CA1229826A - Device and method providing liquid mixing outside containers - Google Patents

Abstract

DEVICE AND METHOD PROVIDING LIQUID MIXING
OUTSIDE CONTAINERS
Abstract A device and method are described for forming a drop of two liquids pendent each from a separate plat-form. Means are included for moving the platforms from a spaced-apart position to one in which the drops con-tact each other and coalesce, while still pendent from the platforms.

Description

~22~6 DEVICE AND METHOD PROVIDIN& LIQUID MIXIM~
UTSIDE CONTAINERS
FIELD OF THE INVENTION
This invention relates to the metering of small quantities of mixed, low relative viscosity liquids.
BACKGROUND OF THE INVENTION
There is a need for a device that will allow intermixing of two small quantities (from about 5 to about 10 ~1 each) of low relative viscosity liquids~
prior to the mixture being m~tered or dispensed onto or into some other element. An example of such a need is in the field of the immunoassay of biological analytes.
More specifically, recent advances in the analysis of biological liquids such a8 serum have lS allowed the use of as little as 10 ~1 of the liquid, for the test. Examples of test elements suitable for radiometric assays using such small amounts are described in U.S. Patent Nos. 3,992,158, issued on November 16, 1976, and 4,2589001, issued on March 24~
1981. A large number of analytes have been proven to be amenable to such tests.
One portion of olinical analysis which would benefit from the use of such test elements is the fleld of immunoassay. Immunoassays usually involve the formation of an antibody-antigen complex ir~ which known amourlts of labeled antigen (or antlbody) compete with unlabeled, unknown amounts of the same antigen ~or anti body) from the p~tient. In conducting such tests, one procedure adds the labeled antigen or antibody as a dil-uent to the patient's sample immedlately prior to addingthe sample to the test element. The total liquid as diluted still preferably is only from about 10 ~1 to about 20 ~1, to minimiæe the amount of labeled antigen or antibody that is required. Because of the porosity and high rates of flow present in test elements of the types described in the aforesnid U.S. patent~, it ~s ,~.

