<p>Microfluidics-based biochips combine electronics with biochemistry to open new application
areas such as point-of-care medical diagnostics, on-chip DNA analysis, automated drug
discovery and protein crystallization. Bioassays can be mapped to microfluidic arrays using
synthesis tools and they can be executed through the electronic manipulation of sample and
reagent droplets. The 2007 International Technology Roadmap for Semiconductors articulates
the need for innovations in biochip and microfluidics as part of functional diversification
("Higher Value Systems" and "More than Moore"). This document also highlights "Medical"
as being a System Driver for 2009
This thesis envisions an automated design flow for microfluidic biochips, in the same
way as design automation revolutionized IC design in the 80s and 90s. Electronic
design-automation techniques are leveraged whenever possible, and new design-automation
solutions are developed for problems that are unique to digital microfluidics. Biochip users
(e.g., chemists, nurses, doctors and clinicians) and the biotech/pharmaceutical industry will
adapt more easily to new technology if appropriate design tools and in-system automation
methods are made available.
The thesis is focused on a design automation framework that addresses optimization
problems related to layout, synthesis, droplet routing, testing, and testing for digital
microfluidic biochips. Optimization goal includes the minimization of time-to-response, chip
area, and test complexity. The emphasis here is on practical issues such as defects, fabrication
cost, physical constraints, and application-driven design. To obtain robust, easy-to-route chip
designs, a unified synthesis method has been developed to incorporate droplet routing and
defect tolerance in architectural synthesis and physical design. It allows routing-aware
architectural-level design choices and defect-tolerant physical design decisions to be made
simultaneously.
v
In order to facilitate the manufacture of low-cost and disposable biochips, design methods
that rely on a small number of control pins have also been developed. Three techniques have
been introduced for the automated design of such pin-constraint biochips. First, a
droplet-trace-based array partitioning method has been combined with an efficient pin
assignment technique, referred to as the "Connect-5 algorithm". The second pin-constrained
design method is based on the use of "rows" and "columns" to access electrodes. An efficient
droplet manipulation method has been developed for this cross-referencing technique. The
method maps the droplet-movement problem to the clique-partitioning problem from graph
theory, and it allows simultaneous movement of a large number of droplets on a microfluidic
array.
The third pin-constrained design technique is referred to as broadcast-addressing. This
method provides high throughput for bioassays and it reduces the number of control pins by
identifying and connecting control pins with "compatible" actuation sequences.
Dependability is another important attribute for microfluidic biochips, especially for
safety-critical applications such as point-of-care health assessment, air-quality monitoring,
and food-safety testing. Therefore, these devices must be adequately tested after manufacture
and during bioassay operations. This thesis presents a cost-effective testing method, referred
to as "parallel scan-like test", and a rapid diagnosis method based on test outcomes. The
diagnosis outcome can be used for dynamic reconfiguration, such that faults can be easily
avoided, thereby enhancing chip yield and defect tolerance. The concept of functional test for
digital biochip has also been introduced for the first time in this thesis. Functional test
methods address fundamental biochip operations such as droplet dispensing, droplet
transportation, mixing, splitting, and capacitive sensing.
To facilitate the application of the above testing methods and to increase their
effectiveness, the concept of design-for-testability (DFT) for microfluidic biochips has been
introduced in this thesis. A DFT method has been proposed that incorporates a test plan into
vi
the fluidic operations of a target bioassay protocol.
The above optimization tools have been used for the design of a digital microfluidic
biochip for protein crystallization, a commonly used technique to understand the structure of
proteins. An efficient solution-preparation algorithm has been developed to generate a
solution-preparation plan that lists the intermediate mixing steps needed to generate target
solutions with the required concentrations. A multi-well high-throughput digital microfluidic
biochip prototype for protein crystallization has also been designed.
In summary, this thesis research has led to a set of practical design tools for digital
microfluidics. A protein crystallization chip has been designed to highlight the benefits of this
automated design flow. It is anticipated that additional biochip applications will also benefit
from these optimization methods.</p> / Dissertation
| Identifer | oai:union.ndltd.org:DUKE/oai:dukespace.lib.duke.edu:10161/896 |
| Date | 11 December 2008 |
| Creators | Xu, Tao |
| Contributors | Chakrabarty, Krishnendu |
| Source Sets | Duke University |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
| Format | 2733322 bytes, application/pdf |
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