Layout-Aware Solution Preparation for Biochemical Analysis on a Digital Microfluidic Biochip (original) (raw)
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Optimization of Dilution and Mixing of Biochemical Samples Using Digital Microfluidic Biochips
IEEE Transactions on Computer-aided Design of Integrated Circuits and Systems, 2010
The recent emergence of lab-on-a-chip (LoC) technology has led to a paradigm shift in many healthcare-related application areas, e.g., point-of-care clinical diagnostics, high-throughput sequencing, and proteomics. A promising category of LoCs is digital microfluidic (DMF)-based biochips, in which nanoliter-volume fluid droplets are manipulated on a 2-D electrode array. A key challenge in designing such chips and mapping lab-bench protocols to a LoC is to carry out the dilution process of biochemical samples efficiently. As an optimization and automation technique, we present a dilution/mixing algorithm that significantly reduces the production of waste droplets. This algorithm takes O(n) time to compute at most n sequential mix/split operations required to achieve any given target concentration with an error in concentration factor less than [1/(2n)]. To implement the algorithm, we design an architectural layout of a DMF-based LoC consisting of two O(n)-size rotary mixers and O(n) storage electrodes. Simulation results show that the proposed technique always yields nonnegative savings in the number of waste droplets and also in the total number of input droplets compared to earlier methods.
Droplet Routing in the Synthesis of Digital Microfluidic Biochips
Proceedings of the Design Automation & Test in Europe Conference, 2006
same level of system-level CAD support that is now commonplace in the IC industry. Recent advances in microfluidics are expected to lead to sensor systems for high-throughput biochemical analysis. CAD tools are needed to handle increased design complexity for such systems. Analogous to classical VLSI synthesis, a top-down design automation approach can shorten the design cycle and reduce human effort. We focus here on the droplet routing problem, which is a key issue in biochip physical design automation. We develop the first systematic droplet routing method that can be integrated with biochip synthesis. The proposed approach minimizes the number of cells used for droplet routing, while satisfying constraints imposed by throughput considerations and fluidic properties. A real-life biochemical application is used to evaluate the proposed method. Analogous to classical VLSI synthesis, a top-down system-level design automation approach can be used to relieve biochip users from the burden of manual optimization of assays and time-consuming hardware design. We can divide the synthesis procedure for a digital microfluidic biochip into two major phases, i.e., architectural-level synthesis and physical design. A behavioral model for a set of bioassays is first obtained from their laboratory protocols. Architectural-level synthesis is then used to generate a macroscopic structure of the biochip; this is analogous to a structural RTL model in electronic CAD [5]. Next, physical design creates the final layout of the biochip, consisting of the placement of microfluidic modules such as mixers and storage units, the routes that droplets take between different modules, and other geometrical details [6].
Droplet-based microsystem for multi-step bioreactions
Biomedical Microdevices, 2010
A droplet-based microfluidic platform was used to perform on-chip droplet generation, merging and mixing for applications in multi-step reactions and assays. Submicroliter-sized droplets can be produced separately from three identical droplet-generation channels and merged together in a single chamber. Three different mixing strategies were used for mixing the merged droplet. For pure diffusion, the reagents were mixed in approximately 10 min. Using flow around the stationary droplet to induce circulatory flow within the droplet, the mixing time was decreased to approximately one minute. The shortest mixing time (10 s) was obtained with bidirectional droplet motion between the chamber and channel, and optimization could result in a total time of less than 1 s. We also tested this on-chip droplet generation and manipulation platform using a two-step thermal cycled bioreaction: nested TaqMan ® PCR. With the same concentration of template DNA, the two-step reaction in a well-mixed merged droplet shows a cycle threshold of ~6 cycles earlier than that in the diffusively mixed droplet, and ~40 cycles earlier than the droplet-based regular (single-step) TaqMan ® PCR.
Module-Based Synthesis of Digital Microfluidic Biochips with Droplet-Aware Operation Execution
ACM Journal on Emerging Technologies in Computing Systems, 2013
Microfluidic biochips represent an alternative to conventional biochemical analyzers. A digital biochip manipulates liquids not as continuous flow, but as discrete droplets on a two-dimensional array of electrodes. Several electrodes are dynamically grouped to form a virtual device, on which operations are executed by moving the droplets. So far, researchers have ignored the locations of droplets inside devices, considering that all the electrodes forming the device are occupied throughout the operation execution. In this article, we consider a droplet-aware execution of microfluidic operations, which means that we know the exact position of droplets inside the modules at each time-step. We propose a Tabu Search-based metaheuristic for the synthesis of digital biochips with droplet-aware operation execution. Experimental results show that our approach can significantly reduce the application completion time, allowing us to use smaller area biochips and thus reduce costs.
