U.S. patent application number 10/678342 was filed with the patent office on 2004-04-08 for electrically-conductive patterns for monitoring the filling of medical devices.
Invention is credited to Kermani, Mahyar Z., Ohara, Timothy J., Shartle, Robert Justice.
Application Number | 20040068165 10/678342 |
Document ID | / |
Family ID | 24154935 |
Filed Date | 2004-04-08 |
United States Patent
Application |
20040068165 |
Kind Code |
A1 |
Shartle, Robert Justice ; et
al. |
April 8, 2004 |
Electrically-conductive patterns for monitoring the filling of
medical devices
Abstract
A flexible diagnostic device has a measurement cell that is
sandwiched between the conductive surfaces of two conductive-coated
insulating layers. At least one of the conductive surfaces is
scored with an insulating pattern, so that the flow of a conductive
fluid sample into the cell can be monitored.
Inventors: |
Shartle, Robert Justice;
(Livermore, CA) ; Ohara, Timothy J.; (San Ramon,
CA) ; Kermani, Mahyar Z.; (Pleasanton, CA) |
Correspondence
Address: |
PHILIP S. JOHNSON
JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
24154935 |
Appl. No.: |
10/678342 |
Filed: |
October 3, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10678342 |
Oct 3, 2003 |
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09540319 |
Mar 31, 2000 |
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Current U.S.
Class: |
600/345 |
Current CPC
Class: |
G01N 27/3272
20130101 |
Class at
Publication: |
600/345 |
International
Class: |
A61B 005/05 |
Claims
We claim:
1. A medical diagnostic device for measuring an analyte
concentration of an electrically conductive biological fluid,
comprising a multilayer structure having a first layer and a second
layer sandwiching an intermediate layer, a) the first and second
layers each comprising an insulating sheet, having a conductive
surface adjoining the intermediate layer, b) the intermediate layer
being an insulating layer with a cutout, having a first end and a
second end, which, together with the first and second layers,
defines a flow channel to permit the sample to flow from the first
end to the second end, c) the flow channel comprising (i) a dry
reagent on the conductive surface of one of the layers for reacting
with the sample to yield a change in an electrical parameter that
can be related to the analyte concentration of the fluid and (ii)
an electrochemical cell, within which the electrical parameter is
measured, d) the conductive surface of one of the layers having a
first insulating pattern scored into its conductive surface to
divide the second layer into two regions, insulated from each
other, whereby sample that flows across the pattern provides a
conductive path from the first end to the second end.
2. The device of claim 1, in which the first end of the cutout is
at a first edge of the intermediate layer and the second end is at
a second edge of the intermediate layer, opposite the first
edge.
3. The device of claim 1, in which the dry reagent is on the
conductive surface of the first layer and the insulating pattern is
scored into the conductive surface of the second layer.
4. The device of claim 1, in which sample that enters the flow
channel at the first end flows through the electrochemical cell,
before it reaches the first insulating pattern.
5. The device of claim 1, in which the biological fluid is blood
and the analyte being measured is glucose.
6. The device of claim 1, in which the first and second layers each
comprise metallized thermoplastic sheets.
7. The device of claim 1, in which the intermediate layer comprises
a thermoplastic sheet having adhesive on both surfaces for adhering
to the first and second layers.
8. The device of claim 1, in which the reagent on the conductive
surface comprises a buffer, a mediator, and an enzyme.
9. The device of claim 1, in which the flow channel is a capillary
channel and the insulating pattern scored into the conductive
surface has at least one serration within the flow channel.
10. The device of claim 9, in which the insulating pattern has at
least one serration within the flow channel pointing toward each
end of the channel.
11. The device of claim 1, further comprising a second insulating
pattern scored into the conductive surface of the scored layer
between the first end and the first insulating pattern to divide
the scored layer into three regions, insulated from each other.
12. The device of claim 11, in which sample that enters the flow
channel at the first end reaches the second insulating pattern
before it flows through the electrochemical cell.
13. The device of claim 1, further comprising electrical circuit
means for detecting the flow of fluid through the flow channel.
14. A method for preparing an electrically-conductive pattern
comprising passing a web of a conductive-coated flexible insulator
between a cutting die and anvil, in which the cutting die has a
cutting element that is raised a height greater than the thickness
of the conductive coating for scoring through preselected portions
of the conductive coating.
15. The method of claim 14, in which the cutting die and anvil are
rollers.
16. The method of claim 14, in which the conductive coating has a
thickness in the range from about 5 to about 100 nm and the cutting
element is raised about one thousand times the coating thickness.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] This invention relates to a diagnostic device that has an
insulating pattern scored into a conductive coating on the device
to facilitate analytical measurements; more particularly, to
monitor filling of the device.
[0003] 2. Description of the Related Art
[0004] A variety of medical diagnostic procedures involve tests on
biological fluids, such as blood, urine, or saliva, to determine an
analyte concentration in the fluid. The procedures measure a
variety of physical parameters--mechanical, optical, electrical,
etc.,--of the biological fluid.
[0005] Among the analytes of greatest interest is glucose, and dry
phase reagent strips incorporating enzyme-based compositions are
used extensively in clinical laboratories, physicians' offices,
hospitals, and homes to test samples of biological fluids for
glucose concentration. In fact, reagent strips have become an
everyday necessity for many of the nation's estimated 16 million
people with diabetes. Since diabetes can cause dangerous anomalies
in blood chemistry, it can contribute to vision loss, kidney
failure, and other serious medical consequences. To minimize the
risk of these consequences, most people with diabetes must test
themselves periodically, then adjust their glucose concentration
accordingly, for instance, through diet, exercise, and/or insulin
injections. Some patients must test their blood glucose
concentration as often as four times or more daily.
[0006] One type of glucose measurement system operates
electrochemically, detecting the oxidation of blood glucose on a
dry reagent strip. The reagent generally includes an enzyme, such
as glucose oxidase or glucose dehydrogenase, and a redox mediator,
such as ferrocene or ferricyanide. This type of measurement system
is described in U.S. Pat. No. 4,224,125, issued on Sep. 23, 1980,
to Nakamura et al.; and U.S. Pat. No. 4,545,382, issued on Oct. 8,
1985, to Higgins et al., incorporated herein by reference.
[0007] Hodges et al., WO 9718464 A1, published on May 22, 1997,
discloses an electrochemical device for measuring blood glucose
that includes two metallized polyethylene terephthalate (PET)
layers sandwiching an adhesive-coated PET intermediate layer. The
metallized layers constitute first and second electrodes, and a
cutout in the adhesive-coated layer defines an electrochemical
cell. The cell contains the reagent that reacts with the glucose in
a blood sample. The device is elongated, and the sample is
introduced at an inlet on one of the long sides.
[0008] Nakai et al., U.S. Pat. No. 5,266,179, issued on Nov. 30,
1993, discloses an electrochemical system for measuring blood
glucose, in which the sample application time is determined by a
resistance drop between a pair of electrodes to which a constant
voltage was applied.
[0009] White et al., U.S. Pat. No. 5,366,609, issued on Nov. 22,
1994, describes the same principle of monitoring the resistance
drop between the electrodes to determine the time at which blood
was applied to a dry glucose reagent strip. In both patents, a
constant voltage is applied between working and reference
electrodes to track resistance changes that result from the
introduction of a blood sample to a dry reagent strip.
[0010] Accurately determining an analyte concentration generally
requires a sufficient supply of sample. Yoshioka et al., U.S. Pat.
No. 5,264,103, issued on Nov. 23, 1993, discloses a biosensor for
electrochemically measuring concentration of an analyte, such as
glucose, in a biological fluid. An impedance change indicates that
a sufficient supply of sample has been supplied to the sensor.
[0011] Littlejohn et al., U.S. Pat. No. 4,940,945, issued on Jul.
10, 1990, discloses a portable apparatus that can measure pH of a
blood sample. The apparatus detects the presence of a sample in a
cell by injecting a constant current between a fill electrode
outside the sample chamber and one of two electrodes inside the
chamber. When the impedance decreases by at least two orders of
magnitude, the meter recognizes that sufficient sample has been
provided and emits a beep. The fill electrode is then cut out of
the circuit that includes the two electrodes inside the sample
cell, and measurements are made potentiometrically.
[0012] Crismore et al., U.S. Pat. No. 5,997,817, issued on Dec. 7,
1999, discloses an electrochemical sensor strip that includes a
window through which a user can determine visually whether enough
sample has been applied to the strip.
[0013] None of the above references discloses a mechanism for
monitoring the movement of a blood sample into (and through) an
electrochemical cell.
SUMMARY OF THE INVENTION
[0014] This invention provides a medical diagnostic device for
measuring an analyte concentration of an electrically conductive
biological fluid. The device comprises a multilayer structure
having a first layer and a second layer sandwiching an intermediate
layer,
[0015] a) the first and second layers each comprising an insulating
sheet, having a conductive surface adjoining the intermediate
layer,
[0016] b) the intermediate layer being an insulating layer with a
cutout, having a first end and a second end, which, together with
the first and second layers, defines a flow channel to permit the
sample to flow from the first end to the second end,
[0017] c) the flow channel comprising (i) a dry reagent on the
conductive surface of one of the layers, for reacting with the
sample to yield a change in an electrical parameter that can be
related to the analyte concentration of the fluid, and
[0018] (ii) an electrochemical cell, within which the electrical
parameter is measured,
[0019] d) the conductive surface of one of the layers having a
first insulating pattern scored into its conductive surface to
divide the layer into two regions, insulated from each other,
whereby sample that flows across the pattern provides a conductive
path from the first end to the second end.
[0020] For convenience, we refer to "one of" the layers in the
above description and the claims, but we do not intend that phrase
to exclude "both" layers.
[0021] A method for preparing an electrically conductive pattern of
the present invention comprises passing a web of a
conductive-coated flexible insulator between a cutting die and
anvil, in which the cutting die has a cutting element that is
raised a height greater than the thickness of the conductive
coating for scoring through preselected portions of the conductive
coating.
[0022] The present invention provides a medical diagnostic device
that can easily sense when an adequate sample of a conductive
biological fluid has been introduced into the device, without
relying on the vision of the user. When the device measures glucose
concentration, the user generally has diabetes and is frequently
vision-impaired. In another embodiment, the invention provides a
method for preparing an element of the diagnostic device. The
method is well adapted for a high-speed, continuous line production
process.
BRIEF DESCRIPTION OF THE DRAWINGS.
[0023] FIG. 1 is an exploded perspective view of a device of the
present invention.
[0024] FIG. 2 is a plan view of another device of the present
invention.
[0025] FIG. 3A schematically depicts the operation of a stop
junction in stopping fluid flow through a capillary channel.
[0026] FIGS. 3B, and 3C schematically depict fluid flow through a
capillary channel of the device of FIG. 2.
[0027] FIG. 4 is a cross-section through the device of FIG. 2.
[0028] FIG. 5 is a block diagram of a fill-detection circuit of the
present invention.
[0029] FIG. 6 is an exploded perspective view of an alternative
embodiment of the device of FIG. 1.
[0030] FIG. 7 depicts an apparatus for practicing a method of the
present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0031] This invention relates to an electrochemical method of
measuring an analyte concentration of an electrically conductive
biological fluid. In the interest of brevity, the description below
emphasizes amperometrically measuring glucose concentration in
samples of whole blood; however, the person of ordinary skill in
the medical diagnostics art will recognize how the description can
be adapted to measure other analytes (such as cholesterol, ketone
bodies, alcohol, etc.) in other fluids (such as saliva, urine,
interstitial fluid, etc.)
[0032] The electrochemical (amperometric) method for measuring an
analyte concentration in an aqueous sample involves placing the
sample into an electrochemical cell that has at least two
electrodes and an impedance that is suitable for the amperometric
measurement. The analyte is allowed to react directly with an
electrode or with a redox reagent to form an oxidizable (or
reducible) substance in an amount that corresponds to the analyte
concentration. The quantity of oxidizable (or reducible) substance
is then determined electrochemically.
[0033] In order to obtain an accurate measurement of the substance,
it is important to assure that sufficient sample is provided to the
cell. For example, if the sample is insufficient, it can reduce the
effective electrode area and give an incorrect result. Assurance
that the sample is sufficient is provided by the device of this
invention, shown in FIG. 1.
[0034] FIG. 1 is an exploded view of an embodiment of multilayer
device 10. Top insulating sheet 12 has an electrically conductive
surface 14, which is typically a metal, plated on a surface of
insulating sheet 12 by vacuum deposition, sputtering,
electroplating, or any other suitable method for providing a
conductive surface, well known in the art. In from a longitudinal
edge of surface 14 is scored insulating line 16. Scored line 16
extends through the thickness of surface 14, to provide a gap in
the conductive path across the width of the device.
[0035] Intermediate insulating layer 18 is sandwiched between
conductive surface 14 of top insulating sheet 12 and conductive
surface 20 of bottom insulating sheet 22. Intermediate layer 18 is
preferably a thermoplastic sheet with adhesive on both surfaces for
adhering to sheets 12 and 22. Conductive surface 20 is typically a
metal plated on sheet 22 by one of the methods mentioned earlier.
Cutout 30 in intermediate layer 18 provides--between
conductive-coated sheets 12 and 22--inlet 32, outlet 34, and the
electrochemical cell 36 that lies between the inlet and outlet. An
optional serration 17 in scored line 16 enhances flow from inlet 32
to outlet 34, by a mechanism that is described later. Within
channel 30, a dry reagent, consisting of buffer, mediator, and
enzyme, is deposited on conductive surface 20 and/or, 14.
Electrochemical cell 36 is the region within which is measured an
electrical parameter of the fluid/reagent combination. The region
in which the reagent is coated generally, but not necessarily,
corresponds to the cell 36. For simplicity, that correspondence is
assumed in the description below. The reagent and electrochemical
cell 36 may be limited to the region between insulating line 16 and
the inlet 32. Alternatively, the reagent coating (and cell) may
extend over the entire cutout region between the edges of the
device.
[0036] FIG. 2 is a plan view of another embodiment of the device of
FIG. 1. The device 10' of FIG. 2 includes a second scored line 16A,
in from the other longitudinal edge of conductive surface 14. Thus,
the device of FIG. 2 is symmetrical, so that the sample can be
admitted from either edge; i.e., there is no distinction between
inlet and outlet. Score lines 16 and 16A divide conductive surface
14 into three regions--14A, 14B, and 14C--each insulated from the
other two. As is clear in FIG. 2, score lines 16 and 16A have
serrations 40 and 40A, respectively, that form angles, whose
vertices "point" to both edges of the device. The serrations are
provided to enhance flow through channel 30 in both directions, as
described below.
[0037] When fluid flows through a capillary channel, such as
channel 30, a discontinuity in channel cross section can form a
"stop junction," which can stop the fluid flow, as described in
U.S. Pat. Nos. 4,426,451; 5,230,866; and 5,912,134, incorporated
herein by reference. Score lines 16 and 16A create such cross
section discontinuities. The stop junction results from surface
tension that creates a back pressure that stops the fluid meniscus
from proceeding through the discontinuity. The stop junction is
weakened, and flow thereby enhanced, when the leading edge of the
meniscus encounters the vertex of an acute angle and is then
stretched along the arms of the angle. This may be described as the
angle "pointing" in a direction opposite to the direction of fluid
flow. This process may be better understood by reference to FIGS.
3A, 3B, and 3C.
[0038] FIG. 3A depicts the action of the stop junction when the
serration is absent. The fluid (flowing left-to-right in the
figure) is stopped at score line 16. A serration in score line 16
(such as serration 17 in FIG. 1) serves to weaken the stop junction
and facilitates flow through the scored region. Although serration
17 would weaken the stop junction, and thereby facilitate fluid
flow in both directions through capillary channel 30, the effect is
not the same for both directions.
