Analyzer for liquid samples

United States Patent

[11] 3,607,097

<td> [72]</td><td> Inventors</td><td> Michel Auphan</td><td> [56]</td><td> References Cited</td><td></td>

<td></td><td></td><td> d’Orleans-Neuilly;</td><td></td><td> UNITED STATES PATENTS</td><td></td>

<td></td><td></td><td> Jean Perilhou, Arnoux-Bourg la Reine,</td><td> 3,266,298</td><td> 8/1966 Whitehead et al............</td><td> 23/253 X</td>

<td> [21 ]</td><td rowspan="2"> Appl. No. Filed Patented</td><td> 750,654</td><td> 3,297,558</td><td> 1/1967 Hillquist.......................</td><td> 23/253 X</td>

<td> [22| |45|</td><td> Aug. 6,1968 Sept. 21,1971</td><td> 3,306,229 3,490,876</td><td> 2/1967 Smythe......................... 1/1970 Auphan et al................</td><td> 23/253 UX 23/253</td>

<td> |73|</td><td> Assignee</td><td> U.S. Philips Corporation</td><td colspan="2"> Primary Examiner— Morris O. Wolk</td><td></td>

<td></td><td></td><td> New York, N.Y.</td><td colspan="2"> Assistant Examiner— R. E. Serwin</td><td></td>

<td> (32|</td><td> Priority</td><td> Aug. 9,1967</td><td> Attorney—</td><td> Frank R. Trifari</td><td></td>

<td> [33]</td><td></td><td> France</td><td></td><td></td><td></td>

<td> [31]</td><td></td><td> 117,367</td><td></td><td></td><td></td>

[54] ANALYZER FOR LIQUID SAMPLES ABSTRACT: An apparatus for automatically transporting a

Claims, 3 Drawing Figs. plurality of liquid samples, such as blood through a series of ’ ’ programmed steps for colorimetric analysis of the samples. A

[52] U.S. Cl........................................................ 23/259, first conveyor belt carries the samples to be analyzed, an ad23/253, 73/425.6, 356/39 jacent belt carries working tubes in which the tests occur, and

[51] Int. Cl......................................................... GOln 1/14, a third belt carries substances to be added to the samples durGOln 33/16 ing the tests. Needles and tubes are provided between the con[50] Field of Search............................................ 23/259, tainers of substances on the three belts for piercing containfer

253, 230 A; 73/423,421.5,425.6 walls and then transferring liquids between the containers.

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PATENTED SEP211971

3,607,097

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INVENTORS

AUPHAN

MICHEL . .........

JEAN PERILHOU

BY

<img file="US3607097A_D0003.tif" />

GENT

3,607,097

ANALYZER FOR LIQUID SAMPLES

This invention relates to U.S. Pat. No. 3,490,876 in which an automatic analyzer for liquid samples is described, in which colorimetry is used in the liquid phase or in the flame. Such an apparatus is particularly suitable for the automatic quantitive analysis of the main chemical constituents of blood (urea, glucose, cholesterol, sodium, potassium, etc., by means of a minimum number of operations on a large number of samples to be subjected to the same analysis. 1

In the apparatus described a sequence of tubes having flexible walls and filled with the liquid samples to be analyzed (termed herein working tubes) are arranged parallel to each other on a belt which is adapted to run around drums carrying out predetermined movements, means being provided for carrying out the treatments required for the analysis in a given order of succession of the sample in each tube, for instance, injection of auxiliary liquids, mixtures and so on.

For this purpose the apparatus comprises rows of thrust feet arranged parallel to the tubes, each row cooperating with a single stationary member associated with a row, the number of rows being at least equal to the number of auxiliary liquids to be introduced into the samples. A programming device controls the thrust feet, each of which can be pressed against the wall of the opposite tube so that the liquid is displaced against ' the wall of the length of the tube and the predetermined treatment can be carried out. Each working tube comprises in its interior filters for performing the number of required filtrations during the analysis.

The invention has for its object to provide further mechanization of the apparatus, and accordingly the invention there is provided a second belt having parallel tubes for the auxiliary liquids consisting of flexible material and being displaceable by actuating at least one pushbutton into a position near the working tube, each auxiliary liquid tube having an injection needle for injecting the auxiliary liquid into the working tube.

The invention will be described more fully with reference to the accompanying drawing, in which:

FIG. 1 shows schematically an elevation of the various belts provided with tubes in an apparatus according to the invention,

FIG. 2 is a sectional view of an auxiliary liquid tube comprising two chambers, and

FIG. 3 is a schematic elevation of a detail of the cooperating tubes connected with thrust feet.

