Directed Placement for mVLSI Devices

Continuous-flow microfluidic devices based on integrated channel networks are becoming increasingly prevalent in research in the biological sciences. At present, these devices are physically laid out by hand by domain experts who understand both the underlying technology and the biological functions that will execute on fabricated devices. The lack of a design science that is specific to microfluidic technology creates a substantial barrier to entry. To address this concern, this article introduces Directed Placement, a physical design algorithm that leverages the natural "directedness" in most modern microfluidic designs: fluid enters at designated inputs, flows through a linear or tree-based network of channels and fluidic components, and exits the device at dedicated outputs. Directed placement creates physical layouts that share many principle similarities to those created by domain experts. Directed placement allows components to be placed closer to their neighbors compared to existing layout algorithms based on planar graph embedding or simulated annealing, leading to an average reduction in laid-out fluid channel length of 91% while improving area utilization by 8% on average. Directed placement is compatible with both passive and active microfluidic devices and is compatible with a variety of mainstream manufacturing technologies

Scheduling and Fluid Routing for Flow-Based Microfluidic Laboratories-on-a-Chip

Microfluidic laboratories-on-a-chip (LoCs) are replacing the conventional biochemical analyzers and are able to integrate the necessary functions for biochemical analysis on-chip. There are several types of LoCs, each having its advantages and limitations. In this paper we are interested in flow-based LoCs, in which a continuous flow of liquid is manipulated using integrated microvalves. By combining several microvalves, more complex units, such as micropumps, switches, mixers, and multiplexers, can be built. We consider that the architecture of the LoC is given, and we are interested in synthesizing an implementation, consisting of the binding of operations in the application to the functional units of the architecture, the scheduling of operations and the routing and scheduling of the fluid flows, such that the application completion time is minimized. To solve this problem, we propose a list scheduling-based application mapping (LSAM) framework and evaluate it by using real-life as well as synthetic benchmarks. When biochemical applications contain fluids that may adsorb on the substrate on which they are transported, the solution is to use rinsing operations for contamination avoidance. Hence, we also propose a rinsing heuristic, which has been integrated in the LSAM framework

Microfluidic very large-scale integration for biochips: Technology, testing and fault-tolerant design

Microfluidic biochips are replacing the conventional biochemical analyzers by integrating all the necessary functions for biochemical analysis using microfluidics. Biochips are used in many application areas, such as, in vitro diagnostics, drug discovery, biotech and ecology. The focus of this paper is on continuous-flow biochips, where the basic building block is a microvalve. By combining these microvalves, more complex units such as mixers, switches, multiplexers can be built, hence the name of the technology, “microfluidic Very Large-Scale Integration” (mVLSI). A roadblock in the deployment of microfluidic biochips is their low reliability and lack of test techniques to screen defective devices before they are used for biochemical analysis. Defective chips lead to repetition of experiments, which is undesirable due to high reagent cost and limited availability of samples. This paper presents the state-of-the-art in the mVLSI platforms and emerging research challenges in the area of continuous-flow microfluidics, focusing on testing techniques and fault-tolerant design

MakerFluidics: low cost microfluidics for synthetic biology

Recent advancements in multilayer, multicellular, genetic logic circuits often rely on manual intervention throughout the computation cycle and orthogonal signals for each chemical “wire”. These constraints can prevent genetic circuits from scaling. Microfluidic devices can be used to mitigate these constraints. However, continuous-flow microfluidics are largely designed through artisanal processes involving hand-drawing features and accomplishing design rule checks visually: processes that are also inextensible. Additionally, continuous-flow microfluidic routing is only a consideration during chip design and, once built, the routing structure becomes “frozen in silicon,” or for many microfluidic chips “frozen in polydimethylsiloxane (PDMS)”; any changes to fluid routing often require an entirely new device and control infrastructure. The cost of fabricating and controlling a new device is high in terms of time and money; attempts to reduce one cost measure are, generally, paid through increases in the other. This work has three main thrusts: to create a microfluidic fabrication framework, called MakerFluidics, that lowers the barrier to entry for designing and fabricating microfluidics in a manner amenable to automation; to prove this methodology can design, fabricate, and control complex and novel microfluidic devices; and to demonstrate the methodology can be used to solve biologically-relevant problems. Utilizing accessible technologies, rapid prototyping, and scalable design practices, the MakerFluidics framework has demonstrated its ability to design, fabricate and control novel, complex and scalable microfludic devices. This was proven through the development of a reconfigurable, continuous-flow routing fabric driven by a modular, scalable primitive called a transposer. In addition to creating complex microfluidic networks, MakerFluidics was deployed in support of cutting-edge, application-focused research at the Charles Stark Draper Laboratory. Informed by a design of experiments approach using the parametric rapid prototyping capabilities made possible by MakerFluidics, a plastic blood--bacteria separation device was optimized, demonstrating that the new device geometry can separate bacteria from blood while operating at 275% greater flow rate as well as reduce the power requirement by 82% for equivalent separation performance when compared to the state of the art. Ultimately, MakerFluidics demonstrated the ability to design, fabricate, and control complex and practical microfluidic devices while lowering the barrier to entry to continuous-flow microfluidics, thus democratizing cutting edge technology beyond a handful of well-resourced and specialized labs