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difficult in all embodiments to achieve such dilution or mixing by applying first a drop of the sample to such a test element, and then a drop of the diluent. The rapid absorption by the test element in such embodiments prevents the two sequentially added drops from mixing.
However, if the mixing of the diluent and pati-ent sample occur within a container prior to contact with the test element, one or two problems are likely to occur: either the liquids will not intermix well be-cause their small quantities will be spread out onto thewalls of the container, or if intermixed, they still will be primarily on the container walls, with very little left to meter. The problem is particularly acute when, as in i~munoassays, the diluent and the patient sample occupy about equal volumes, e.g., from about 5 ~1 to about 10 ~1 each.
Although conventional metering devices of var-ious kinds have been available prior to this invention, none of them have been adequate to solve the afore-mentioned problems. For example, very complex devices have been constructed to cause a stream of drops to impinge on each other in mid-air. Such a system is gen-erally unacceptable for clinical analysis metering, due to its complexity and instability.
SUMMARY OF THE INVENTION
As a solution to ~he afore-described problems, this invention provides a device and a method for mixing two low relative viscosity liquids outside of a con-tainer. The manner in which this ;s achieved is par-~0 ticularly useful to subsequent use oE the coalesced and mixed drops in a clinical assay.
More specifically, in accord with one aspect of the invention there is provided a device comprising first and second dispensing chambers each constructed to dispense a low relative viscosity liquid therefrom, such as biological liquids. The device is improved in that it includes means for mixing the liquids outside the chambers, the mixing means comprising means or pres-surizing the dispensing chambers, and moving means for providing relative movement of the dispensing chambers from a first position in which the chambers are spsced apart, to a second position in which the chambers are sufficiently proximate as to cause liquid dispensed from one chamber to coalesce and intermix with liquid dispensed from the other chamber, and thence to the first position-In accord with ~he method aspect oE the inven-tion, a method of mixing two low relative viscosity liquids outside a container is provided. The method comprises the steps of a) forming a drop of each of the lS liquids so as to be pendent from a platform, and b) before, during or after step a), moving the platforms from a first spaced-apart position to a second position in which the formed drops coalesce while still pendent from the platforms, and intermix.
Thus, it is an advantage of the device and method of the present inven~ion that very small quan-tities of liquid can be intermixed in a form that per-mits substantially all of the intermixed llquid to be subsequently dispensed onto a test element.
It is a related advant~ge of this device and method that small amounts of diluent containing a labelPd antigen or antibody can be admixed with a patient's serum sample prior to the mixture being dls-pensed onto an immunoassay test element.
It is a further advantage of this device ~nd method that such mixing can be achieved without inter-fering with the function of aspirating to obtain the liquids in the first place.
Other features and advantages will become apparent upon reference to the followlng Description of the Preferred Embodiment, when read in light of the attached drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is an elevational view, partially broken away and sectioned along the midplane of a device con-structed in accordance with the invention;
Fig. 2 is an enlarged, fragmentary and sectioned view of the dispensing end of the disposable container used with the device;
Fig. 3 is a fragmen~ary sectional view taken generally along the lirle III-III of Fig. 1, but with the moving means omitted for clarity;
Fig. 4 is an enlarged, fragmentary elevational view similar to that of Fig. 1~ showing the parts moved to a second, dispensing and mixlng position;
Fig. 5 is an enlarged fragmentary view in sec-tion, of a different portion of ~he elevationsl view of Fig. 1, with the piston rods and control knob removed for clarity;
Fig. 6 is a fragmentary ~ection view taken gen-erally along the line VI-YI of Fig. 1, but with a piston chamber re~oved for clarlty;
Fig. 7 is the same view as Fig. 5, but wlth the parts moved to a different position adapted for mixing;
Figs. 8A through 8D are schematic views of the disposable containers and the~r pendent drops, illustra-ting the operating sequence of the de~ice;
Fig. 8E is a schematic view slmilar to Figs.
8A-8D, but illustrating sn ~lternative use of the device; and Fig. 9 is an elevational view similar to that of Flg. 5, illustrating an alternate embodiment.
DESCRIPTION OF T~lE PREFERRED EMBODIMENTS
We have discovere-l means by wh~ch small amounts 35 of low relative viscoslty liquids can be mlxed outside a container, while ~aintained in a generally stable format.

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The invention is hereinafter described as a hand-held pipette that is particularly useful in dis-pensing biological liquid for an immunoassay, the pre-ferred embodiment, using disposable containers. In addition, the in~ention is useful as a device for pro-viding mixing of low relative viscosity liqulds outside of a container for any end use whatsoever, whether or not the device i8 a pipette. For example, low relative viscosity industrial liquids can be ~dmixed by this invention. Furthermore, although the inven~ion is par-ticularly useful in admixing very small quantities, it is applicable to larger quantities as well. Still fur-ther, although the preferred embodiment is hand-held, the invention is also applicable to a metering device that is completely automated. Still further, the inven-tion is applicable to such a device whether the dis-pensing chambers for the liquid are integral with the device, or are disposahle containers.
As used herein, "biological liquids" means all liquids obtained from animals, including whole blood, serum, sweat, spinal fluid and urine, and low relative viSc06ity liquids compatible with these animal liquids, such as saline solutions and immunoassay diluents con-taining labeled antlgens or antibodies. "Low rela~ive viscosity", as used h~rein, means relative viscosities no greater than about 20 when measured at 25~C. Liquids having relative viscosities larger than thi~ do not intermix well, over a reasonable time period, e.g.~ a few seconds, merely by coalescing with a drop of liquid having a dlfferent surface tension. For example, epoxies with a relative visc06ity of 100 do not mix well enough by this mechanism, within a reasonable length of time, to allow ~heir usage with this invention~
As shown in Flg. l~ a pipette lO constructed in accordance with the invention comprises a gener~lly hol~
low frame 12 having a front or dispensin~ end 14 and a ~2~

