U.S. patent application number 12/330583 was filed with the patent office on 2009-06-18 for microfluidic element for thoroughly mixing a liquid with a reagent.
This patent application is currently assigned to ROCHE DIAGNOSTICS OPERATIONS, INC.. Invention is credited to Christoph Boehm.
Application Number | 20090155925 12/330583 |
Document ID | / |
Family ID | 40589987 |
Filed Date | 2009-06-18 |
United States Patent
Application |
20090155925 |
Kind Code |
A1 |
Boehm; Christoph |
June 18, 2009 |
MICROFLUIDIC ELEMENT FOR THOROUGHLY MIXING A LIQUID WITH A
REAGENT
Abstract
A microfluidic element for thoroughly mixing a liquid with a
reagent used for the analysis of the liquid for an analyte
contained therein and a method thereof are disclosed. The
microfluidic element has a substrate and a channel structure. The
channel structure includes an elongate mixing channel and an output
channel. The mixing channel has an inlet opening and an outlet
opening, and is implemented to mix the reagent contained therein
with the liquid flowing through the inlet opening into the mixing
channel. The outlet opening of the mixing channel is in fluid
communication to the output channel. The outlet opening is
positioned closer to the middle of the length of the mixing channel
than the inlet opening.
Inventors: |
Boehm; Christoph;
(Viernheim, DE) |
Correspondence
Address: |
DINSMORE & SHOHL, LLP;ONE DAYTON CENTRE
ONE SOUTH MAIN STREET, SUITE 1300
DAYTON
OH
45402
US
|
Assignee: |
ROCHE DIAGNOSTICS OPERATIONS,
INC.
Indianapolis
IN
|
Family ID: |
40589987 |
Appl. No.: |
12/330583 |
Filed: |
December 9, 2008 |
Current U.S.
Class: |
436/174 ;
422/400 |
Current CPC
Class: |
B01F 15/0233 20130101;
B01L 2400/0409 20130101; B01F 1/0022 20130101; B01F 15/0201
20130101; B01L 2400/0688 20130101; B01L 2200/16 20130101; G01N
21/07 20130101; B01F 15/0404 20130101; B01L 2300/087 20130101; B01L
3/50273 20130101; Y10T 436/25 20150115; B01F 13/0059 20130101; G01N
1/38 20130101; G01N 2001/386 20130101; B01L 2300/0887 20130101 |
Class at
Publication: |
436/174 ; 422/99;
422/103 |
International
Class: |
B01F 13/00 20060101
B01F013/00; G01N 1/38 20060101 G01N001/38; B01F 5/00 20060101
B01F005/00 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 13, 2007 |
EP |
07 024 210.2 |
Claims
1. A microfluidic element for thoroughly mixing a liquid with a
reagent used for analyzing the liquid for an analyte contained
therein, the microfluidic element comprising: a cover layer; a
substrate; and a channel structure enclosed by the substrate and
the cover layer, wherein the channel structure includes an elongate
mixing channel and an output channel, wherein the mixing channel
has an inlet opening and an outlet opening, and the mixing channel
is adapted for mixing the reagent contained therein with the liquid
flowing through the inlet opening into the mixing channel, and
wherein the outlet opening of the mixing channel is in fluid
communication with the output channel, and the outlet opening is
located closer to the middle of the length of the mixing channel
than the inlet opening.
2. The microfluidic element according to claim 1, wherein the
microfluidic element is a test carrier.
3. The microfluidic element according to claim 1, wherein the
channel structure is a sample analysis channel which includes a
sample inlet opening and a measuring zone.
4. The microfluidic element according to claim 1, wherein the
microfluidic element is rotatable about an axis of rotation.
5. The microfluidic element according to claim 4, wherein the
mixing channel is so shaped that the distance of the outlet opening
from the axis of rotation is greater than the distance of the inlet
opening from the axis of rotation.
6. The microfluidic element according to claim 1, further
comprising a capillary stop which forms a flow resistance for the
liquid flowing from the mixing channel into the output channel in
such a manner that spontaneous emptying of the mixing channel into
the output channel is prevented until the flow resistance is
overcome by an external force.
7. The microfluidic element according to claim 6, wherein the
external force is a centrifugal force generated by rotation of the
microfluidic element and/or a pressure force which acts on the
liquid in the mixing channel.