The improvement provided by the invention relates particularly to the quantitative analysis of one or more constituents of the blood of a large number of patients. The analysis of glucose described before is chosen by way of example. For the blood analysis of a patient all treatments are carried out within a single working tube 2 of small diameter, for example, of a synthetic resin resistant to the chemical reagents. The working tubes 2 are arranged parallel to each other on a belt 1, termed the working belt. The belt is adapted to move along two drums, one of which is shown at 3. In the spaces 4 between every two tubes 2 the working belt is provided with the patient’s data and the coded analysis in the form of perforations.

In the example described each working tube has at one end a hollow needle 5 for taking in the blood serum, which will be described more fully hereinafter. The working belt is associated with a number of rows of thrust feet (not shown in FIG. 1), the number of rows being at least equal to the number of reagents or auxiliary liquids to be introduced during the same analysis into the sample to be analyzed.

According l<> the invention there is added to the working belt I η second belt 7. which can be moved by a drum 8 and which is provided with tubes 9 of flexible synthetic resin containing the substances to be added during the analysis. The belt 7 has a given thickness so that the tubes 9, arranged parallel to each other, can be fixed in openings in the direction of thickness of the belt 7. The tubes 9 can be pressed out of the openings by means of a thrust pin 10 and be moved to the area above a working tube 2 on the belt 1. Each tube 9 has a needle 11, which is .capable of piercing the wall of a working tube 2.

Some reagents may be stored for a long time in a sealed glass ampulla. In this case a tube 9 contains the glass ampulla sealed by a “pigtail,” which can be broken across the tube, for example, by means of a thrust pin. However, if the reagent cannot be kept for sufficient time not even in sealed ampullae, and if it has to be freshly produced, the tube 9 may be shaped in the form shown in FIG. 2. This tube comprises two separate chambers 91 and 92, communicating with each other through openings 96, the chamber 91 being divided into separate spaces 93, separated from each other by closed partitions 94. Each space contains a constituent of the reagent, for example, in the sealed ampullae 95. Each separate space 93 communicates with the chamber 92 via a hollow needle 96. For producing the reagent “pigtails” are broken by exerting pressure across the synthetic resin wall so that the liquids flow into the spaces concerned. Thrust members (not shown) permit of introducing into the chamber 92 the desired quantities of the constituents which form the final reagent by mixing, if necessary with the supply of heat. The chamber 92 has a hollow needle 11.

In the example chosen and in particular for the analysis of blood the apparatus comprises a third belt 12, termed herein take-in belt, adapted to be moved between two drums 13 and supporting parallel tubes 14, each of which contains blood of a patient. The tubes 14 are provided at one end with a lancet 15 and the blood can be taken in, for example, from the patient’s ear lobe manually or automatically by means of an apparatus independent of the analyzer into which the belt 12 has to be introduced subsequently. The tubes 14 are fixed on the belt 12 in rigid supports by means of a spring (not shown) arranged on the tube.

The free space 16 between two tubes 14 contains all data relating to the patient and the desired analysis in the form of coded perforations which data can be transferred to the belt 1 by means of a photoelectric cell. The take-in tubes 14 with the blood are first centrifuged before the belt 12 is inserted into the analyzer so that serum and corpuscles are separated from each other.

The operation of the analyzer will now be described briefly with reference to the assessment of the glucose content of blood. The drum 13 and the take-in belt 12 are moved so that invariable a tube 14 is located opposite a working tube 2. The belt 1 with the working tubes 2 is arranged so that the needle of a working tube 2 can penetrate into the take-in tube 14 just above the portion filled with corpuscles, after which the desired quantity of serum can be sucked into the working tube 2. At the same time the associated coded information of the belt 12 is read and punched in the belt 1. A programming 1 device receiving the punched information of the belt 12 will control the course of the three belts 1,7 and 12.

All desired analyses can be carried out in order of succession. After the serum of the tube concerned is taken in, the . belt 12 moves on by one step so that the tube 14 of a further ’ patient occupies the emptied space opposite a next-following working tube 2, which has arrived at the area of the preceding tube due to the propagation of the belt 1. The serum of the next patient is taken in and the coded indications of the belt 12 are transferred to the belt 1.

The drum 8 and the belt 7 with the tubes 9 containing the reagents are moved in accordance with the punched coded indications so that each reagent is present at the area where it has to be inserted into the working tube 2. For this purpose the belt 7 is suitable arranged at the side of belt 1 so that the thrust pins 10 are capable of removing the tubes 9 from their places and passing them to the area above the relevant working tube 2. The desired quantity of reagent can be sucked in by the needle 11 piercing the wall. When all analyses are of the same nature, the belt 7 comprises a number of tubes 9 containing reagents corresponding with the number of patients.

