U.S. patent application number 13/819064 was filed with the patent office on 2014-02-27 for lateral flow assay analysis.
The applicant listed for this patent is Stanley E. Charm, Paul E. Graham, Robert J. Markovsky, Richard T. Skiffington. Invention is credited to Stanley E. Charm, Paul E. Graham, Robert J. Markovsky, Richard T. Skiffington.
Application Number | 20140057362 13/819064 |
Document ID | / |
Family ID | 45724064 |
Filed Date | 2014-02-27 |
United States Patent
Application |
20140057362 |
Kind Code |
A1 |
Markovsky; Robert J. ; et
al. |
February 27, 2014 |
LATERAL FLOW ASSAY ANALYSIS
Abstract
Lateral flow assay analysis is shown and described. In one
embodiment, the lateral flow assay comprises a surface having a
reflectance profile that is adapted to enable monitoring of the
assay continuously until the detection of an analyte. In other
embodiments, a lateral flow assay system includes an incubator and
a reader, wherein the incubator incubates the assay concurrently as
the reader generates a test result. Further, an assay measurement
apparatus may include an optical detector to perform continuous
image detection of the assay to generate a diagnostic test
result.
Inventors: |
Markovsky; Robert J.;
(Brentwood, NH) ; Charm; Stanley E.; (Boston,
MA) ; Graham; Paul E.; (Dracut, MA) ;
Skiffington; Richard T.; (North Reading, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Markovsky; Robert J.
Charm; Stanley E.
Graham; Paul E.
Skiffington; Richard T. |
Brentwood
Boston
Dracut
North Reading |
NH
MA
MA
MA |
US
US
US
US |
|
|
Family ID: |
45724064 |
Appl. No.: |
13/819064 |
Filed: |
August 25, 2011 |
PCT Filed: |
August 25, 2011 |
PCT NO: |
PCT/US11/49170 |
371 Date: |
November 11, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61377287 |
Aug 26, 2010 |
|
|
|
61454771 |
Mar 21, 2011 |
|
|
|
Current U.S.
Class: |
436/171 ;
422/82.05 |
Current CPC
Class: |
G01N 21/8483 20130101;
G01N 2201/0627 20130101; G01N 21/75 20130101; G01N 21/78
20130101 |
Class at
Publication: |
436/171 ;
422/82.05 |
International
Class: |
G01N 21/75 20060101
G01N021/75 |
Claims
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2. An assay measurement apparatus to generate a diagnostic test
result from an assay, said apparatus comprising: a. an optical
detector aligned in an optical path with said assay, wherein said
optical detector is adapted to acquire an image detection on said
assay due to an aberration on said assay; and b. a microprocessor
in communication with said optical detector, wherein said
microprocessor is adapted to signal said optical detector to
perform continuous image detection of said assay to generate said
diagnostic test result.
3. The apparatus of claim 2, wherein said optical detector
comprises a decoding sensor adapted to align with said assay and
decode a reference coding on said assay.
4. The apparatus of claim 3, wherein said reference coding
activates a corresponding diagnostic test in said optical
detector.
5. The apparatus of claim 3, wherein said apparatus includes a
multichannel reader and said reference coding activates a
corresponding channel in said multichannel reader.
6. The apparatus of claim 5, wherein said corresponding channel
includes an associated feature chosen from a standard curve, a
does-response curve, a positive cutoff value, a negative cutoff
value and a combination thereof.
7. The apparatus of claim 3, wherein said apparatus includes an
incubator and said reference coding activates a corresponding
incubation temperature.
8. The apparatus of claim 3, wherein said decoding sensor is a
color sensor.
9. The apparatus of claim 8, wherein said color sensor is a
photodiode with sensitivity to wavelengths chosen from red, blue,
green and a combination thereof.
10. The apparatus of claim 3, wherein said decoding sensor is
reader chosen from an RFID reader, a bar code reader and a
combination thereof.
11. The apparatus of claim 2, including a light source.
12. The apparatus of claim 11, wherein said light source is an
array of discrete light sources.
13. The apparatus of claim 12, wherein said discrete light sources
comprise light emitting diodes.
14. The apparatus of claim 11 wherein said light emitting diodes
are colored diodes chosen from red, green, blue and a combination
thereof.
15. The apparatus of claim 11, wherein said light source comprises
an illumination profile suitable for reflecting on a test strip
assay.
16. The apparatus of claim 11, wherein said light source is aligned
with a light aperture exposing said light source on said assay.
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22. The apparatus of claim 3, wherein said optical detector will
not generate a test result until said decoding sensor decodes said
reference coding.
23. The apparatus of claim 2, wherein said optical detector is a
light-to-voltage sensor.
24. The apparatus of claim 2, wherein said optical detector
comprises a photodiode coupled to an integrated circuit in said
optical path with said assay.
25. The apparatus of claim 24, wherein said integrated circuit is a
monolithic integrated circuit.
26. The apparatus of claim 2, wherein said optical detector
includes an amplifier.
27. The apparatus of claim 26, wherein the amplifier is a
translucence amplifier.
28. The apparatus of claim 2, including a memory adapted to store
information corresponding to an imaging parameter for said image
detection.
29. The apparatus of claim 2, including a decoding sensor chosen
from a color sensor, a RFID reader, a bar code reader and a
combination thereof.
30. The apparatus of claim 2, wherein said optical detector
includes an optical window adapted to block debris from contact
with said optical detector.
31. The apparatus of claim 2, wherein said optical detector
includes an optics housing to enclose said optical detector and is
adapted to block debris from contact with said optical
detector.
32. The apparatus of claim 2, wherein said optical detector
monitors a diagnostic test progress.
33. The apparatus of claim 32, wherein said optical detector
monitors a pre-test parameter prior to generating a diagnostic test
result.
34. The apparatus of claim 32, wherein said optical detector
monitors at least one pre-test parameter after said optical
detector has acquired at least one image detection on said
assay.
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102. A method of detecting an analyte from an assay, the method
comprising: a. aligning an optical detector in an optical path with
said assay; b. acquiring an image detection on said assay due to an
aberration on said assay; and c. signaling said optical detector to
perform continuing image detection of said assay to generate said
test result.
103. The method of claim 102, wherein signaling said optical
detector includes instructing said optical detector to monitor a
pre-test analysis on said assay.
104. The method of claim 103, wherein instructing said optical
detector to monitor said pre-test analysis includes decoding a
reference coding on said assay.
105. The method of claim 104, including activating a corresponding
channel in a multichannel reader.
106. The method of claim 104, including activating an incubation of
said assay.
107. The method of claim 102, wherein signaling said optical
detector includes instructing said optical detector to generate
said test result.
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198. A lateral flow assay system to generate a test result from an
assay, said system comprising: a. an incubator adapted to incubate
said assay; and b. a reader adapted to read a diagnostic test on
said assay that undergoes a change when contacted with a sample to
generate said test result, wherein said incubator incubates said
assay concurrently as said reader generates said test result.
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221. The apparatus of claim 198, wherein said reader performs
continuous image detection of said assay to generate said test
result.
222. The apparatus of claim 221, wherein said continuous image
detection includes monitoring a pre-flow development along said
assay.
223. The apparatus of claim 198, wherein said reader includes a
light source oriented in a predetermined pattern with respect to
said assay.
224. The apparatus of claim 223, wherein said light source includes
a first mirror below said light source.
225. The apparatus of claim 224, wherein said light source includes
a focusing lens adapted to receive light from said first
mirror.
226. The apparatus of claim 225, wherein said light source includes
a second mirror positioned to direct light from the focusing lens
to said reader.
227. The apparatus of claim 198, wherein said reader includes a
sensor.
228. The apparatus of claim 227, wherein said sensor is an optical
detector aligned with a light source for detecting transmission of
light through said assay.
229. The apparatus of claim 227, wherein said sensor is a decoding
sensor.
230. The apparatus of claim 229, wherein said decoding sensor
adapted to decode at least one reference code having a
corresponding testing sequence on said assay.
231. The apparatus of claim 198, wherein said reader includes
multiple channels.
232. The apparatus of claim 231, wherein each said channel includes
an associated feature chosen from a standard curve, a does-response
curve, a positive cutoff value, a negative cutoff value and a
combination thereof.
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Description
[0001] This application is based on and claims priority to
PCT/US2011/49170, filed Aug. 25, 2011; U.S. provisional application
No. 61/377,287, filed Aug. 26, 2010 and U.S. provisional
application No. 61/454,771, filed Mar. 21, 2011, all of which are
incorporated herein by reference in their entireties.
FIELD OF THE TECHNOLOGY
[0002] The present disclosure relates generally to analytical
testing, and more particularly to improved detection of an analyte
in a lateral flow assay.
BACKGROUND
[0003] Reagent strips and films are often a helpful analytical tool
in the fields of clinical chemistry, analytical medicine and food
sanitation diagnostics. For example, it is advantageous to
determine or to test, through quantitative or qualitative methods,
various matrices, including body fluids such as serum and urine,
and food, such as meat products, fruit, vegetables, milk, honey and
the like. Such matrices can be tested for a variety of analytes
including a variety of chemicals, biochemicals and biological
molecules such as bacteria, antibiotics, for example, sulfa drugs,
tetracyclines, beta-lactam drugs; toxins, such as aflatoxin,
zearalonone, ochratoxin, T-2, and vomitoxin, pesticides such as
organophosphates and carbamates, and active metabolites, either in
materials or on the surface of materials or a combination
thereof.
