Hardware Reference
In-Depth Information
However, flash chemistry introduces the following challenges: (i) organic synthesis
procedures require the precise manipulation of liquids in small volumes [
1
]; (ii)
the underlying fast reactions (with time scale of less than a second) require highly
precise time-control in each step of chemical synthesis—a requirement that is
beyond the capability of today's benchtop laboratory instruments. These challenges
can be potentially tackled using miniaturized microfluidic biochips.
Digital (droplet-based) microfluidics is an emerging technology that enables the
integration of fluid-handling operations and reaction-outcome detection on a biochip
[
4
] and it is a potential candidate for the implementation of flash chemistry. Liquid
droplets with nanoliter or picoliter volumes in a digital microfluidic biochip can be
manipulated on an array of discrete unit cells [
5
]. Fluid-handling operations, such as
dilution of samples and reagents [
6
], transportation of droplets, and crystallization
of protein molecules [
7
], can be implemented on the biochip by applying appropriate
voltages to the electrodes [
4
,
8
]. The sequences of actuation voltages are pre-
determined (i.e., before the implementation of the fluid-handling operations), and
they are stored in a microcontroller or in computer memory [
9
]. Under clock control,
the microcontroller can transfer pre-loaded actuation data to the biochip, thereby
making it feasible for laboratory researchers to automatically execute chemical
experiments on the biochip. Precise control of the reaction times for each step
in the experiment can also be achieved [
4
]. Furthermore, operations implemented
on the biochip can be dynamically reconfigured by reprogramming the actuation
sequences [
4
]. The sequence of actuation voltages can be derived from bioassay
protocols using synthesis methods [
9
-
13
].
As discussed in Chap.
2
, in order to improve the qualify of product droplets, a
cyberphysical system implementation of a biochip has been recently proposed [
14
].
Despite of its novelty and advantages, the error-recovery method proposed in [
14
]
suffers from the following shortcomings:
1. It requires on-line re-synthesis, which involves software-based dynamic regener-
ation of electrode actuation sequences. Such a resynthesis step leads to increased
bioassay response times when errors occur [
14
]. When on-line re-synthesis is
carried out using software, all fluid-handling operations are interrupted. On the
other hand, the reaction time for flash chemistry lies in the range of milliseconds
to seconds. For example, in Swern-Moffatt-type oxidation, the reaction time is
approximately 10 ms at 20
ı
C[
2
]. For such organic synthesis, it is essential to
precisely control reaction time; these reactions will fail due to the additional time
introduced by re-synthesis [
1
,
3
]. Thus the cyberphysical system in [
14
] cannot
be used for flash chemistry.
2. The error recovery approach in [
14
] must be implemented by the control software
running on a computer, which increases the complexity of the cyberphysical
system. The computer-in-loop is not always desirable, e.g., for field deployment
and handheld devices.
3. The complex nature of the coupling between the biochip and the control software
may introduce reliability problems. The communication between the biochip
and the software is implemented using three components connected in series:
