Computational Engineering (CE)

Titled Design-Simulate-Fabricate Micro-/Nano-fluidics for Cell and Biomolecule Manipulation, the CE Flagship Research Project (FRP) is focused on numerical design tools for biological applications of micromachining, also known as BioMEMS. We chose this application, in part, because effective BioMEMS design tools will enable an emerging industry that is certain to play a key role in biological research and biomedical devices. In addition, the BioMEMS design problem, which couples mechanics, fluids, electrostatics, and non-continuum effects, serves the important pedagogical function of driving research in multidisciplinary simulation, optimisation and methodology specialisation.

Systematic investigation and understanding of biological systems depends on the tools available with which to probe their function. From micropipette to microarray, different interfaces with the biological world provide different functionalities. The vast majority of biological components—from small molecules to cells—exist in solution, and the ability to manipulate these components in microfluidic systems has already led to significant advances in experimental bioscience, from rapid DNA sequencing to micro-engineered tissues. A significant barrier to fully realising these micro- and nano-fluidic systems is a limitation in our ability to model complex molecular and cellular phenomena within such devices, from the squeezing of DNA molecules through nano-sized channels to the mutual interactions of two cells in fluid flow. The goal of this FRP is to use radically improved modelling and optimisation methodologies to streamline the design of microfluidic systems and the micro- and nano-elements within.

The objectives of this project are (i) to develop multidisciplinary simulation and optimisation tools for designing micro-/nano-machined devices intended for biological or biomedical applications, and (ii) to use these tools to assist and enhance the design and fabrication process of micro- and nano-devices for manipulating biological cells and biomolecules. Specifically, we focus on the development of essential simulation and optimization tools, and design and fabrication, for three demonstration bio-fluidic devices:

(*) Nanofluidic biomolecule/bioparticle filters
(*) Electrostatic traps for massively parallel single-cell manipulation
(*) Mechanical filters for biomolecule and cell separation.

The above three devices are excellent drivers for simulation and modeling tool development, and they also represent important technology advances. In the near term, successful bio-molecule filters and cell-manipulation devices will make possible a wide variety of rapid in-vitro medical diagnostics. In the future, these devices could form the core of artificial tissues and/or organs.

In the process of developing and using simulation and optimisation tools for designing these advanced micro- and nano-systems, we will expand the design tools available to developers of high-volume micro-systems for biomedical, chemical and sensor applications. The lack of such design tools has led to a longer-than-needed timeframe to market such micro-systems, and the high cost of mistakes has led to extremely conservative design practices. The new set of simulation and optimisation tools could dramatically reduce this development cost, and therefore the risk, thus creating the opportunity for a much more aggressive expansion of the micro-systems industry.

For the simulation and optimisation tools, we will develop methodologies to efficiently simulate a range of physical interaction among biomolecules, device structures and fluids, which are critical to manipulating cells and biomolecules in micro-/nano-fluidic systems. These methodologies will be realised as software for modeling multi-domain physics that is fast enough for use in design phase. We will use these methodologies to design and fabricate the three devices, each of which will take advantage of several of the methodologies. At the same time, experimental data from well-characterized micro- / nano-fluidic devices will be used to refine and verify the effectiveness of the methodologies.

These prototype devices will be manufactured with participation from the A*STAR Research Institutes and verified by laboratory testing (including field tests), and may lead to possible commercialisation. The computational methodologies and codes developed for this specific project will be of great relevance and importance to the design of future novel Bio-MEMS, as well as to the design of various tiny tools and systems, made from both bottom-up (chemical nanotechnology) and top-down (MEMS/NEMS) approaches.

The activities in this flagship research project include:

(*) The design and demonstration of cell arrays capable of unprecedented control on cell and bio-molecule manipulation. The vast potential of such technology has yet to be exploited
(*) The design of MEMS-based nano-fluidic filters for subcellular organelles and viruses to serve as advanced molecular sieves, thus drastically reducing, for instance, the time required to carry out DNA analyses
(*) The development of methods to reduce design cycle times through simulation in Bio-MEMS by at least an order of magnitude, such as has happened over the last 10 years in the integrated circuit industry
(*) The development of designs that explicitly account for uncertainty. Given that the Bio-MEMS are built at the limit of manufacturability, uncertainty is unavoidable and often has a large impact on the design. By incorporating uncertainty in the design we maximize the chances of first-pass success.

The Inter-University Projects (IUP) are focused on broadly applicable methods for simulation and optimization in the face of uncertainty, and play both a pedagogical and a flagship research role. The IUPs will engage students in an aspect of simulation and optimisation methodology that is of growing importance, while also providing tools for overcoming the manufacturing yield issues that have hindered BioMEMS commercialisation.

IUPs represent both an extension of our educational programme and also provide some of the methodological foundation for our FRPs. Although there a range of projects, the primary focus is to push the frontiers of fundamental problems in the fields of simulation and optimisation under uncertainty. Three IUP projects are currently undergoing. They are:

IUP-I: Effective computation: reduced order models and uncertainty management in numerical simulations;

IUP-II: Advanced optimization methods: theory and computation for emerging applications;

IUP-III: Robust optimization: a tractable approach to address optimization and equilibrium problems under uncertainty