Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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Device for handling liquid samples
Technical field
[0001] The present invention relates to the field of devices for handling
liquid
samples.
Background
[0002] Devices for handling liquid samples of various kinds are desirable to
use for
instance within point of care analyses. Moreover such devices can be used to
analyse various samples including of blood, plasma, serum, sweat, saliva,
urine, lachrymal fluid, water samples, and suspensions or solutions of food
samples.
[0003] Such assay devices are described in for instance WO 2005/118139 (AM IC
AB), WO 2005/089082 (AMIC AB), and WO 03/103835 (AMIC AB).
[0004] Other assay devices are described in for instance US 5,458,852
(BIOSITE)
and EP 1120164 (ROCHE DIAGNOSTICS GMBH).
[0005] GB 2410086 (BRITISH BIOCELL INTERNAT LTD) discloses an assay device
comprising a flow block to determine flow of liquids.
[0006] US 6,296,020 (BIOMICRO SYSTEMS, INC.) discloses methods of controlling
fluid flow through micro channels by use of passive valves or stopping means.
Disclosure of the invention
Technical problem
[0007] In some of the known assay devices a sample comprising an analyte is
added, which sample flows along a flow path where a dried reagent is
dissolved. The sample now comprising the reagent flows to an analysis point
where the sample is analysed with regards to one or more properties. This
type of technology has a number of problems.
[0008] One problem concerning the above mentioned technique is how to let the
sample reach the analysis point before the reagent. This is desired in some
applications.
[0009] Another problem is how to accurately and reproducible define a certain
volume of sample which passes the analysis point before the reagent reaches
the analysis point.
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[0010] Another problem is how to let the sample react at the analysis point
for a
prolonged time before the reagent reaches the analysis point.
[0011] A further problem is to eliminate effects from the fact the reagent may
dissolve differently depending on for instance age of the reagent and how dry
the reagent is.
[0012] The measured signal in some assays depends on the amount of reagent and
the amount of sample. In many assays some kind of particles and/or some
kind of molecules are detected and therefore the sample volume must be well
defined.
Technical solution
[0013] It is an object of the present invention to alleviate at least some of
the
problems in the state of the art.
[0014] This is achieved by using the present invention which in a first aspect
provides a device for handling liquid samples, said device comprising: a)
projections substantially perpendicular to the surface of said device, said
projections having a height, diameter and a distance between the projections
capable of generating capillary flow, lateral to said surface, of a fluid, b)
at
least one zone for receiving a sample, c) at least one sink with a capacity of
receiving said liquid, said at least one sink exerting at least two different
capillary forces on said liquid, d) at least two flow paths connecting said at
least one zone for receiving a sample and said at least one sink, said flow
paths exerting at least two different capillary forces on said liquid, e) at
least
one connection between said at least two flow paths.
[0015] The assay device utilises projections substantially perpendicular to
the
surface to create a capillary force so that the liquid flows. The device
utilises
the fact that the capillary force can be different for different flow channels
depending on the distance, geometry, diameter, and height of the projections.
The difference in capillary force is used to direct the flow in the desired
direction.
[0016] Also encompassed within the present invention is a method of analysing
a
sample as well as a kit of parts.
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Advantageous effects
[0017] Advantages of the present invention include that it is possible to let
a sample
reach an analysis point before a reagent. Another advantage is that it is
possible to define a certain volume of sample that passes an analysis point
before the reagent reaches the analysis point. A further advantage is that it
is
possible to eliminate or alleviate effects from reagents which dissolve
differently.
Brief description of the drawings
[0018] Fig 1 a-d depicts various embodiments of devices according to the
present
invention.
[0019] Fig 2a-d depicts various stages during use of a device according to the
present invention.
[0020] Fig 3 is an electron micrograph of a part of an analysis device
according to
the present invention. It depicts a cross of two flow channels as used for
instance in the device depicted in Fig 2.
[0021] Fig 4 depicts a section of a flow channel comprising a gate which can
be
used in an assay device according to the present invention.
Definitions
[0022] Before the invention is disclosed and described in detail, it is to be
understood that this invention is not limited to particular configurations,
process steps, and materials disclosed herein as such configurations,
process steps, molecules, and materials may vary somewhat. It is also to be
understood that the terminology employed herein is used for the purpose of
describing particular embodiments only and is not intended to be limiting
since the scope of the present invention is limited only by the appended
claims and equivalents thereof.
[0023] It must be noted that, as used in this specification and the appended
claims,
the singular forms "a", "an" and "the" include plural referents unless the
context clearly dictates otherwise. The following terms are used throughout
the description and the claims.
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[0024] "Analysis" is used herein to denote the process where a sample is
examined
to gain an understanding of it, regarding for instance its qualitative and/or
quantitative composition.
[0025] "Analysis point" is used herein to denote a point or an area on an
assay
device where a measurement is performed.
[0026] "Analyte" is used herein to denote a substance, chemical constituent,
or
biological constituent that is analysed.
[0027] "Reagent" is used herein to denote a chemical or biological constituent
participating in the analysis.
[0028] "Sample" is used herein to denote any matter comprising an analyte.
Detailed description
[0029] At least some of the above mentioned advantages are achieved by using
an
assay device of a special design. The assay device utilises projections
substantially perpendicular to the surface to create a capillary force so that
the liquid flows. The assay device assay utilises the fact that the capillary
force can be different for different flow channels depending on the distance,
geometry, diameter, and height of the projections. The difference in capillary
force is used to direct the flow in the desired direction.
[0030] In one embodiment depicted in Fig 1 a the device for handling liquid
samples
comprises one zone for receiving a sample, shown as the circular zone.
There are two separate rectangular sinks with a capacity of receiving said
liquid, and two flow paths each connected to one sink respectively, and one
connection between said at least two flow paths. In this embodiment a
reactant is dried onto the substrate on the area marked with a "k". The
embodiment further comprises a gate, which allows flow of liquid when it is in
contact with liquid from at least two directions, indicated with a "g" in Fig
1.
[0031] It must be noted that such a gate only allows a flow of liquid when it
is in
contact with liquid from more that one side. An example of a gate which can
be used in the present invention is depicted in Fig 4. It must be noted that
the
gates which can be used in the present invention is not limited to the gate
depicted in Fig 4. Any type of gate can be used which blocks flow of liquid
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when it is in contact with liquid from one side only and which allows flow of
liquid when it is in contact with liquid from more than one side.
[0032] When liquid flows from the left to the right in the flow path depicted
in Fig 4
the flow is blocked and when liquid flows from the right to the left the gate
allows flow in both directions. A flow of liquid from the right to the left
will flow
in small flow paths in the side of the main flow path and will allow the
liquid
from both sides to join and thereby allows flow across the gate. This is
possible to achieve when the capillary force of the gate is adapted to the
intended liquid by adjusting the position, distance, geometry, diameter, and
height of the projections as well as the width and positions of the smaller
flow
paths.
[0033] In one embodiment the gate comprises projections with adjusted
positions,
distance, geometry, diameter, and height.
[0034] In an alternative embodiment there is no gate. Instead the flow in at
least one
of the flow paths is made slower than in the other by making the flow path
longer and/or lowering the capillary force exerted on the liquid.
[0035] The distance, geometry, diameter, and height of the projections is
adapted so
that the capillary force is higher in the at least a part of the flow path and
one
of the sinks as compared to the flow path leading to the other sink.
[0036] In one embodiment at least one reagent is adsorbed on the surface of at
least
one of the flow paths. In another embodiment the reagent is adsorbed on the
flow path which exerts the lowest capillary force.
[0037] The flow paths exerting different capillary force on the liquid have in
one
embodiment different flow rates for the liquid, due to the different capillary
force.
[0038] One embodiment of the cross of flow paths in Fig 2 is depicted in Fig 3
and
consists in this particular embodiment of projections with different space to
create different capillary force.
[0039] In one embodiment as depicted in Fig 1 a there are two different sinks
exerting different capillary forces on the liquid. In an alternative
embodiment
as depicted in Fig 1 d there is one sink divided into two parts which are
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exerting different capillary force on the liquid. The border between the parts
is
indicated with a dashed line in Fig 1 d. When the part exerting the highest
capillary force is completely filled the liquid will start to flow in the
areas
exerting a lower capillary force on the liquid so that the action is similar
to that
in Fig 1 a and 1 b.