8. The microfluidic element according to claim 6, wherein the
capillary stop is formed by a geometric valve, which includes a
primary section and a secondary section downstream from the primary
section in the flow direction, the cross-sectional area of the
primary section being smaller than the cross-sectional area of the
secondary section.
9. The microfluidic element according to claim 6, wherein the
capillary stop includes a channel section having at least one
hydrophobic channel wall.
10. The microfluidic element according to claim 1, wherein the
reagent is contained in the mixing channel in dried form.
11. The microfluidic element according to claim 1, wherein the
reagent is contained in the mixing channel in lyophilized form.
12. The microfluidic element according to claim 1, wherein the
outlet opening is positioned from the middle of the total length of
the mixing channel at a distance that is at most 20% of the total
length of the mixing channel.
13. The microfluidic element according to claim 1, wherein the
inlet opening is positioned from one end of the mixing channel at a
distance that is at most 20% of the total length of the mixing
channel.
14. The microfluidic element according to claim 1, wherein the
volume of the mixing channel is larger than the volume of the
output channel.
15. The microfluidic element according to claim 1, wherein the
mixing channel has a rectangular cross-section.
16. A method for providing a homogeneous thoroughly mixed liquid
comprising: providing a microfluidic element having a substrate and
a channel structure, wherein the channel structure includes an
elongate mixing channel and an output channel, wherein the mixing
channel has an inlet opening and an outlet opening in fluid
communication with the output channel, and wherein the outlet
opening is located closer to the middle of the length of the mixing
channel than the inlet opening; allowing a flow of liquid through
the inlet opening into the mixing channel; dissolving a reagent
contained in the mixing channel; exerting a force on the liquid in
the mixing channel; and allowing the liquid to flow into the output
channel through the outlet opening of the mixing channel so that
thorough mixing of the liquid and the reagent occur.
17. The method according to claim 16, wherein the mixing channel
has a feed section between the inlet opening and the outlet opening
and a complementary section, downstream from the outlet opening in
the flow direction and opposite to the inlet opening, wherein the
method further comprises flowing partial volumes from the feed
section and the complementary section of the mixing channel through
the outlet opening into the output channel such that mixing of the
two liquid partial volumes is supported by exertion of the force on
the liquid.
18. The method according to claim 16, wherein the exerted force is
a centrifugal force which is generated by rotating the microfluidic
element.
19. The method according to claim 16, wherein the microfluidic
element is a test carrier and the channel structure is a sample
analysis channel, which comprises a sample inlet opening and a
measuring zone.
Description
FIELD OF THE INVENTION
[0001] The present invention relates generally to mixing
structures, and in particularly to a microfluidic element for
thoroughly mixing a liquid with a reagent and a method thereof.
BACKGROUND OF THE INVENTION
[0002] Microfluidic elements for thoroughly mixing a liquid with a
reagent are used, for example, in diagnostic tests (in vitro
diagnostics), using the microfluidic elements bodily fluid samples
are analyzed for an analyte contained therein for medical purposes.
The term thoroughly mixing comprises both the possibility that the
reagent is provided in liquid form, i.e., that two liquids are
mixed with one another, and also that the reagent is provided as a
solid and is dissolved in a liquid and homogenized. An important
component of the analysis is a so-called test carrier, on which,
for example, microfluidic elements having channel structures for
receiving a liquid sample (in particular a bodily fluid) are
provided, to allow the performance of complex multistep test
protocols. A test carrier can comprise one or more microfluidic
elements.
[0003] For example, in immunochemical analyses having a multistep
test sequence, in which a separation of bound and free reaction
components occurs ("bound/free separation"), fluidic test carriers
are used, using which a controlled liquid transport is possible.
The control of the fluidic process sequence can be performed using
internal measures (inside the fluidic element) or using external
measures (e.g., provided in the device). The (external) control can
be based on the application of pressure differentials or a change
of forces, the latter being able to result from the change of the
action direction of gravity, for example, but also from centrifugal
forces which act on a rotating microfluidic element or a rotating
test carrier and are a function of the rotational velocity and the
distance from the axis of rotation, for example.
[0004] Microfluidic elements and also test carriers of this type
comprise a carrier material, typically made of a substrate made of
plastic material. The elements and test carriers have a sample
analysis channel enclosed by the substrate and a cover or a cover
layer, which often comprises a sequence of multiple channel
sections and chambers lying between them, which are widened in
comparison to the channel sections. The structures and dimensions
of the sample analysis channel having its channel sections and
chambers are defined by structuring of plastic parts of the
substrate, which are generated, for example, by injection molding
techniques or other methods for producing suitable structures.
[0005] To perform the analyses, the sample analysis channel
contains a reagent which reacts with a liquid introduced into the
sample analysis channel. The liquid sample and the reagent are
mixed in the test carrier with one another in such a manner that a
reaction of the sample liquid with the reagent results in a change
of a measured variable which is characteristic for the analyte
contained in the sample liquid. The measured variable is measured
on the test carrier itself. Above all, optically analyzable
measuring methods are typical, in which a color change or another
optically measurable variable is detected.
[0006] Predominantly laminar flow conditions prevail in the sample
analysis channel having its capillary channel structures and small
dimensions. Liquids and/or liquids and solids mix thoroughly only
poorly in such capillary channels. Multiple procedures are known in
the prior art for improving the thorough mixing of reagent and
sample liquid.
[0007] For example, in rotating test carriers which are rotated
around a rotation axis in an analysis system, the thorough mixing
is encouraged by rapid changes of the rotational direction or by
changing the rotational velocity. This "shake mode" places high
demands on the drive unit of the analysis system, however. The wear
and the danger of occurring malfunctions and breakdowns are
comparatively greater.
[0008] A further method known in the prior art for improving the
thorough mixing of sample liquid and reagent is the introduction of
magnetic particles which are set into motion by the action of an
electromagnetic or permanent magnet. The outlay in the production
of the test carrier rises due to the integration of the particles.
In addition, the analysis systems must have a further component,
namely the magnets.
[0009] Furthermore, elements are known whose capillary channels
contain special flow obstructions, such as ribs. The production of
obstructions of this type, which are often implemented as a
microstructure, makes the production process of the test carrier
more costly and difficult. In addition, structures of this type are
not suitable for all mixing processes and/or for all reagents and
sample liquids.
[0010] In spite of the many attempts to improve mixing procedures
and microfluidic elements, such as test carriers, in particular the
thorough mixing of reagent and sample liquid, there is a further
need for a microfluidic element improved in this regard.
SUMMARY OF THE INVENTION
[0011] It is against the above background that the present
invention provides embodiments which improve the thorough mixing of
reagent and sample liquid.
[0012] In one embodiment, a microfluidic element for thoroughly
mixing a liquid with a reagent used for analyzing the liquid for an
analyte contained therein is disclosed. The microfluidic element
comprises a cover layer, a substrate, and a channel structure
enclosed by the substrate and the cover layer. The channel
structure includes an elongate mixing channel and an output
channel, wherein the mixing channel has an inlet opening and an
outlet opening. The mixing channel is adapted for mixing the
reagent contained therein with the liquid flowing through the inlet
opening into the mixing channel, and wherein the outlet opening of
the mixing channel is in fluid communication with the output
channel, and the outlet opening is located closer to the middle of
the length of the mixing channel than the inlet opening.
[0013] In another embodiment, a method for providing a homogeneous
thoroughly mixed liquid is disclosed. The method comprises
providing a microfluidic element having a substrate and a channel
structure, wherein the channel structure includes an elongate
mixing channel and an output channel. The mixing channel has an
inlet opening and an outlet opening in fluid communication with the
output channel, and wherein the outlet opening is located closer to
the middle of the length of the mixing channel than the inlet
opening. The method further comprises allowing a flow of liquid
through the inlet opening into the mixing channel; dissolving a
reagent contained in the mixing channel; exerting a force on the
liquid in the mixing channel; and allowing the liquid to flow into
the output channel through the outlet opening of the mixing channel
so that thorough mixing of the liquid and the reagent occur.
[0014] These and other features and advantages of the present
invention will become apparent after reading the detailed
description of the various embodiments thereof in reference to the
accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] The present invention is illustrated by way of example and
not with limitations in the accompanying figures, in which like
references indicate similar elements, and in which:
[0016] FIG. 1 shows a test carrier having a sample analysis channel
and a mixing channel;
[0017] FIG. 2 shows a detail illustration of a capillary stop at an
outlet opening of the mixing channel from FIG. 1; and
[0018] FIGS. 3a and 3b show a schematic outline to explain the
thorough mixing achieved using the invention.
DETAILED DISCUSSION
[0019] Skilled artisans appreciate that elements in the figures are
illustrated for simplicity and clarity and have not necessarily
been drawn to scale. For example, the dimensions of some of the
elements in the figures may be exaggerated relative to other
elements to help to improve understanding of embodiment(s) of the
present invention. In addition, throughout the specification, and
in the claims, the meaning of "a", "an", and "the" may include
plural references. The meaning of "in" may include "in" and on
[0020] It is noted that recitations herein of a component of an
embodiment being "adapted" or "configured" in a particular way or
to embody a particular property, or function in a particular
manner, are structural recitations as opposed to recitations of
intended use. More specifically, the references herein to the
manner in which a component is either "adapted" or "configured"
denotes an existing physical condition of the component and, as
such, is to be taken as a definite recitation of the structural
characteristics of the component.
[0021] It is noted that terms like "generally," "commonly," and
"typically," when utilized herein, are not utilized to limit the
scope of the claimed embodiments or to imply that certain features
are critical, essential, or even important to the structure or
function of the claimed embodiments. Rather, these terms are merely
intended to identify particular aspects of an embodiment or to
emphasize alternative or additional features that may or may not be
utilized in a particular embodiment.
[0022] For the purposes of describing and defining embodiments
herein it is noted that the terms "substantially," "significantly,"
and "approximately" are utilized herein to represent the inherent
degree of uncertainty that may be attributed to any quantitative
comparison, value, measurement, or other representation. The terms
"substantially," "significantly," and approximately are also
utilized herein to represent the degree by which a quantitative
representation may vary from a stated reference without resulting
in a change in the basic function of the subject matter at
issue.
[0023] The invention and its advantages are described and explained
hereafter with reference in one embodiment to a test carrier for
the analysis of a bodily fluid sample for an analyte contained
therein without restriction of the generality of the microfluidic
element.
[0024] The microfluidic element according to one embodiment is
produced by appropriate structuring of a substrate, as described,
for example, in M. Madou, Fundamentals of Microfabrication, CRC
Press, Boca Raton, Fla., USA, 2002, the disclosure of which is
herein incorporated fully by reference. The channel structure
implemented in one embodiment as a channel includes an elongate
mixing channel, which has an inlet opening and an outlet opening
according to the invention and is implemented to mix a reagent
contained therein with a liquid flowing through the inlet opening
into the mixing channel. According to one embodiment, the mixing
channel is in fluid communication with an output channel via the
outlet opening.
[0025] In the meaning of the invention, a microfluidic element is
understood in one embodiment as an element having a channel
structure whose smallest dimension is greater than or equal to 5
.mu.m and whose largest dimension (for example, length of the
channel) is less than or equal to 10 cm.
[0026] An "elongate" channel is understood in the meaning of the
application as a channel whose length is significantly greater than
any cross-sectional dimension of its cross-sectional area. It is
implied that the length is at least 10 times as large as the
greater cross-sectional dimension in one embodiment. However, in
another embodiment, the length of the channel is at least 20 times
as large as the square root of the mean cross-sectional area of the
channel. In still another embodiment, the length is at least 50
times and in still yet another embodiment, 100 times as great as
the square root of the mean cross-sectional area. For a channel
having a circular cross-sectional area, the length is in one
embodiment 20 to 30 times as large as the radius.
[0027] It thus results for the dimensions that the largest
cross-sectional dimension of a channel structure of a microfluidic
element is at most in one embodiment 10 mm, and in another
embodiment at most 5 mm. The largest cross-sectional dimension is
more in one embodiment at most 2 mm, and in another embodiment at
most 1 mm.
[0028] In the context of the invention, the fact is taken into
consideration that a concentration gradient of the reagent arises
within the mixing channel in the flow direction. Under conditions
prevailing in microfluidic elements and/or test carriers, the
concentration is normally least in the area of the inlet opening of
the reagent and rises in the flow direction.
[0029] According to one embodiment of the invention, the outlet
opening is positioned closer to the middle of the length of the
mixing channel than the inlet opening. The mixing channel has a
feed section between the inlet opening and the outlet opening and a
complementary section downstream from the outlet opening (in the
flow direction) and opposite to the inlet opening, wherein after
the liquid flows into the mixing channel, the concentration of the
reagent in the complementary section being different, typically
higher, than the concentration in the feed section. The outlet
opening is positioned on the length of the mixing channel so that
the liquid flowing in the output channel through the outlet opening
contains partial volumes from the feed section and the
complementary section of the mixing channel in such a manner that
the two liquid partial volumes are mixed in an accelerated way. The
partial volumes (each flowing simultaneously through the outlet
opening) from the feed section and from the complementary section
have different concentrations of the reagent and are thoroughly
mixed upon flowing into the output channel.
[0030] In other words, the microfluidic element is implemented in
such a manner in one embodiment that the inlet opening of the
mixing channel is positioned closer to one end of the mixing
channel than the outlet opening. A liquid flowing through the inlet
opening into the mixing channel of the channel (such as a bodily
fluid sample) therefore flows from a position closer to the end of
the mixing channel toward the outlet opening and thus toward a
position closer to the middle of the length of the mixing
channel.
[0031] The feed section of the mixing channel thus extends from a
position closer to the end of the mixing channel to the outlet
opening position closer to the middle of the length of the mixing
channel. The complementary section is the part of the mixing
channel between the outlet opening (more in the middle of the
length) and the end of the mixing channel diametrically opposite to
the inlet opening. During the supply into the output channel of the
sample analysis channel, partial volumes flow simultaneously from
both sections of the mixing channel through the outlet opening, the
partial volumes of the particular section having different
concentrations. Mixing of the liquid is encouraged in this way, so
that a liquid having a homogeneous composition results rapidly.
Through the output channel (possibly through further channel
sections and/or channel chambers), the mixed liquid then reaches a
zone in which the mixed liquid is processed further.
[0032] The microfluidic element according to another embodiment is
part of a test carrier for the analysis of a bodily fluid sample
for an analyte contained therein. The test carrier in one
embodiment has a sample analysis channel enclosed by the substrate
and a cover layer, which in one embodiment is the channel structure
of the microfluidic element implemented as a channel. The term
"substrate" is understood to mean that it is a carrier material in
which the channel structure is introduced by structuring. For this
purpose, methods for production and also materials typical to those
skilled in the art are presumed, as are explained, for example, in
the above-mentioned reference, M. Madou, Fundamentals of
Microfabrication.
[0033] The sample analysis channel in one embodiment has a sample
inlet opening (inlet opening) at its beginning. At its end, the
sample analysis channel in one embodiment includes a measuring
zone, which corresponds to the zone for further processing of the
liquid in the microfluidic element. The liquid thoroughly mixed as
it flows into the output channel reaches the measuring zone of the
sample analysis channel through the output channel. In the
measuring zone of the sample analysis channel a measured variable
characteristic for the analyte is determined in one embodiment.
[0034] It is taken into consideration in the context of another
embodiment of the invention that a higher concentration gradient
occurs within the channel (sample analysis channel) if one or more
dried, for example, lyophilized reagents are contained in the
channel and are dissolved. Especially high concentration gradients
arise in one embodiment upon the re-suspension of the dried
reagents, because a liquid flowing into the mixing channel
dissolves the dried reagents and they are washed further in the
flow direction. In one embodiment, the reagents are already
dissolved and transported further in the area of the inlet opening
of the mixing channel upon entry of a liquid through the inlet
opening, so that the concentration of the reagents or the reagent
increases in the flow direction.
[0035] The element having its mixing channel with the inlet opening
in one embodiment is positioned at one end of the channel and the
outlet opening in one embodiment is positioned in the middle, which
connects to the output channel in the mixing channel, is also
capable of being used for other homogenization. For example, the
mixing of two different solutions as is required for dilution, for
example, is also improved hereby. The element and/or the test
carrier is thus not only restricted to dry reagents, but rather can
also be employed for mixing two liquids, in particular reagents
provided in liquid form.
[0036] The element according to various embodiments of the
invention such as, for example, the test carrier, has the following
noted advantages, but not limited thereto. The production costs of
the element or test carrier are practically not increased by the
mixing apparatus, because microstructures, such as ribs or
additional constrictions, are dispensed with. The analysis device,
with which the test carrier forms an analysis system, does not
require any special design. In particular, for rotating analysis
systems, no additional outlay is required for the drive (as for
systems using the shaking method, for example). The production
costs of the device are therefore also low. Additional substances,
such as magnetic particles (magnet beads), which have to be
introduced into the test carrier, are not necessary. The analyses
are therefore cost-effective and the (partially manual) effort is
low. Finally, the element is also suitable for thoroughly mixing
solutions having a large concentration gradient.
