Microfluidic systems, with their feature size similar to that of biological cells, have great potential for cell manipulation and interrogation. On the other hand, the process of drug discovery involves vast amount of tests of candidate drug molecules with cells, and hence requires intensive manipulation and interrogation of cells. Therefore, it is conceivable that microfluidics can be and should be sufficiently exploited to facilitate drug discovery process. This dissertation investigates two of the most frequently performed cell operations in drug discovery, which are often performed in series, i.e., chemical stimulation of cells (cell treatment and chemotaxis) and cell sorting. For chemical stimulation of cells, rapid and novel designs of concentration gradient generation (CGG) devices are presented; for cell sorting, a magnetically The most prevalent type of CGG devices, i.e., complete mixing-based laminar-flow CGG devices, involves massive channel networks. The design of alternative laminar-flow CGG devices suffers lack of efficient and systematic design framework, and is currently implemented through time-consuming numerical simulations.
Therefore, we first propose passive mixing-based laminar-flow CGG devices, for which an analytical diffusion-convection model is developed and incorporated into an iterative design framework to achieve modular design. Secondly, to eliminate the undesirable stimulation of fluid flow on cells as existing in both complete and partial mixing-based laminar-flow CGG devices, a novel class of CGG devices featuring two-layer design sandwiching a semipermeable membrane is presented. The devices effectively eliminate fluid flow while maintain a stable concentration gradient in the gradient generation region. Thirdly, the flow-free CGG devices are extended to realize arbitrary concentration gradients, which significantly enhance the CGG capability of the devices. The designs of all CGG devices are realized through microfabrication and tested against complex concentration gradients. The generated gradients generally agree with the specified gradients in less than 10%. Magnetic-activated cell sorting (MACS) is a high-throughput cell sorting scheme that recognizes cells specifically by their membrane proteins.
The quality of magnetic incubation largely determines the final separation efficiency. To enhance magnetic incubation prior to separation, a magnetic incubator is designed utilizing a target acquisition by repetitive traversal (TART) mechanism, which significantly improves target capture efficiency and reduces incubation time. The magnetic incubator module is then integrated to the separator module, with both modules using the same magnetic setup, which facilitates the entire MACS process and promotes the target separation efficiency to over 90%. The microfluidic methods and tools developed in this work are potentially used for cell manipulation and interrogation and thus can be expected to facilitate the drug discovery process that involves intensive cell operations and testing.