[0040] In one embodiment a substance is adsorbed and/or bound to the analysis
point. In one embodiment such a substance has the capability to bind to at
least one analyte. Examples of such a substance include an antibody.
[0041] In one embodiment at least one reagent is adsorbed or dried onto at
least
one flow channel. Such a reagent can be any chemical or biological entity
that is participating in an analysis. Examples of reagents include antibodies,
antibodies comprising a detectable entity, other detectable molecules, and
molecules with the ability to bind to an analyte.
[0042] In an alternative embodiment it is possible to perform a multistep
analysis
where for instance two, three or more reagents are added sequentially with a
time difference. Such an embodiment is shown in Fig 1 c, where two separate
reagents k and k' are added after each other. In one embodiment at least
three different capillary forces are exerted on said liquid; a first capillary
force
form a first sink, a second capillary force form a second sink and a third
capillary force from a third sink. In one embodiment there are different sizes
of the sinks shown in Fig 1 c. In another embodiment the projections are
adapted so that the exerted capillary force is different for the different
sinks
and flow paths.
[0043] In another embodiment it is possible to perform an analysis comprising
two or
more steps. In one embodiment an integrated analysis comprising three steps
is performed. A specific example of such an analysis is a device according to
Fig 1 c, where a first antibody directed against the analyte is bound to the
analysis point. In a first step the sample passes the analysis point and the
analyte is bound to a fraction of the first antibodies on the surface. In the
second step a second antibody directed against the analyte, which antibody
comprises a general binding unit passes the analysis point. In the second
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step the second antibody will bind to the analyte which is bound to the first
antibodies at the analysis point. In a third step a detectable molecule with
the
capability of binding to the general binding unit on the second antibodies
passes the analysis point. In the third step the detectable molecules are
bound to the antibodies. An advantage of this three step analysis is that the
third step is the same for all types of tests and that it thus can be
optimised
once for many different kinds of tests.
[0044] In a second aspect of the present invention there is provided a method
of
analysing a sample, wherein the analysis is performed using a device as
described above. In such a method the sample is preferably added to the
zone for receiving the sample. The method preferably comprises a step of
reading a result of the analysis.
[0045] In a third aspect there is provided a kit of parts comprising the
device as
described above and at least one reagent. Optionally the kit of parts
comprises a further assay device. Examples of such an assay device include
a holder for the device, a measurement apparatus where said device is
inserted or another device which facilitates the analysis. In one embodiment
such kit of parts comprises at least one package. In another embodiment the
kit of parts comprises a written instruction. In another embodiment the kit of
parts comprises a reader capable of performing a measurement on said
device. Such a reader may make a measurement on the analysis point.
[0046] When a liquid sample in one embodiment is added to the zone for
receiving a
sample, the liquid flows up to the gate in one flow path and a reagent is
dissolved by the sample. This is depicted in Fig 2a. Black rectangles
symbolises a reactant in Fig 2. In the other flow path the liquid flows into
the
zone for receiving a sample. The sample flows over the analysis point where
the measurement is performed. Due to the higher capillary force in one of the
flow paths the liquid flows along the flow path with the highest capillary
force
and fills the sink with the higher capillary force. Not until the sink with
the
higher capillary force is completely filled, the liquid will start to flow
into the
region with the lower capillary force. The time and the volume of sample that
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passes the analysis point in the first step is defined by filling the sink
with the
higher capillary force. In Fig 2b the sink with the higher capillary force is
completely filled and the sample starts to flow in the areas exerting a lower
capillary force on the liquid.
[0047] The liquid will then flow towards the gate and when the gate thus is in
contact
with a liquid from both sides the liquid can flow across the gate in both
directions. The liquid with the dissolved reactant will flow towards the other
sink as depicted in Fig 2c. In Fig 2c it is shown that the dissolved reactant
symbolised by a black rectangle passes the analysis point. In Fig 2d the
measurement is completed and all sinks are completely filled and/or there is
no more available sample volume. The time before the gate is opened can
thus be well defined and the time is adjusted so that the reagent is allowed
to
dissolve to a sufficient degree.
