Abstrict A flow meter enables a time-of-flight method for non-invasively
measuring liquid flow in a fluid conduit. The flow meter comprises
a perturbing element in the form of a phase changing device, a heat
transfer device, an electrochemical perturbing device or a photochemical
perturbing device, and a conductivity detection device spaced downstream
from the perturbing element. The perturbing element is applied to
a small section of the conduit to cause a perturbation in a portion
of the liquid flowing therethrough. This perturbation causes a change
in conductivity a liquid plug, and the affected liquid plug continuous
to flow in the fluid conduit toward the conductivity detection device.
The conductivity detection device then senses the change in conductivity
resulting from the perturbation, and flow rate or velocity is determined
from the time of detection and the distance between the point of
perturbation and the point of conductivity change detection.
Claims What is claimed is:
1. A liquid flow meter apparatus comprising: (a) a fluid conduit
including a non-conductive conduit wall; (b) a perturbing device
adapted to produce a localized perturbation in a liquid flowing
through a section of the fluid conduit; and (c) a conductivity detection
device disposed downstream of the perturbing device in relation
to the conduit wall.
2. The apparatus according to claim 1 wherein the conduit wall
is constructed from a fused silica material.
3. The apparatus according to claim 1 wherein the conduit wall
has an inside diameter of approximately 1 mm or less.
4. The apparatus according to claim 3 wherein the conduit wall
has an inside diameter of approximately 0.2 mm or less.
5. The apparatus according to claim 4 wherein the conduit wall
has an inside diameter of approximately 0.05 mm or less.
6. The apparatus according to claim 1 wherein the perturbing device
includes a phase changing device adapted to change the phase of
a portion of the liquid flowing through the fluid conduit.
7. The apparatus according to claim 6 wherein the phase changing
device includes a rapid cooling unit.
8. The apparatus according to claim 7 wherein the rapid cooling
unit includes a source of pressurized heat transfer fluid and an
outlet member adapted to emit at least a portion of the heat transfer
fluid toward a section of the fluid conduit.
9. The apparatus according to claim 6 wherein the phase changing
device includes a rapid heating unit.
10. The apparatus according to claim 1 wherein the perturbing device
includes a heat transfer device adapted to cause a transfer of heat
in a portion of the liquid flowing through a section of the fluid
conduit.
11. The apparatus according to claim 10 wherein the heat transfer
device includes a heating unit.
12. The apparatus according to claim 10 wherein the heat transfer
device includes a cooling unit.
13. The apparatus according to claim 1 wherein the perturbing device
includes an electrochemical perturbation device adapted to cause
an electrochemical perturbation in a portion of the liquid flowing
through a section of the fluid conduit.
14. The apparatus according to claim 13 wherein the electrochemical
perturbation device includes an electrode inserted into the fluid
conduit in contact with the liquid flowing through the fluid conduit.
15. The apparatus according to claim 1 wherein the perturbing device
includes a photochemical perturbation device adapted to cause a
photochemical perturbation in a portion of the liquid flowing through
a section of the fluid conduit.
16. The apparatus according to claim 15 wherein the photochemical
perturbation device includes a light-emitting device adapted to
direct light energy towards the section of the fluid conduit.
17. The apparatus according to claim 16 wherein the light-emitting
device includes a laser.
18. The apparatus according to claim 1 wherein the conductivity
detection device includes an AC signal source and first and second
electrodes connected to the AC signal source, wherein the first
and second electrodes are disposed adjacent to the conduit wall
and are axially spaced from each other.
19. The apparatus according to claim 18 wherein at least one of
the first and second electrodes is a metal band disposed coaxially
about the conduit wall.
20. The apparatus according to claim 18 wherein the conductivity
detection device includes an electrically isolating shield disposed
between the first and second electrodes.
21. The apparatus according to claim 18 wherein the first and second
electrodes are radially spaced from an outer surface of the conduit
wall to form a contactless conductivity detection device.
22. The apparatus according to claim 18 wherein the first and second
electrodes are at least partially disposed within the fluid conduit.
23. The apparatus according to claim 1 comprising an electronic
control device electrically communicating with the perturbing device
and the conductivity detection device and adapted to control respective
operations of the perturbing device and the conductivity detection
20 device.
24. A liquid flow meter apparatus comprising: (a) a fluid conduit
including a non-conductive conduit wall; (b) a perturbing device
adapted to produce a localized perturbation in a liquid flowing
through a section of the fluid conduit; (c) an AC signal source;
and (d) first and second electrodes connected to the AC signal source,
wherein the first and second electrodes are disposed adjacent to
the conduit wall downstream of the perturbing device and are axially
spaced from each other.
25. The apparatus according to claim 24 wherein the perturbing
device includes a phase changing device adapted to change the phase
of a portion of the liquid flowing through the fluid conduit.
26. The apparatus according to claim 24 wherein the perturbing
device includes a heat transfer device adapted to cause a transfer
of heat in a portion of the liquid flowing through a section of
the fluid conduit.
27. The apparatus according to claim 24 wherein the perturbing
device includes an electrochemical perturbation device adapted to
cause an electrochemical perturbation in a portion of the liquid
flowing through a section of the fluid conduit.
28. The apparatus according to claim 24 wherein the perturbing
device includes a photochemical perturbation device adapted to cause
a photochemical perturbation in a portion of the liquid flowing
through a section of the fluid conduit.
29. The apparatus according to claim 24 wherein the first and second
electrodes are radially spaced from an outer surface of the conduit
wall to form a contactless conductivity detection device.
30. A liquid flow meter apparatus comprising: (a) a fluid conduit
including a non-conductive conduit wall; (b) a phase changing device
adapted to change the phase of a portion of the liquid flowing through
the fluid conduit; and (c) a conductivity detection device disposed
adjacent to the conduit wall downstream of the phase changing device.
31. The apparatus according to claim 30 wherein the phase changing
device includes a rapid cooling unit.
32. The apparatus according to claim 30 wherein the conductivity
detection device includes an AC signal source and first and second
electrodes connected to the AC signal source, wherein the first
and second electrodes are disposed adjacent to the conduit wall
and are axially spaced from each other.
33. A liquid flow meter apparatus comprising: (a) a fluid conduit
including a non-conductive conduit wall; (b) a heat transfer device
adapted to cause a transfer of heat in a portion of the liquid flowing
through a section of the fluid conduit; and (c) a conductivity detection
device disposed adjacent to the conduit wall downstream of the heat
transfer device.
34. The apparatus according to claim 33 wherein the heat transfer
device includes a heating unit.
35. The apparatus according to claim 33 wherein the conductivity
detection device includes an AC signal source and first and second
electrodes connected to the AC signal source, wherein the first
and second electrodes are disposed adjacent to the conduit wall
and are axially spaced from each other.