[0004] Generally, lateral flow assays are membrane-based test
devices in which a sample that is suspected of containing the
analyte of interest is placed at or near one end of the membrane
strip. The sample is carried to the opposite end of the membrane
strip by a mobile phase that traverses the membrane strip, for
example by capillary action. While traversing the membrane strip,
the analyte in the test sample, if any, encounters one or more
reagents. The reagents can include binders for the analyte. Binders
can be mobile and, therefore, flow with the sample, or be
immobilized on the test strip as a capture agent. Depending on the
test configuration, either the analyte binder, the analyte itself,
or some other reagent in the test system will be captured by the
immobilized capture agent and, thereby, produce a detectable
signal. The signal can be generated by a label provided within the
assay. The detectable signal can be measured, such as by an optical
reader.
[0005] The presence and, in some cases, the concentration, of an
analyte on a reagent strip may be determined by measuring the
optical reflectance from an area of development on the strip. For
example, the area of development on the strip may be an area of
color development. Percent reflectance can be used to determine the
result.
[0006] Testing commonly occurs in a controlled environment, such as
a laboratory, but testing in non-laboratory settings is also
common. In some applications speed and ease of use is particularly
important. For example, in food processing it would be advantageous
for tests to be run in non-laboratory settings because processors
must wait for results. Further, it would also be advantageous for
tests to be run on trucks during transport of the items. For that
reason, it would be advantageous to accelerate the speed of
testing, reduce the cost of equipment and tests, improve the
ruggedness of the apparatus, and enhance the ease of use and
simplicity of operation. In addition, it is advantageous to have
confidence that test results are valid. Therefore, systems, methods
and devices herein also assist in preventing fraudulent use of
pre-run, known negative assays in place of true samples or use of
assays pre-marked to provide a negative result that does not
reflect the true nature of the sample. It is also desirable to
increase the ruggedness of the assays, systems and test
procedures.
[0007] Therefore, Applicants desire systems and methods for analyte
detection without the drawbacks presented by traditional lateral
flow assay systems and methods.
SUMMARY
[0008] This disclosure provides improved analyte detection that is
convenient, efficient, and safe for the user, particularly when
used to simplify test operation, improve test reliability, improve
test ruggedness, improve testing speed, reduce the possibility of
mistakes, reduce the chances of incorrect results from dirt/debris
contamination, and reduce the options for trickery and mistake by
limiting operator (human) interaction and/or dynamically assessing
assay, including test strip, development during testing.
[0009] In one embodiment, an assay measurement apparatus to
generate a diagnostic test result from an assay includes an optical
detector and a microprocessor. The optical detector may be aligned
in an optical path with said assay. The optical detector may be
adapted to acquire an image detection on said assay due to an
aberration on said assay. The microprocessor may be in
communication with said optical detector. The microprocessor may be
adapted to signal said optical detector to perform continuous image
detection of said assay to generate said diagnostic test
result.
[0010] The optical detector may comprise a decoding sensor that is
adapted to align with said assay and decode a reference coding on
said assay. The reference coding may activate a corresponding
diagnostic test in said optical detector. The apparatus may include
a multichannel reader and said reference coding may activate a
corresponding channel in said multichannel reader. The apparatus
may include an incubator and said reference coding may activate a
corresponding incubation temperature.
[0011] The decoding sensor may be a color sensor. The color sensor
may be a photodiode with sensitivity to wavelengths chosen from
red, blue, green and a combination thereof. The decoding sensor may
be an RFID reader. The decoding sensor may be a bar code
reader.
[0012] In one example, the apparatus includes a light source. The
light source may be an array of discrete light sources. For
instance, the discrete light sources may comprise one light
emitting diode and/or multiple light emitting diodes. The light
emitting diodes may be colored diodes chosen from red, green, blue
and a combination thereof. The light source may comprise an
illumination profile suitable for reflecting on a test strip assay.
The light source may be aligned with a light aperture, exposing
light from said light source on said assay. A first mirror may be
below said light aperture. A focusing lens may receive light from
said first mirror. A second mirror may be positioned to direct
light from said focusing lens to said optical detector. A lighting
processor may be adapted to trigger said light source to emit light
for a desired pattern. The lighting processor may include data
storage for said desired light-emission pattern.
[0013] In another example, the optical detector will not generate a
test result until said decoding sensor decodes said reference
coding. The optical detector may be a light-to-voltage sensor. The
optical detector may comprise a photodiode in said optical path
with said assay coupled to an integrated circuit. The integrated
circuit may be a monolithic integrated circuit. The optical
detector may include an amplifier. The amplifier may be a
translucence amplifier.
[0014] The apparatus may include a memory adapted to store
information corresponding to an imaging parameter for said image
detection. The decoding sensor may be chosen from a color sensor, a
RFID reader, a bar code reader and a combination thereof. The
optical detector may include an optical window that is adapted to
block debris from contact with said optical detector. The optical
detector may include an optics housing to enclose said optical
detector and that is adapted to block debris from contact with said
optical detector. The optical detector may monitor a diagnostic
test progress. The optical detector may monitor a pre-test
parameter prior to generating a diagnostic test result. The optical
detector may monitor at least one pre-test parameter after said
optical detector has acquired at least one image detection on said
assay.
[0015] In another embodiment, in an assay measurement apparatus
having an imaging detector and a microprocessor, a memory that is
in communication with said microprocessor and is adapted to store
information corresponding to an imaging parameter. The memory may
include an instruction for monitoring a pre-test analysis on said
assay. The memory may include an instruction for generating a
diagnostic test result on said assay. The pre-test parameter may
include a theoretical reflectance value.
[0016] In one example, the assay may include at least one test line
and at least one control line, and whereby said theoretical
reflectance value is a comparison between a reflectance value at
said test line and a reflectance value at said control line. A
reflectance value on said assay that is inconsistent with said
theoretical reflectance value may indicate an inadequate flow on
said assay. The inadequate flow may trigger a detectable signal to
generate a no-result response. The reflectance value on said assay
that is inconsistent with said theoretical reflectance value may
indicate a prior analyte development on said assay. The reflectance
values may suggest prior analyte development may trigger a
detectable signal to deactivate said assay measurement apparatus.
The reflectance value on said assay that is inconsistent with said
theoretical reflectance value may indicate a contaminated optical
path.
[0017] The contaminated optical path may trigger a detectable
signal to generate a no-result response. The instruction for
generating a test result may correspond to an image detection on
said assay. The image detection may be an optical reflectance value
or a transmission value. The assay may include at least one test
line and at least one control line, and whereby said optical
reflectance value is a comparison between a reflectance value at
said test line and a reflectance value at said control line. The
apparatus may be adapted to perform a continuous image detection of
said assay. The assay may be a lateral flow assay. The assay may
also be a lateral, capillary-flow, elongated test strip.
[0018] The test result may be determined within about thirty
seconds of optical detector activation. The test result may be
determined within about sixty seconds of optical detector
activation. The apparatus may include a power source. The power
source may be a vehicle battery. Further, the optical detector may
be in communication with an onboard vehicle system.
[0019] In other embodiments, an assay measurement apparatus to
generate a test result from an assay may include an imaging
detector and a microprocessor with an associated memory in
communication with said microprocessor. The imaging detector may be
adapted to decode a reference coding on said assay and to acquire
an image detection on said assay due to an aberration on said
assay. The microprocessor may be adapted to signal said imaging
detector to generate said test result. The memory may be in
communication with said microprocessor and may be adapted to store
information corresponding to a plurality of imaging parameters. The
memory may include a parameter for monitoring a pre-test analysis
on said assay. The memory may include a parameter for generating
said diagnostic test result from said assay.
[0020] A reference coding may activate a corresponding diagnostic
test in said optical detector. A multichannel reader and said
reference coding may activate a corresponding channel in said
multichannel reader. The apparatus may include an incubator and
said reference coding may activate a corresponding incubation
temperature.
[0021] The imaging detector may be adapted to decode said test
reference coding and comprise a decoding sensor. The decoding
sensor may be a color sensor. The color sensor may be a photodiode
with sensitivity to wavelengths chosen from red, blue, green and a
combination thereof. The decoding sensor may be an RFID reader. The
decoding sensor may also be a bar code reader.
[0022] Typically, the apparatus includes a light source. The light
source may be an array of discrete light sources. The discrete
light sources may comprise light emitting diodes. The light
emitting diodes may be colored diodes chosen from red, green, blue
and a combination thereof. The light source may comprise an
illumination profile suitable for reflecting on a test strip assay.
The light source may be aligned with a light aperture exposing said
light source on said assay. The light source may include a first
mirror below said light aperture. A focusing lens may receive light
from said first mirror. A second mirror may be positioned to direct
light from said focusing lens to said optical detector. A lighting
processor may be adapted to trigger said light source to emit light
for a desired pattern. The lighting processor may include data
storage for said desired light-emission pattern. The optical
detector may not generate a test result, or even initiate reading
of the test, until said decoding sensor decodes said reference
coding.
[0023] The optical detector may be a light-to-voltage sensor. The
optical detector may comprise a photodiode coupled to an integrated
circuit in said optical path with said assay. The integrated
circuit may be a monolithic integrated circuit. The optical
detector may include an amplifier. The amplifier may be a
translucence amplifier. The optical detector may include an optical
window that is adapted to block debris from contact with said
optical detector. The optical detector may also include an optics
housing to enclose said optical detector and that is adapted to
block debris from contact with said optical detector.
[0024] In some examples, the optical detector may monitor a
diagnostic test progress. The optical detector may monitor a
pre-test parameter prior to generating a diagnostic test result.
