Pressure-driven microfluidic networks using electric circuit analogy for on-chip cell assay applications
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The objective of this thesis is to study pressure-driven microfluidic networks using electric circuit analogy and to demonstrate precise controls of liquid and particle using the microfluidic network for on-chip cell assay applications. The hydraulic-electric circuit analogy is used to design such microfluidic networks, in which the pressure drop is analogous to the voltage drop, the volumetric flow rate to the current, and the hydraulic resistance to the electric resistance. This analogy describes behaviors of the pressure-driven laminar flow in a circular or even non-circular channel. Several devices were accomplished by the analogy, specifically concentration dependent networks (e.g., serial network, hybrid network, combinatorial network, and hybrid combinatorial network) and flow dependent networks (e.g., flow fraction network and flow distribution network) for on-chip cell assay applications. For desirable concentrations and flow rates in each segment of the microfluidic networks, the network was mathematically generalized using the electric circuit analogy. Based on the generalized model, linear and non-linear dilution gradients were achieved by a serial network with four cascaded-mixing stages. In order to accommodate a large number and wide range of dilution concentrations with a relatively small device, a two-layer microfluidic dilution generator was configured by a means of a combination of a serial and a proportional networks for optimization researches. In addition, as a proof-of-concept, the half maximal inhibitory concentration of a drug (called IC 50 ) was found by the fitting of a dose response curve obtained from the proposed dilution device. As well as the single dilution, a microfluidic combinatorial dilution device was also developed by three-dimensional structured geometry as a first demonstration. Another microfluidic network-based combinatorial device with an initial concentration controller, capable of concentration-on-demand screening in the range of the three-dimensional simplex-centroid, was also successfully developed and tested for cell cytotoxicity assay. Effective handling of particles and cells was realized by using flow dependent microfluidic networks. First, size-dependent particle filtration was achieved by hydrodynamic focusing network and its geometrical modification. By applying valve systems into the device, selective particle filtration was realized. Second, a straightforward method to form cell spheroids was achieved by a flow distribution network and a very simple concept of turning the device vertically. This gravity-oriented distribution network advanced challenging technical barriers, such as easy fabrication, in-situ culture and retrieval of spheroids, size regulation, long term culture, and high throughput for the formation of the three-dimensional cellular spheroid. In conclusion, pressure-driven microfluidic networks using the electric circuit analogy was successfully studied and applied for the precise controls of liquid and particle for on-chip cell assay applications. Thus, these strategies in designing concentration and flow dependent microfluidic networks can be used not only for high throughput drug screening but also for many optimization researches in biology, chemistry, medicine and material sciences.