The Development and Assessment of a 3-D Bone-On-A-Chip Device

Microfluidic-based organ-on-a-chip devices have generated significant research interest for biomedical applications such as pre-clinical pharmaceutical development. These platforms are ideal for studying the effects of pharmaceutical agents on tissue-mimics. These organ-on-a-chip devices are evolving, advancing from basic 2D cell cultures incorporated into microfluidic devices to complex 3D approaches. Additionally, modern chips are also designed to recapitulate the complex dynamic and mechanical environment of the native tissue they represent. Research in organ-on-a-chip devices has concentrated on the development of organs crucial for drug uptake, metabolism and removal (e.g. lung, skin, liver and kidney); however, reliable models of target organs will provide information on efficacy of the drugs. Therefore, this thesis explored the feasibility of developing a bone-on-a-chip microfluidic device that recapitulates both the 3D cell environment and fluid shear stresses present in bone.
This inexpensive, easy to fabricate system based on polymerised High Internal Phase Emulsions (polyHIPEs) produced by emulsion templating supports the proliferation and differentiation of mesenchymal progenitor cells (hES-MPs), and their extracellular matrix production, over extended time periods (up to 21 days). Cells exhibited a positive response to both chemical and mechanical stimuli of osteogenic differentiation, with an intermittent flow profile containing rest periods between bouts of loading strongly promoting differentiation and matrix formation in comparison to static and continuous flow. Primary cilia, mechanosensory organelles, were detectable on cells within the channels of the microfluidic device demonstrating this mechanosensor is present in the complex 3D culture environment. Flow behaviour and corresponding shear stresses within the chip were modelled using computational fluid dynamics.
Our data suggests that this device could serve as a powerful in vitro tool for investigating novel therapeutics for bone and sequestering of toxins into bone in comparison to standard in vitro and in vivo testing. Therefore, five therapeutic compounds, lactoferrin, icariin, oestrogen, menaquinone-4, lithium chloride were first tested on hES-MPs in 2D static models. Subsequently, preliminary comparison of lithium chloride treatment result, between 2D static model and 3D bone-on-a-chip device, showed the suitability of the device for bone pharmaceutical investigations.