Further, the optical detector may monitor at least one pre-test
parameter after said optical detector has acquired at least one
image detection on said assay. The pre-test parameter may include a
theoretical reflectance value. The assay may include at least one
test line and at least one control line, and whereby said
theoretical reflectance value is a comparison between a reflectance
value at said test line and a reflectance value at said control
line. Theoretical reflectance values may also be a pre-set preset
parameter value for the control line or the test line. For
instance, the control line may be the theoretical reflectance
value. A reflectance value on said assay that is inconsistent with
said theoretical reflectance value may indicate an inadequate flow
on said assay. The inadequate flow may trigger a detectable signal
to generate a no-result response. Further, a reflectance value on
said assay that is inconsistent with said theoretical reflectance
value may indicate a prior analyte development on said assay. The
prior analyte development may trigger a detectable signal to
generate a no-result response. Yet further, a reflectance value on
said assay that is inconsistent with said theoretical reflectance
value may indicate a contaminated optical path. The contaminated
optical path may trigger a detectable signal to get a no-result
response reading, and/or deactivate said assay measurement
apparatus.
[0025] An instruction for generating a test result may correspond
to an image detection on said assay. The image detection may be an
optical reflectance value. The assay may include at least one test
line and at least one control line, and whereby said optical
reflectance value is a comparison between a reflectance value at
said test line and a reflectance value at said control line. The
apparatus may be adapted to perform a continuous image detection of
said assay. The assay may be a lateral flow assay. For instance,
the assay may be a lateral, capillary-flow, elongated test strip.
Further, the apparatus may include a means for a power source.
[0026] In yet another embodiment, a lateral flow assay for the
detection of an analyte and having a test zone and a control zone,
a surface having a reflectance profile includes at least one flow
reference and at least one test result reference. The at least one
flow reference area may be adapted to enable monitoring of a
pre-flow development along said assay. The at least one test result
reference area may be adapted to enable monitoring a pre-test
detection of said analyte on said assay.
[0027] The reflectance profile may include a theoretical light
reflectance measurement. The theoretical light reflectance
measurement may comprise a no-flow development theoretical value.
The no-flow development value may be a reflectance value of about
85. A reflectance value of greater than about 85 may generate a
signal to deactivate said detection of said analyte. The flow
reference area may include at least one downstream flow reference
line. The downstream flow reference line may include a theoretical
reflectance value after said flow reference line receives reagent
flow thereon. The flow reference area may include both an
intermediary flow reference line and a downstream flow reference
line. The intermediary flow reference line may include a
theoretical reflectance value after said flow reference line
receives reagent flow thereon. The theoretical light reflectance
measurement may comprise a no-analyte pre-test development
theoretical value. The flow reference may also be the control
zone.
[0028] The test result reference area may include at least one test
line having a theoretical reflectance value. The test result
reference area may include at least one control line having a
theoretical reflectance value. The test result reference area may
include at least one test line having a theoretical reflectance
value and at least one control line having a theoretical
reflectance value. A pre-set difference between said at least one
test line's theoretical reflectance value and said at least one
control line's theoretical reflectance value may activate a test
result. Further, a pre-set difference between said at least one
test line's theoretical reflectance value and said at least one
control line's theoretical reflectance value may trigger an error.
The error may withhold a test result.
[0029] In other embodiments, a lateral, capillary-flow elongated
test strip includes a test zone, a control zone and a surface
having a reflectance profile. The lateral, capillary-flow elongated
test strip may have at least one reagent for the detection of at
least one analyte in a sample. The test zone may include
immobilized thereon a test zone capture agent that is adapted for
capturing said at least one reagent. The control zone may include
at least one control zone capture agent having a different binding
affinity for said at least one reagent. The reflectance profile may
be adapted to enable monitoring of said test strip continuously
until the detection of said analyte. Typically, the test strip
generates a detectable signal for detecting said analyte in said
sample. In some examples, inadequate control line development, for
instance according to reflectance and/or transmission at the
control line, may trigger an error. In these examples, the error
may trigger a signal to generate a no-result response.
[0030] The test strip may comprise a coding system having at least
one reference code with a corresponding testing sequence. The
testing sequence may include at least one temperature adjustment
parameter. Further, the testing sequence may include an optical
reader test parameter. The optical reader test parameter may
include a reader channel selection. The reader test parameter may
include an associated feature chosen from a standard curve, a
does-response curve and a combination thereof. The reader test
parameter may include at least one associated positive control
point and at least one associated negative control point. The
coding system may include a color matrices. The color matrices may
include a color chosen from red, blue, green and combination
thereof. The color matrices may be associated with a corresponding
diagnostic test. The coding system may include a bar code. The
coding system may include an RFID tag.
[0031] The test strip may include a first end having a sample
absorbing material. The test strip may include a peel strip to
introduce sample onto the sample absorbing material. The peel strip
may include a peel tab at one end of the peel strip to facilitate
movement of said peel strip. The sample absorbing material may be
adapted to receive about 0.1 to about 1.0 mL of a fluid. The sample
absorbing material may comprise a dry cellulosic material. Further,
the test strip may include an opposed second end having a reactor
detector material. The test strip may include a releasing area
having a mobile phase receptor for the at least one analyte. The
test strip may be sized and adapted to be enclosed within a test
strip cavity. Further, the test strip may be sized and adapted to
be enclosed within a test strip cavity of a removable incubation
module. Typically, the test strip is adapted for selecting the
detection of a diagnostic test group chosen from an antibiotic
analyte, toxic analyte, analyte class, a combination thereof and
the like.
[0032] The test zone may include at least one analyte reference
line having a theoretical reflectance value. The theoretical
reflectance value may be associated with a flow parameter on said
test strip. The test zone surface may include a first analyte
reference line having a first theoretical reflectance value and a
second analyte reference line having a second theoretical
reflectance value. The control zone surface may include at least
one control line having a theoretical reflectance value. For
instance, the theoretical reflectance value may be an optical
reflectance value. The control zone may include a first control
line having a first theoretical reflectance value and a second
control line having a second theoretical reflectance value. In some
examples, the reflectance profile is adapted to enable monitoring
of said test strip prior to the detection of said analyte. Further,
the test result may be detected within about thirty to about sixty
seconds.
[0033] In yet another embodiment, a lateral, capillary-flow
elongated test strip includes a test zone including immobilized
thereon a test zone capture agent adapted for capturing at least
one binder, a control zone including at least one control zone
capture agent having a different binding affinity for said at least
one binder, a surface having a reflectance profile adapted to
enable monitoring of said test strip and a coding system having at
least one coding signal, for instance a coding to correspond to a
testing sequence to characterize said test strip. The reflectance
profile may include at least one flow reference area adapted to
enable monitoring of a flow development along said assay, and at
least one monitor reference area adapted to enable monitoring of
detection of said analyte on said assay.
[0034] The testing sequence may include at least one temperature
adjustment parameter. The testing sequence may include an optical
reader test parameter. The optical reader test parameter may
include a reader channel selection. The optical reader test
parameter may include an associated feature chosen from a standard
curve, a does-response curve and a combination thereof. Further,
the optical reader test parameter may include at least one
associated positive control point and at least one associated
negative control point. The coding system may include a color
matrix. The color matrices may be associated with a corresponding
diagnostic test. The coding system may include a bar code. The
coding system may include an RFID tag.
[0035] In some examples, the test strip may include a first end
having a sample absorbing material. The test strip may include a
peel strip to introduce sample onto the sample absorbing material.
The peel strip may include a peel tab at one end of the peel strip
to facilitate movement of said peel strip. The sample absorbing
material may be adapted to receive about 0.1 to about 1.0 mL of a
fluid. The sample absorbing material may comprise a dry cellulosic
material. The test strip may include an opposed second end having a
reactor detector material. The test strip may include a releasing
area having a mobile phase receptor for the at least one analyte.
The test strip may be sized and adapted to be enclosed within a
test strip cavity. Further, the test strip may be sized and adapted
to be enclosed within a test strip cavity of a removable incubation
module. Typically, the test strip is adapted for selecting the
detection of a diagnostic test group chosen from an antibiotic
analyte, toxic analyte, analyte class, a combination thereof and
the like, either quantitatively, qualitatively or both.
[0036] The test zone may include at least one analyte reference
line having a theoretical reflectance value. Typically, the
theoretical reflectance value is associated with a flow parameter
on said test strip. The test zone may include a first analyte
reference line having a first theoretical reflectance value and a
second analyte reference line having a second theoretical
reflectance value. The control zone may include at least one
control line having a theoretical reflectance value. The
theoretical reflectance value may be an optical reflectance value.
A control zone may include a first control line having a first
theoretical reflectance value and a second control line having a
second theoretical reflectance value. The theoretical light
reflectance measurement may comprise a no-flow development
theoretical value. The no-flow development value may be a
reflectance value of about 85. The reflectance value of greater
than about 85 may generate a signal to deactivate said detection of
said analyte.
[0037] In other examples, the flow reference area may include at
least one downstream flow reference line. The downstream flow
reference line may include a theoretical reflectance value after
said flow reference line receives reagent flow thereon. The flow
reference area may include an intermediary flow reference line and
a downstream flow reference line. The intermediary flow reference
line may include a theoretical reflectance value after said flow
reference line receives reagent flow thereon. The theoretical light
reflectance measurement may comprise a no-analyte pre-test
development theoretical value. The test result reference area may
include at least one test line having a theoretical reflectance
value. The test result reference area may include at least one
control line having a theoretical reflectance value. The test
result reference area may include at least one test line having a
theoretical reflectance value and at least one control line having
a theoretical reflectance value. A pre-set difference between said
at least one test line's theoretical reflectance value and said at
least one control line's theoretical reflectance value may activate
a test result. Further, a pre-set difference between said at least
one test line's theoretical reflectance value and said at least one
control line's theoretical reflectance value may trigger an error.
