Layout-Aware Solution Preparation for Biochemical Analysis on a Digital Microfluidic Biochip
02 Jan 2011-pp 171-176
TL;DR: This work presents an efficient approach for automated mixing of three or more fluids on a droplet based digital micro fluidic biochip and designs a layout for implementing this algorithm.
Abstract: A biochemical analysis is based on several laboratory protocols that require repeated mixing of samples with reagents. Sample preparation and analyte identification steps in such bioassays often involve mixing for solution preparation, i.e., various fluids are to be mixed in a certain volumetric ratio in their resulting mixture. We present an efficient approach for automated mixing of three or more fluids on a droplet based digital micro fluidic biochip and design a layout for implementing this algorithm. The proposed method reduces the droplet transportation time from boundary reservoirs to on chip mixers as well as cross-contamination among overlapping droplet routing paths. Simulation of several example solutions reveals encouraging results.
Citations
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05 Nov 2012
TL;DR: REMIA is proposed, the first reactant minimization approach during sample preparation on digital microfluidic biochips (DMFBs) and can be extended to tackle the sample preparation problem with multiple target concentrations, and the extended version also successfully decreases the reactant usage further.
Abstract: Sample preparation is an indispensable process to biochemical reactions. Original reactants are usually diluted to the solutions with desirable concentrations. Since the reactants, like infant's blood, DNA evidence collected from a crime scene, or costly reagents, are extremely valuable, the usage of reactant must be minimized in the sample preparation process. In this paper, we propose the first reactant minimization approach, REMIA, during sample preparation on digital microfluidic biochips (DMFBs). Given a target concentration, REMIA constructs a skewed mixing tree to guide the sample preparation process for reactant minimization. Experimental results demonstrate that REMIA can save about 31%~52% of reactant usage on average compared with three existing sample preparation methods. Besides, REMIA can be extended to tackle the sample preparation problem with multiple target concentrations, and the extended version also successfully decreases the reactant usage further.
82 citations
Cites background from "Layout-Aware Solution Preparation f..."
...The count of dilution operations basically determines the preparation time and thus should be minimized....
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TL;DR: This paper proposes the first reagent-saving mixing algorithm for biochemical samples of multiple target concentrations, which not only minimizes the consumption of reagents, but it also reduces the number of waste droplets and the sample preparation time by preparing the target concentrations concurrently.
Abstract: Recent advances in digital microfluidics have led to the promise of miniaturized laboratories, with the associated advantages of high sensitivity and less human-induced errors. Front-end operations such as sample preparation play a pivotal role in biochemical laboratories, and in applications in biomedical engineering and life science. For fast and high-throughput biochemical applications, preparing samples of multiple target concentrations sequentially is inefficient and time-consuming. Therefore, it is critical to concurrently prepare samples of multiple target concentrations. In addition, since reagents used in biochemical reactions are expensive, reagent-saving has become an important consideration in sample preparation. Prior work in this area does not address the problem of reagent-saving and concurrent sample preparation for multiple target concentrations. In this paper, we propose the first reagent-saving mixing algorithm for biochemical samples of multiple target concentrations. The proposed algorithm not only minimizes the consumption of reagents, but it also reduces the number of waste droplets and the sample preparation time by preparing the target concentrations concurrently. The proposed algorithm is evaluated on both real biochemical experiments and synthetic test cases to demonstrate its effectiveness and efficiency. Compared to prior work, the proposed algorithm can achieve up to 41% reduction in the number of reagent droplets and waste droplets, and up to 50% reduction in sample preparation time.
76 citations
Cites background or methods from "Layout-Aware Solution Preparation f..."
...The problem of automated dilution and mixing arises in numerous biochemical assays for preparation of samples or mixtures, e.g., cDNA for real-time polymerase chain reaction and immunoassays for detecting cytokines in serum samples [8], [23], [27], [28]....
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...The proposed reagent-saving mixing algorithm decomposes the given inputs to minimize the number of required reagent droplets....
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...Finally, conclusions are drawn in Section VII....
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...For bioassay that requires high-throughput or a large number of target concentrations, concurrent preparation of all the target concentrations is critical, because sequential preparation of individual target concentrations will significantly degrade the efficiency and throughput of the entire…...
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TL;DR: A multitarget sample preparation algorithm that extensively exploits the ideas of waste recycling and intermediate droplet sharing to reduce both reactant usage and waste amount for digital microfluidic biochips is proposed.