Design Automation for Embedded Systems, 2018
Droplet-based microfluidic biochips (or DMFBs) are rapidly becoming a revolutionizing lab-on-a-chip technology. Numerous application specific protocols bridging the crossdisciplinary fields necessitate DMFBs as their prime need. The main goal at the fluid level is to minimize bioassay schedule length. Also, for a safe assay outcome, contamination among droplet routes must be avoided. Size restriction of a chip and reconfigurable nature of the operational modules in DMFB introduce contaminated cells which necessarily require washing as an urgent need. As the sub-tasks of fluid level possess their own constraints for a successful DMFB design, rip-up and reiteration of sub-tasks may become unavoidable if all of those constraints are not satisfied mutually. To achieve a shorter time for chip realization a crucial need in fluid-level design is to avoid rip-up and re-iteration; hence, design convergence is to be incorporated that collectively considers the fluid-level sub-tasks, instead of solving them individually. Thus, this paper focuses on the fluid level of DMFBs while considering design convergence, contamination avoidance, and washing issues. Obtained results are compared with several existing benchmarks. Keywords Contamination • Design automation • Microfluidics • NP-complete • One-pass synthesis • Washing This work was supported by the Visvesvaraya fellowship for Ph.D. scheme under Ministry of Electronics and Information Technology of the Government of India.
Integration, the VLSI Journal, 2012
Current development of micro fabrication and microfluidic technology enables the digital microfluidic biochips (DMFB) to offer a platform for developing diagnostic applications with the advantages of portability, increased automation, low-power consumption, ease of mass manufacturing, and high throughput. A digital microfluidic system typically consists of a planar array of cells with electrodes that control individual droplets of biological samples. Chemical analysis is performed by moving, mixing, and splitting of droplets. A major issue in biochip layout design is the coordination of simultaneous movement of multiple droplets. It involves the scheduling of movement of a number of droplets in a time-multiplexed manner to avoid their cross-contamination. In this paper we propose a clustering technique to achieve routing of maximum number of samples from a given set of sub-problems in the same planar array with intelligent collision avoidance. A new cluster-based route-aware placement technique is also proposed that enhances the performance of droplet routing, accommodating larger number of concurrently routed sub-problems in the same planar array. The objectives considered are minimizing the latest arrival time of droplets, total routing time of droplets and the overall cell utilization. Experimental simulation results obtained using testbenches for benchmark suite III are found to be better than the recent existing works.
Sample preparation with multiple dilutions on digital microfluidic biochips
IET Computers & Digital Techniques, 2014
Digital microfluidic (DMF) biochips offer a versatile platform for implementing several laboratory based biochemical protocols. These tiny chips can electrically control the dynamics of nanoliter volume of discrete fluid droplets on an electrode array by application of actuation patterns. One important step in biochemical sample preparation is dilution, where the objective is to prepare a fluid with a desired concentration factor. The protocols implemented on DMF biochips may require several different concentration values of a sample. In this study, the authors propose a scheme to produce such target droplets from a supply of an input sample and a buffer solution. Simulation results show a significant amount of savings in the number of mix-split steps and waste droplets in comparison to other methods for generating multiple concentration factors.
Multiphase bioreaction microsystem with automated on-chip droplet operation
Lab on a Chip, 2010
A droplet-based bioreaction microsystem has been developed with automated droplet generation and confinement. On-chip electronic sensing is employed to track the position of the droplets by sensing the oil/aqueous interface in real time. The sensing signal is also used to control the pneumatic supply for moving as well as automatically generating four different nanoliter-sized droplets. The actual size of droplets is very close to the designed droplet size with a standard deviation less than 3% of the droplet size. The automated droplet generation can be completed in less than 2 sec, which is 5 times faster than using manual operation that takes at least 10 sec. Droplets can also be automatically confined in the reaction region with feedback pneumatic control and digital or analog sensing. As an example bioreaction, PCR has been successfully performed in the automated generated droplets. Although the amplification yield was slightly reduced with the droplet confinement, especially while using the analog sensing method, adding additional reagents effectively alleviated this inhibition.
Proceedings of SPIE - The International Society for Optical Engineering, 2004
An ideal on-site chemical/biochemical analysis system must be inexpensive, sensitive, fully automated and integrated, reliable, and compatible with a broad range of samples. The advent of digital microfluidic lab-on-a-chip (LoC) technology offers such a detection system due to the advantages in portability, reduction of the volumes of the sample and reagents, faster analysis times, increased automation, low power consumption, compatibility with mass manufacturing, and high throughput. We describe progress towards integrating sample collection onto a digital microfluidic LoC that is a component of a cascade impactor device. The sample collection is performed by impacting airborne particles directly onto the surface ofthe chip. After the collection phase, the surface ofthe chip is washed with a micro-droplet of solvent. The droplet will be digitally directed across the impaction surface, dissolving sample constituents. Because ofthe very small droplet volume used for extraction ofthe sample from a wide collection area, the resulting solution is relatively concentrated and the analytes can be detected after a very short sampling time (1 mm) due to such pre-concentration. After the washing phase, the droplet is mixed with specific reagents that produce colored reaction products. The concentration of the analyte is quantitatively determined by measuring absorption at target wavelengths using a simple light emitting diode and photodiode setup. Specific applications include automatic measurements of major inorganic ions in aerosols, such as sulfate, nitrate and ammonium, with a time resolution of 1 mm and a detection limit of 30 ng/m3. We have already demonstrated the detection and quantification of nitroaromatic explosives without integrating the sample collection. Other applications being developed include airborne bioagent detection.