US 3620678 A
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Description (OCR text may contain errors)
United States Patent Oct. 5, 1966, France, No. 78946; Mar. 24, 1967, France, No. 100324; July 4, 1967, France, No. 113080 INSTALLATION FOR MULTWLE AND AUTOMATIC ANALYSES 8 Claims, 28 Drawing Figs.
US. 23/253 R, 23/230 R, 23/259 R Int. Cl. G011! 33/16, GOln 21/00 Field oiSearch 23/230, 230 A, 253, 253 A References ited UNITED STATES PATENTS Natelson Natelson Natelson Whitehead et al. Natelson Forestiere Johnson et al.
Primary Examiner-Morris 0. Walk Assistant Examiner-R. E. Scrwin Attorney-Sughrue, Rothwell, Mion, Zinn & Macpeak 23/253 X 23/253 X 23/253 23/253 X 23/253 23/253 23/253 X ABSTRACT: Device for multiple and automatic analysis including means for picking up a given substance to be analyzed at least one means for transferring a given quantity of liquid from one container to another, at least one means for mechanical treatments and at least one measuring means, said substance being conveyed from one of said means to another one in vessels carried by conveyors constituted by two pliant strips.
DDDDUDDDUDDUD PATENTEDuuv 15 ml 3, 20, 78
SHEET 01 or 12 PATENTEDunv 1s ISTI 3, 620,678
sum 02 0F 12 PATENTEDNUV 1 6 I971 SHEET 03 [1F 12 FIG.6
PATENTEnuuv 1s ISYI I 3, 620 67 8 sum 05 0F 12 PATENTEBuuv 16 I971 13. 620 67 8 sum 07 0F 12 FIG/13 FIG/I4 PAIENTEBuuv 16 I971 SHEET 09 OF 12 FIG.2O
PATENTEUNLW 16 m1 SHEET 10 [1F 12 FIG.22'
PATENIEDunv 1s ISTI sum 11 [1F 1 FIG. 24
INSTALLATION FOR MULTIPLE AND AUTOMATIC ANALYSES The invention relates to an installation for multiple and automatic analyses, which is intended particularly but not necessarily for measuring physiological data such as the amount of urea, the amount of cholesterol, the number of leucocytes per unit of blood volume, the amount of sugar, etc., from various samples such as blood, urine, etc.
Systems for carrying out multiple and automatic analyses are known. Such systems generally comprise a sampling apparatus which makes it possible to obtain a mixture of determined proportions of the substance to beanalyzed and of reagents.
It is this mixture of substanceto be analyzed and reagents which is called the sample. A measuring apparatus inwhich the sample is placed measures a physical quantity connected with the sample, making it possible to determine the amounts of the various components in the substance to be analyzed. The measuring apparatus most frequently used in the installations for multiple and automatic analyses is the colorimeter, which comprises a source of luminous radiation of a given wave length. The radiation passes through the sample to a photoelectric cell. The cell supplies an electric voltage which is a function of the amount of the substance being studied in the sample.
Between the samples and the measuring apparatus, the sample undergoes certain treatments, such as mixing, heating, cooling, irradiation, etc.
The automatic analysis systems known at present have provided greater possibilities than the manual methods which have hitherto been practiced.
Nevertheless, these systems still require very numerous manual interventions which are frequently the origin of very serious errors. The main disadvantages inherent in the existing systems may be briefly mentioned as comprising:
1. Possible identification errors,
2. Contamination of the samples with one another,
3. Considerable consumption of frequently costly reagents,
4. Low measurement rate,
5. Unsatisfactory adaptation to the possibilities offered by the data processors, because the work to be carried out is of too long duration for the computers,
6. Low overall reliability (a piece of fibrin can stop an entire sequence), and
7. Fairly poor measurement safety: for example, the cellsof photometers in contact with all the products can become opaque and cause considerable random variations which are costly to verify and eliminate.
In the existing multiple or automatic analysis installations, the samples are generally placed at the outlet of the sampling apparatus into individual containers or receptacles such as tubes or dishes. The handling of these separate containers toward the measuring apparatus, while passing through the intermediate treatments, makes .it necessary to have complicated devices such as turntables carrying the individual containers as soon as it is desired to multiply the analyses or make them automatic. Furthermore, the manufacturing cost of the separate containers is sufficiently high to necessitate them being used again, and this involves the necessity of the containers or dishes being washed. Moreover, these containers do not permit the measurements, particularly with a colorimeter, to be made through their walls, so that it is necessary for thecontents to be poured into the measuring apparatus. This complicates the multiple and frequently automatic analysis operations. Finally, the mixing of the products is effected by means of mechanical or magnetic agitators brought into contact with the sample, which involves a risk of contamination.
Other installations are in existence which represent an advance with respect to the preceding installations. In such systems, the product to be analyzed and the reactants are taken in determined proportions by any appropriate means, usually by means of a dosage pump, and circulated in a tube to the measuring apparatus under the action of the pump. The
liquid samples are separated by gaseous segments. The tube is connected to the measuring apparatus, into which the samples flow in succession. The tube is generally made of a plastic, flexible and transparent material.