renr or ~ctu~ting end 16. To aspirate biological liquids into, and force ~ pendent drop to form on, two disposable contniners Cl and C2, piston chambers 40, 42 and piston rods 50, 52 at end 14 are ~ctu~ed by a connecting cross-member 70 opera~ed by ~ plung2r 80 and button 82 at end 16.
Considering first the dlspensing end 14, pipette 10 is intended to be used with disposable con-t~iners Cl and C2, constructed as describ~d, forex~mple, in U.S. Patent No. 4,347,875, issued on September 7, 1982, That is, these contalners have ~n intern~l bore 20 sloped to ~llow end 22 thereof to be force-fitted onto a tapered nipple 24 of piston chambers 40 ~nd 42. The opposite ends 26 of contalners Cl and C2 have a tapered structure adapted to prevent liquid that remains on the exterior sfter Rspiration, from flowing down to an interfering posltion ad~acent to platfor~ 28 of the container. Platform 28, Fig. 2, i~
especially constructed as described in U.S. Patent No.
4,041,995, to allow liquid expressed rom aperture 30 surrounded by ~nd cen~ered generally within pl~tform 2~, to remaln pendent from the platform ~s shown by the dotted meniscus shape.
Piston ch~mbers 40 ~nd 42 have an l~ter~l di~-meter 44 and 46, Figs. 1 ~nd 3, constructed to ~cco~-modate ends 48 o piston rods 50 snd 52, AS is con~en-tional. Se~ls such as 0-rlngs or qu~d se~ls 54 allow the insertion ~nd withdr~wAl of rvds 50 und 52 to ~en-erate pressure or Qn aspirAting ~cuum, respectively, wlthin the ch~mbers and thus on liquid ln or outslde of, respectively, containers Cl and C2. Each entire piston ch~mber 40 ~nd 42 is mounted wlthin frame 12 by flAnge 55 thnt is seeured ~ d~scribed herelnsfte .

3;26 Ends 56 of piston rods 50 and 52 are secured to cross-member 70 so that both rods are simultaneously moved when cross-member 70 is moved. More specifically, Figs. 3 and 4, ends 56 are hooked at 58 to accommodate within the hook a pin 60. Pin 60 in turn extends thP
thickness of member 70, through slots 62. Cross-member 70 preferably is a U-shaped channel having flanges 64, the end portions 66 of which bear slots 62, Fig. 4. The depth of slots 62 is such that pin 60 i6 free ~o slide into cross member 70, as indicated by arrow 68, Fig. 4, when cross-~ember 70 is depressed and containers Cl and C2 are moved together, as described hereinafter.
Cross-member 70 is joined to plunger 80 at end 84 of the plunger~ Fig. 1. A locking flange 86 is secured around plunger 80 intermediate button 82 ~nd end 84. A compression ~eturn spring 88 is mounted between flange 86 and a portion of frame 12. To control the amount of return travel of plunger 80 and of the with-drawal of rods 50 and 52 from chambers 40 and 42, a locking flange 90 is adjustably secured around plunger 80 within frame 12 ~t end 16 thereof.
In accordance with one aspect of ~he lnvention, to move cont~iners Cl and C2 from their spaced-apart position shown in Fig. 1~ ~o one in whlch the containers are so close as to cause their pendent drops to contact each other, moving means are provided. Such means com-prlse, Figs. 5 and 6, a rotatable disc 100 mounted on or integral with ~ rotatable pin 102 ~ourn~lled to frame 12. Links 104 and 10~ are pivotally connected at their ends 108 to disc 100, off-center rom pin 102. The opposite ends 110 o links 104 and 106 are respectively ~ournalled to a portion of chambers 40 and 42 that is preferably recessed at 112) Fig. 5, to receiv~ the links. Pin 102 extends outward beyond Erame 12 at one 3S surface 114~ Figs. 1 and 6~ to accommodate a con~rol knob 116 secured thereto.