[0039] FIGS. 3B and 3C show the fluid before and just after the
meniscus breaks through a stop junction having serrations whose
vertices point in opposite directions (like that of FIG. 2). Note
that the breakthrough occurs first at the vertex that "points"
opposite to the direction of fluid flow. The effectiveness of the
serration in enhancing flow through a stop junction in a capillary
channel depends on the angle and the length of the legs that form
the angle. The smaller the angle and the longer the legs, the
greater the effectiveness of the serration. Thus, if the angle is
small and the legs long, only a small hydraulic pressure
differential across the scored region will cause the sample to flow
through it.
[0040] FIG. 4 is a cross section along the line 4-4 of FIG. 2. As
is clear from FIG. 4, score lines 16 and 16A interrupt conductive
surface 14 and extend into insulating sheet 12. Conductive surface
14 is typically gold, and conductive surface 20 is typically
palladium, but each may alternatively be any other conductive
material that does not react with the reagent or sample and that
can be applied to an insulating surface. Suitable materials include
tin oxide, platinum, iridium, stainless steel, and carbon. The
thickness of the coating should at least be sufficient to provide
adequate. conductivity--generally, about. 10 ohms per square, or
less. Gold coatings are typically about 10-20 nm, palladium
typically about 20-40 nm. The conductive coatings preferably have a
hydrophilic overcoating to enhance filling when channel 30 is a
capillary channel. The overcoat must adhere to the conductive
coating but not react with the sample fluid. Insulating sheets 12
and 22 may be any suitable thermoplastic sheet, such as polyester,
polyethylene, polypropylene, polycarbonate, polyimide, etc.
Polyester of about 0.2 mm thickness is suitable and
inexpensive.
[0041] As seen in FIGS. 4 and 5, a fill-detection device 10' of the
type shown in FIG. 2 has available four discrete electrodes--14A,
14B, 14C, and 20. Thus, an electrochemical meter could, in
principle, measure the current or voltage output across six
different electrode pairs--14A, 20; 14B, 20; 14C, 20; 14A, 14B;
14B, 14C; and 14A, 14C. In a preferred embodiment, a meter
periodically (e.g., every 0.1 second) measures the voltages (at
constant current) across 14A, 20 and 14C, 20. In that way, the
meter detects sample entry and identifies which side of channel 30
the sample is entering. For example, if (conductive) sample enters
at the left edge, as shown in FIGS. 4 and 5, voltage 14A, 20 drops.
Thereafter, a drop in any of 14A, 14C; 14B, 14C.; or 14C, 20
voltages signals that the volume of channel 30 is filled between 16
and 16A. If the time to fill under normal conditions is known,
simple error trapping allows a strip to be rejected if fill time
exceeds a preset maximum. Similarly, if sample enters at the right
edge, voltage 14C, 20 drops, and a drop in 14A, 14C; 14A, 14B, or
14A, 20 signals that channel 30 is filled (at least beyond the
serration most distant from the sample entry).
[0042] Instead of, or in addition to, monitoring 14A, 20 and 14C,
20 to detect sample entry, 14A, 14B, and 14B, 14C could be
monitored to detect partial filling of channel 30. The time at
which the cell has filled is determined as described above.
[0043] Another alternative for monitoring partial filling is to
just measure voltage 14B, 20. That alternative requires less
switching and simple controls. By not requiring very rapid
switching there may also be a cost saving. The time at which the
cell has filled is then signaled by a drop in voltage 14A, 14C.
More generally, changes in current or voltage across one or more of
the pairs can be used to track the progress of sample into and
through the cell. Of course, if only a single score is used (as
shown in FIG. 1), there are only three discrete electrodes, and the
monitoring options are correspondingly reduced. Inversely, if
surface 20 is scored, instead of or in addition to 14, sample flow
can be monitored using other, or additional, voltage pairs.
[0044] FIG. 5 depicts a block diagram that shows circuitry which
can accomplish the fill detection described above. Initially, a
constant current source (101) is applied to one of the electrode
pair combinations, using switches 105 and 106. With no sample on
the strip, the resistances between all six electrode pairs are very
large, and the current passing through the strip is negligible. The
output voltage of voltage buffer 104(V) is high in this condition.