Typically, the error withholds a test result, including generating
a no-result response.
[0038] In yet another embodiment, in an assay system having an
incubator and a reader to generate a test result from an assay, a
sensor may be adapted to continuously monitor said assay while said
incubator incubates said assay and said reader generates said test
result. The sensor may be adapted to deactivate said incubator when
said sensor detects an aberration on said assay. The sensor may be
an optical detector. The optical detector may be adapted to detect
a reflectance value. The assay may include at least one test zone
and at least one control zone, and whereby said reflectance value
is a comparison between a reflectance value at said test zone and a
reflectance value at said control zone. Further, if the reader
and/or incubator hood is opened during incubation or reading, a
signal may generate a no-result response. Additionally, if said
assay is removed before a test result is generated, a signal may
generate a no-result response.
[0039] In some examples, the incubator may be deactivated when said
sensor detects a reflectance value on said assay that is
inconsistent with a predetermined theoretical reflectance value on
said assay. For instance, a reflectance value on said assay that is
inconsistent with said theoretical reflectance value may indicate
an inadequate flow on said assay. Further, a reflectance value on
said assay that is inconsistent with said theoretical reflectance
value may indicate a prior analyte development on said assay.
Similarly, a reflectance value on said assay that is inconsistent
with said theoretical reflectance value may indicate a contaminated
optical path.
[0040] In other examples, the sensor may be adapted to deactivate
said reader when said sensor detects an aberration on said assay.
The sensor may be an optical detector. The optical detector may be
adapted to detect a reflectance value. The assay may include at
least one test zone and at least one control zone, and whereby said
reflectance value is a comparison between a reflectance value at
said test zone and a reflectance value at said control zone. A
no-result response may be generated when said sensor detects a
reflectance value on said assay that is inconsistent with a
predetermined theoretical reflectance value on said assay. A
reflectance value on said assay that is inconsistent with said
theoretical reflectance value may indicate an inadequate flow on
said assay. Further, reflectance value on said assay that is
inconsistent with said theoretical reflectance value may indicate a
prior analyte development on said assay. Likewise, a reflectance
value on said assay that is inconsistent with said theoretical
reflectance value may indicate a contaminated optical path.
[0041] The sensor may be a decoding sensor. The decoding sensor may
be chosen from a color sensor, a RFID reader, a barcode reader and
a combination thereof. Typically, the sensor is triggered with an
activation element chosen from a hood sensor, an incubator sensor,
a trigger switch and a combination thereof.
[0042] The apparatus may include a housing that is adapted to
substantially enclose said reader and said incubator. The housing
may include insulation adapted to withstand deformation during said
incubation. The housing may also include a cavity adapted to secure
said assay and receive light from said reader. The cavity may
include an optical aperture to receive light from said reader. The
cavity may include an adjustable fastener adapted to position said
cavity in an optical path with said reader. The cavity may include
insulation adapted to withstand deformation during an incubation
period. The assay may be a lateral, capillary-flow test strip. And
thereby the housing may include a removable optical window adapted
to block debris from said sensor. The removable optical window may
include a handle. The removable optical window may be cleanable.
Similarly, the removable optical window may be disposable.
Additionally, the removable optical window may be slide-mounted.
The housing may include an air opening. The air opening may include
a cap.
[0043] In particular examples, the system may include a user
interface. The user interface may include an integrated circuit
board, for example to support a display board. The user interface
may also be adapted to view flow development. Similarly, the user
interface may be adapted to view the test result, including a
no-result response. The user interface may also be adapted to view
flow development after said reader has detected at least one flow
development on said assay.
[0044] In another embodiment, a lateral flow assay system to
generate a test result from an assay includes an incubator that is
adapted to incubate said assay and a reader that is adapted to read
a diagnostic test on said assay. The assay may undergo a change
when contacted with a sample to generate said test result
[0045] In some examples, the system includes a removable assay
module. The removable assay module may include an assay cavity
adapted to align said assay with said reader. The assay may be a
lateral flow test strip. Thereby, the assay cavity may be sized to
receive said lateral flow test strip. The removable assay module
may include a hood. The hood may enclose said assay in a closed
testing position and expose said assay in an open access
position.
[0046] Further, the removable assay module may include a bottom
face adapted to align with at least one light aperture on said
reader. The bottom face may include an adjustment fastener adapted
to secure said assay cavity in an optical alignment with said
reader. The bottom face may also include an engagement lip to
position said bottom face with said reader. The removable assay
module may include at least one optical window. The removable assay
module may be adapted to be removed from said system and cleaned
from debris.
[0047] In some examples, the incubator includes an insulated base.
The incubator may be a temperature adjustable incubator. The
temperature adjustable incubator may include at least one
temperature control. Thereby, the temperature adjustable incubator
may include localized temperature variations. For instance, the
incubator may compensate for localized temperature variations. The
incubator may compensate for localized temperature variations with
an analog, proportional circuit. In other examples, the incubator
may compensate for localized temperature variations with a digital
control circuit, for instance by utilizing a PID algorithm or HD
controller. Further, the temperature adjustable incubator may
include an embedded temperature sensor. The temperature adjustable
incubator may include a potentiometer. The incubator may include a
heater. The heater may be chosen from a ceramic heater, a resister
heater element and the like. Similarly, the incubator may include a
cooling system. In yet other examples, the incubator incubates said
assay in a means for creating an incubation environment.
[0048] The reader may perform continuous image detection of said
assay to generate said test result. The continuous image detection
may include monitoring a pre-flow development along said assay,
including monitoring for excessive flow and inadequate flow along
said assay. The reader may include a light source oriented in a
predetermined pattern with respect to said assay. The light source
may include a first mirror below said light source. The light
source may include a focusing lens adapted to receive light from
said first mirror. Further, the light source may include a second
mirror positioned to direct light from the focusing lens to said
reader.
[0049] In particular examples, the reader may include a sensor. The
sensor may be an optical detector that is aligned with a light
source for detecting transmission of light through said assay. For
instance, transmission embodiments herein may include analysis of
refracted light from the assay. The sensor may be a decoding
sensor. The decoding sensor may be adapted to decode at least one
reference code having a corresponding testing sequence on said
assay. Further, the reader may include multiple channels. Each of
said channels may include an associated feature chosen from a
standard curve, a does-response curve, a positive cutoff value, a
negative cutoff value and the like.
[0050] In yet further embodiments, a method of generating a test
result from an assay includes incubating said assay in an
incubation environment and reading a diagnostic test on said assay
concurrently as said incubator incubates said assay. The method may
include sensing said assay continuously while said incubator is
incubating said assay. The method may include deactivating said
incubator when sensing an aberration on said assay. The method may
include removing a removable assay module, for example for cleaning
debris, or the like, from said assay module. The method may include
adding a test sample to a test medium to create said assay. The
method may also include enclosing said test medium within said
reader. The method may include positioning a sensor relative to
said test medium so that a change on said test medium is detectable
by said sensor. The method may include decoding a reference coding
on said assay. Thereby, the method may include selecting a channel
in said reader corresponding to said reference coding on said
assay. Further, the method may include incubating said assay within
the incubator according to said reference coding on said assay.
[0051] The above summary was intended to summarize certain
embodiments of the present disclosure. Embodiments will be set
forth in more detail in the figures and description of embodiments
below. It will be apparent, however, that the description of
embodiments is not intended to limit the present inventions, the
scope of which should be properly determined by the appended
claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0052] Embodiments of the disclosure will be better understood by a
reading of the Description of Embodiments along with a review of
the drawings, in which:
[0053] FIG. 1 is a front perspective view of one embodiment of a
lateral flow assay system, with an open hood illustrating cavity
and base components;
[0054] FIG. 2 is a front perspective view of the lateral flow assay
system embodiment of FIG. 1, with the hood in a substantially
closed position;
[0055] FIG. 3 is a front perspective view of the embodiment of FIG.
1, illustrating examples of cavity and adjustment components;
[0056] FIG. 4 is an isolated side perspective view of assay base
module elements;
[0057] FIG. 5 is a top view of the lateral flow assay system
embodiment of FIG. 1 in a closed position;
[0058] FIG. 6 is a sectional view of the lateral flow assay system
embodiment of FIG. 1 taken along lines 6-6, showing circuit board
components;
[0059] FIG. 7 is a front perspective view of one embodiment of a
lateral flow assay system and assay components;
[0060] FIG. 8 is a front perspective view of the embodiment of FIG.
7 in a closed position;
[0061] FIG. 9 is a partial cross-section of one example of the
embodiment introduced in FIG. 7 taken along 9-9;
[0062] FIG. 10 is a front perspective view of one embodiment of a
lateral flow assay system and assay components;
[0063] FIG. 11 is a front perspective view of one embodiment of a
lateral flow assay system and assay components;
[0064] FIG. 12 is an isolated view of the assay illustrated in FIG.
11, showing one example of a prior analyte development before
testing triggering an error;
[0065] FIG. 13 is a front perspective view of one embodiment of a
lateral flow assay system with debris on the imaging detector;
and
[0066] FIG. 14 is a front perspective view of one embodiment of a
lateral flow assay system having a removable assay module.
