scaffolds. Skeletal tissue engineering using 3D flows has produced promising outcomes, but 3D flow conditions (e.g., shear stress vs. chemotransport) and scaffold characteristics should further be tailored. Ideally, data gained from 2D flows may be utilized to engineer improved 3D bone tissue constructs. Recent microfluidics approaches suggest a strong potential to mimic in vivo microscale interstitial flows in bone. Though there have been few microfluidics studies on bone cells, it was demonstrated that microfluidic platform can be used to conduct high throughput screening of bone cell mechanotransduction behavior under biomimicking flow conditions.

Fluid-flow-induced mesenchymal stem cell migration: role of focal adhesion kinase and RhoA kinase sensors

“…We investigated MSC migration under fluid flow mechanical conditions with the rationale described above. Cells under flow-induced shear may react through various molecular sensors [11]. Integrinmediated focal adhesion and cytoskeletal structures anchored to it are likely to be the primary sites that resist fluid shear, and may provide a mechanism through which migration traction force is exerted.…”

Systems-Based Identification of Temporal Processing Pathways during Bone Cell Mechanotransduction

“…Importantly, this spectrum of pathways will only increase as new genome annotation databases and bioinformatics tools are developed. In addition, new technologies that enable high-throughput mechanotransduction studies [43], [44], [45] and transcriptomic analyses [46] are rapidly emerging. In this case, our studies may serve as the experimental foundation for future investigations that map the temporal trajectory of every single gene upon mechanical stimulation, and their variations in response to different rest intervals.…”

Mechanical Control of Mesenchymal Stem Cell Adipogenesis

“…A positive role of fluid flow-induced shear stress stimulation in facilitating MSC osteogenesis has been relatively well established (see our review [14]). Cells embedded in bone are exposed to shear stress from interstitial flow through lacunar-canalicular channels.…”