36. A liquid flow meter apparatus comprising: (a) a fluid conduit
including a non-conductive conduit wall; (b) an electrochemical
perturbation device adapted to cause an electrochemical perturbation
in a portion of the liquid flowing through a section of the fluid
conduit; and (c) a conductivity detection device disposed adjacent
to the conduit wall downstream of the electrochemical perturbation
device.
37. The apparatus according to claim 36 wherein the electrochemical
perturbation device includes an electrode inserted into the fluid
conduit in contact with the liquid flowing through the fluid conduit.
38. The apparatus according to claim 36 wherein the conductivity
detection device includes an AC signal source and first and second
electrodes connected to the AC signal source, wherein the first
and second electrodes are disposed adjacent to the conduit wall
and are axially spaced from each other.
39. A liquid flow meter apparatus comprising: (a) a fluid conduit
including a non-conductive conduit wall; (b) a photochemical perturbation
device adapted to cause a photochemical perturbation in a portion
of the liquid flowing through a section of the fluid conduit; and
(c) a conductivity detection device disposed adjacent to the conduit
wall downstream of the photochemical perturbation device.
40. The apparatus according to claim 39 wherein the photochemical
perturbation device includes a light-emitting device adapted to
direct light energy towards the section of the fluid conduit.
41. The apparatus according to claim 39 wherein the conductivity
detection device includes an AC signal source and first and second
electrodes connected to the AC signal source, wherein the first
and second electrodes are disposed adjacent to the conduit wall
and are axially spaced from each other.
42. A method for measuring the velocity at which a liquid is flowing
through a fluid conduit comprising the steps of: (a) conducting
a liquid through a fluid conduit, the fluid conduit including a
non-conductive wall; (b) causing a volume of the liquid disposed
in a first section of the fluid conduit to undergo a perturbation;
and (c) at a second section of the fluid conduit spaced downstream
of the first section at a predetermined distance, detecting a change
in conductivity in the liquid occurring as a result of the perturbation.
43. The method according to claim 42 comprising the step of timing
the detection of the change in conductivity so as to occur at a
predetermined time after the perturbation.
44. The method according to claim 42 wherein the step of causing
the volume of liquid to undergo a perturbation includes causing
the volume of liquid to undergo a phase change.
45. The method according to claim 44 wherein the step of causing
the liquid volume to undergo a phase change includes directing a
rapidly evaporating heat transfer fluid toward the first section
of the fluid conduit.
46. The method according to claim 44 wherein the step of causing
the liquid volume to undergo a phase change includes causing at
least a portion of the liquid volume to change into a solid phase
by causing heat energy to be rejected out of the fluid conduit.
47. The method according to claim 44 wherein the step of causing
the liquid volume to undergo a rapid phase change includes causing
at least a portion of the liquid volume to change into a gas phase
by causing heat energy to be added into the fluid conduit.
48. The method according to claim 42 wherein the step of causing
the liquid volume to undergo a perturbation includes the step of
causing a transfer of heat to occur in at least of portion of the
liquid volume.
49. The method according to claim 48 wherein the step of causing
a transfer of heat to occur includes the step of adding heat energy
to the portion of the liquid volume.
50. The method according to claim 48 wherein the step of causing
the transfer of heat to occur includes the step of removing heat
energy from the portion of the liquid volume.
51. The method according to claim 42 wherein the step of causing
the liquid volume to undergo a perturbation includes the step of
causing an electrochemical perturbation in at least of portion of
the liquid volume.
52. The method according to claim 51 wherein the step of causing
the electrochemical perturbation includes the steps of placing an
electrode in contact with the liquid volume and energizing the electrode.
53. The method according to claim 42 wherein the step of causing
the liquid volume to undergo a perturbation includes the step of
causing a photochemical perturbation in at least of portion of the
liquid volume.
54. The method according to claim 53 wherein the step of causing
a photochemical perturbation includes the step of directing light
energy towards the liquid volume.
55. The method according to claim 42 wherein the step of detecting
a change in conductivity includes using a contactless conductivity
detection device.
56. The method according to claim 42 comprising the steps of providing
an AC signal source in electrical communication with at least two
electrodes, and placing the electrodes adjacent to the conduit wall
at the second section of the fluid conduit.
57. The method according to claim 42 wherein the step of detecting
the change in conductivity includes capacitively coupling an AC
signal between a first electrode and the liquid, and between a second
electrode and the liquid.
58. A method for measuring the velocity at which a liquid is flowing
through a fluid conduit comprising the steps of: (a) conducting
a liquid through a fluid conduit, the fluid conduit including a
non-conductive wall; (b) at a first section of the fluid conduit,
causing a displacement of ions in the liquid to produce a zone of
increased ionic concentration in the liquid and a zone of decreased
ionic concentration in the liquid; and (c) at a second section of
the fluid conduit spaced downstream of the first section at a predetermined
distance, detecting a change in conductivity in the liquid occurring
as a result of the ion displacement.
59. The method according to claim 58 wherein the step of causing
a displacement of ions includes causing a volume of the liquid disposed
in the first section of the conduit to undergo a phase change.
60. A method for measuring the velocity at which a liquid is flowing
through a fluid conduit comprising the steps of: (a) providing a
fluid conduit having a non-conductive wall; (b) causing a volume
of the liquid disposed in a first section of the fluid conduit to
undergo a perturbation; (c) providing an AC signal source; (d) at
a second section of the fluid conduit spaced downstream of the first
section at a predetermined distance, placing at least two electrodes
adjacent to the conduit wall and in electrical communication with
the AC signal source; and (e) capacitively coupling an AC signal
supplied from the AC signal source between the first electrode and
the liquid, and between the second electrode and the liquid.
61. A microfluidic device adapted to perform conductivity change
detection operations, the chip comprising: (a) a substrate; (b)
a fluid conduit formed on the substrate and including a non-conductive
conduit wall; (c) a perturbing device adapted to produce a localized
perturbation in a liquid flowing through a section of the fluid
conduit; and (d) a conductivity detection device including at least
two electrodes formed on the substrate, the at least two electrodes
disposed adjacent to the conduit wall and downstream of the section
or the fluid conduit at which the perturbation is produced.
62. A liquid flow monitoring and control apparatus comprising:
(a) a fluid conduit including a conduit wall; (b) a perturbing device
adapted to produce a localized perturbation in a liquid flowing
through a section of the fluid conduit; (c) a conductivity detection
device operatively disposed downstream of the perturbing device
in relation to the fluid conduit; (d) a comparator device electrically
communicating with the conductivity detection device and adapted
to compare a value indicative of measured flow rate with a value
indicative of preset flow rate; and (e) a flow rate adjustment device
operatively communicating with the comparator device.
Description TECHNICAL FIELD
[0001] The present invention relates generally to measuring of
liquid flow in fluid conduits. More specifically, the present invention
relates to non-invasive measuring of flow rate using time-of-flight
techniques involving the detection of conductivity change in the
liquid.
BACKGROUND ART
[0002] Capillaries constructed from fused silica, polymers and
other types of small-diameter tubes are utilized by scientists and
researchers for a variety of purposes. One example is the performance
of chemical separations for analytical purposes such as liquid chromatography.
As will be appreciated by those skilled in the art, there exists
a need to be able to monitor very low flow rates in real time inside
of capillaries and small tubes in order to improve reproducibility
in experimentation and analysis, and to troubleshoot problems commonly
arising in these types of conduits. Standard techniques for measuring
flow in large tubes are not applicable to smaller-scale tubes such
as capillaries with low flow rates.
[0003] Several methods presently exist for measuring flow rate
in capillaries, including time-of-flight flow monitoring with solvent
additive, thermal time-of-flight flow monitoring with refractive
index detection, and end-of-column solvent collection. Each of these
conventional approaches suffers from drawbacks.
[0004] Time-of-flight flow monitoring with solvent additive does
have several good characteristics. This technique can provide real-time
measurements and, in certain implementations, does not require capillary
modifications. There are, however, several disadvantages which limit
the usefulness of this technique. First, it requires that a marker
chemical be added to the solvent. Although this type of chemical
is selected to interfere as little as possible with the analytes
present in the column and with the chemistry occurring therein,
it is impossible for the chemical additive to have no interference
at all. The extra chemical present can also interfere with detection
methods, especially mass spectrometry, a technique which is gaining
in popularity as a detection method for microcolumn separations.
The marker chemical can interfere with the ionization process and
thus reduce the sensitivity of the detector. It is also likely that
the marker chemical shows up in the mass spectra to give extra,
unwanted peaks. Moreover, such solvent additives are typically detected
by fluorescence measurements or other optical techniques, all of
which are expensive and require precise alignment.
[0005] Thermal time-of-flight monitoring using a refractive index
detector is a viable technique which meets many of the requirements
for an ideal microcolumn flow sensor, but again there are several
disadvantages to employing this method. A refractive index detector
is a complex device which requires precise optical alignment, thus
making it impractical for routine use. In addition, this technique
often requires capillary modification in the form of an optical
window for the refractive index detector. The technique has not
been shown to perform with changing solvent conditions, such as
a solvent gradient, since every solvent change also changes the
refractive index. Moreover, the technique has not been shown to
function at the low flow rates commonly encountered in capillary
separation processes.
[0006] The technique of post-column collection of samples can be
used to measure flow rate by weighing the liquid eluting from the
tube. This procedure, however, is difficult to perform with small
capillaries due to the extremely low flow rates and rapid solvent
evaporation. Since this is a post-column technique, it cannot be
used with post-column detectors such as mass spectrometry. The technique
does not provide good real-time information, since a significant
amount of solvent from the column must be gathered before the measurement
can be obtained.
[0007] An ideal method for measuring flow rate in capillaries and
other small tubes has the properties of being simple, not requiring
capillary modification, not requiring solvent additives, giving
real-time measurements, and being compatible with advanced separation
and detection techniques such as those employed in mass spectrometry.
Accordingly, the desirability of such improvements over existing
flow metering technology can be readily appreciated by those skilled
in the art.
[0008] The present invention is provided to solve these and other
problems associated with the prior technology. As described hereinbelow,
the present invention is characterized in part by its use of a contactless
conductivity detection device. The use of contactless conductivity
detectors in conjunction with capillary electrophoresis has been
disclosed by Zemann et al. in "Contactless Conductivity Detection
for Capillary Electrophoresis," Analytical Chemistry, Vol.
70 No. 3 Feb. 1 1998 pp. 563-567 in which cationic and anionic
compounds are detected after capillary electrophoretic separation;
by Fracassi da Silva et al. in "An Oscillometric Detector for
Capillary Electrophoresis," Analytical Chemistry, Vol. 70
No. 20 Oct. 15 1998 pp. 4339-4343 in which an oscillometric
detection cell is developed; and by Mayrhofer et al. in "Capillary
Electrophoresis and Contactless Conductivity Detection of Ions in
Narrow Inner Diameter Capillaries," Analytical Chemistry, Vol.
71 No. 17 Sep. 1 1999 pp. 3828-3833 in which the detector disclosed
by Zemann et al. is further developed.
DISCLOSURE OF THE INVENTION
[0009] Broadly stated, the present invention is provided to meet
the need for accurate flow metering in fused silica capillaries,
polymer capillaries and other small tubes or channels in which low
flow rates typically occur, and to meet the ideal criteria delineated
hereinabove. The present invention provides an apparatus for measuring
low flow rates in capillaries in real time, without any modification
to the capillary itself and without the need for solvent additives.
The measuring apparatus provided in accordance with the present
invention is compatible with most known detectors, including post-column
detectors such as mass spectrometry. The real-time measurement of
flow rate performed by the present invention enables real-time control
of flow rate, thereby obtaining better results and reproducibility
than heretofore known.
[0010] In particular, the present invention can be successfully
and advantageously applied to small diameter capillaries and other
tubes or channels, although it will be understood that application
of the present invention is not limited to such systems. For purposes
of the present invention and convenience, the term "capillary"
as used herein is taken to mean any type of fluid conduit, such
as a tube or a channel, having a small diameter. Preferably, the
inside diameter of the capillary is approximately 1 mm or less.
More preferably, the inside diameter is approximately 0.2 mm or
less or, even more preferably, 0.05 mm or less.
[0011] The present invention can further be characterized as providing
several variations of a time-of-flight method. Each method utilizes
a device or component that produces a localized perturbing effect
in a flowing liquid, and a conductivity detection device for detecting
a change in conductivity resulting from the perturbation or disturbance.
One specific embodiment can be characterized as an ionic concentration
differential time-of-flight method, which utilizes a phase changing
element in conjunction with a conductivity detection device. The
phase changing element is applied to a small section of a capillary
to rapidly change a portion of the liquid flowing therethrough into
the solid or gas phase, which subsequently reverts back to the liquid
phase. This rapid phase change causes ions to be displaced within
the capillary. The conductivity detection device, which preferably
is of the contactless type and is positioned downstream of the phase
changing element, then senses a change in conductivity resulting
from the displacement of ions in the liquid or solution flowing
through the capillary. Other specific embodiments, described more
fully hereinbelow, can be characterized as thermal, electrochemical
and photochemical time-of-flight methods, respectively.
[0012] Since the flow monitoring device provided by the present
invention does not require optical components (although optical
means could be used to carry out some of the perturbing processes
described hereinbelow), it can be made smaller than other types
of monitoring devices. The device can be made small enough to be
integrated onto a microchip if desired. The device requires no precise
alignment or expensive components, thus rendering the device more
robust and inexpensive in comparison to devices which require optics.
Moreover, the device according to the present invention does not
depend as heavily on the internal diameter of the capillary as do
devices which rely on optical methods.
[0013] As will be appreciated by those skilled in the art, the
real-time monitoring provided by the present invention of flow rate
in capillaries or other small-diameter tubes is important for reproducibility,
and allows a feedback system which can maintain a constant flow
rate even with varying solvent and/or temperature conditions. The
capabilities provided by the present invention allow for faster,
more reproducible separations and make some separation techniques
more practicable. One example is capillary electrophoresis (CE).
CE has become fairly common in the past few years, but many persons
skilled in the art have cited poor reproducibility as a deterrent
to switching from liquid chromatography or other methods. The poor
reproducibility observed by those skilled in the art is due mainly
to ambient temperature fluctuations which cause a change in flow
rate. The flow metering device provided in accordance with the present
invention, however, allows for much greater reproducibility by either
adjusting the flow rate through feedback or by simply informing
the user of the current flow rate so that an adjustment can be made.
[0014] In one exemplary implementation, an instrument provided
in accordance with the present invention can be utilized as a stand-alone
device for measuring flow rate in capillaries or other small tubes
such as capillary chromatography columns. The present invention
can successfully function in conjunction with fused silica capillaries,
polymer capillaries as well as other non-conductive tubing.
[0015] In another implementation, the device according to the present
invention can be integrated into a system to function as part of
a flow rate control loop.
[0016] Yet another implementation relates to the current interest
in chip-based separations in which "lab-on-a-chip" devices
are being developed. A flow sensor provided in accordance with the
present invention can be integrated with a micro-fluidic device
to monitor flow and provide diagnostics. Because the inventive device
can be completely electrical in operative nature, the device can
be built into the chip without any external components, thus making
the device quite inexpensive and robust.
[0017] According to one embodiment of the present invention, a
liquid flow meter apparatus comprises a fluid conduit including
a non-conductive conduit wall, a perturbing device, and a conductivity
detection device. The perturbing device is adapted to produce a
localized perturbation in a liquid flowing through a section of
the fluid conduit. The conductivity detection device is disposed
adjacent to the conduit wall downstream of the perturbing device.
In a preferred embodiment, a contactless conductivity detection
device is provided wherein electrodes are disposed outside the conduit
wall.
[0018] According to another embodiment of the present invention,
a liquid flow meter apparatus comprises a fluid conduit including
a non-conductive conduit wall, a perturbing device adapted to produce
a localized perturbation in a liquid flowing through a section of
the fluid conduit, and an AC signal source. The first and second
electrodes are connected to the AC signal source. The first and
second electrodes are disposed adjacent to the conduit wall downstream
of the perturbing element and are axially spaced from each other.
[0019] According to yet another embodiment of the present invention,
a liquid flow meter apparatus comprises a fluid conduit including
a non-conductive conduit wall, a phase changing device, and a conductivity
detection device disposed adjacent to the conduit wall downstream
of the phase changing device. The phase changing device is adapted
to change the phase of a portion of the liquid flowing through the
fluid conduit.
[0020] According to still another embodiment of the present invention,
a liquid flow meter apparatus comprises a fluid conduit including
a non-conductive conduit wall, a heat transfer device, and a conductivity
detection device disposed adjacent to the conduit wall downstream
of the heat transfer device.
[0021] The heat transfer device is adapted to cause a transfer
of heat in a portion of the liquid flowing through a section of
the fluid conduit.
[0022] According to a further embodiment of the present invention,
a liquid flow meter apparatus comprises a fluid conduit including
a non-conductive conduit wall, an electrochemical perturbation device,
and a conductivity detection device disposed adjacent to the conduit
wall downstream of the electrochemical perturbation device. The
electrochemical perturbation device is adapted to cause an electrochemical
perturbation in a portion of the liquid flowing through a section
of the fluid conduit.
[0023] According to a still further embodiment of the present invention,
a liquid flow meter apparatus comprises a fluid conduit including
a non-conductive conduit wall, a photochemical perturbation device,
and a conductivity detection device disposed adjacent to the conduit
wall downstream of the photochemical perturbation device. The photochemical
perturbation device is adapted to cause a photochemical perturbation
in a portion of the liquid flowing through a section of the fluid
conduit.
[0024] According to an additional embodiment of the present invention,
a method is provided for measuring the velocity or the rate at which
a liquid is flowing through a fluid conduit. A liquid is conducted
through a fluid conduit which includes a non-conductive wall. A
volume of the liquid disposed in a first section of the fluid conduit
is caused to undergo a perturbation. At a second section of the
fluid conduit spaced downstream of the first section at a predetermined
distance, a change in conductivity in the liquid is detected. This
conductivity change occurs as a result of the perturbation. The
perturbation produced by the present invention can involve an ionic
concentration differential resulting from a change in the phase
of the liquid, a thermal effect, an electrochemical effect, or a
photochemical effect.
[0025] According to another embodiment of the present invention,
a method is provided for measuring the velocity or the rate at which
a liquid is flowing through a fluid conduit. A liquid is conducted
through a fluid conduit which includes a non-conductive wall. At
a first section of the fluid conduit, a displacement of ions is
caused in the liquid to produce a zone of increased ionic concentration
in the liquid and a zone of decreased ionic concentration in the
liquid. At a second section of the fluid conduit spaced downstream
of the first section at a predetermined distance, a change in conductivity
in the liquid is detected. This change in conductivity occurs as
a result of the ion displacement.
[0026] According to still another embodiment of the present invention,
a method is provided for measuring the velocity or the rate at which
a liquid is flowing through a fluid conduit. A fluid conduit having
a non-conductive wall is provided. A volume of the liquid disposed
in a first section of the fluid conduit is caused to undergo a perturbation.
An AC signal source is provided. At a second section of the fluid
conduit spaced downstream of the first section at a predetermined
distance, at least two electrodes are placed adjacent to the conduit
wall and in electrical communication with the AC signal source.
An AC signal supplied from the AC signal source is capacitively
coupled between the first electrode and the liquid, and between
the second electrode and the liquid.
[0027] According to a further embodiment of the present invention,
a "lab-on-a-chip" or a microfluidic device is adapted
to perform conductivity change detection operations. The chip comprises
a substrate, a fluid conduit formed on the substrate, and a conductivity
detection device including at least two electrodes formed on the
substrate. The fluid conduit preferably includes a non-conductive
conduit wall. A perturbing device is provided for producing a localized
perturbation in a liquid flowing through a section of the fluid
conduit. The electrodes of the conductivity detection device are
disposed adjacent to the conduit wall.