DESCRIPTION OF EMBODIMENTS
[0067] In the following description, like reference characters
designate like or corresponding parts throughout the several views.
Also in the following description, it is to be understood that such
terms as "forward," "rearward," "left," "right," "upwardly,"
"downwardly," and the like are words of convenience and are not to
be construed as limiting terms. It will be understood that the
illustrations are for the purpose of describing embodiments of the
disclosure and are not intended to limit the disclosure or any
invention thereto.
[0068] As introduced in FIG. 1, a lateral flow assay system 1 is
shown embodied according to the present disclosure. Lateral flow
assay system 1 includes a combined reader 100 and incubator 102.
Reader 100 typically includes an imaging detector, such as a
sensor, while incubator 102 typically includes an insulated base 4.
In some embodiments, the insulated base is a removable assay module
104. Typically, reader 100 first monitors an assay for one, or
more, monitoring values, including flow rate, prior analyte
development and debris. In various examples, if a proper monitoring
value is detected by system 1, incubator 102 incubates the assay
and reader 100 generates a test result. However, if an inconsistent
monitoring value is detected, system 1 may generate a no-result
response.
[0069] As shown in FIG. 1, lateral flow assay system 1 is
configured to receive an assay and analyze the assay to generate a
diagnostic test result. Typically, the assay is a capillary-flow
test strip. However, it is within the spirit of this disclosure for
any of the assays herein to be other lateral flow assays.
[0070] FIG. 1 shows a housing enclosing the reader 100 and
incubator 102 as an integral diagnostic unit. Other embodiments
include a housing that partially encloses components of lateral
flow assay system 1. Typically, the reader includes cavity 3 to
receive the assay, and a hood 2 to enclose the assay. The housing
may have an exterior and interior, and may be opened, for instance
hood 2, to receive an assay into cavity 3. As illustrated in FIG.
1, hood 2 may be lifted and the assay inserted into a heating
cavity such as a metallic, for example aluminum, cavity within
incubator 102. Typically, cavity 3 is surrounded by insulating
material, such as a plastic material, for example a thermoplastic
such as polyoxymethylene, known as Delrin (DELRIN is a registered
trademark of DuPont) to insulate cavity 3, and does not deform when
heated to the temperatures required for generating a test
result.
[0071] As shown in FIG. 1, hood 2 may be opened into an access
position to receive and/or remove an assay within cavity 3 of
insulated base 4. Hood 2 may also be configured to substantially
seal cavity 3 to enclose the assay in a closed testing position.
Openings 25, 26 and 27, in hood 2 allow access to adjustment
fasteners 11, 12 and 13 (see FIG. 8), including screws and the
like, when hood 2 is in a closed position. In other examples,
adjustment fasteners may also be accessed when hood 2 is positioned
in an open access position. Typically, adjustment fasteners align
cavity 3 in relation to optics, for instance an imaging detector
described hereinafter, so that changes on the assay may be
detected. For example, test strips may have multiple line
developments in various areas on the test strip, as described
hereinafter and introduced in FIG. 7. By allowing fine cavity
adjustment with the adjustment fasteners through openings 25, 26
and 27, costly and cumbersome system recalibration may be
minimized, or avoided. For instance, depending on a particular
assay, flow, test and control lines may be in a variety of
different position along the assay, as explained below, which may
trigger an unexpected reflection, or transmission, value if cavity
3 is not properly adjusted.
[0072] As introduced above, cavity 3 may be configured to receive
the assay, such as a lateral flow test strip, to position and
maintain the assay in an optical alignment with reader 100. In some
examples, cavity 3 is shaped with an elongated channel, for
instance to receive a lateral, capillary-flow test strip.
[0073] Some embodiments of reader 100 are optical analysis readers,
which often include a light source and an imaging detector, for
example a sensor, that is aligned such that the light from the
light source shines onto the assay and is then reflected onto the
imaging sensor. An example of optical reader components useful in
embodiments herein is described in U.S. Pat. No. 6,124,585
(Apparatus for measuring the reflectance of strips having
non-uniform color), issued Sep. 26, 2000, and incorporated herein
by reference. Typically, the presence and, in some cases, the
concentration, of an analyte on an assay may be determined by
measuring, for instance, the optical reflectance from an area of
development on the assay. In some examples, percent reflectance may
be used to determine the result. In other examples, transmission
may be used to detect the result. For instance, the assay may be
transparent and include a surface having a transmission profile,
similar to the reflectance profile discussed below. This structure
and function described in that patent may be adapted by those of
ordinary skill in the art in accordance with the disclosure herein
to obtain a functioning unit.
[0074] Reader 100 may comprise a variety of light sources,
including an incandescent bulb, a fluorescent tube, a light
emitting diode or the like. In some examples, the light source may
be an array of discrete light sources, for instance colored light
emitting diodes chosen from red, green, blue and a combination
thereof. In yet other examples, the light source may be an
individual light source, for instance a singular diode. Typically,
the light source is configured and current driven to emit an
illumination pattern suitable for reflecting onto the assay, for
instance along an elongated test strip. As shown in FIG. 1, light
can be directed to the assay, for example through aperture 5 in
cavity 3, and then reflected off the assay, back through the cavity
aperture 5 and directed to an optical detector.
[0075] In one example, an optics circuit board 31 (see FIG. 6) may
have a plurality of light emitting diodes (LEDs) mounted thereon,
for instance in a predetermined pattern around light-emitting
aperture 5. The LEDs may be mounted on one side of optics circuit
board 31. An optical detector array may be mounted to the reverse
side of the same optics circuit board 31. Further, a first mirror
may be positioned below the light-emitting aperture at a
pre-determined angle, for instance about three hundred and fifteen
degrees, to circuit board 31. A second mirror may be positioned
beneath the optical detector, for instance at an angle of about
two-hundred and twenty degrees to circuit board 31, such that a
substantially 90-degree angle exists between first and second
mirrors. A focusing lens may be positioned between the first and
second mirrors. Thereby, the light emitted from the LED array may
illuminate an assay and then light is reflected therefrom through
light-emitting aperture 5, for instance to the first mirror, from
the first mirror through the focusing lens to the second mirror,
and from the second mirror onto the optical detector. In that
respect, the light striking the optical detector may cause the
optical detector to generate a measurable voltage. In some
examples, the optical detector can output a data stream that can be
converted, for example by an on onboard central processing unit,
into a series of 128 distinct one-dimensional numeric readings. The
128 readings can be taken multiple separate times and averaged.
[0076] In additional examples, a light processor may be coupled to
the light source to actuate the light source and provide each light
with the appropriate current to generate the desired emission
pattern. The light processor may be used to read and store data
from the optical detector. The light processor may also be used to
adjust the output of an array of discrete light sources such that
the emission pattern striking the light detector array has a
uniform intensity. The lighting processor may include data storage
for said desired light-emission pattern.
[0077] Further, the light source may be an LED light source,
including a red, green, blue LED device in a single package. For
instance, the LED light source for the color sensor can also be
three discrete LEDs. Similarly, a single white LED and three
discrete photodiodes, with narrow bandwidth responses at the red,
green and blue wavelengths, can be used as a detector
front-end.
[0078] In yet other examples, one LED is used with an optional
feedback loop. The feedback loop can use a photodiode to sense
light output variation from the single LED. If light output
changes, a signal is sent so that an appropriate adjustment can be
made, for example, an increase or decrease in current to the LED.
Reflectance changes can be the result of the binding of a label,
including color particles such as gold beads. Reflectance changes
may also be a result of contaminants and interferences in the
optical path.
[0079] As seen in FIG. 2, optical window 8 may be positioned
between the assay and reader 100, for instance between a test strip
and a sensor. Typically, optical window 8 blocks debris from the
assay from contaminating the imaging detector itself, or other
system parts used with the sensor, such as lenses and mirrors. In
some examples, optical window 8 is clear and includes a handle so
that optical window 8 is removable from reader 100 for cleaning. In
other examples, the removable optical window may be disposable. In
one example, the window material includes clear polyvinyl chloride
(PVC) plastic. Window 8 may be mounted on a slide and inserted into
reader 100 between cavity 3 and the sensor. The figures show only
one removable and cleanable window to block debris, however, other
embodiments include additional optical windows covering to protect
portions of the optics and/or incubator 102 components.
[0080] Regardless of the presence of an optical window, it is
possible that dust and debris will infiltrate into reader 100, for
example the optical sensor mechanism. To provide an additional
cleaning option, air inlet 6 can be provided for compressed air.
Air inlet 6 may be covered with a tethered cap 10. In use, clear,
optical window 8 is removed, and tethered cap 10 is detached.
Compressed air is then blown through reader 100, so that debris
collected on, or near, the reader sensor is blown out through the
opening previously occupied by window 8.
[0081] Some embodiments of reader 100 are programmed with multiple
channels, each of which may have separate parameters associated
with a related diagnostic test. Each channel selection parameter
may include a standard curve, a does-response curve and the
like.
[0082] FIG. 3 shows cavity adjustment fastener 13 in cavity 3, and
base adjustment fasteners 11 and 12 in insulated base 4. Openings
25, 26 and 27, in hood 2 allow access to adjustment fasteners 11,
12 and 13, including screws and the like, when hood 2 is in a
closed position. In other examples, adjustment fasteners may also
be accessed when hood 2 is positioned in an open access position.
Typically, cavity adjustment fastener 13 aligns cavity 3 in
relation to optics, for instance an imaging detector described
hereinafter, so that changes on the assay may be detected.