To allow ch~mbers 40 and 42 to pivo~ under the action of knob 116, pin 102, disc lOO and links 104 and 106, flanges 55 of the chambers are p~votally mounted on frame 12, Figs. 3 and 5, at end 120 thereof.
Operation The moving action of knob 116 and its inter-connections to chambers 40 and 42 is apparent from Figs.
5 and 7. When knob 116, not shown in these views, is rotated counterclockwise, disc 100 rotates counterclock-wise (arrow 130). Links 104 and 106 in turn pivot also, Fig. 7, so as to come closer together~ This in turn pulls chambers 40 and 42 closer together about their plvot points at ends 120. More specifically, each axis 140 of chambers 40 and 42, Fig. 7, is rotated ~hrough an equal but opposite angle alpha measured from the g2n-erally parallel positlons the chambers previously occupied as shown in Fig. 5. To move the chambers back to the posltion of Fig. 5, rotation is re~ersed, as indicated by the clockwise arrow 150, Fig. 7.
~he preferred, overall use of the pipette, apparent from the preceding discussion~ is as follows.
With the piston chambers 40 and 42 in their spaced-~part position as shown in Fig. 1, empty dlsposable containers Cl and C2 are itted onto nipples 24 so as to be generally parallel to each other with plat~orms 28 aligned in generally a common plane. Plpett~ 10 ~s then positioned above two rel~tively larger containers of liquids 7 not shown, spaced apart on center the same dis-tance that containers Cl and C2 are spaced apart.
Most preferably, one of the liquids i~ a patient's sam ple o~ body liquid, such as serum, and the other is a diluent, such as a water-based solution or mixture of la`beled antigens or antlbodies. Button 82 is fully depressed until it contacts A stop such as the top surface oE end 16. While button 82 is held down, ~;~Z~8%if~
g containers Cl and C2 are inserted into their respective liquids. Bu~ton 82 is then released to aspirate the liquids into their respectîve containers Cl and C2.
Pipette 10 is then removed, preferably to a station containing a teæ~ element. As shown in Fig. 8A, button 82 is depressed an amount sufficient to form drops 200 and 202, pendent from platforms 28. If the pipette is a "single-shot" pipette, the volume of such drops is approximately the same as was aspirated, for example, between about 5 and about 10 ~1.
While button 82 is still depr~ssed to keep the drops pendent from their platforms, knob 116 is rotated counterclockwise, Fig. 1, to cause chambers 40 and 42, and their containers Cl and C2, to pivot towards each other, Fig. 8B. The pivot angle alpha for both containers is ~1 at this time. Slot 62 allows end 56 of rods 50 and 52 to move towards each other, Fig.
4. Knob 116 is rotated further, until angle ~lpha equals ~2 and platforms 28 are so close that drops 200 and 202 coalesce, FLg. 8C. Mixing immedia~ely com-mences, at a rate that is generally proportional to the difference between the surface tensions of the llquids of the two drops, and inversely proportional to their viscosities. If desired, sprlng-biased detents, not shown, are useful to t~mporarily hold the pis~on cham-bers and thelr containers Cl and C2 in elther oE
their two extreme positlons that produce angle alpha equal to ~ero (Fig. 8A) or to ~2 (Fig. 8C). Such detents, if used, are mounted on the undersurfAce of knob 116 so as to ride over surface 114 of Erame 12, Fig. 6, until they seat ln recesses, also not shown, that are aligned with such values of angle alpha.
AEter the desired a~ount of mixing has occur-red, the coalesced drop 200-202, Fig. 8D, is touched ofE
onto a suitable ~est element 3000.