[0028] According to a still further embodiment of the present invention,
a liquid flow monitoring and control apparatus comprises a fluid
conduit including a conduit wall, a perturbing device, a conductivity
detection device, a comparator device electrically communicating
with the conductivity detection device, and a flow rate adjustment
device operatively communicating with the comparator device. The
perturbing device is adapted to produce a localized perturbation
in a liquid flowing through a section of the fluid conduit. The
conductivity device is operatively disposed downstream of the perturbing
device in relation to the fluid conduit. The comparator device is
adapted to compare a value indicative of measured flow rate with
a value indicative of preset flow rate.
[0029] It is therefore an object of the present invention to provide
an accurate liquid flow metering apparatus adapted to operate non-invasively
on fluid conduits.
[0030] It is another object of the present invention to provide
a non-invasive flow-metering apparatus which is particularly advantageous
in measuring low flow rates typically encountered in capillaries
and other small-diameter tubes.
[0031] Some of the objects of the invention having been stated
hereinabove, other objects will become evident as the description
proceeds when taken in connection with the accompanying drawings
as best described hereinbelow.
BRIEF DESCRIPTION OF THE DRAWINGS
[0032] FIG. 1 is a schematic diagram of a flow metering apparatus
provided in accordance with the present invention;
[0033] FIG. 2A is a schematic diagram illustrating an example of
a phase changing process accomplished by the present invention,
in which a burst of cold fluid is applied to a capillary;
[0034] FIG. 2B is a schematic diagram illustrating the phase changing
process, in which a portion of the liquid in the capillary freezes
and ions are displaced;
[0035] FIG. 2C is a schematic diagram illustrating the phase changing
process, in which the frozen portion of the liquid in the capillary
melts and results in a zone of lower ionic concentration;
[0036] FIGS. 3A, 3B and 3C are respective sequential schematic
diagrams of the flow metering apparatus illustrated in FIG. 1 during
operation thereof;
[0037] FIG. 4A is a schematic diagram of a contactless conductivity
detection device provided as part of the flow metering apparatus
illustrated in FIG. 1 during operation thereof, illustrating the
capacitive coupling of an AC signal to the core of a capillary;
[0038] FIG. 4B is a schematic diagram of the contactless conductivity
detection device during operation thereof, illustrating the conduction
of the AC signal through the core of the capillary;
[0039] FIG. 4C is a schematic diagram of the contactless conductivity
detection device during operation thereof, illustrating the capacitive
coupling of the AC signal out of the core of the capillary;
[0040] FIG. 5 is a schematic diagram of an equivalent electrical
circuit modeling the conductivity detection device illustrated in
FIGS. 4A, 4B, and 4C;
[0041] FIG. 6 is a schematic diagram of a testing arrangement set
up for purposes of evaluating of the flow metering apparatus illustrated
in FIG. 1;
[0042] FIG. 7 is an output trace produced as a result of the operation
of the flow metering apparatus;
[0043] FIG. 8 is a plot of linear velocity of the liquid flowing
through the capillary, as measured by the flow metering apparatus,
as a function of fluid pressure;
[0044] FIG. 9 is a plot of the volumetric liquid flow rate of the
liquid flowing through the capillary, as measured by a testing apparatus,
as a function of fluid pressure and obtained for the purpose of
validating the operation of the flow metering apparatus;
[0045] FIG. 10 is a plot of linear velocity calculated from the
flow rate measured by the testing apparatus referred to in FIG.
9 versus linear velocity measured by the flow metering apparatus;
[0046] FIG. 11 is a schematic diagram of a flow metering apparatus
provided in accordance with another embodiment of the present invention;
[0047] FIG. 12 is a schematic diagram of the flow metering apparatus
provided in accordance with yet another embodiment of the present
invention;
[0048] FIG. 13 is a topological diagram of a chip or a region thereof
in which a flow metering apparatus is integrated in accordance with
the present invention; and
[0049] FIG. 14 is a schematic diagram illustrating an application
of the present invention providing real-time control of flow rate
in a capillary electrophoresis process.
DETAILED DESCRIPTION OF THE INVENTION
[0050] Referring now to FIG. 1 a non-limiting example is illustrated
of a flow metering apparatus, generally designated 10 according
to the present invention. Flow metering apparatus 10 is designed
to non-invasively measure liquid flow rate in real-time inside of
fused silica or other non-conductive capillaries (as defined hereinabove)
by means of a localized perturbation caused in the liquid flowing
in the capillary. This perturbation generally flows with the liquid
for a period of time before dissipating or returning to equilibrium.
Hence, the perturbation or its effect on the liquid can be detected
through the positioning of an appropriate detection device spaced
downstream at a suitable distance from the point at which the perturbation
is caused. Flow metering apparatus 10 can be broadly described as
a liquid flow meter comprising two primary components: a perturbing
element, generally designated 20 and a conductivity detection device
(or conductivity detector), generally designated 30. Conductivity
detector 30 preferably has a contactless design and thus is non-invasive
with respect to the liquid or its conduit. Flow metering apparatus
10 operates in conjunction with a capillary 50 whose capillary wall
52 defines a generally cylindrical, hollow capillary core 54 through
which a liquid 56 flows. Such liquid 56 could be a solution, a solvent,
or some other type of fluid. In FIG. 1 the direction of fluid is
arbitrarily illustrated by the arrow as being from left to right.
Conductivity detection device 30 is disposed at a location downstream
of perturbing element 20. A computer or other electronic processing
device 40 and any associated control and/or signal conditioning
and amplification circuitry can be provided to communicate with
both perturbing element 20 and conductivity detector 30 over electrical
lines 42 and 44 respectively, and thus coordinate the timing of
the respective functions of perturbing element 20 and conductivity
detector 30.
[0051] In one embodiment, flow metering apparatus 10 measures liquid
flow rate based on an ion displacement due to a temporary phase
change deliberately caused in the liquid flowing in capillary 50.
In this embodiment, perturbing element 20 is provided in the form
of a phase changing element which, for purposes of describing the
present embodiment, will also be designated 20 as shown in FIG.
1.
[0052] Phase changing element 20 is provided in the form of a heating
or cooling unit adapted to induce a phase change in a volume or
plug of liquid 56 flowing through capillary 50 at some region of
capillary 50. That is, phase changing element 20 can alternatively
be provided as a rapid heating unit capable of boiling liquid 56
in capillary 50 or as a rapid cooling unit capable of at least
partially freezing liquid 56. Several types of rapid heating or
cooling units could be provided to serve as phase changing element
20. Non-limiting examples of suitable means for effecting rapid
heating include providing an external heat source, dielectric heating,
microwave heating, inductive heating, and light absorption. Non-limiting
examples of suitable means for effecting rapid cooling include spraying
refrigerated liquid, Joule-Thompson cooling, and using Peltier cooling
devices. In the broad context of the present invention, the exact
mechanism used is not important, so long as the phase change can
be effected rapidly to a small section of capillary 50 and then
be rapidly returned to the liquid phase.