With the glucose analysis and with the aid of reduction of ferric cyanide it is necessary to introduce the following three reagents in a given order of succession of the desired instant and at the desired area of the working tube 2:

3,607,097

Reagent A (for expelling protein) copper sulfate 5 H₂0 0.31g.

sodium tungstenate 2H₂0 1.22 gs.

barium chloride 2H₂0 0.26g.

distilled water 100 cc.

Reagent B (ferric-ferrous cyanide) pure potassium ferro-cyanidc 0.006g.

pure potassium ferri-cyanide 0.033g.

pure dry sodium carbonate 0.4 g.

distilled water 100 cc.

Reagent C (ferric phosphate) pure potassium fcrri-cyanide 0.04 g.

85%-ic phosphoric acid 4.7 gs.

distilled water 100 cc.

Since the first reagent having a pH value exceeding 8 can be kept in good condition, it may be provided in the ready state in a glass ampulla in a tube 9 and the sealing tip of the ampulla can be broken at the exact instant.

The tube 9 is then moved to above the belt 1 with the working tubes 2, where the tube 9 stands still until the termination of the glucose analysis. The hollow needle of the tube 9 can penetrate by pressure into the working tube 2 by means of thrust feet. This is shown in detail in FIG. 3. The tube 9 with the filled chamber 92 is located above the working tube 2 and the needle 11 has pierced the wall. The thrust feet 17 press the working tube 2 flat against the member 18 and after the return movement of the feet the tube 2 sucks in a quantity of reagent. By pressing the correct number of feet 17 against the member 18 a quantity of 10 pL. is urged 20 times in order of succession forwardly in the tube portion serving for the analysis and for taking in serum.

The serum is taken in the same manner by means of the needle 5. In order to cause this needle to penetrate into the centrifuged take-in tubes 14, the latter are pressed against the needle by a thrust foot. The needles are adjusted so that they penetrate just above the blood clot so that no serum gets lost.

After the serum is taken into the working tube 2, It is mixed with the reagent by the alternate displacement of the evennumbered and odd-numbered thrust feet 17. The mixture is then filtered by a hard-glass filter 6 in the interior of the working tube 2. By the action of the thrust feet the liquid is injected under pressure through the walls of the filter. Then the working tube 2 is displaced by one step, after which the same cycle is repeated for the analysis of the glucose content of a further patient and so on until the doses to be analyzed are exhausted or the tube 9 is empty.

The second treatment of the filtrate consists in the introduction of the ferri-ferro-cyanide, the glucose reduction of which is measured. This reagent has to be produced separately, The tube 9 has in this case two chambers, one of which is divided into three separate spaces 93 which contain the previously weighed quantities of ferrous cyanide, ferric cyanide and a solution of sodium carbonate in a glass ampulla. By a technique similar to the preceding technique a quantity of, for example, 25 cc. accurately determined by means of thrust pins can be readily supplied from the ampulla containing sodium carbonate under gas pressure. This quantity of the solution is then inserted into the other chamber 92 and mixed therein with the ferrous cyanide and the ferric cyanide.

After these treatments the tube 9 is moved near the working tube 2 for the injection of the reagent. For each working tube 2 the process is then as follows: In an accurately determined portion of the tube 2 30 pL. of the filtrate of the first treatment is absorbed, after which this quantity is shifted upwards.

In the same tube portion is then absorbed a quantity of 4X30 pL. of the ferri-ferro-cyanide. The filtrate is mixed as before with the reagent and the same treatment is carried out on all tubes.

The reaction is completed by heating at near the boiling point of the liquid for one quarter of an hour, for example, in a bath, which may be a circulating heating bath. Each tube is passed through the bath for the same period of time. After the bath a quantity of 120 pL. of ferric phosphide is introduced in the same way as described above. For color stabilization the belt is held for about 15 minutes at 20° C. in a drying furnace. The tubes 2 are then subjected to colorimetric analysis.

When several sequences of analyses have to be performed (glucose, urea etc.), the belt 12 is moved back to its initial position after termination of the first sequence of analyses and a new sequence of tubes 2 is applied to the belt 1, each of which can take in a new quantity of serum. At the same time the belt 7 with the reagents is moved so that the tubes 9 are disposed in accordance with the new sequence of analyses. By the supply of fresh tubes with the reagents to above the working tubes 2, the tubes employed for the preceding analysis are conducted away and rejected. For the invention it is not essential whether the disposition of the belts in this example, the shape of the tubes containing the reagents and the displacing members are different.