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Storage-Aware Algorithms for Dilution and Mixture Preparation With Flow-Based Lab-on-Chip
(2020-04-01)
Bhattacharjee, Sukanta
;
Wille, Robert
;
Huang, Juinn-Dar
;
Bhattacharya, Bhargab B.
;
電子工程學系及電子研究所
Lab-on-chip (LoC) technology has emerged as one of the major driving forces behind the recent surge in biochemical protocol automation. Dilution and mixture preparation with fluids in a desired ratio, constitute basic steps in sample preparation for which several LoC-based architectures and algorithms are known. The optimization of cost and time for such protocols requires proper sequencing of fluidic mix-and-split steps, and storage-units for holding intermediate-fluids to be reused in the later steps. However, practical design constraints often limit the amount of on-chip storage in microfluidic LoC architectures and thus can badly affect the performance of the algorithms. Consequently, results generated by previous work may not be useful (in the case they require more storage-units than available) or more expensive than necessary (in the case when storage-units are available but not used, e.g., to further reduce the number of mix/split operations or reactant-cost). In this paper, we propose new algorithms for dilution and mixing with continuous-flow-based LoCs that explicitly take care of storage constraints while optimizing reactant-cost and time of sample preparation. We present a symbolic formulation of the problem that captures the degree of freedom in algorithmic steps satisfying the specified storage constraints. Solvers based on Boolean satisfiability are used to achieve the optimization goals. The experimental results show the efficiency and effectiveness of the solution as well as a variety of applications where the proposed methods would prove beneficial.
Reliability Hardening Mechanisms in Cyber-Physical Digital-Microfluidic Biochips
(2018-10-01)
Lu, Guan-Ruei
;
Banerjee, Ansuman
;
Bhattacharya, Bhargab B.
;
Ho, Tsung-Yi
;
Chen, Hung-Ming
In the area of biomedical engineering, digital-microfluidic biochips (DMFBs) have received considerable attention because of their capability of providing an efficient and reliable platform for conducting point-of-care clinical diagnostics. System reliability, in turn, mandates error-recoverability while implementing biochemical assays on-chip for medical applications. Unfortunately, the technology of DMFBs is not yet fully equipped to handle error-recovery from various microfluidic operations involving droplet motion and reaction. Recently, a number of cyber-physical systems have been proposed to provide real-time checking and error-recovery in assays based on the feedback received from a few on-chip checkpoints. However, to synthesize robust feedback systems for different types of DMFBs, certain practical issues need to be considered such as co-optimization of checkpoint placement, error-recoverability, and layout of droplet-routing pathways. For application-specific DMFBs, we propose here an algorithm that minimizes the number of checkpoints and determines their locations to cover every path in a given droplet-routing solution. Next, for general-purpose DMFBs, where the checkpoints are pre-deployed in specific locations, we present a checkpoint-aware routing algorithm such that every droplet-routing path passes through at least one checkpoint to enable error-recovery and to ensure physical routability of all droplets. Furthermore, we also propose strategies for executing the algorithms in reliable mode to enhance error-recoverability. The proposed methods thus provide reliability-hardening mechanisms for a wide class of cyber-physical DMFBs.
Multi-Level Droplet Routing in Active-Matrix Based Digital-Microfluidic Biochips
(2018-01-01)
Lu, Guan-Ruei
;
Bhattacharya, Bhargab B.
;
Ho, Tsung-Yi
;
Chen, Hung-Ming
;
電子工程學系及電子研究所
Active-Matrix (AM) technology is currently being used to implement a superior class of EWOD-based biochips, which consist of a dense 2D-array of microelectrodes. These chips offer many advantages over conventional biochips such as the capability of handling variable-size droplets, more flexibility in droplet movement, precise control over droplet navigation, and as a sequel, ease of implementing complex bioprotocols on-chip. However, the new technology poses a number of challenges concerning droplet routing. In order to enhance routability, we propose, in this paper, a multi-level hierarchical approach that takes appropriate decisions on droplet splitting and reshaping. Compared to the most recent routing methods used for EWOD, the proposed multi-level router reduces maximum latest-arrivaltime by an average 18% and achieves 7% less average latest-arrival-time.
On Reliability Hardening in Cyber-Physical Digital-Microfluidic Biochips
(2017-01-01)
Lu, Guan-Ruei
;
Huang, Guan-Ming
;
Banerjee, Ansuman
;
Bhattacharya, Bhargab B.
