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Exact Design of Digital Microfluidic Biochips 2019.pdf
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Many biological or medical experiments today are conducted manually by highly trained experts. Usually, a large laboratory requiring a lot of equipment is needed as welOliver keszocze· Robert wille· Rolf drechsler
Exact Design of Digital
Microfluidic Biochips
Springer
Oliver keszoczo
Robert wille
University of Bremen and dFKI Gmbh
Johannes Kepler University Linz
Bremen, germany
Linz. austria
Rolf drechsler
University of Bremen and dFkI Gmbh
Bremen, germany
ISBN978-3-31990935-6
ISBN978-3-319-90936-3( e book)
https://doi.org/10.10071978-3-319-90936-3
Library of Congress Control Number: 2018942500
o Springer International Publishing AG, part of Springer Nature 2019
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Preface
Many biological or medical experiments today are conducted manually by highly
trained experts. Usually, a large laboratory requiring a lot of equipment is needed
as well. This makes the whole process expensive and does not allow for very high
throughput This led to the development of automated laboratory equipment such as
automated robots. These devices already allow for a high level of automation and
integration. Unfortunately, laboratory robots are usually bulky(and expensive) and
also use rather large amounts of liquids which may be very expensive on their own
To further reduce the size of laboratory devices, researchers investigated how
to manipulate liquids at a nanoliter or even picoliter volume scale. This led to the
development of microfluidic biochips, also known as lab-on-a-chip The technical
capabilities of microfluidic devices have been widely illustrated in the literature. An
essential step for being able to actually make use of Digital Microfuidic Biochips
(MFBS) is to properly design(or synthesize)those. This process includes to take a
medical or biological assay description, a biochip geometry, and further constraints
and determine a precise execution scheme for running the assay on the biochip
As biochips grow in size and more complex assays are to be conducted, manual
design of these devices is often not feasible anymore. Moreover, manual designs
are often far from being optimal. Instead. high-quality design methodologies are
ired which relieve the design burden of manual optimizations of assays time-
consuming chip designs, as well as costly testing and maintenance procedures
This book presents exact, that is minimal, solutions to individual steps in the
design process as well as to a one-pass approach that combines all design steps i
single step. The presented methods are easily adaptable to future needs. In addition
to the minimal methods, heuristic approaches are provided and the complexity
classes of (some of) the design problems are determined
By this, the book summarizes the results of several years of intensive research at