Abstract: Sample preparation is one of essential processes in biochemical reactions. Raw reactants are diluted in this process to achieve given target concentrations. A bioassay may require several different target concentrations of a reactant. Both the dilution operation count and the reactant usage can be minimized if multiple target concentrations are considered simultaneously during sample preparation. Hence, in this paper, we propose a multitarget sample preparation algorithm that extensively exploits the ideas of waste recycling and intermediate droplet sharing to reduce both reactant usage and waste amount for digital microfluidic biochips. Experimental results show that our waste recycling algorithm can reduce the waste and operation count by 48% and 37%, respectively, as compared to an existing state-of-the-art multitarget sample preparation method if the number of target concentrations is ten. The reduction can be up to 97% and 73% when the number of target concentrations goes even higher.
54 citations
Cites methods or result from "Layout-Aware Solution Preparation f..."
...Unlike approaches [26]–[28] and [33] based on the dilution graph, all of BS [25], RMA [29], DBG [30], and REMIA [32] adopt another strategy, named mixing tree....
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...Other related previous works include the bit-scanning (BS) method [25], the algorithm for dilution and mixing with reduced wastage (DMRW) [26], the improved dilution/mixing algorithm (IDMA) [27], IDSA [28], the ratioed mixing algorithm (RMA) [29], the De Bruijn graph-based multitarget preparation scheme (DBG) [30], the reactant minimization algorithm (REMIA) [32], and the graph-based optimal reactant minimization algorithm [33]....
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...this paper, just as the previous works [25], [29], [30], [32],...
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05 Jun 2016
TL;DR: The first biochip synthesis approach that can be used for MEDA is presented, which targets operation scheduling, module placement, routing of droplets of various sizes, and diagonal movement ofdroplets in a two-dimensional array.
Abstract: A digital microfluidic biochip (DMFB) is an attractive technology platform for automating laboratory procedures in biochemistry. However, today's DMFBs suffer from several limitations: (i) constraints on droplet size and the inability to vary droplet volume in a fine-grained manner; (ii) the lack of integrated sensors for real-time detection; (iii) the need for special fabrication processes and reliability/yield concerns. To overcome the above problems, DMFBs based on a micro-electrode-dot-array (MEDA) architecture have recently been demonstrated. However, due to the inherent differences between today's DMFBs and MEDA, existing synthesis solutions cannot be utilized for MEDA-based biochips. We present the first biochip synthesis approach that can be used for MEDA. The proposed synthesis method targets operation scheduling, module placement, routing of droplets of various sizes, and diagonal movement of droplets in a two-dimensional array. Simulation results using benchmarks and experimental results using a fabricated MEDA biochip demonstrate the effectiveness of the proposed co-optimization technique.
50 citations
Cites methods from "Layout-Aware Solution Preparation f..."
...Three real-life benchmarks, namely PCR [15], sample preparation [16], and protein dilution [17], are used to evaluate...
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TL;DR: This work presents the first synthesis approach that can be used for MEDA biochips and presents the proposed synthesis method targeting reservoir placement, operation scheduling, module placement, routing of droplets of various sizes, and diagonal movement ofdroplets in a two-dimensional array.
Abstract: A digital microfluidic biochip (DMFB) is an attractive technology platform for automating laboratory procedures in biochemistry. In recent years, DMFBs based on a microelectrode-dot-array (MEDA) architecture have been demonstrated. However, due to the inherent differences between today's DMFBs and MEDA, existing synthesis solutions for biochemistry mapping cannot be utilized for MEDA biochips. We present the first synthesis approach that can be used for MEDA biochips. We first present a general analytical model for droplet velocity and validate it experimentally using a fabricated MEDA biochip. We then present the proposed synthesis method targeting reservoir placement, operation scheduling, module placement, routing of droplets of various sizes, and diagonal movement of droplets in a two-dimensional array. Simulation results using benchmarks and experimental results using a fabricated MEDA biochip demonstrate the effectiveness of the proposed synthesis technique.
49 citations
Cites methods from "Layout-Aware Solution Preparation f..."
...ration [35], and protein dilution [36], are used to evaluate the proposed method....
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References
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TL;DR: In this article, a microactuator for rapid manipulation of discrete microdroplets is presented, which is accomplished by direct electrical control of the surface tension through two sets of opposing planar electrodes fabricated on glass.
Abstract: A microactuator for rapid manipulation of discrete microdroplets is presented. Microactuation is accomplished by direct electrical control of the surface tension through two sets of opposing planar electrodes fabricated on glass. A prototype device consisting of a linear array of seven electrodes at 1.5 mm pitch was fabricated and tested. Droplets (0.7–1.0 μl) of 100 mM KCl solution were successfully transferred between adjacent electrodes at voltages of 40–80 V. Repeatable transport of droplets at electrode switching rates of up to 20 Hz and average velocities of 30 mm/s have been demonstrated. This speed represents a nearly 100-fold increase over previously demonstrated electrical methods for the transport of droplets on solid surfaces.
1,471 citations
"Layout-Aware Solution Preparation f..." refers background in this paper
...Detailed descriptions of DMF biochips and their applications can be found in [1], [2], [5]....
