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

A Software Toolchain for Physical System Description and Synthesis, and Applications to Microfluidic Design Automation

Microfluidic circuits are currently designed by hand, using a combination of the designer’s domain knowledge and educated intuition to determine unknown design parameters. As no microfluidic circuit design software exists to assist designers, circuits are typically tested by physically constructing them in silico and performing another design iteration should the prototype fail to operate correctly. Similar to how electronic design automation tools revolutionized the digital circuit design process, so too do microfluidic design packages have the potential to increase productivity for microfluidic circuit designers and allow more complex devices to be designed. Two of the primary software engineering problems to be solved in this space relate to design entry and design synthesis. First, the circuit designer requires a programming language to describe the behaviour and properties of the device they wish to build, and a compiler toolchain to convert this description into a model that can then be processed by other software tools. Second, once such a model is constructed, the remaining portions of the design toolchain must be constructed. It is necessary to implement software that can find unknown design parameters automatically to relieve the designer of much of the complexity that goes into creating such a circuit. Furthermore, automated testing and verification tools must be used to simulate the device and check for correctness and safety requirements before the engineer can have confidence in their design. In this thesis I outline work that has been done towards both of these goals. First, I describe a new programming language that has been developed for the purpose of describing and modelling physical systems, including but not limited to microfluidic circuits. This programming language, called “Manifold”, has been implemented following principles and features of modern functional programming languages, as well as drawing inspiration from VHDL and Verilog, the two industry-standard programming languages for EDA. The Manifold high-level language compiler carries out the process of translating a system description into a domain-agnostic intermediate representation. This representation is then passed to a domain-specific backend compiler which can perform further operations on the design, such as creating simulations, performing verification, and generating appropriate output products. Second, I perform a case study with respect to the creation of such a domain-specific backend for the domain of multi-phase microfluidic circuits. The process involved in taking a circuit description from design entry to device specification has a number of significant steps. I discuss in detail these steps with respect to the design of a multi-way droplet generator circuit. Such a circuit is difficult to design because of the behaviour of the key design parameter, the volume of generated droplets. The design goal is for each droplet generator on the device to produce droplets of a certain specified volume. However, the equation relating the properties of a droplet generator to the predicted droplet volume is complex and contains several nonlinearities, making it very difficult to solve by traditional methods. Recent advances in constraint solvers which can reason about nonlinear equations over real-valued terms make it possible to solve this equation efficiently for a given set of design constraints and goals, and produce many feasible specifications for droplet generators that meet the requirements. Another difficulty in designing these circuits is due to interactions between droplet generators. As the produced droplets have a significant hydrodynamic resistance, they affect the behaviour of the circuit by causing perturbations in the flow rates into the droplet generators. This has the potential to alter the volume of droplets that are being produced. Therefore, a means of regulating or controlling the flow rates must be found. I describe a potential solution in the form of a passive element analogous to a capacitor in an electrical circuit. Once an appropriate value for the capacitor is chosen, it remains to verify that it operates correctly under manufacturing variances in fabrication of the device. To perform this verification, a bounded model checker for real-valued differential equations is employed to demonstrate correctness or discover robustness issues. Furthermore, a simulation file for the MapleSim numerical simulation engine is generated in order to perform whole-design tests for further validation. The sequence in which these steps are performed closely follows the concept of “abstraction refinement” in formal methods, in which successively more detailed models are checked and a failure in one step can invoke a previous step with new information, allowing errors to be caught early and introducing the ability to iterate on the design. I describe such a refinement loop in place in the microfluidics backend that integrates these three steps in a coherent design flow, able to synthesize and verify many specifications for a microfluidic circuit, thereby automating a significant portion of the design process. The combination of the Manifold high-level language and microfluidics backend introduces a new design automation toolchain that demonstrates the effectiveness of constraint solvers in the tasks of design synthesis and verification. Further enhancements to the performance and capabilities of these solvers, as well as to the high-level language and backend, will in the future produce a general-purpose design package for microfluidic circuits that will allow for new, complex designs to be created and checked with confidence

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

Towards Microfluidic Design Automation

Microfluidic chips, lab-on-a-chip devices that have channels transporting liquids instead of wires carrying electrons, have attracted considerable attention recently from the bio-medical industry because of their application in testing assay and large-scale chemical reaction automation. These chips promise dramatic reduction in the cost of large-scale reactions and bio-chemical sensors. Just like in traditional chip design, there is an acute need for automation tools that can assist with design, testing and verification of microfluidics chips. We propose a design methodology and tool to design microfluidic chips based on SMT solvers. The design of these chips is expressed using the language of partial differential equations (PDEs) and non-linear multi-variate polynomials over the reals. We convert such designs into SMT2 format through appropriate approximations, and invoke Z3 and dReal solver on them. Through our experiments we show that using SMT solvers is a not only a viable strategy to address the microfluidics design problem, but likely will be key component of any future development environment. In addition to analysis of Microfluidic Chip design, we discuss the new area of Microhydraulics; a new technology being developed for the purposes of macking dynamic molds and dies for manufacturing. By contrast, Microhydraulics is more concerned on creating designs that will satisfy the dynamic requirements of manufacturers, as opposed to microfludics which is more concerned about the chemical reactions taking place in a chip. We develop the background of the technology as well as the models required for SMT solvers such as Z3 and dReal to solve them

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

Design and verification tools for continuous fluid flow-based microfluidic devices

This paper describes an integrated design, verification, and simulation environment for programmable microfluidic devices called laboratories-on-chip (LoCs). Today's LoCs are architected and laid out by hand, which is time-consuming, tedious, and error-prone. To increase designer productivity, this paper introduces a Microfluidic Hardware Design Language (MHDL) for LoC specification, along with software tools to assist LoC designers verify the correctness of their specifications and estimate their performance. © 2013 IEEE

Design and verification tools for continuous fluid flow-based microfluidic devices

This paper describes an integrated design, verification, and simulation environment for programmable microfluidic devices called laboratories-on-chip (LoCs). Today's LoCs are architected and laid out by hand, which is time-consuming, tedious, and error-prone. To increase designer productivity, this paper introduces a Microfluidic Hardware Design Language (MHDL) for LoC specification, along with software tools to assist LoC designers verify the correctness of their specifications and estimate their performance. © 2013 IEEE