[0037] In one embodiment, the microfluidic element is rotatable
around an axis of rotation. The axis of rotation in one embodiment
extends through the element. Test carriers or microfluidic elements
which rotate around their center are especially suitable.
[0038] In another embodiment of the microfluidic element, a
capillary stop is positioned in the element, which forms a flow
resistance for liquid flowing from the mixing channel into the
output channel in such a manner that spontaneous emptying of the
mixing channel into the output channel is prevented until the flow
resistance is overcome by an external force. This prevents liquid
from entering the output channel through the outlet opening from
the mixing channel solely because of the capillary effect. The
capillary stop is in one embodiment positioned directly after the
outlet opening of the mixing channel.
[0039] The external force which is necessary for overcoming the
flow resistance in one embodiment is a centrifugal force which is
generated by rotation of the microfluidic element. The centrifugal
force and thus the reaction process and/or the thorough mixing
process can be controlled by suitable selection of the rotational
velocity or by change of the rotational velocity, for example, the
dwell time of a liquid in the mixing channel can be controlled.
[0040] The external force is also in one embodiment a pressure
force which acts on the liquid in the mixing channel. For example,
the pressure force can be implemented by generating an overpressure
or a partial vacuum within the test carrier.
[0041] The capillary stop in one embodiment has a channel section
which includes at least one hydrophobic channel wall. The channel
wall in one embodiment is made hydrophobic using a hydrophobizing
substance. A hydrophobic channel capillary block of this type also
prevents the independent flow through the channel section of this
channel.
[0042] An exemplary embodiment of a microfluidic element is
described hereafter on the basis of a test carrier (without
restriction of the generality) and on the basis of the drawings.
The technical features shown therein may be used individually or in
combination to provide other embodiments of the invention. They do
not represent any restriction of the generality.
[0043] FIG. 1 shows a test carrier 101 according to the invention
having a substrate 102 and a hole 103 in the center of the test
carrier 101, through which an axis of rotation extends, around
which the disc-shaped test carrier 101 rotates.
[0044] A sample analysis channel 104 includes a sample inlet
opening 105 at its beginning, through which a liquid sample, which
in one embodiment is blood, for example, can be introduced into the
sample analysis channel 104. For example, a sample liquid can be
dispensed by a user manually (using a pipette) into the sample
inlet opening 105. Alternatively, a sample can be dosed by a dosing
station of an analysis device through the sample inlet opening 105
into the sample analysis channel 104. At its end, the sample
analysis channel 104 enclosed by the substrate 102 includes a
measuring zone 106, in which a measured variable characteristic for
an analyte in the sample liquid is detected, and in one embodiment
also optically measured.
[0045] The sample analysis channel 104 includes a mixing channel
107, in which a reagent is contained in dried form, in one
embodiment in lyophilized form. The dried reagent is dissolved by
the inflowing liquid in the mixing channel 107.
[0046] The mixing channel 107 has an inlet opening 108, which has a
fluid connection to the sample inlet opening 105, at one end
(beginning). At its other end, a barrier 109 is provided, which is
implemented as a geometric valve, and is used to ventilate the
mixing channel.
[0047] An outlet opening 110 is positioned in the middle of the
length of the mixing channel 107, via which the mixing channel 107
has a fluid connection to an output channel 111. A capillary stop
112, which is implemented as a geometric valve, is positioned
between the outlet opening 110 and the output channel 111. It is
shown in detail in FIG. 2. The capillary stop 112 prevents a liquid
contained in the mixing channel 107 from flowing automatically
(self-acting) into the output channel 111. The capillary forces
acting on the liquid in the channels 107, 111 are insufficient to
overcome the capillary stop 112. This ensures that the mixing
channel 107 can be filled by a defined sample volume. The flow
resistance of the capillary flow 112 is first overcome when the
rotational velocity, at which the test carrier 101 is rotated,
generates a sufficiently great centrifugal force, which acts on the
liquid in the mixing channel 107. The action (action time) of the
sample liquid on the reagent contained in the mixing channel 107
can thus be controlled.