[0053] The rapid heating or cooling of liquid 56 in capillary 50
creates a sharp ionic concentration boundary in the heated or cooled
liquid plug, and thereby facilitates detection. Due to the short
section of capillary 50 involved in the phase change operation and
the rapid heat transfer of small conduits, the phase change can
be a short event which does not greatly affect other processes occurring
in capillary 50. Indeed, it is preferable to heat or cool the liquid
for only a short amount of time in order to allow repeated measurements
to be performed quickly.
[0054] The operation of phase changing element 20 is illustrated
generally in FIGS. 2A-2C. Referring specifically to FIG. 2A, in
order for flow metering apparatus 10 to measure flow rate, phase
changing element 20 is activated for a short amount of time to either
freeze or boil a small plug of liquid 56 flowing in capillary 50.
In the specific embodiment illustrated, a burst of cold fluid 61
has been applied to capillary 50. Referring to FIG. 2B, the liquid
plug is subject to indirect thermal contact with the cold burst
primarily through a combination of conductive and convective heat
transfer modes. Consequently, at least a portion 63 of the liquid
plug temporarily freezes into a solid phase. This phase change process
displaces ions present in the liquid plug. Referring to FIG. 2C,
the solid phase material melts soon thereafter. The rapid phase
change occurring during this process causes a region or zone of
higher ionic concentration in solution 56 to form either before
or after liquid plug, and a region or zone of lower ionic concentration
generally within the central vicinity of liquid plug itself. In
FIG. 2C, the region of lower ionic concentration is generally designated
65 and the region of higher ionic concentration is generally designated
67. In the case where the liquid plug temporarily freezes, it is
believed at the present time that salts are separated out from the
liquid plug and lead to the creation of zone of higher ionic concentration
67.
[0055] Referring to FIG. 3A, contactless conductivity detection
device 30 having first been positioned downstream of phase changing
element 20 is activated after the phase change occurs. This activation
may be accomplished by providing a timer or clock (for example,
using computer 40 in FIG. 1) that is initiated upon operation of
phase changing element 20. As shown in FIG. 3B, region 65 of lower
ionic concentration associated with the melted liquid plug continues
to flow through capillary 50 toward conductivity detector 30. Due
to the regions of higher and lower ionic strength now residing in
capillary 50 when these regions reach conductivity detector 30
as shown in FIG. 3C, conductivity detector 30 can detect the change
in conductivity resulting from this ionic strength differential.
By accurately knowing the distance between phase changing element
20 and conductivity detector 30 the flow rate of the liquid can
be calculated from the period of time the differing ionic regions
take to traverse this distance.
[0056] Referring to FIGS. 4A-4C, contactless conductivity detection
device 30 includes an AC signal source 32 electrically coupled by
lead wires 34A and 34B, respectively, to two electrodes 36A and
36B disposed in proximity to each other and mounted adjacent to
the outside of capillary wall 52. Electrodes 36A and 36B are spaced
at a distance from each other, and preferably are provided in the
form of metallic bands or tubes which are coaxially disposed about
capillary wall 52. Contactless conductivity detection device 30
essentially functions by applying an AC signal to these electrodes
36A and 36B, and by capacitively coupling the AC voltage to conductive
solution 56 across the dielectric material which forms capillary
wall 52. A shield 38 is preferably interposed between electrodes
36A and 36B to reduce their direct capacitive coupling to each other.
In preferred embodiments, shield 38 is constructed from a brass
or copper material.
[0057] While the non-invasive, contactless design described hereinabove
for conductivity detection device 30 is preferred, it will be understood
that the electrodes employed in the present invention could be installed
through capillary wall 52 such that the ends of the electrodes are
in direct contact with solution 56.
[0058] As a result of the design of contactless conductivity detection
device 30 and the dielectric properties of capillary wall 52 the
AC signal is capacitively coupled between electrode 36A and the
conductive liquid in capillary core 54. Referring specifically to
FIG. 4A, this capacitive coupling is depicted by arrow A. Referring
to FIG. 4B, a potential difference is established within capillary
core 54 and causes a current to be conducted through the liquid
in the direction generally represented by arrow B. Referring to
FIG. 4C, when the current reaches the vicinity of other electrode
36B, the AC signal is capacitively coupled out as depicted by arrow
C. Since the capacitance of capillary wall 52 remains fairly constant,
the conductivity of the liquid between the two electrodes 36A and
36B is measured without direct contact or the need to perform modifications
to capillary 50.
[0059] Referring to FIG. 5 the equivalent circuit for conductivity
detector 30 is illustrated. AC signal source 32 is placed in parallel
with the electrical resistance of the solution flowing through capillary
50. This resistance is represented by a resistor R.sub.solution.
Given that resistance varies with temperature and is inversely related
to conductance, the present invention could be characterized as
being adapted to measure the value for resistor R.sub.solution.
The capacitance of capillary wall 52 at each electrode 36A and 36B
is represented by capacitor C.sub.wall, and is placed in series
with each lead connection of AC signal source 32. This capacitance
accounts for the capacitance of that portion of capillary wall 52
between electrode 36A or 36B and conductive solution 56. As described
hereinabove, capillary wall 52 is constructed from a non-conductive
material such as silica glass. Capillary wall 52 is therefore a
dielectric material which, rather than conducting current, can only
allow electrical charges to accumulate on electrode 36A or 36B and
in adjacent solution 56. AC signal source 32 is also placed in parallel
with a capacitor C.sub.cylinder. This circuit element accounts for
both the direct capacitance of capillary wall 52 (i.e., electrode
36A through capillary wall 52 to electrode 36B) and the capacitance
of capillary wall 52 plus that of solution 56 (i.e., electrode 36A
through capillary wall 52 through solution 56 through capillary
wall 52 to electrode 36B). Under most conditions, the magnitude
of capacitor C.sub.cylinder will be negligible in comparison to
the magnitude of capacitor C.sub.wall.
EXAMPLE
[0060] FIG. 6 illustrates an initial test setup for exemplary flow
metering apparatus 10 with an arrangement of primary components
employed therefor. Phase changing element 20 is provided in the
form of a rapid cooling unit. Phase changing element 20 generally
includes a vessel 22 containing a supply of pressurized heat transfer
fluid and a solenoid valve 24 in fluid communication therewith.