[0083] FIG. 4 shows one example of insulated base 4 and hood 2 in
an opened access position. As shown, the bottom face of base 4
includes openings for cavity adjustment fastener 13, openings for
base adjustment fasteners 11 and 12 and light-emitting aperture
5.
[0084] FIG. 5 shows a top view of lateral flow assay 1 with hood 2
in closed testing position. Window 8 is positioned on the side of
the housing to allow the user to remove window 8 for cleaning. As
introduced above, air may be inserted through air inlet 6 to
further clean debris from optic components.
[0085] FIG. 6 is a bottom schematic view showing optics board 30,
circuit board 31 and display board 32. As shown, LEDs may be
mounted on one side of optics circuit board 31. Further, as shown
throughout the various figures, lateral flow assay system 1 may
include user interface 7. User interface 7 includes an integrated
circuit board 31 supporting a display board 32. In one example,
user interface 7 allows a user to view flow development. Further,
user interface 7 may allow a user to monitor a subsequent flow
development after reader 100 has already detected at least one flow
development on the assay. Similarly, user interface 7 may display a
final test result, including a no-result response.
[0086] FIG. 7 illustrates one embodiment of hood 2 in open access
position with assay 21 secured within test strip enclosure 20,
which is adapted to be received by cavity 3. Examples of assay
elements for particular diagnostic tests having components useful
for embodiments herein include those described in U.S. Pat. No.
7,410,808, issued Aug. 12, 2008; U.S. Pat. No. 7,097,983, issued
Aug. 29, 2006; U.S. Pat. No. 6,475,805, issued Nov. 5, 2002; U.S.
Pat. No. 6,319,466, issued Nov. 20, 2001; U.S. Pat. No. 5,985,675,
issued Nov. 16, 1999 and U.S. patent application Ser. No.
11/883,784, filed Aug. 6, 2007, all of which are hereby
incorporated herein by this reference.
[0087] Generally, lateral flow assay 21 is membrane-based test
device, in which a sample that is suspected of containing the
analyte of interest is placed at or near one end of the membrane
strip. The sample is carried to the opposite end of the membrane
strip by a mobile phase that traverses the membrane strip, for
example by capillary action. While traversing the membrane strip,
the analyte in the test sample, if any, encounters one or more
reagents. The reagents can include binders for the analyte. Binders
can be mobile and, therefore, flow with the sample or be
immobilized on the test strip as a capture agent. Depending on the
test configuration, either the analyte binder, the analyte itself,
or some other reagent in the test system, will be captured by the
immobilized capture agent and, thereby, produce a detectable
signal. The signal can be generated by a label provided within the
assay. The detectable signal can be measured, such as by optical
reader 100.
[0088] Assay 21 may include at least one test line 40 in a test
zone and at least one control line 42 in a control zone. A
theoretical reflectance value may be a comparison between a
reflectance value at test line 40 and a reflectance value at
control line 42. A pre-set difference between a theoretical
reflectance value at test line 40 and a theoretical reflectance
value at control line 42 may activate lateral flow assay system 1,
including reader 100, to generate a test result. Further, a
separate pre-set difference between a theoretical reflectance value
at test line 40 and a theoretical reflectance value at control line
42 may trigger an error. Triggering of the error may cause the
microprocessor to withhold a test result, including generating a
no-result response, or deactivating reader 100 and/or incubator
102. Other embodiments include a comparison between a transmission
value at test line 40 and a reflectance value at control line
42.
[0089] A reflectance value on the assay that is inconsistent with
the theoretical reflectance value may indicate an inadequate flow
in a the mobile phase on the assay. For instance, assay 21 may have
a flow line 44 with a corresponding theoretical light reflectance
measurement. A no-flow development value may be a reflectance value
of about 85 on a reflectance scale. Such an inadequate flow may
trigger a detectable signal to generate a no-result response.
Additional examples include deactivating the lateral flow assay
system 1, including deactivating reader 100 and/or incubator 102.
In other examples, the flow reference area may include both an
intermediate flow reference line 46 with a corresponding
theoretical reflectance value and a flow reference line 44.
[0090] Similarly, a reflectance value on the assay that is
inconsistent with the theoretical reflectance value may also
indicate a prior analyte development on the assay. Such a prior
analyte development may trigger a detectable signal to generate a
no-result response. Further, if the assay is removed prior
generating a test result, system 1 may generate a no-response
result.
[0091] In some embodiments, assays 21 also include a coding
reference component with a corresponding testing sequence for
lateral flow assay system 1. The coding may be, for example, a
color coding, a bar code, an RFID tag or the like, and may be
positioned anywhere along the assay so that decoder sensor can
decode the reference code, for example on the assay's surface. For
instance, in some examples, the coding reference is positioned
along the distal end of assay 21. Depending on the type of coding
on the test strip, reader 100 may require an integrated decoding
sensor for example, a bar code reader, an RFID decoder or a color
sensor.
[0092] Typically, the testing sequence is at least one temperature
adjustment parameter within incubator 102 and/or a channel
selection of reader 100. Further, the reader test parameter may
include an associated feature chosen from a standard curve, a
does-response curve and the like. Other embodiments include a
variety of testing sequence parameters for the associated
diagnostic test being run on the assay.
[0093] In some examples, a color matrix, or matrices, reference
coding, including a color chosen from red, blue, green and
combination thereof, may be associated with a corresponding
diagnostic test parameter. When a color coding is used on assay 21,
the color can be read by the reader either by a separate optical
reading system or the same system that reads the test result. That
is, the assay can include a color portion that, after enclosure
within the system and test initiation, will be read by the color
sensor to determine the reader channel and/or the appropriate
incubator temperature. For example, a photodiode with a wide
dynamic range of sensitivity to red, green and blue wavelengths can
be used as the detector. Red, green and blue LEDs can be used as
the light source. Each LED can be turned on sequentially and the
detector used to determine the reflectance of each of the colors. A
black surface (totally absorbent as containing no color) will
produce no reflectance of the given LEDs wavelength and, therefore,
the detector will produce low output readings. A white surface will
produce maximum reflectance of all three LEDs. Various colors
(depending on its content in the surface measured) will produce
output from the detector at varying levels.
[0094] Such color sensor component may be configured as a separate
sensing component within reader 1, or depending on the sensor used
to read the test strip result, a singular component that detects
both development on the test strip and color coding. In various
examples, assays may be coded with a color that defines the test
being run. For example, a red color can indicate a test strip to be
used to detect beta-lactam antibiotics. Various matrices can also
be delineated by the color system. In the red example, after system
1 detects the red color on the test strip, reader 100 and/or
incubator 102 may be automatically configured for that specific
assay 21, for example by temperature adjustment of incubator 100
and selection of appropriate reflectance test parameters within
reader 102. Therefore, in some embodiments, system 1 may an
integral diagnostic test unit that is triggered by specific
reference codings on the assay.
[0095] In other examples, the coding reference may comprise a radio
frequency identification (RFID) tag. Such radio frequency signal
transmits a signal from the tag to a decoding RFID sensor module.
This signal can be used to start the analytic testing sequence,
event, channel, temperature or the like in the reader and/or
incubator. Similarly, the reference coding may be a bar code,
wherein the bar code is placed on the assay and a bar code reader
decodes the reference coding and associated testing sequence
information.
[0096] FIG. 8 shows assay 21 and assay enclosure 20 positioned
within the reader, with hood 2 in a closed position. As shown, hood
2 is pivoted down in a closed testing position, wherein a sensor in
the reader is in an optical alignment with assay 21 to generate a
test result or a no-result response.
[0097] In the closed testing position, incubator 102 may incubate
assay 21 in an incubation environment. For instance, incubator 102
may heat and/or cool assay 21 to provide the proper incubation
environment for a corresponding assay and diagnostic test.
Typically, incubator 102 is in communication to the cavity 3 and is
capable of maintaining a consistent temperature within cavity 3
either by heating or cooling at a pre-defined rate. In some
examples, incubator 102 includes insulated base 4. In other
examples, incubator 102 incubates removable assay module 104, as
described hereinafter. The incubator may be a temperature
adjustable incubator. In these examples, the temperature adjustable
incubator may include a temperature control. In additional
embodiments, the temperature adjustable incubator may allow for
localized temperature changes.
[0098] Incubator 102 may include a heater. The heater may be a
ceramic heater, a resister heater element and the like. Typically,
cavity 3 is designed to be small so that the heater need only draw
minimum current. In that way, heating only essential areas and
providing insulation around those areas minimizes power
requirements. Use of various heating algorithms can be useful. For
example, a proportional integrated derivative (PID) can be used. In
other examples, incubator 102 may compensate for localized
temperature variations from the selected target temperature, for
instance a target temperature according a corresponding testing
sequence. Incubator 102 may also compensate for localized
temperature variations with an analog, proportional control
circuit. In other examples, incubator 102 may also compensate for
localized temperature variations with a digital control circuit,
for instance by utilizing a PID algorithm or a PID controller.
Further, those of ordinary skill would recognize that PI, PD, P or
I controllers, and/or algorithms, do not preclude any of the
inventions herein. For instance, temperature adjustable incubator
may include a digitally controlled potentiometer to allow the
microprocessor selection of temperature. In other examples,
algorithms are particularly useful when test results are affected
by small temperature variations. Embodiments include incubator
control systems that eliminate the need for manual adjustment by
use of embedded, digital temperature sensors and digital
potentiometer that provides both accurate temperature reporting and
a mechanism by which a micro-controller can adjust a stand-alone,
analog, incubator control circuit.