Membrane Deflection-based Fabrication and Design Automation for Integrated Acoustofluidics

Continuous-flow microfluidic large-scale integration (mLSI) is a developing field first introduced in the early 2000s, that continues to offer promising solutions to many biochemical, biophysical and biomedical problems. In his seminal paper, Thorsen et al. 2002 demonstrated the fabrication of high-density microfluidic systems capable of complex fluidic routing in combinatory arrays of multiplexors, mixers, and storage assemblies integrated with micromechanical valves. mLSI has been a powerful tool for scientific research by allowing for dramatic reduction in the volume of reagent needed for experimentation and offering highly parallelizable and dynamic process flows. These systems have since been the focus of strong interdisciplinary academic research efforts. Despite the success in scientific applications, the mLSI technologies have not found widespread use in commercial environments. One critical issue preventing mLSI to realize its full potential is the need for specialized fabrication techniques that are scalable and more suitable for the unique requirements of biology. The work presented here demonstrates an mLSI integrated acoustofluidic platform that offers versatility while maintaining a robust fabrication process. In particular, conductive liquid metal-based acoustic transducers integrated with micromechanical valves to facilitate dynamic switching of the resonant frequency of the device and generated surface acoustic waves (SAWs) is demonstrated. Shortcomings in the fabrication of fluidic channels for mLSI integrated acoustofluidic applications are examined, and solutions to these problems are presented. A novel and scalable soft-lithographic method is introduced, that allows for the fabrication of large valvable channels with tunable height that exceeds practical limitations dictated by previous photolithographic techniques. A thorough characterization of this method and demonstration of its robustness are included here as a promising data to promote further exploration of the technique as a viable commercial solution for the fabrication of many classes of mLSI bio-devices. The testing of a computeraided design software, Columba, is briefly discussed

Fluigi: an end-to-end software workflow for microfluidic design

One goal of synthetic biology is to design and build genetic circuits in living cells for a range of applications with implications in health, materials, and sensing. Computational design methodologies allow for increased performance and reliability of these circuits. Major challenges that remain include increasing the scalability and robustness of engineered biological systems and streamlining and automating the synthetic biology workflow of “specify-design-build-test.” I summarize the advances in microfluidic technology, particularly microfluidic large scale integration, that can be used to address the challenges facing each step of the synthetic biology workflow for genetic circuits. Microfluidic technologies allow precise control over the flow of biological content within microscale devices, and thus may provide more reliable and scalable construction of synthetic biological systems. However, adoption of microfluidics for synthetic biology has been slow due to the expert knowledge and equipment needed to fabricate and control devices. I present an end-to-end workflow for a computer-aided-design (CAD) tool, Fluigi, for designing microfluidic devices and for integrating biological Boolean genetic circuits with microfluidics. The workflow starts with a ``netlist" input describing the connectivity of microfluidic device to be designed, and proceeds through placement, routing, and design rule checking in a process analogous to electronic computer aided design (CAD). The output is an image of the device for printing as a mask for photolithography or for computer numerical control (CNC) machining. I also introduced a second workflow to allocate biological circuits to microfluidic devices and to generate the valve control scheme to enable biological computation on the device. I used the CAD workflow to generate 15 designs including gradient generators, rotary pumps, and devices for housing biological circuits. I fabricated two designs, a gradient generator with CNC machining and a device for computing a biological XOR function with multilayer soft lithography, and verified their functions with dye. My efforts here show a first end-to-end demonstration of an extensible and foundational microfluidic CAD tool from design concept to fabricated device. This work provides a platform that when completed will automatically synthesize high level functional and performance specifications into fully realized microfluidic hardware, control software, and synthetic biological wetware