Actuation of solenoid valve 24 is controlled by an appropriate control
signal fed over an electrical line 42 from a computer or other suitable
electronic processing device 40. The output side of solenoid valve
24 fluidly communicates with a heat transfer fluid ejection component
26 which could be a nozzle or orifice. Ejection component 26 is
directed at a section of capillary 50 where the phase change is
desired to occur, which in the present example may be termed a freezing
point FP of capillary 50. A suitable rapid cooling unit is a GUST
AIR DUSTER.TM. unit, which is commercially available from Stoner
Company in Quarryville, Pa. The operation of this particular cooling
unit is based on the extremely fast expansion and evaporation of
the initially compressed heat transfer fluid out of ejection component
26 which causes a rapid rejection of heat energy out of the liquid
in capillary 50 at freezing point FP according to known thermodynamic
principles.
[0061] Capillary 50 has a 110 cm length and 50 .mu.m inner diameter.
One end of capillary 50 is connected to a pressurized reservoir
71 which supplies a buffered solution or other liquid to be transported
through capillary 50. In this particular test setup, a distal end
73 of capillary 50 conducts liquid to waste. Conductivity detector
30 is disposed with its electrodes 36A and 36B operatively positioned
with respect to capillary 50 as described hereinabove with reference
to FIGS. 4A-4C. In this particular test setup, conductivity detector
30 is accurately spaced at a known distance from freezing point
FP. In order to time the respective operations of phase changing
element 20 and conductivity detector 30 conductivity detector 30
communicates with computer 40 over an electrical line 44.
[0062] A test run utilizing the arrangement described hereinabove
can be conducted as follows. A small amount of heat transfer fluid
stored in vessel 22 is sprayed onto a short section of capillary
50 i.e., at freezing point FP. The ejected heat transfer fluid
quickly evaporates, freezing this section of capillary 50 in the
process. The output from conductivity detector 30 is then monitored
for the peak and trough values which respectively indicate the regions
of high and low ionic strength in the liquid flowing through capillary
50.
[0063] FIG. 7 illustrates an example of a typical output trace
generated by conductivity detector 30 as a result of the phase change
occurring at freezing point FP upstream of conductivity detector
30. The output trace is a plot of voltage in microvolts as a function
of time in seconds, with the "0" value on the x-axis corresponding
to the time of activation of phase changing element 20. The output
trace includes a point 81 at which the freezing pulse was applied,
and a point 83 at which flow resumed. The output trace describes
a region of increased ionic strength, generally designated 85 under
the peak value, and a region of decreased ionic strength, generally
designated 87 above the trough value.
[0064] The peak travel times from several trial runs at six different
fluid pressures (10 12 15 18 20 and 25 psi) are listed in Table
1 below. For the test runs corresponding to the first three pressures,
the spacing between conductivity detector 30 and freezing point
FP was 7 cm. For the test runs corresponding to the last three pressures,
the spacing was 7.3 cm. Values for standard deviation and percent
standard deviation are also given in Table 1 for each group of test
runs corresponding to each pressure. In order to obtain more reproducible
results, capillary 50 was held in a heated brass block to accelerate
the thawing of the frozen section of capillary 50. This addition
decreased the standard deviation of the measurements to less than
1%, and made data analysis much easier due to the increased sharpness
in the output signal.
1TABLE 1 Distance Pressure Time (sec) (mm/sec) (cm) 10 22.6 3.10
Stdev 7 10 22.6 3.10 0.01 10 22.6 3.10 % Stdev 10 22.6 3.10 0.40
10 22.4 3.13 15 12.4 5.65 Stdev 15 12.3 5.69 0.05 15 12.1 5.79 %
Stdev 15 12.2 5.74 0.87 15 12.3 5.69 15 12.3 5.69 15 12.4 5.65 20
8.8 7.95 Stdev 20 8.7 8.05 0.08 20 8.6 8.14 % Stdev 20 8.65 8.09
1.04 20 8.7 8.05 20 8.6 8.14 20 8.5 8.24 20 8.6 8.14 12 17.65 4.14
Stdev 7.3 12 17.6 4.15 0.02 12 17.5 4.17 % Stdev 12 17.65 4.14 0.42
12 17.5 4.17 12 17.6 4.15 12 17.45 4.18 12 17.55 4.16 18 10.45 6.99
Stdev 18 10.45 6.99 0.09 18 10.4 7.02 % Stdev 18 10.25 7.12 1.32
18 10.25 7.12 18 10.1 7.23 18 10.15 7.19 18 10.2 7.16 25 7.4 9.86
Stdev 25 7.3 10.00 0.10 25 7.2 10.14 % Stdev 25 7.25 10.07 0.99
25 7.3 10.00 25 7.3 10.00 25 7.3 10.00 25 7.3 10.00 25 7.2 10.14
25 7.25 10.07 25 7.3 10.00 25 7.25 10.07 25 7.1 10.28
[0065] FIG. 8 is a graph of data corresponding to Table 1 showing
linear velocity in mm/sec measured by flow metering apparatus 10
as a function of pressure in psi. FIG. 8 demonstrates the good linearity
of the test results.
[0066] in order to validate these measured flow rates, the volumetric
flow through capillary 50 was measured by connecting a small syringe
to the output of capillary 50 and recording the amount of time required
for the meniscus to move a certain distance. Again, capillary 50
illustrated in FIG. 6 was used, with a length of 110 cm, an inner
diameter of 50 .mu.m, and a cross-sectional flow area of about 2.0E-05
cm.sup.2. This validation procedure was performed several times
at three different pressures. The data are given in Table 2 below.
2TABLE 2 Calculated Calculated Linear Pressure Time Volume Flow
Rate Velocity Travel time (psi) (sec) (.mu.L) (.mu.L/min) (mm/sec)
(sec) 15 194 2.5 0.773 6.6 7.7 15 202 2.5 0.743 6.3 15 157 2 0.764
6.5 20 85 1.5 1.059 9.0 5.5 20 140 2.5 1.071 9.1 20 83 1.5 1.084
9.2 30 34.8 1 1.724 14.6 3.4 30 140 4 1.714 14.6
[0067] FIG. 9 is a graph corresponding to Table 2 demonstrating
the linearity of the results. A comparison of the measured linear
velocities in FIG. 8 to the calculated linear velocities based on
the measured volumetric flow rate in FIG. 9 shows a good correlation,
which indicates that flow metering apparatus 10 successfully and
accurately measures flow rates as intended.
[0068] In FIG. 10 the linear velocities measured with flow metering
apparatus 10 are compared to the linear velocities calculated from
the measured volumetric flow rate. This direct comparison illustrates
that flow metering apparatus 10 is functioning as intended, and
helps to counter inaccuracies in other measurements. If the pressure
gauge used to supply the gas pressure to give the flow were inaccurate,
then this would cause errors in all the calculations of flow rates
based on this reading. If, however, the flow rate is measured using
two different methods which use the same (and possibly erroneous)
pressure measurement, these two numbers can be directly compared
to each other. This is because the problematical value is the same
in each case and will affect each calculation in the same way. This
comparison of measure linear velocities should generate a straight
line with a slope of 1. In the comparison shown in FIG. 10 the
slope using these two methods does indeed generate a slope of very
nearly 1--specifically, 1.0221.
