Microfluidic technologies are an excellent candidate to achieve the goal set forth by NHGRI to reduce the total sequencing cost by two- or four-orders of magnitude from the current cost of sequencing a human-sized genome. Microfluidic chips enable highly reduced use of the sample/reagent and integration of all sequencing steps from sample preparation to separation and detection into a single analytical instrument. Current chip design methods rely primarily on trial-and-error experiments or employ prohibitively expensive high-fidelity computational analysis. These approaches are time consuming, costly, and require experimental or numerical modeling expertise that cannot be expected of chip designers and manufacturers. In addition, the lack of direct interfacing between design analysis tools and microfabrication processes leads to additional cost and delay in the development of functional prototypes. There is a clear and unmet need for design tool that can deliver multi-functional microfluidic prototypes with superior performance at a low cost and fast turn-around times. We propose to develop a novel, integrated, paradigm-transforming microfluidic design toolkit, based on system- level simulation and reduced-order model methodology to enable rapid simulation, optimization, and prototyping of next-generation microfluidic systems for genomic analysis. In Phase II, we will develop multi-physics, reduced-order models for liquid filling, genomic sample extraction and purification, and DNA hybridization, which in conjunction with our models of electrophoresis and PCR in Phase I will establish a self-contained, complete design capability for critical microfluidic genomic applications. Constraint-based optimizers using nonlinear programming will be developed for rapid chip design. Interfaces bridging the design-microfabrication gap will be developed and expanded to accommodate both maskless and mask-based fabrications. Novel functionalities and capabilities will be incorporated into the development of the integrated design environment for improved ease-of-use, integration, and automation. Through industrial and academic collaboration, we will validate and demonstrate the proposed prototyping methodology by developing optimized design of genomic microchips for microfluidic PCR and DNA separation and sequencing. Beyond Phase II, we will carry out software engineering and packaging activities and optimize the toolkit performance in terms of execution efficacy, reliability, interface diversity, and ease-of-use for commercial release and sales in partnership with Intellisense Corp. An experienced, multi-disciplinary team with expertise in all aspects of the proposed study - reduced-order modeling &simulation, optimization, software development, microfluidic fabrication and testing has been assembled for successful completion of the Phase II research. The developed design tool will have critical applications in microfluidics, life sciences, biomedical and biodefense arena. The proposed effort will beneficially impact the genomic analysis and diagnostics community in terms of shrinking the overall R&D cycles (from concepts to optimized physical prototype within ~days) and reducing the cost via elimination of trial-and-error-based design and manual transfer of the layout information to the microfabrication process. PUBLIC HEALTH RELEVANCE: The project is to develop a novel, integrated, paradigm-transforming microfluidic design tool to enable rapid simulation, optimization, and prototyping of next-generation microfluidic systems for genomic analysis. The Phase II end-product will find applicability in the microfluidic/integrated biomicrosystem section of the overall biotechnology market, engaged in life science research. Target commercial applications for the developed technology include several established and emerging market sectors including pharmaceutical, biotechnology, clinical diagnostics, medical devices, and drug delivery.