;
Ho, Tsung-Yi
In the area of biomedical engineering, digital-microfluidic biochips (DMFBs) have received considerable attention, because of their capability of providing an efficient and reliable platform for conducting point-of-care clinical diagnostics. System reliability, in turn, mandates error-recoverability while implementing biochemical assays on-chip for medical applications. Unfortunately, the technology of DMFBs is not yet fully equipped to handle error-recovery from various microfluidic operations involving droplet motion and reaction. Recently, a number of cyber-physical systems have been proposed to provide real-time checking and error-recovery in assays based on the feedback received from a few on-chip checkpoints. However, in order to synthesize robust feedback systems for different types of DMFBs, certain practical issues need to be considered such as co-optimization of checkpoint placement and layout of droplet-routing pathways. For application-specific DMFBs, we propose here an algorithm that minimizes the number of checkpoints and determines their locations to cover every path in a given droplet-routing solution. Next, for general-purpose DMFBs, where the checkpoints are pre-deployed in specific locations, we present a checkpoint-aware routing algorithm such that every droplet-routing path passes through at least one checkpoint to enable error-recovery and to ensure physical routability of all droplets. Our experiments on assay benchmarks show encouraging results in terms of latest-arrival-time and routability of droplets. The proposed methods thus provide convenient reliability-hardening mechanisms for a wide class of cyber-physical DMFBs.
Storage-Aware Sample Preparation Using Flow-Based Microfluidic Labs-on-Chip
(2018-01-01)
Bhattacharjee, Sukanta
;
Wille, Robert
;
Huang, Juinn-Dar
;
Bhattacharya, Bhargab B.
;
電子工程學系及電子研究所
Recent advances in microfluidics have been the major driving force behind the ubiquity of Labs-on-Chip (LoC) in biochemical protocol automation. The preparation of dilutions and mixtures of fluids is a basic step in sample preparation for which several algorithms and chip-architectures are well known. Dilution and mixing are implemented on biochips through a sequence of basic fluid-mixing and splitting operations performed in certain ratios. These steps are abstracted using a mixing graph. During this process, on-chip storage-units are needed to store intermediate fluids to be used later in the sequence. This allows to optimize the reactant-costs, to reduce the sample-preparation time, and/or to achieve the desired ratio. However, the number of storage-units is usually limited in given LoC architectures. Since this restriction is not considered by existing methods for sample preparation, the results that are obtained are often found to be useless (in the case when more storage-units are required than available) or more expensive than necessary (in the case when storage-units are available but not used, e.g., to further reduce the number of mixing operations or reactant-cost). In this paper, we present a storage-aware algorithm for sample preparation with flow-based LoCs which addresses these issues. We present a SAT-based approach to construct a mixing graph that enables the best usage of available storage-units while optimizing sample-preparation cost and/or time. Experimental results on several test cases reveal the scope, effectiveness, and the flexibility of the proposed method.
Dilution and Mixing Algorithms for Flow-Based Microfluidic Biochips
(2017-04-01)
Bhattacharjee, Sukanta
;
Poddar, Sudip
;
Roy, Sudip
;
Huang, Juinn-Dar
;
Bhattacharya, Bhargab B.
Albeit sample preparation is well-studied for digital microfluidic biochips, very few prior work addressed this problem in the context of continuous-flow microfluidics from an algorithmic perspective. In the latter class of chips, microvalves and micropumps are used to manipulate on-chip fluid flow through microchannels in order to execute a biochemical protocol. Dilution of a sample fluid is a special case of sample preparation, where only two input reagents (commonly known as sample and buffer) are mixed in a desired volumetric ratio. In this paper, we propose a satisfiability-based dilution algorithm assuming the generalized mixing models supported by an N-segment, continuous-flow, rotary mixer. Given a target concentration and an error limit, the proposed algorithm first minimizes the number of mixing operations, and subsequently, reduces reagent-usage. Simulation results demonstrate that the proposed method outperforms existing dilution algorithms in terms of mixing steps (assay time) and waste production, and compares favorably with respect to reagent-usage (cost) when 4- and 8-segment rotary mixers are used. Next, we propose two variants of an algorithm for handling the open problem of k-reagent mixture-preparation (k >= 3) with an N-segment continuous-flow rotary mixer, and report experimental results to evaluate their performance. A software tool called flow-based sample preparation algorithm has also been developed that can be readily used for running the proposed algorithms.