[0099] In additional embodiments, cooling might be advantageous to
reduce the incubation environment temperature, for example to
stabilize the environment of a test medium and/or sample prior to
incubation.
[0100] As shown in FIG. 9, test strip 21 may include a first end
having a sample absorbing material 23. Further, as introduced in
FIG. 10, test strip 21 may have a peel strip 50 to introduce sample
onto sample absorbing material 23. Peel strip 50 may include a peel
tab at one end of peel strip 50 to facilitate movement of said peel
strip 50. Sample absorbing material 50 may be sized and configured
to receive about 0.1 to about 1.0 mL of a fluid. Further, sample
absorbing material 50 may be composed a dry cellulosic material.
Other embodiments include other materials of sample absorbing
material 50.
[0101] Typically, assay 21 also includes an opposed second end
having a reactor detector material. Assay 21 may support a
releasing area having a mobile phase receptor for the at least one
analyte. Further, assay 21 may be sized and adapted to be enclosed
within test strip cavity 3. Similarly, assay 21 is typically sized
and adapted to be enclosed, for example enclosed tightly, within an
assay cavity 3 of a removable incubation module 104, as seen in
FIG. 14. Typically, assay 21 is adapted for selecting the detection
of a diagnostic test group chosen from an antibiotic analyte, toxic
analyte, analyte class, a combination thereof and the like.
[0102] Reader 100 may include a sensor to monitor a test progress,
for example on a lateral flow assay, and/or determine a test result
from the lateral flow assay. The sensor is positioned relative to
assay 21, so that a change on assay 21 can be detected by the
sensor. Typically, the sensor is activated when the lateral flow
assay is both positioned within cavity 3 and exposed to the
consistent temperature within cavity 3 from incubator 102. For
example, the sensor can be activated by closing hood 2 that
encloses cavity 3. The sensor may include an optical detector and a
microprocessor. Typically, the optical detector is aligned in an
optical path with the assay and is adapted to acquire an image
detection on the assay and is performing a continuous image
detection acquisition of the assay.
[0103] The sensor may be a single photodiode, multiple photodiodes,
a linear photodiode array, a charged couple device, a complementary
metal oxide semiconductor and a combination thereof. Therefore, at
the same time as incubation and flow, or before, or after
incubation and flow is complete, the optical sensors can monitor
the assay and compare optical readings, such as reflectance and/or
transmission readings, to determine various aspects including
sample flow, interference with the optical path such as by debris
in the optical path, line development and test result. When the
assay and line development falls within preset parameters, the test
can continue to completion and provide a final result. Checking of
the assay by the optical sensor prior to test completion can
provide the user with additional confidence that the test was
processed properly.
[0104] Typically, the output may be a voltage, current or a digital
output proportional to light intensity as determined by signal
conditioning circuitry. Some examples of reader 100 include the
TSL12T and TSL13T sensors available from TAOS (Texas Advanced
Optolectronic Solutions). The TSL12T and TSL13T sensors are
cost-optimized, highly integrated light-to-voltage optical sensors,
each combining a photodiode and a transimpedance amplifier
(feedback resistor=80 M.OMEGA. and 20 M.OMEGA. respectively) on a
single monolithic integrated circuit. The photodiode active area is
0.5 mm.times.0.5 mm and the sensors respond to light in the range
of 320 nm to 1050 nm. Output voltage is linear with light intensity
(irradiance) incident on the sensor over a wide dynamic range.
[0105] In some examples, the microprocessor may be in communication
with the optical detector, and in particular with the sensor. In
other examples, the optical detector outputs to other logic means.
Further, the microprocessor may be adapted to signal the optical
detector to perform continuous image detection of said assay to
generate said diagnostic test result. The microprocessor may
include, or have associated, memory to store information
corresponding to an imaging parameter. The memory may include
instructions for monitoring a pre-test analysis on the assay and
for generating a diagnostic test result on the assay.
[0106] In some embodiments having assays with coding references, as
discussed herein, the optical detector may have a decoding ability
to decode a reference code on the assay. Thereby, the decoding
sensor may thereby active a corresponding diagnostic test in reader
100. For instance, the decoding sensor may activate a corresponding
channel in a multichannel reader 100 and/or activate a
corresponding incubation temperature profile within incubator
102.
[0107] The decoding sensor may be a color sensor. For example, the
color sensor may be a photodiode with sensitivity to wavelengths
chosen from red, blue, green and a combination thereof. In such an
example, a color reading an arrangement of photodiodes, each with a
specific color filter, is used as the decoding sensor and a white
LED (which provides a wide spectrum of light through the 3
bandwidths (Red, Green and Blue)) is used as the light source. When
the LED is turned on, the output from each of the photodiodes is
obtained to determine the reflectance of that specific color. The
decoding sensor may also be an RFID reader or a bar code
reader.
[0108] Although reference is often made herein to optical
reflectance, and optical reflectance readers, a variety of readers
may be usefully employed including, for example, transmittance
reader, fluorometers, luminometers, bar code readers, radiation
detectors (such as scintillation counters), UV detectors, infrared
detectors, electrochemical detectors or optical readers, such as
spectrophotometers, charged coupled device (CCD) or complimentary
metal oxide semiconductor (CMOS) can be used as an image sensor. An
optical reflectance reader can be programmed to analyze the test
strip through two-dimensional readings, rather than through the one
dimensional, 1.times.128, readings. For example, a 5.times.128 or
512.times.492 matrix of "pixels." Such a 2-dimensional reading
widens the reflectance capture area to capture reflectance directly
from the sides of the test strip.
[0109] In other examples, a transmittance reader, such as an
ultraviolet Visible Near-Infra red (UV-Vis-NIR) spectroscopy may
provide a characterization of the absorption, transmission, and/or
reflectivity of the assay. For instance, such an analytical
technique may measure the amount of light absorbed on the assay at
a given wavelength. Those of ordinary skill in the art would
appreciate that a molecule, or part of a molecule, can be excited
by absorption. Typically, organic chromophores which absorb
strongly in the UV or visible portions of the spectrum nearly
always involve multiple bonds, such as C.dbd.C, C.dbd.O or C.dbd.N.
This molecular excitation energy may be dissipated as heat, for
instance kinetic energy, by the collision of the excited molecule
with another molecule, e.g., a solvent molecule, as the molecule
returns to the ground state. In other embodiments, the excitation
energy may be dissipated by the emission of light in a via
fluorescence. Regardless of the process, an excited molecule may
possess any one of a set of discrete amounts of energy, for
instance as described by the laws of quantum mechanics. In examples
herein, the major energy levels may be determined primarily by the
possible spatial distributions of the electrons, and to a lesser
extent by vibrational energy levels, which arise from the various
modes of vibration of the molecule.
[0110] Therefore, in particular examples herein, absorbance
measurements may be determined by the concentration of a solute on
the assay. For instance, the progress of such a chemical reaction
may be followed using a spectrophotometer in reader 100 to measure
the concentration of either a reactant or a product over time. In
other examples, a transmission spectroscopy may be used for solid,
liquid, and gas sampling. Typically, light is passed through the
assay and compared to light that has not. The resulting spectrum
may depends on the pathlength or sample thickness, the absorption
coefficient of the sample, the reflectivity of the sample, the
angle of incidence, the polarization of the incident radiation,
and, for particulate matter, on particle size and orientation.
[0111] In some embodiments, the sensor monitors assay 21 for prior
analyte development before generating a test result. As shown in
FIG. 12, prior analyte development on test line 40 and control line
42 indicates an error. For instance, assay 21 may have a
theoretical reflectance value that is a comparison between a
reflectance value at test line 40 and a reflectance value at
control line 42. A reflectance value on assay 21 that is
inconsistent with the theoretical reflectance value may indicate a
prior analyte development on assay 21, including a pre-run assay,
contaminated assay or the like. The prior analyte development may
trigger a detectable signal to generate a no-result, for instance a
no-run, response and/or deactivate assay system 1. Other outputs
may be indicative of the detected condition and are also within the
scope of these inventions.
[0112] Further, the sensor may monitor flow development along assay
21 to assess whether an inadequate sample volume has been applied
to assay 21, or that excess volume has been applied. For instance,
prior to determining the test result, the sensor may monitor the
flow progress on assay 21 along flow line 44. In other examples,
the sensor will monitor flow progress at both flow line 44 and
along the assay, for instance at intermediary flow line 46. The
sensor may be configured to sense whether an adequate flow of a
reagent occurred on assay 21, while assay 21 was within cavity 3,
and/or whether one or more lines, i.e. reflectance or transmission
values, were present on assay 21 prior to contact of assay 21 with
the sample to be tested.
[0113] In addition, the sensor may be configured to detect whether
dirt/debris is contaminating the optical path. For instance, the
sensor may monitor the optical path for interference such as by
debris. To determine that a test has run properly, or that the
assay is free of dirt/debris, predetermined optical measurements,
such as reflectance values or transmission values, may be stored
electronically. The preset values, or preset parameters, can
include a theoretical reflectance, or transmission, value from an
unused assay (prior to receiving reagents). Preset values may also
include values may be one or more theoretical test lines and/or one
more theoretical control lines on the assay, and may also include a
difference between the theoretical reflectance values for the one
or more control lines and the theoretical value for the one or more
test lines.
[0114] FIG. 13 shows one embodiment of lateral assay system 1, with
debris 60 over light aperture 5. In use, a reflectance value on an
assay that is inconsistent with the theoretical reflectance value
may indicate a contaminated optical path, such as debris 60 as
shown here. Lateral assay system 1 may be adapted to generate a
no-run response and/or deactivate reader 100 and/or incubator 102
when the sensor detects such an aberration.
