Abstract
Microfluidic-based tissue-on-a-chip devices have generated significant research interest for biomedical applications, such as pharmaceutical development, as they can be used for small volume, high throughput studies on the effects of therapeutics on tissue-mimics. Tissue-on-a-chip devices are evolving from basic 2D cell cultures incorporated into microfluidic devices to complex 3D approaches, with modern designs aimed at recapitulating the dynamic and mechanical environment of the native tissue. Thus far, most tissue-on-a-chip research has concentrated on organs involved with drug uptake, metabolism and removal (e.g., lung, skin, liver, and kidney); however, models of the drug metabolite target organs will be essential to provide information on therapeutic efficacy. Here, we develop an osteogenesis-on-a-chip device that comprises a 3D environment and fluid shear stresses, both important features of bone. This inexpensive, easy-to-fabricate system based on a polymerized High Internal Phase Emulsion (polyHIPE) supports proliferation, differentiation and extracellular matrix production of human embryonic stem cell-derived mesenchymal progenitor cells (hES-MPs) over extended time periods (up to 21 days). Cells respond positively to both chemical and mechanical stimulation of osteogenesis, with an intermittent flow profile containing rest periods strongly promoting differentiation and matrix formation in comparison to static and continuous flow. Flow and shear stresses were modeled using computational fluid dynamics. Primary cilia were detectable on cells within the device channels demonstrating that this mechanosensory organelle is present in the complex 3D culture environment. In summary, this device aids the development of ‘next-generation’ tools for investigating novel therapeutics for bone in comparison with standard laboratory and animal testing.
Highlights
One of the main impediments to drug development is the associated cost of assessing potential hazards, side effects and toxicity using pre-clinical animal testing
Traditional microfluidic devices are a clear improvement in physiological relevance when compared to traditional static cell culture due to the presence of fluid flow and fluid shear stress (FSS)
We set out to design a bone microfluidic chip that fulfilled the requirements of being suitable for osteoblast culture by incorporating a 3D bone tissue engineering scaffold and physiologically relevant flow conditions, as well as being simple to manufacture en masse, reproducible, and cost effective
Summary
One of the main impediments to drug development is the associated cost of assessing potential hazards, side effects and toxicity using pre-clinical animal testing. Most in vitro approaches have consisted of culturing cells as a monolayer on planar, “two-dimensional (2D)” surfaces Whilst being informative, these simple systems fail to recreate the structural and dynamic mechanical complexity of the three-dimensional (3D) environment observed within tissues and organs and only provide limited information about potential tissue responses (Owen et al, 2020a). Microfluidic cell culture platforms and “organ-on-achip” devices have the potential to considerably advance biological research, drug development, and resource efficiency by combining both structural and dynamic cues within in vitro models (Hadida and Marchat, 2019). Traditional microfluidic devices are a clear improvement in physiological relevance when compared to traditional static cell culture due to the presence of fluid flow and fluid shear stress (FSS) Despite these advances, many microfluidic devices remain “2D” at the cell-scale as cells are still cultured on a planar surface. Different flow rates and flow profiles were examined, comparing metabolic activity, osteogenic differentiation, and mineralized matrix deposition
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