Aspirating and mixing of liquids within a probe tip

Details Aspirating and mixing of liquids within a probe tip Aspirating and mixing of liquids within a probe tip

2000-02-22

2003-11-04

Le, Long V. (Department: 1641)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

C366S053000, C366S058000, C366S091000, C366S305000, C366S307000, C422S051000, C422S051000, C422S091000, C422S105000, C422S105000, C422S174000, C436S514000, C436S810000, C073S836000, C073S863420, C073S864010, C073S864230, C073S864240, C073S864510, C073S864610, C073S864910, C073S864110, C073S864120, C073S864140

Reexamination Certificate

active

06641993

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to apparatus and a method for mixing two liquids within a tip on an aspirating probe, to ensure a reaction between the liquids.
BACKGROUND OF THE INVENTION
It is known from U.S. Pat. Nos. 5,773,305 and 5,174,162 to mix a fluid sample such as blood and a diluent, inside a probe tip by first aspirating both liquids into the tip, and then drawing said liquids further up into the tip into a mixing chamber having an enlarged inside diameter compared to the rest of the tip. The mixing can be achieved, for example, by reciprocating the mass of liquids up and down numerous times.
In the examples shown in U.S. Pat. No. 5,773,305, the liquids are retained in the enlarged chamber and simply sloshed back and forth in that chamber to achieve mixing.
FIG. 3
thereof makes it clear that simply aspirating the liquids into the enlarged chamber past a step discontinuity created by the enlarged inside diameter, is ineffective in creating a mixture. That is, a single movement past the step discontinuity is shown as not mixing the fluids homogeneously. An air bubble can also be included between the liquids when first aspirated. Cross-over contamination between bodies of liquid being aspirated is preferably prevented by ejecting an inert oil shield around the outside of the tip,
FIGS. 7 through 11
thereof.
Such a construction is generally equivalent to transferring two liquids from a pipette into a larger diameter container (the mixing chamber) and attempting mixing by sloshing the liquids vertically within the container. Although mixing can occur in such a fashion for relatively large volumes, it is not as effective for small volumes, e.g., volumes that total 100 to 600 microliters. That is, in a constant diameter channel, inertial mixing is reduced if the volumes are small, as here. It is this phenomenon that requires the movement of the liquids back and forth in the mixing chamber, as much as 20 times, to achieve homogeneous mixing. Such reiterations of the mix step are time-consuming, and beg for an improvement.
Furthermore, it is not the case that cross-contamination is preventable only by using such an oil shield. That is, in some cases, the first-aspirated liquid can be removed from the tip simply be repeated washing with a diluent, or by wiping. In any event, should washing prove to be unsatisfactory, there has been a need for a more reliable method of preventing contamination than by using the oil shield. (The oil shield is not guaranteed to form completely around the tip just because a plurality of dispensing nozzles are disposed about the circumference of the exterior of the tip.) Furthermore, some proteins can destroy the shield effect of the oil.
In the examples of U.S. Pat. No. 5,174,162, all the liquids to be mixed are moved completely into the enlarged mixing chamber, completely out of the chamber, then back into it, and so forth. The sharp transition at surface
15
causes turbulent mixing,
16
,
FIG. 2
thereof. This is a more efficient mixing method than that of the '305 patent. Nevertheless, there are improvements that are needed in such a mixing system as described in the '162 patent. For example, no optimization is described for the geometry of FIG.
2
. Nothing is described regarding any use of air bubbles to separate the liquids as they are aspirated. As noted however in the '305 patent, such an air bubble provides an effective prevention against cross-contamination. Yet, any air bubble must be rapidly eliminated during mixing.
Furthermore, the '162 patent is notably deficient in any teaching to prevent cross-contamination when aspirating liquid
6
immediately after liquid
4
, between the two liquids within the bulk container of liquid
6
. Although the oil shield of the '305 patent might seem to be applicable to the probe of the '162 patent as well, such a shield has disadvantages as noted above. Alternative protection methods against cross-contamination, besides the oil-shield method, are thus desirable.
Yet another disadvantage of the teachings of the '162 patent is that when the two disparate liquids are moved back and forth across the boundary
15
, unmixed “tails” of one or both liquids can be left behind as coatings on either the enlarged chamber or the narrower intake portion. Such residual tails do not get mixed when the main body of liquids is moved across boundary
15
, so that the tails are undesirable.
Thus, although substantial development has already occurred in probes designed to mix two liquids entirely with the probe, there remains the need for improvements.
SUMMARY OF THE INVENTION
We have devised a mixing method and a probe tip for doing the mixing therein, that provide the above-noted needed improvements.
More specifically, in accord with one aspect of the invention, there is provided a method of mixing a plurality of liquids, comprising the steps of:
a) providing a probe tip with an internal cavity having a plurality of different inside diameters;
b) providing by aspiration a plurality of liquids inside a portion of the probe tip;
c) moving at least most of said liquids back and forth at least several times between a part of said cavity with a smaller inside diameter and a part with a larger inside diameter, said larger and smaller diameters being sufficient to provide a sufficient rotation of liquid as it moves between diameters to cause mixing of said liquids;
the improvement wherein the capillary number resulting from the mixing in step c) does not exceed about 0.01, the capillary number being defined as the ratio of liquid velocity times viscosity and surface tension, so that any tails formed during the mixing step c) are minimized.
In accord with another aspect of the invention, there is provided a method of mixing a plurality of liquids comprising the steps of a) through c) listed above, wherein the improvement comprises that the cavity parts comprise two separate but matable tip portions, and the method further includes the step of mounting a tip portion of one of the inside diameters onto the tip portion of the other inside diameter in-between aspiration of liquids, such that carry-over contamination between liquids is prevented.
In accord with still another aspect of the invention, there is provided a method of mixing a plurality of liquids comprising the steps of a) through c) listed above, wherein the improvement comprises the inside diameters each provide a cross-sectional flow-through area of the cavity part, and the cross-sectional flow-through area of the larger inside diameter is at least three times the cross-sectional flow through area of the smaller inside diameter, for maximum mixing efficiency.
In accord with yet another aspect of the invention, there is provided a method of mixing a plurality of liquids comprising the steps of a) through c) listed above, wherein the improvement comprises the larger inside diameter being obtained by i) selecting as a first tip portion a tapered tip at least a portion of which has an inside diameter that is much larger than the smaller inside diameter of the probe tip, and ii) joining the tapered tip to the probe tip having the smaller inside diameter.
In accord with yet another aspect of the invention, there is provided a method of mixing a plurality of liquids comprising the steps of a) through c) listed above, wherein the improvement comprises providing a total amount of liquid in step b) such that if all liquid is moved into the part with the larger inside diameter, the larger inside diameter is greater than the height of the total liquid, but less than twice the height of the total liquid, so that mixing as per step c) is maximized.
In accord with yet another aspect of the invention, there is provided a method of mixing a plurality of liquids comprising the steps of a) through c) listed above, wherein the improvement comprises moving in the step c) at least most of the liquids back and forth at least between the cavity part with the smaller inside diameter and a part of the cavity of a larger inside diameter l

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