Thereafter~ knob 116, Fig. 1, ls rotated clock-wise to return the containers Cl and C2 to their Fig. 1, spaced-apart position (wherein angle alpha equals zero3. Containers Cl and C2 are then pref-erably removed for discarding.
Xt will be readily appreciated that an advaD-tage in having the containers moved from their first position, shown in Fig. 8A, to the position shown in Fig. 8C, and back again is that it is the first position in which the disposable containers Cl and C2 are readily mounted and demounted. Furthermore, the first position is preferred, and indeed required compared to the position of Fig. 8C, for aspiration. Still further, it is preferred, though not essential, that the pendent lS drops be formed while the containers are in the posi-tions shown in Figs. 8A or 8B, rather than 8C. The reason is that, such spaced-apart positions allow each drop to form independently, a step that is visually or optically detectable.
The alternative use suggested above is demon-strated in Fig 8E, wherein ejection of the liquids to form pendent drops does not occur until the containers are moved to their proxima~e positions, wherein ~ =
~2~ When button 82 is depressed, the liquids almost immediately form a single pendent drop 204 that increases in diameter, as shown in dashed lines, until the drop ls fully formed.
Alternatively, unlike the previously described embodiments, it is not necessary that the moving means be connected to the piston chambers and the containers so as to move both containers simultflneously, through equal but opposite angles of rotation from their spaced-apart, parallel position. Fig. 9 illustrates an alternate embodiment wherein each container is indepen-dently movable from its flrst, parallel positlon, with-out necessarily equalling the amount or the time of movement of the other container. Parts similar to those previously described bear the same reference numeral, to which the distinguishing suffix "a" has been added.
Thus, pipette lOa Eeatures a dispensing end 14a, and an actuating end (not shown), provided with piston chambers 40a and 42a, and piston rods and plunger (not shown) constructed as described beÇore. However, the moving means comprises buttons 300 and 302, each for its own piston chamber, mounted on a plunger 304 and 306, respectively, that connects with flange 55a of the piston chamber. Compression return springs 310 surround plungers 304 and 306, mounted between buttons 300 and 302 and the Erame 12a oE the pipette. When a button 300 or 302 is pressed against the action of its spring, each container independently pivots inwardly, arrows 320, towards ~he other container. Preferably, but not neces-sarily, the pivot amounts of the two containers are selected to be generally equal by applying generally equal pressure to buttons 300 and 302. Holes 350 in frame 12a for the passage of plungers 304 and 306 are made wide enough to accommodate the slight vertical dis-placement due to the pivotal motion.
In yet another alternative embodiment~ a multi-drop pipette can incorporate the invention so that a multiple of the volume of the pendent drop i9 aspirated into cootainers Cl and C~ for sequential, multiple drop ~ormation. In such a case, a conventional ratchet mechanism, not shown, is added to insure that liquid increments of from about 5 ~o about 10 ~l are 3~ metered in successive drops.
The invention has been described in detail with particular reEerence to preferred embodiments thereoÇ, but it will be understood that variations and modifica-tions can be effected within the ~pirit and scope of the invention.

Claims (19)

WHAT IS CLAIMED IS

1. In a pipette device comprising first and second dispensing chambers each constructed to dispense a low relative viscosity liquid therefrom, means for aspirating a quantity of such liquid into said chambers, and means for pressurizing said chambers to form a dis-pensable drop of such liquid from each chamber;
the improvement wherein said pipette device includes moving means for providing relative movement of said dispensing chambers from a) a first position in which said chambers are spaced apart, to b) a second position in which said chambers are sufficiently proximate as to cause a drop dispensed from one, to coalesce and intermix with a drop dispensed from the other, and c) thence to said first position.

2. In a dispensing device comprising first and second dispensing chambers each constructed to dispense a low relative viscosity liquid therefrom;
the improvement wherein the device includes means for mixing said liquids outside said chambers, said mixing means comprising means for pressurizing said dispensing cham-bers, and moving means for providing relative movement of said dispensing chambers from a) a first position in which said chambers are spaced apart, to b) a second position in which said chambers are sufficiently proximate as to cause liquid dispensed from one, to coalesce and intermix with liquid dispensed from the other, and c) thence to said first position.

3. A device as defined in claim 1 or 2, where-in said chambers are interconnected through said moving means.

4. A device as defined in claim 1 or 2, where-in said first position is one in which said chambers are generally parallel, and said second position is one in which both of said chambers are pivoted away from their orientation in said first position by generally the same, but opposite, amount.

5. In a device for use with two containers having each an apertured platform constructed to suspend a pendent drop of liquid having a low relative viscosity, said device including holding means for mount-ing said containers in a side-by-side relationship and pressurizing means for developing pressure effective to form such a pendent drop at said each platform, the improvement wherein said device further includes moving means for providing relative movement of said holding means from a first position in which said holding means are spaced apart, to a second position effective to cause said pendent drops, when formed by said pressurizing means, to contact each other so as to coalesce and intermix outside said containers, and thence to said first position.