Concentration-Resilient Mixture Preparation with Digital Microfluidic Lab-on-Chip
(2018-04-01)
Bhattacharjee, Sukanta
;
Chen, Yi-Ling
;
Huang, Juinn-Dar
;
Bhattacharya, Bhargab B.
;
電子工程學系及電子研究所
Sample preparation plays a crucial role in almost all biochemical applications, since a predominant portion of biochemical analysis time is associated with sample collection, transportation, and preparation. Many sample-preparation algorithms are proposed in the literature that are suitable for execution on programmable digital microfluidic (DMF) platforms. In most of the existing DMF-based sample-preparation algorithms, a fixed target ratio is provided as input, and the corresponding mixing tree is generated as output. However, in many biochemical applications, target mixtures with exact component proportions may not be needed. From a biochemical perspective, it may be sufficient to prepare a mixture in which the input reagents may lie within a range of concentration factors. The choice of a particular valid ratio, however, strongly impacts solution-preparation cost and time. To address this problem, we propose a concentration-resilient ratioselection method from the input ratio space so that the reactant cost is minimized. We propose an integer linear programming-based method that terminates very fast while producing the optimum solution, considering both uniform and weighted cost of reagents. Experimental results reveal that the proposed method can be used conveniently in tandem with several existing sample-preparation algorithms for improving their performance.
Flexible Droplet Routing in Active Matrix-Based Digital Microfluidic Biochips
(2018-04-01)
Lu, Guan-Ruei
;
Kuo, Chun-Hao
;
Chiang, Kuen-Cheng
;
Banerjee, Ansuman
;
Bhattacharya, Bhargab B.
The active matrix (AM)-based architecture offers many advantages over conventional digital electrowetting-on-dielectric (EWOD) microfluidic biochips, such as the capability of handling variable-size droplets, more flexible droplet movement, and precise control over droplet navigation. However, a major challenge in choosing the routing paths is to decide when the droplets are to be reshaped depending on the congestion of the intended path, or split- and route sub droplets,and merging them at their respective destinations. As the number of microelectrodes in AM-EWOD chips is large, the path selection problem becomes further complicated. In this article, we propose a negotiation-guided flow based on routing of subdroplets that obviates the explicit need for deciding when the droplets are to be manipulated, yet fully utilizing the power of droplet reshaping, splitting, and merging them to facilitate their journey. The proposed algorithm reduces routing cost and provides more freedom in deadlock avoidance in the presence of multiple routing tasks by assigning certain congestion penalty for sibling subdroplets and fluidic penalty for heterogeneous droplets. Compared to existing techniques, it reduces latest arrival time by an average of 29% for several benchmark and random test suites. Furthermore, our method is observed to provide 100% routability of nets for all test cases, whereas existing and baseline routers fail to produce feasible solutions in many instances. We also propose a reliable mode droplet routing strategy where the number of unreliable splitting operations can be reduced by paying a small penalty on latest arrival time.
Design and Optimization of a Cyberphysical Digital-Microfluidic Biochip for the Polymerase Chain Reaction
(2015-01-01)
Luo, Yan
;
Bhattacharya, Bhargab B.
;
Ho, Tsung-Yi
;
Chakrabarty, Krishnendu
;
資訊工程學系
The amount of DNA strands available in a biological sample is a major limitation for many genomic bioanalyses. To amplify the traces of DNA strands, polymerase chain reaction (PCR) is widely used for conducting subsequent experiments. Compared to conventional instruments and analyzers, the execution of PCR on a digital microfluidic biochip (DMFB) can achieve short time-to-results, low reagent consumption, rapid heating/cooling rates, and high integration of multiple processing modules. However, the PCR biochip design methods in the literature are oblivious to the inherent randomness and complexity of bioanalyses, and they do not consider the interference among the neighboring devices and the cost of droplet transportation. We present an integrated design solution to optimize the complete PCR procedure, including: 1) DNA amplification and termination control; 2) resource placement that satisfies proximity constraints; and 3) droplet transportation. Based on the sensor feedback data, a statistical model is developed to optimize and control the DNA amplification sequence in real-time on a cyberphysical biochip. Next, we present a geometric algorithm for avoiding device interference and for reducing droplet routing cost. A novel optical sensing system is deployed based on the physical visibility of droplets. Simulation results for three laboratory protocols demonstrate that the proposed design method results in a compact layout and produces an execution sequence for efficient control of PCR operations on a cyberphysical DMFB.

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