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reversible volume changes in response to varying environmental conditions,
e.g. changes in pH, temperature, light, or electric fields. 21,30 Microfluidic
valves have been fabricated from thermally responsive 31 as well as pH sen-
sitive 30,32 hydrogels and self-regulating fluidic systems have been created
using pH sensitive hydrogels. 33 The disadvantage of using hydrogels is the
long response times, on the order of tens of seconds.
There are many examples of mechanical valves incorporated into
microfluidic systems, most of which involve the use of a deflectable mem-
brane that closes off a fluidic channel when pressure is applied. 21 Unger
et al. demonstrated pneumatically actuated valves using a cross-channel
architecture in which pressure applied to the upper channel deflects a
PDMS membrane downward closing the lower channel. 24 Such valves
offer a low dead volume, rapid response times, and their small size allows
for a high density of valves to be incorporated on one chip. However, to
achieve complete closure of the lower channel, bell-shaped channels are
required and the manufacturing procedure limits the aspect ratios pos-
sible. 34 In addition, low aspect ratios are necessary since otherwise, the
actuation pressures required would be impractically high. 35 Li et al. have
developed a normally closed microvalve allowing for vertical walls and a
variety of aspect ratios for portable microfluidic point-of-care devices 34
and Studer et al. have reported on a microfluidic valve requiring lower
actuation pressures facilitating the use of different aspect ratios. 35 Ismag-
ilov et al. developed an elastomeric switch involving two crossing chan-
nels in different layers. 36 Application of pressure to the crossing affected
the aspect ratio and thus the direction of fluid flow could be controlled.
As device complexity increases it is essential to be able to independently
actuate valves, which has lead to the development of a multiplexed latch-
ing valves system. 37
In all the above systems the valves are incorporated into the microflu-
idic system which ensures a low dead volume. However, the incorporation
of valves inside devices obviously increases the complexity of the system
and may complicate fabrication. An alternative strategy is to interface to
external valves. External valves integrated with microfluidic flow systems
have been used to control and pump fluid flows, 25 to generate sequential
exposures, 38-40 and to mix fluids. 25,38 Disadvantages with external valves
include large dead volumes and thus slow solution exchange times. A sys-
tem utilizing two external valves was developed to speed up exchange of
the dead volume. This system allows for easy interfacing to microfluidic
systems without the need for complex microfabrication. 5
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