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...Droplet movement is achieved by a special phenomenon called electrowetting-on-dielectric (EWOD) effect [5]....
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TL;DR: To understand the opportunities and limitations of EWD microfluidics, this paper looks at the development of lab-on-chip applications in a hierarchical approach.
Abstract: The suitability of electrowetting-on-dielectric (EWD) microfluidics for true lab-on-a-chip applications is discussed. The wide diversity in biomedical applications can be parsed into manageable components and assembled into architecture that requires the advantages of being programmable, reconfigurable, and reusable. This capability opens the possibility of handling all of the protocols that a given laboratory application or a class of applications would require. And, it provides a path toward realizing the true lab-on-a-chip. However, this capability can only be realized with a complete set of elemental fluidic components that support all of the required fluidic operations. Architectural choices are described along with the realization of various biomedical fluidic functions implemented in on-chip electrowetting operations. The current status of this EWD toolkit is discussed. However, the question remains: which applications can be performed on a digital microfluidic platform? And, are there other advantages offered by electrowetting technology, such as the programming of different fluidic functions on a common platform (reconfigurability)? To understand the opportunities and limitations of EWD microfluidics, this paper looks at the development of lab-on-chip applications in a hierarchical approach. Diverse applications in biotechnology, for example, will serve as the basis for the requirements for electrowetting devices. These applications drive a set of biomedical fluidic functions required to perform an application, such as cell lysing, molecular separation, or analysis. In turn, each fluidic function encompasses a set of elemental operations, such as transport, mixing, or dispensing. These elemental operations are performed on an elemental set of components, such as electrode arrays, separation columns, or reservoirs. Examples of the incorporation of these principles in complex biomedical applications are described.
1,094 citations
TL;DR: This paper presents BioStream, a portable language for describing biology protocols, and the Fluidic ISA, a stable interface for microfluidic chip designers, and develops abstraction layers that decouple software development from changes in the underlying device technology.
Abstract: Microfluidic devices are emerging as an attractive technology for automatically orchestrating the reactions needed in a biological computer. Thousands of microfluidic primitives have already been integrated on a single chip, and recent trends indicate that the hardware complexity is increasing at rates comparable to Moore's Law. As in the case of silicon, it will be critical to develop abstraction layers--such as programming languages and Instruction Set Architectures (ISAs)--that decouple software development from changes in the underlying device technology. Towards this end, this paper presents BioStream, a portable language for describing biology protocols, and the Fluidic ISA, a stable interface for microfluidic chip designers. A novel algorithm translates microfluidic mixing operations from the BioStream layer to the Fluidic ISA. To demonstrate the benefits of these abstraction layers, we build two microfluidic chips that can both execute BioStream code despite significant differences at the device level. We consider this to be an important step towards building scalable biological computers.
163 citations
"Layout-Aware Solution Preparation f..." refers background or methods in this paper
...Prior Art on Mixing Algorithm A bit-scanning (BS) method for complex mixture preparation was proposed in [6]....
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...Mixing and dilution of fluids are fundamental preprocessing steps in almost all bioanalytical protocols [6]–[10]....
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...(a) Mixing tree obtained by [6] and (b) Bit-representations of the ratio....
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08 Dec 2004
TL;DR: In this article, the authors describe progress towards integrating sample collection onto a digital microfluidic LoC that is a component of a cascade impactor device, where the sample collection is performed by impacting airborne particles directly onto the surface of the chip.
Abstract: 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 of the chip. After the collection phase, the surface of the chip is washed with a micro-droplet of solvent. The droplet will be digitally directed across the impaction surface, dissolving sample constituents. Because of the very small droplet volume used for extraction of the sample from a wide colection area, the resulting solution is realatively concentrated and the analytes can be detected after a very short sampling time (1 min) 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 min and a detection limit of 30 nm/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.
138 citations
"Layout-Aware Solution Preparation f..." refers background in this paper
..., bioassays) on a single chip of a few square centimeters in size [1]–[4]....
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TL;DR: The first microfluidic method for extracting proteins from heterogeneous fluids by precipitation is presented, which is compatible with proteins representing a range of different physicochemical properties, as well as with complex mixtures such as fetal bovine serum and cell lysate.
Abstract: We present the first microfluidic method for extracting proteins from heterogeneous fluids by precipitation. The new method comprises an automated protocol for precipitation of proteins onto surfaces, rinsing the precipitates to remove impurities, and resolubilization in buffer for further analysis. The method is compatible with proteins representing a range of different physicochemical properties, as well as with complex mixtures such as fetal bovine serum and cell lysate. In all cases, the quantitative performance (measured using a fluorescent assay for % recovery) was comparable to that of conventional techniques, which are manual and require more time. Thus, this work represents an important first step in efforts to develop fully automated microfluidic methods for proteomic analyses.
122 citations