6. In a pipette device for use with two dis-posable containers having each an apertured platform constructed to suspend a pendent drop of a biological liquid, said pipette device including holding means for mounting said containers in a side-by-side relationship, means for aspirating a quantity of such liquid into such containers when held by said holding means, and pres-surizing means for developing pressure effective to form a drop of such aspirated liquid pendent from said each platform, the improvement wherein said pipette device further includes moving means for providing relative movement of said holding means from a first position in which said holding means are spaced apart so as to permit said aspirating means to draw such liquids from two different sources, to a second position in which said pendent drops contact each other so as to coalesce and intermix, and thence to said first position.

7. In a dispensing device comprising holding means for mounting two containers of low relative vis-cosity liquid, in a side-by-side relationship, said con-tainers being constructed to dispense said liquids under pressure from said containers through an aperture in a platform surface on each of said containers;
the improvement wherein the device includes means for mixing said liquids outside such containers while pendent from said platform surfaces as drops, said mixing means comprising means for simultaneously pres-surizing said holding means and such containers mounted thereon, and moving means for providing relative movement of said holding means from a first position in which said holding means are spaced apart, to a second position in which said drops, when formed by said pressurizing means, contact each other while still pendent so as to coalesce and intermix outside the containers, and thence to said first position.

8. A device as defined in claim 5, wherein said holding means are interconnected through said moving means.

9. A device as defined in claim 8, wherein said first position is one in which said holding means and such containers are generally parallel, and said second position is one in which both of said holding means and such containers are pivoted away from their orientation in said first position by generally the same, but opposite, amount.

10. A device as defined in claim 5, 6, or 7, wherein said moving means permits one of said holding means to be moved without moving said other holding means.

11. In a pipette device including two con-tainers having each an apertured platform constructed to suspend a pendent drop of a biological liquid, holding means for mounting said containers in a side-by-side relationship, means for aspirating a quantity of such liquid into such containers held by said holding means, and pressurizing means for developing pressure effective to form a drop of such aspirated liquid pendent from said each platform, the improvement wherein said pipette device further includes moving means for providing relative movement of said containers, from a first position in which said containers are spaced apart so as to permit said aspirating means to draw such liquids from two different sources, to a second position in which said pendent drops contact each other so as to coalesce and intermix, and thence to said first position.

12. In a dispensing device including two con-tainers for low relative viscosity liquid, constructed to dispense such liquids under pressure from said con-tainers through an aperture in a platform surface on each of said containers, and holding means for mounting said containers in a side-by-side relationship;
the improvement wherein the device includes means for mixing said liquids outside such containers while pendent from said platform surfaces as drops, said mixing means comprising means for pressurizing said holding means and such containers mounted thereon, and moving means for providing relative movement of said containers from a first position in which said containers are spaced apart, to a second position in which said drops, when formed by said pressurizing means, contact each other while still pendent so as to coalesce and intermix outside the containers, and thence to said first position.

13. A device as defined in claim 11 or 12, wherein said containers are interconnected through said moving means.

14. A device as defined in claim 13, wherein said first position is one in which said containers are generally parallel, and said second position is one in which both of said containers are pivoted away from their orientation in said first position, by generally the same, but opposite, amount.

15. A device as defined in claim 11 or 12, wherein said moving means permits one of said containers to be moved without moving said other container.

16. A method of mixing two low relative vis-cosity liquids, the method comprising the steps of a) forming drops of said liquids which are respectively pendent from separate platforms, and b) before, during or after said step a), moving said platforms from a first spaced-apart position to a second position in which drops pendent from said platforms coalesce while still pendent from said platforms, and intermix.

17. A method as defined in claim 16, wherein said forming step comprises the step of forcing the respective liquid to flow out of a container through an aperture that is generally centered on said platform, in an amount that will cause said drop to be pendent from said platform.

18. A method of mixing two low relative vis-cosity liquids outside of a container, the method com-prising the steps of forming drops of said liquids so as to be pendent from respective platforms, and thereafter moving said platforms from a first spaced-apart position to a second position in which the drops coalesce while still pendent from said platforms, and intermix.

19. A method as defined in claim 18, wherein said forming step comprises the step of forcing the respective liquid to flow out of a container through an aperture that is generally centered on said platform, in an amount that will cause said drop to be pendent from said platform.