Synthetic biology and microdevices : a powerful combination

Recent developments demonstrate that the combination of microbiology with micro-and nanoelectronics is a successful approach to develop new miniaturized sensing devices and other technologies. In the last decade, there has been a shift from the optimization of the abiotic components, for example, the chip, to the improvement of the processing capabilities of cells through genetic engineering. The synthetic biology approach will not only give rise to systems with new functionalities, but will also improve the robustness and speed of their response towards applied signals. To this end, the development of new genetic circuits has to be guided by computational design methods that enable to tune and optimize the circuit response. As the successful design of genetic circuits is highly dependent on the quality and reliability of its composing elements, intense characterization of standard biological parts will be crucial for an efficient rational design process in the development of new genetic circuits. Microengineered devices can thereby offer a new analytical approach for the study of complex biological parts and systems. By summarizing the recent techniques in creating new synthetic circuits and in integrating biology with microdevices, this review aims at emphasizing the power of combining synthetic biology with microfluidics and microelectronics

Transport or Store? Synthesizing Flow-based Microfluidic Biochips using Distributed Channel Storage

Flow-based microfluidic biochips have attracted much atten- tion in the EDA community due to their miniaturized size and execution efficiency. Previous research, however, still follows the traditional computing model with a dedicated storage unit, which actually becomes a bottleneck of the performance of bio- chips. In this paper, we propose the first architectural synthe- sis framework considering distributed storage constructed tem- porarily from transportation channels to cache fluid samples. Since distributed storage can be accessed more efficiently than a dedicated storage unit and channels can switch between the roles of transportation and storage easily, biochips with this dis- tributed computing architecture can achieve a higher execution efficiency even with fewer resources. Experimental results con- firm that the execution efficiency of a bioassay can be improved by up to 28% while the number of valves in the biochip can be reduced effectively.Comment: ACM/IEEE Design Automation Conference (DAC), June 201

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

A Design of Digital Microfluidic Biochip along with Structural and Behavioural Features in Triangular Electrode Based Array

AbstractDigital microfluidic based biochip manoeuvres on the theory of microfluidic technology, having a broad variety of applications in chemistry, biology, environmental monitoring, military etc. Being concerned about the technological advancement in this domain, we have focused on equilateral triangular electrodes based DMFB systems. Accepting the associated design issues, here, we have addressed many facets of such electrodes regarding their structural and behavioural issues in comparison to the existing square electrodes. As the requisite voltage reduction is a key challenging design issues, to implement all the tasks using triangular electrodes that are possible in square electrode arrays as well, is a tedious job. Furthermore, to deal with this new design deploying triangular electrodes, we have analyzed all the necessary decisive factors including fluidic constraints to ensure safe droplet movements and other modular operations together with mixing and routing. Moreover, an algorithm has been developed to find a route for a given source and destination pair in this newly designed DMFB. Finally, we have included a comparative study between this new design and the existing one while encountering the above mentioned issues

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