When sample bridges the gap of a monitored pair, the resistance and
voltage drop significantly. V then is fed to microcontroller 104
through analog-to-digital converter 103. Microcontroller 104,
recognizing this reduced voltage as sample detection, switches 105
and 106 to probe one of the other electrode pairs, to confirm that
the cell is filled.
[0045] FIG. 6 is an exploded perspective view of an alternative
embodiment of a device of this invention, in which sample is
applied to the end, rather than side, of the device. Top layer 112
has a coating 114 of a conductor, such as gold, on its underside.
The coating has insulating line 116 scored into the surface, and
serration 140 in score line 116 facilitates flow of sample into
channel 130 of insulating layer 118. Bottom layer 122 has a coating
120 of palladium, or other conductor. Electrical contact with
coating 120 is made through access hole 142 in top layer 112 and
gap 144 in insulating layer 118. Electrical contact with coating
114 is made through openings 146 in bottom layer 122 and gap 144 in
insulating layer 118. Electrochemical cell 136 is formed by channel
130 and the metal-coated top and bottom layers. Note that after the
device is assembled, through-hole 148 is punched through all three
layers to provide a vent in top layer 112 to permit filling of
channel 130 and to provide a stop junction at the distal end of the
channel (where hole 148 is cut into insulating layer 118). At the
same time, the proximal (open) end of the channel is cut, together
with the adjoining ends of layers 112 and 122. The two cuts, made
simultaneously in the assembled layers, provide accurate and
reproducible channel length, which in turn permits accurate and
reproducible measurements.
[0046] A device of the type described above can use a glucose
oxidase (GOD)/ferricyanide system to determine glucose
concentrations via the following reactions, in which GOD* is the
reduced enzyme.
glucose+GOD.fwdarw.gluconic acid+GOD* Reaction 1
GOD*+2ferricyanide.fwdarw.GOD+2ferrocyanide. Reaction 2
[0047] Ferricyanide ([Fe(CN).sub.6].sup.3-) is the mediator, which
returns the GOD* to its catalytic state. GOD, an enzyme catalyst,
will continue to oxidize glucose so long as excess mediator is
present. Ferrocyanide ([Fe(CN).sub.6].sup.4-) is the product of the
total reaction. Ideally, there is no ferrocyanide initially,
although in practice there is often a small quantity. After the
reaction is complete, the concentration of ferrocyanide (measured
electrochemically) indicates the initial concentration of glucose.
The total reaction, reaction 3, is the sum of reactions 1 and 2.
1
[0048] "Glucose" refers specifically to .beta.-D-glucose.
[0049] Details of this system are described in U.S. Pat. No.
5,942,102, issued on Aug. 24, 1999, and incorporated herein by
reference.
[0050] A second embodiment of the present invention is a method for
providing an electrically-conductive pattern on a conductive-coated
flexible insulator, such as sheet 12 of FIG. 2. An apparatus for
preparing a pattern such as that designated 16 and 16A in
conductive coating 14 is depicted in FIG. 7.
[0051] As shown in FIG. 7, web 42, comprising conductive coating 44
on flexible insulator 46 passes between anvil 48 and cutting die 50
to score selected areas of coating 44. The knife regions of die 50
are raised a height h, greater than the thickness of coating 44, so
that the cut areas become insulating regions in the coating.
However, the knife regions should not be raised so high that the
mechanical strength of insulator 46 is undermined. Preferably, the
knife height h is about one thousand to ten thousand times the
thickness of coating 44, depending on the uniformity and precision
of the tooling for cutting. Preferably, as shown, anvil 48 and
cutting die 50 are rollers that the web passes between.
[0052] Alternative methods for providing a pattern of score lines
in a conductive coating will be apparent to a person of ordinary
skill in the art. For example, if insulator 46 is deformable, then
standard relief patterning methods can be used, such as those used
in microreplication. (See, e.g., U.S. Pat. Nos. 5,642,015;
5,514,120; and 5,728,446.)
[0053] It will be understood by those skilled in the art that the
foregoing descriptions are illustrative of practicing the present
invention, but are in no way limiting. Variations of the detail
presented herein may be made, without departing from the scope and
spirit of the present invention.
* * * * *