[0115] In other examples, the optical detector may monitor at least
one pre-test parameter after the optical detector has already
acquired at least one image detection on the assay. Similarly,
optical detector generates a test result from assay 21, for
instance by a comparison between at least two lines on the assay,
for examples lines 40 and 42 of the test strip depicted in FIG. 7.
As indicated above and in the incorporated references, optical
detector may compare changes in reflectance values of two lines on
the assay, for instance at least one test line 40 and at least one
control line 42.
[0116] Particular embodiments include configuring the lateral flow
assay system to allow concurrent incubation and reading of assay
21. The combination allows sensors to be used to detect not only
test results, but also to check parameters that might indicate
whether or not flow has occurred on the assay and that such flow
caused a proper test result. That is, while sample, including the
potential analyte, or analytes, of interest, is flowing on assay 21
and binding is occurring in a mobile phase and on assay 21, the
assay is being incubated. By combining reader 100 and incubator 102
into such an integral diagnostic unit 1, results can be achieved
quicker than when assays, such as test strips or other test medium,
are incubated in one device and then moved to a separate device for
reading. For instance, speed-to-result can be enhanced, for example
to as little as less than about 60 seconds or even less than about
30 seconds. Generally, such a combined system can be dynamic,
sensing changes in the assay as they occur by looking for areas of
decreased reflectance and/or transmission anywhere on the unused or
not-fully developed assay.
[0117] A level of protection is provided to prevent pre-run assays
from being read (for example, reader 100 will determine if line
development, for instance at flow line 44, intermediary flow line
44, test line 40 and/or control line 42 occurred prior to the time
when sample flow could have reached such line) and to prevent
incorrect readings caused by debris, or similar interference with
system optics.
[0118] Various triggers may initiate assay analysis of system 1.
For example, closing of hood 2 may initiate test operation,
including optical measurement. Alternatively a separate switch can
be used to initiate test operation after hood 2 is closed. In
either case, a first reading may determine whether a proper assay
is correctly position in the system. If assay 21 is detected, a
reading sequence is initiated. For example, optical measurement,
such as to detect light reflected off assay 21, can utilize values,
such as average reflectance values, in certain areas of assay 21.
Initially system 1 may analyze the assay to determine if the
optical path is clear of interference, such as from debris. Debris
can be in any number of locations in the optical path including on
assay 21 or assay container 22. Concurrently with analyzing the
optical path for debris, or subsequent thereto, the system can
analyze the assay to determine if line development has already
occurred. That is, whether a proper assay has been inserted into
cavity 3. For example, test strips configured to develop within
certain areas, such as a test line and control line, should have no
development in those areas before the analyte and mobile phase have
had adequate time to reach them.
[0119] In some examples, lines configured to develop a change in
reflectance, and/or transmission, when contacted by reagents and
sample should not develop until flow of sample and reagents has
arrived and binding has occurred. That flow will not have arrived
at the time of an initial, for example about three second, read. As
such, if line development is detected at the initial assay
analysis, then an error message will be delivered to the user and
further readings, for example further optical measurements, can be
aborted. In this way, this mechanism can detect the use of pre-run
(known negative) assay or pre-marked assays. Generally, when
reflectance is reduced on an unused assay, either by the presence
of line development or other darkening of the assay away from
baseline, the reduction in reflectance can inform the user that
something has occurred either on the assay or in the optical path,
so that the result should not be accepted.
[0120] After initial optical readings are found satisfactory and
appropriate reader parameters and incubator temperatures are
selected, either manually or automatically, further optical
readings, for example approximately fifteen seconds after sample
has been applied, can be used to determine whether adequate flow
has occurred. For example, optical readings can determine whether
or not reagents have flowed between a sample application region and
a downstream line such as a test line.
[0121] The presence of label, such as colored particles, for
example gold sol beads, flowing in the mobile phase, and the
resulting reflectance changes on the assay between the sample
application area and a first test line, can inform the user that
flow is occurring and return an error message if no flow is
detected. An assay lacking predictable reflectance changes might
either have had no sample flow, or inadequate sample flow. Certain
measurements can also indicate whether excessive flow has occurred,
as in the case where too great a volume of sample has been applied
to a test strip and possible reflectance change due to reagents is
overwhelmed by the excessive sample volume. Reflectance changes
between the sample application area and result detection areas,
such as test line and control line, can be temporary and disappear
as the mobile phase flows. If optical measurements are taken such
temporary/non-permanent changes can be detected.
[0122] If an assay, including a test strip or other assay type, has
passed the preliminary readings, system 1 may initiate readings to
generate a test result. For example, after approximately thirty
seconds test line and control line analysis can begin. When there
is enough differentiation, for example percent reflectance
difference, between the test and control, a result can be provided.
Typically, negative results and more extreme results can be
provided sooner and results closer to threshold levels will take
longer. For example, in the case of a test in which the reflectance
value on the test line relates inversely to the amount of analyte,
if the test line reflectance is reduced to a certain level then a
negative result can be called. In some examples, if hood 2 is
opened while reader 100 is reading the assay, a signal may generate
a no-result response.
[0123] Reader 100 and/or incubator 102 may be powered by a power
source. In some examples for on-site analysis, for instance in
rugged environments, the power source may be a vehicle battery.
Further, reader 100 may be in communication with an onboard vehicle
system.
[0124] As introduced in FIG. 14, lateral flow assay system 1 may
include removable assay module 104 to be removed from system 1 and
cleaned from debris. Typically, removable assay module 104 includes
a similar assay cavity as described above, to align assay 21 with
optics of reader 100 while in a closed testing position. In some
examples, the assay is a lateral flow test strip and the assay
cavity within removable assay module 104 is sized to receive the
lateral flow test strip.
[0125] As discussed above, removable assay module 104 may include a
hood. The hood may enclose the assay in a closed testing position
and be opened to clean away debris in an open maintenance position
when removable assay module 104 is removed from system 1. In some
examples, if the hood of removable assay module 104 is opened while
reader 100 is reading the assay, a signal may generate a no-result
response. Further, removable assay module 104 may have a bottom
face having a window 108 to slide in between reader 100 and the
assay in a manner so that at least one light aperture 5 aligns with
the assay in a closed testing position. Window 108 may be removable
and cleanable as discussed above, and further the bottom face may
include holes to receive an adjustment fastener to secure removable
assay module 104 into an optical alignment with reader 100. In
other examples, bottom face 108 may include engagement lip 106 to
position bottom face 108 securely with reader 100.
[0126] In other embodiments, the disclosure includes a lateral flow
assay system 1 kit. In this embodiment, the kit may comprise an
incubator, e.g. any of the incubators and/or incubator components
previously shown or described, and a reader, e.g. any of the
readers and/or reader components shown or described.
[0127] In yet another embodiment of the disclosure, a method for
analyte analysis includes incubating the assay, e.g. including any
of the embodiments previously shown or described, and reading the
assay to generate a test result, e.g. including any of the
embodiments previously shown or described. In particular examples,
a diagnostic test method for detecting an analyte in a test sample
includes adding a test sample to a test medium, such as a lateral
flow test strip, to create an assay, the test medium configured to
provide a detectable test result after incubation with the test
sample; enclosing the test medium within a hood, the hood
configured to enclose a cavity, the cavity configured to receive
the test medium and connected with a temperature control source,
the temperature control source capable of maintaining a consistent
temperature; positioning a sensor, such as an optical sensor
capable of reading reflectance from the test medium, relative to
the test medium so that a change on the test medium is detectable
by the sensor; and activating the sensor, such as by closing the
hood, the activation causing the sensor to compare the test medium
to a preset parameter. When the test medium is not within the
preset parameter, a test result is not provided, and wherein when
the test medium is within the preset parameter, the test result is
determined from the test medium, the test result indicating whether
an analyte was detected in the test sample.
[0128] In other embodiments of the methods, a preset parameter can
be used to determine either or both whether an adequate flow of
reagents occurred on the test strip while the test strip was within
the cavity and whether one or more test lines are present on the
test strip prior to being contacted by the test sample. To do so
the sensor can be configured to continuously analyze changes on the
test medium until a test result occurs. The test result can be
determined by a comparison between changes, such as reflectance
changes, in a first line, for example a test line, and a second
line, for example a control line, on the test strip.
[0129] A further example of the methods include using preset
parameters to compare the test strip, prior to sample flow thereon,
including prior to sample application, with the actual strip being
used. For example, a blank strip, prior to reagent flow or prior to
sample application, will have a theoretical reflectance profile
within a predictable range. If areas of reduced reflectance are
detected, that did not result from sample/reagent flow on the
strip, then it is possible not only that something untoward has
occurred with the test strip but also it is possible that the
optical path has become contaminated and requires cleaning. Such
contamination can be on the strip or within the reader. Generally,
an unused test strip should have no areas of reduced reflectance.
Any such areas can indicate a problem, whether from dirt/debris,
use of a test strip that was already run, or otherwise. In any
case, the test result may not be valid.
[0130] Numerous characteristics and advantages have been set forth
in the foregoing description, together with details of structure
and function. Many of the novel features are pointed out in the
appended claims. The disclosure, however, is illustrative only, and
changes may be made in detail, especially in matters of shape,
size, and arrangement of parts, within the principle of the
disclosure, to the full extent indicated by the broad general
meaning of the terms in which the general claims are expressed. It
is further noted that, as used in this application, the singular
forms "a," "an," and "the" include plural referents unless
expressly and unequivocally limited to one referent.
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