[0048] The mixing channel 107 in one embodiment has a rectangular
cross-section. In case of a rotating test carrier 101, the mixing
channel 107 is implemented in such a manner that the greater
cross-sectional dimension extends in a plane of rotation running
perpendicularly to the axis of rotation. The other channels, in
particular the output channel 111, are in one embodiment also
implemented as rectangular. They thus have a rectangular
cross-section. Channels or channel structures of this type are very
simple and cost-effective to produce.
[0049] The mixing channel 107 shown in this exemplary embodiment
forms a semicircle, which extends at a constant radius around the
axis of rotation (hole 103) of the test carrier 101. The inlet
opening 108 and the outlet opening 110 of the mixing channel 107
are, as shown here, in one embodiment positioned in such a manner
that the distance of the outlet opening 110 from the axis of
rotation is greater than the distance of the inlet opening 108 from
the axis of rotation. This has the advantage that the mixing
channel 107 can be emptied completely. The entire volume flowing
into the mixing channel 107 can be conducted to the measuring zone
106 and is available for the analysis of the sample liquid. Of
course, another configuration of the mixing channel 107 is also
possible. For rotating test carriers 101, the distance of the
outlet opening from the axis of rotation is in one embodiment
always to be greater than the distance of the inlet opening, so
that the liquid is pressed out of the outlet opening 110 by the
centrifugal forces arising upon the rotation.
[0050] The mixing channel 107 includes a feed section 113 between
the inlet opening 108 and the outlet opening 110 and a
complementary section 114 between the outlet opening 110 and the
barrier 109 at the end of the mixing channel 107. When a sample
liquid flows through the inlet opening 108 into the mixing channel
107, the reagent contained in the mixing channel 107 is dissolved.
The dissolved parts of the sample liquid are transported in the
flow direction through the mixing channel 107. A concentration
gradient results in the mixing channel 107 through the further
transport of the dissolved reagent parts, wherein a lower
concentration of the reagent exists in the feed section 113 than in
the complementary section 114. The concentration in the mixing
channel 107 is greatest in the area of the barrier 109, and lowest
at the inlet opening 108.
[0051] In general, only poor thorough mixing occurs in the mixing
channel 107 because of the capillary flow conditions. Upon reaching
a suitable rotational velocity, at which the flow resistance of the
capillary stop 112 is overcome by the sample liquid, however,
partial volumes flow from the feed section 113 and from the
complementary section 114 through the outlet opening 110 into the
output channel 111. The individual partial volumes are thoroughly
mixed in the output channel 111 rapidly, so that a homogeneous
composition arises.
[0052] The procedure of the thorough mixing is shown in FIGS. 3a
and 3b on the basis of a schematic outline, which shows the mixing
channel 107 and the output channel 111 (without capillary stop
112). The concentration of the reagent in the mixing channel 107 is
schematically shown on the basis of symbolic concentration values 2
through 14 (in arbitrary units). Of course, in practice the
concentration distribution in the mixing channel is not discrete as
shown in the outline here. Typically, a continuous, not necessarily
linear distribution is formed.
[0053] After a liquid has flowed into the mixing channel 107 and
the reagent is dissolved, a concentration distribution shown in
FIG. 3a results. The concentration in the mixing channel 107 is
less in the feed section 113 than in the complementary section 114.
The concentration is lowest at the right end in FIG. 3, and
greatest at the left end in FIG. 3. Partial volumes flow from the
feed section 113 and the complementary section 114 into the output
channel 111 from the filled mixing channel. As shown in FIG. 3b,
the flow paths resulting in the output channel 111 from the
individual sections 113, 114 supplement one another mutually
(ideally complementary) to one another in such a manner that an
optimized and very uniform thorough mixing of the sample liquid
with the reagent occurs.
[0054] It has been shown in the context of the invention that
optimum mixing results are achieved by positioning the inlet
opening 108 at one end of the mixing channel 107 and positioning
the outlet opening 110 in the middle of the mixing channel 107.