the University of Bremen, Germany, the dfkI gmbH Bremen, Germany, and the
Johannes Kepler University Linz, Austria. This included several collaborations
most importantly with the group of Prof Krishnendu Chakrabarty from the Duke
University, USA, and the group of Prof. Tsung-Yi Ho from the National Tsin
Hua University, Taiwan. We would like to sincerely thank both colleagues for
Preface
the very inspiring and fruitful joint work. Besides that, we are thankful to the
coauthors of corresponding research papers which formed the basis of this book,
including (in alphabetical order) Alexander Kroker, Andre Pols, Andreas Grimmer
Jannis Stoppe, Kevin Leonard Schneider, Maximilian Luenert, Mohamed Ibrahim
Tobias Boehnisch, and Zipeng Li. Furthermore, many thanks go to our research
groups in Bremen and Linz for providing us with a comfortable and inspirational
environment from which some authors benefit until today. Finally, we would like
to thank Springer and, in particular, Charles"Chuck "Glaser for making this book
possible
Bremen, germany
Oliver Keszocze
Linz. austria
Robert wille
Bremen, Germany
Rolf drechsler
January 2018
Contents
1 Introduction
2 Background
2.1 Microfluidic biochips
2. 1.1 Microfluidic Operations
2.1.2 Fluidic constraints
12
2.2 Discrete dmfb model
14
2.2.1 Geometry of the biochip
15
2.2.2 Droplet Movement...................... 16
2.2.3 Electrode Actuation. ...........................................17
2.3 Reasoning Engines
19
2.3.1 Boolean Satisfiability......
20
2.3.2 Satisfiability Modulo Theories
20
2.3.3 Integer Linear Programming
21
3 Routing
23
3.1 Problem formulatic
3.2 Compl
of routin
3.3 Heuristic Approaches
28
3.4 Proposed solution
29
3.4.1 SAT Variables
30
3.4.2 SAT Constraints
3.5 Experimental results
34
3.6 Summary
37
4 Pin assignment
4.1 Problem formulation
39
4.2 Complexity of Pin Assignment.….…………,40
4.2.1 Reduction from Pin Assignment to Graph Coloring..... 41
4.2.2 Reduction from Graph Coloring to Pin Assignment......... 42
4.3 Related Work
44
Contents
4.4 Proposed solutions
4.4.1 Heuristic Approach
45
4.4.2 Exact Solution
4.5 Experimental Results
48
4. 5. 1 Evaluation of the Pin Assignment .............. 49
4.5.2 Optimizing the Pin assignment.……
51
4.6 Summary.….…
53
5 Pin-Aware Routing and Extensions .
5.1 Pin-Aware Routing
5.1.1 SMT Formulation
5.1.2 Related Work
57
5.1. 3 Use Cases
57
5.2 Routing with Timing Information
53 Aging- Aware Routing…………………
5. 4 Routing with Different Cell Forms
66
5.4.1 Problem formulation
67
5.4.2 Transformation of routing Problems............68
5.4.3 SMT Formulation
68
5.4.4 Experimental results
69
5.5 Routing for Micro-Electrode-Dot-Array Biochips .......... 70
5. 5. 1 Motivation and background
5.5.2 MEDA Model and problem formulation
5.5.3 Related Work
74
5.5.4 Proposed Exact Routing Appro
5.5.5 Experimental Results
5.6 Summary
84
6 One-Pass Design
6. 1 The Design Gap Problem..........
87
6.2 Proposed Solutions
88
6. 2. 1 Heuristic One-Pass Design
88
6.2.2 Exact One-Pass design
6.3 Experimental Results.…......…...…...102
6.3.1 Considered Benchmarks
102
6.3.2 Implementations
102
6.3.3 Evaluation of the Solution Length. ...........................103
6.3.4 Evaluating Iteration Schemes................. 105
6.3.5 Trade-Off Between Grid Size and Time Steps
106
6.4 Summary
107
7 Conclusion and Future ork
109
Contents
ppendix a Bio gram: a Dedicated grammar for dMFB design
Appendix b Bio Viz: An Interactive Visualization Tool for DMFB
Design
115
B. 1 The Graphical User Interface
..116
B.2 Use Case: Interactive routing∴.….…….,19
B.2. 1 Implementation
120
B.2.2 Routing algorithms.……
120
B.2.3 Case Study
121
Appendix C Notation ............................. 123
References
∴125
Index
131
Chapter 1
Introduction
Check for
Today, many biological or medical experiments are conducted manually by highly
trained experts. Usually, a large laboratory requiring a lot of equipment is needed as
well(see Fig. 1.la which shows a typical laboratory setup). This makes the whole
process expensive and does not allow for very high throughput. Furthermore, as
human beings are no perfectly working robots they are a source of errors especiall
when many repetitive and monotonous steps are involved in a biological assay.
This led to the development of automated laboratory equipment such as the
robots shown in Fig. 1.1b. These devices already allow for a high level of automation
and integration, even though in many cases they only physically imitate the steps a
human being would perform. Despite already significantly easing laboratory work,
this still leaves room for improvement since those laboratory robots are usuall
bulky(and expensive)
To further reduce the size of laboratory devices, researchers investigated how
to manipulate liquids at a nanoliter or even picoliter volume scale. This led to the
development of microfluidic biochips(see Fig. lIc), also known as lab-on-a-chip
These are devices that automatically manipulate small amounts of liquids in order
to perform(a subset of) the same experiments previously conducted in a laboratory
In addition to simply saving liquids, which may be expensive or difficult to obtain
smaller volumes can also result in shorter experiment execution times. In general, a
higher throughput and sensitivity may be achieved
The capabilities of microfluidic devices has been widely illustrated in the
literature. Early works successfully demonstrate the applicability of biochips for
multiplexed real-time polymerase chain reaction(PCR)[Liu+04] and colorimetric
glucose assay for various bodily fluids [sri+03]. In [Fai+07], different applications
for biochips, such as massively parallel dNA analysis, real-time bio-molecular
detection and recognition are presented. In [HZC10], protein crystallization for
drug discovery and glucose measurement for blood serum are reported to have
successfully been implemented. Another area where biochips are of interest is
sample preparation [HLC12, Bha+17a, Bha+17b]. Using biochips, this tedious
O Springer International Publishing AG, part of Springer Nature 2019
O. Keszocze et al., Exact Design of Digital Microfluidic biochips,
https://doi.org/10.10077978-3-319-90936-3
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