[0069] It should be noted that because the inventive technique
described hereinabove is based on detecting a plug of solvent having
a different ionic strength than that of the balance of the solvent,
ions must be present in the solvent. If, for instance, the solvent
is de-ionized water or a non-polar organic liquid, then there would
not be enough ions present to detect the small change that the inventive
flow sensor detects. The solvent must also contain a component that
is either easily vaporized or frozen in order to create a plug of
different ionic strength. The present invention has been successfully
practiced in conjunction with aqueous solvents with different ions
and additives, which solvents are used in approximately ninety percent
of the chromatography procedures performed.
[0070] It should also be noted that the inventive technique requires
that the liquid in the capillary undergo a phase change. This phase
change requires a temperature very different from the ambient air.
Such a temperature change could have detrimental effects on any
analytes present. Freezing has been found to be much gentler on
analytes than heating. Freezing, however, introduces the possibility
of freezing the entire plug of liquid in the capillary, which event
would briefly stop the flow. While freezing does need to occur,
the entire plug does not need to be frozen and the liquid does not
need to stay frozen for a significant length of time. Accordingly,
if excessive freezing is observed to be a problem in a given application
of the present invention, the problem can be overcome with the addition
of a heater to rapidly thaw the capillary or with more precise timing
that prevents full freezing in the first place.
[0071] Referring back to FIG. 1 in addition to the above-described
ionic concentration differential time-of-flight technique, the present
invention can also be implemented as a thermal time-of-flight technique.
In this embodiment, perturbing element 20 is provided in the form
of a heating or cooling unit which, on a localized basis, adds heat
to the liquid plug or removes heat from the liquid plug but in either
case does not transfer enough energy to effect a phase change. The
conductivity of the liquid is a function of temperature, and thus
any temporary change in conductivity resulting from the heating
or cooling pulse applied to the liquid plug can be rapidly detected
by conductivity detector 30.
[0072] Referring now to FIG. 11 a further embodiment of the present
invention is illustrated in which an electrochemical time-of-flight
technique is implemented. In this embodiment, perturbing element
20 is provided in the form of one or more electrodes 91 inserted
directly into capillary 50 in contact with solution 56. A discrete
pulse of electrical energy supplied from an electrical source 95
causes an electrochemical disturbance in a localized region of solution
56. One effect of this disturbance is a change in conductivity in
the liquid plug, which can be detected by conductivity detector
30.
[0073] Referring to FIG. 12 an additional embodiment of the present
invention is illustrated in which a photochemical time-of-flight
technique is implemented. In this embodiment, perturbing element
20 is provided in the form of a light source 91 such as a laser
that directs a pulse of light energy hv at the liquid plug flowing
through capillary 50. As a consequence of the photochemical disturbance
caused by perturbing element 20 in this embodiment, the liquid plug
undergoes a change in conductivity which is detected by conductivity
detector 30.
[0074] Referring to FIG. 13 a simplified topology of a "lab-on-a-chip"
device, generally designated 100 such as a microfluidic device,
is illustrated. In accordance with this embodiment of the present
invention, flow metering apparatus 10 according to any of the embodiments
described hereinabove has been integrated onto a substrate 102.
Substrate 102 represents either a full layer of chip device 100
or at least a region thereof. One or more reservoirs 104A-104D are
formed on or in substrate 102 and are interconnected by fluid channels
106A-106D. In a non-limiting example, reservoir 104A receives and
contains an analyte sample of interest, reservoir 104B receives
and contains a solvent, reservoir 104C receives collects waste,
and reservoir 104D serves as an outlet. In this case, fluid channel
106D serves a function similar to that of fluid conduit or capillary
50 illustrated in FIGS. 1 and 2. Additionally, electrodes 36A and
36B and their respecting lead connections 34A and 34B, as part of
conductivity detector 30 are integrated onto substrate 102 either
in the arrangement shown in FIG. 13 or in that shown in FIG. 4.
Perturbing element 20 in one of the forms described hereinabove,
is also integrated in or on chip in order to produce a controlled
perturbation effect in a liquid plug flowing through capillary 50
at a point of perturbation 108. A highly miniaturized liquid flow
meter is thereby provided. Chip device 100 and its associated components
as described herein can be fabricated and assembled according to
principles known to those skilled in the art.
[0075] Referring now to FIG. 14 flow metering apparatus 10 can
be implemented as a flow sensor for real-time control of liquid
flow rate in any number of applications. In the specific, non-limiting
example illustrated in FIG. 14 flow metering apparatus 10 is utilized
to monitor and control liquid flow rate during capillary electrophoresis
(CE) runs. In the basic arrangement illustrated, capillary 50 runs
from a buffer supply reservoir 121 or equivalent component, through
flow metering apparatus 10 including its associated components as
described for the several embodiments hereinabove, and to a waste
reservoir 123 or equivalent component. As understood by those skilled
in the art of CE techniques, wires 125 and 127 run from a high-voltage
power supply 129 to the solutions in reservoirs 121 and 123 respectively,
to apply a voltage potential across capillary 50. Control of flow
rate is enabled by providing a comparator 131 and associated circuitry,
or its equivalent, and an interface 133 and associated circuitry
for establishing a set point for the flow rate. Comparator 131 communicates
with flow metering apparatus 10 over electrical line 135 with set
point interface 133 over electrical line 137 and with power supply
129 over electrical line 139.
[0076] Flow metering apparatus 10 monitors flow rate in capillary
50 according to one of the methods disclosed hereinabove, produces
a signal indicative of the measured flow rate, and sends this signal
to comparator 131. At predetermined time intervals, the signal for
measured flow rate is compared to the set point signal received
from set point interface 133. If the actual measured flow rate has
deviated from the desired set point, an error or tolerance value
is established in a manner known by those skilled in system control
and circuit design, and a control signal is generated to make the
adjustment needed to bring the actual flow rate back to the desired
set point value. For instance, a control signal can be sent over
electrical line 139 to power supply 129 to change the applied voltage
and thus the flow rate. In other situations, a control signal would
be provided to adjust fluid pressure or a pump or any other means
by which liquid is caused to flow through capillary 50.
[0077] It should be noted that conductivity detection device 30
when provided in its contactless form, only works with tubes that
are non-conductive. Many of the columns and connecting tubes currently
used are made of stainless steel which would not allow this device
to be used. These limitations are inherent in the operation of the
device and cannot be overcome unless a non-conductive section of
capillary or tubing is installed.
[0078] It will be understood that various details of the invention
may be changed without departing from the scope of the invention.
Furthermore, the foregoing description is for the purpose of illustration
only, and not for the purpose of limitation--the invention being
defined by the claims. |