Slight variations of the optimum positioning of the two openings
108, 110 do not result in significant impairment of the mixing
results. In one embodiment, the outlet opening 110 is positioned in
such a manner that it is positioned at most 20% of the length of
the mixing channel 107 distant from the middle of the length of the
mixing channel 107. In another embodiment, the inlet opening 108 is
at most 20% of the length of the mixing channel 107 distant from
one end of the mixing channel 107. If the openings 108, 110 are
positioned within the above mentioned tolerance width, very good
mixing results are achieved. The influence on the mixing results in
comparison to the optimum result is negligible for a distance from
the optimum location up to at most 5%.
[0055] At suitable rotational velocities, a separation of red blood
cells and other cellular sample components already occurs in the
output channel 111. The thoroughly mixed liquid, comprising sample
liquid and reagent dissolved therein, is conducted at suitable
rotational velocities into a collection chamber 115 (plasma
collection chamber) and a collection chamber 116 (erythrocyte
collection chamber). The red blood cells collect in the collection
chamber 116 due to the acting centrifugal forces, while the blood
plasma essentially remains in the collection chamber 115.
[0056] The measuring zone 106 is in one embodiment implemented as a
porous, absorbent matrix. If the rotation of the test carrier is
stopped or slowed, the reagent-sample mixture is absorbed
(suctioned) into the measuring zone 106. A waste chamber 117 is
positioned behind the measuring zone 106 in the flow direction, in
which the reaction participants, sample and/or reagent components,
are disposed of after flowing through the measuring zone 106.
[0057] The test carrier 101 of the exemplary embodiment shown also
has a priming structure 121, which includes a flushing liquid
opening 122 and a flushing liquid collection chamber 123.
[0058] The test carrier 101 has a second channel 124 having a inlet
opening 131. The channel 124 essentially corresponds in its
structure to the sample analysis channel 104. However, it describes
a quarter circle in contrast to the sample analysis channel 104.
The second channel 124, which can also be a sample analysis
channel, includes a mixing channel 125, an output channel 126, and
a capillary stop 127 positioned between them. Its length, at
approximately 25 to 30 mm, is approximately half of the length of
the sample analysis channel 104 (55-65 mm). The width of the two
channels 104, 124 is 3 mm each, while the depth (dimension in the
axial direction of the axis of rotation) is approximately 0.15
mm.
[0059] The channel 124, which is also in fluid communication with
the collection chamber 115, is used in particular to receive a
further liquid, in particular a buffer solution, which is required
for the analysis, for example, for the bound/free separation. A
reagent is in one embodiment contained in the mixing channel 125,
which is used for the analysis of the sample liquid analyzed in the
measuring zone. Alternatively, a further (different) sample and/or
a (different) reagent can also be thoroughly mixed with the sample
in the channel 124. The thoroughly mixed liquid is then conducted
to the measuring zone 106.
[0060] FIG. 2 shows the capillary stop 112 in detail. The capillary
stop 112 is formed by a geometric valve 128, which includes a
primary section 129 and a secondary section 130, which adjoins the
primary section 129 in the flow direction. The cross-sectional area
of the primary section 129 adjoining the outlet opening 110 is less
than the cross-sectional area of the secondary section 130.
[0061] With a rectangular cross-sectional area of the capillary
channels, the primary section 129 of the capillary stop 112 is also
rectangular; it thus also has a rectangular cross-sectional area,
as does the secondary section 130. The cross-sectional dimension of
the primary section 129 in the axial direction of the axis of
rotation is in one embodiment less than the corresponding
cross-sectional dimension of the secondary section 130. The
cross-sectional dimension of the primary section 129 in the
direction transverse to the axis of rotation is also less than the
corresponding cross-sectional dimension of the secondary section
130. The flow resistance of the geometric valve 128 can be set by a
suitable selection of the dimensions of the primary section 129 and
the secondary section 130.
[0062] The required centrifugal force and thus the rotational
velocity of the test carrier 101 which is necessary so that a
liquid can flow through the capillary stop 112 are thus
established.
[0063] The foregoing exemplary descriptions and the illustrative
preferred embodiments of the present invention have been explained
in the drawings and described in detail, with varying modifications
and alternative embodiments being taught. While the invention has
been so shown, described and illustrated, it should be understood
by those skilled in the art that equivalent changes in form and
detail may be made therein without departing from the true spirit
and scope of the invention, and that the scope of the present
invention is to be limited only to the claims except as precluded
by the prior art. Moreover, the invention as disclosed herein, may
be suitably practiced in the absence of the specific elements which
are disclosed herein.
* * * * *