Nevertheless, this arrangement still has serious disadvantages: firstly, as the samples circulate in the same tube, there is produced a contamination of one sample by those which have preceded it,,and this is harmful to the accuracy of the measurements. The influence of this contamination is even greater when working with capillary tubes for effecting analyses on small quantities, because the ratio between the contact surfaces and the volume of the sample increases.
Another disadvantage arises from the fact that the speed of progression of the samples in the tube must be slow so that the flow remains laminar, otherwise the gaseous separation between two successive samples is no longer certain. This limits the rate of the automatic analysis operations, although the sampling and measuring apparatus permit high rates of the order of one analysis per second.
Another disadvantage of this arrangement resides in the fact that its use is limited to the transport of liquid samples.
Finally, in an automatic analysis installation, it is important, for avoiding errors, that each sample can be registered individually throughout its entire travel. The circulation of samples in a tube does not permit this registering to be positively effected.
One object of the invention is to provide a multiple analysis installation which is almost completely automatic and operates at high speed, permitting the exploitation of the results by means of a modern data processor.
Another object is to provide an analysis installation which almost completely eliminates errors in identification of the specimens, and, in the event of such an error occurring, detects it with absolute certainty.
Another object of the invention is togirocluce samples of the extracted specimens, having added thereto doses of reagents which are of small volume but calibrated in very accurate manner.
Another object of the invention is to provide an analysis installation in which the photometers are used under the best conditions of employment without danger of becoming opaque.
Another object of the invention is to provide a reliable analysis installation which permits a large number of physiological data to be measured.
According to one feature of the invention, the specimens are taken at various sampling centers and brought to a central analysis laboratory. The extracted specimens are arranged in cells or small cavities formed in a film of flexible material which is fonned with lateral perforations permitting the film to be driven mechanically in a manner similar to that used in the cinematographic art. One of the faces of the film carries a magnetic track adapted to receive the necessary information for identifying each specimen.
According to another feature of the invention, a label bearing particularly the number of the sampling center, the name and the register number of the patient is ,stuck on one of the faces of the film close to the cell containing the specimen of the said patient. According to another feature of the invention, the specimen device is arranged in such manner that the specimen cannot be taken if the said label has not been stuck on.
According to another feature of the invention, the central analysis laboratory is equipped with a data processor;v according to the invention, the information carried by the specimen film, as soon as the said film reaches the central analysis laboratory, is transferred in coded manner into the data processor and on to the magnetic track of the film opposite the specimen.
According to a feature of the invention, films which are known as analysis films and containing a plurality of samples and a magnetic track are formed at the laboratory. A part of the contents of each cell of the specimen film is transferred into a cell of an analysis film. The analysis film is displaced by a translatory movement so that each cell arrives and is stopped successively at one or more stations for injecting given doses of predetermined reagents, in one or more stations for mixing, heating and cooling; and in front of one or more analysers, for example of the photocolorimeter type, with the object of measuring a certain physiological datum.
The transfer of specimen material from a cell of the specimen film to the analysis film, and also the transfer of reagents, are carried out by means of a sampling apparatus comprising a level gauge, a mechanism with reciprocatory move ment carrying a pipette and associated with the level gauge and means for filling and emptying the pipette. The transfer apparatus is characterized in that the container holding the liquid from which a specimen is to be taken has a fluidtight closure, and is provided with means for establishing an ad justable pressure therein.
In the analysis installation according to the present invention, the samples are transported between the different apparatus by a belt or band carrying a series of regularly spaced containers which are formed of a flexible and transparent material. This arrangement overcomes the disadvantages referred to above and has the following advantages:
the manipulation of the samples is efi'ected in the individual containers, this eliminating the dangers of mutual contamination and permitting a positive identification of each sample;
the handling of samples of small volume, smaller than one cubic centimeter, if possible;
the handling in deformable containers makes it possible for certain operations to be carried out, particularly the mixing and the passage into the measuring apparatus, without the sample coming into contact with a foreign body;
the handling of the samples is effected in a material which is chemically inert with respect to the substances being transported;
the handling of the samples in transparent containers permits the visual observation thereof and permits measurements by colorimeter or by radiations through the walls of the container;
the transport of the samples in closed containers eliminates all evaporation, this being of very great importance in the case of volatile substances;
the transport of samples of high viscosity or of samples in the form of paste or powder is possible; and
the mechanization of the displacement of the samples, particularly for supplying the sequence of multiple or automatic analysis operations, is made easybecause the samples are arranged at a constant spacing on a flexible sheath, similar to a cinematographic film, the step-by-step advance of which is well known. The rapidity of this step-by-step advancing movement easily permits sampling rates of one per second to be achieved.
Finally, the means proposed according to the invention involves such a low cost that it is lower than the expense involved in cleaning. Thus, provision has not been made for it to be used again. This eliminates all danger of contamination. This is very important in those cases where analyses of radioactive products are carried out.
Other features and advantages of the invention will be more readily apparent from the following description of a blood analysis laboratory which is given simply by way of example and by reference to the accompanying drawing, wherein:
FIG. 1 is an elevation of a sample-transporting arrangement;
FIG. 2 is a cross section on the line BB of FIG. 1;
FIG. 3 is an exploded perspective view of a sample-transporting arrangement in a modified form;
FIG. 4 shows the same' arrangement, seen as a section on the line CC of FIG. 3;
FIG. 5 is a perspective view showing another embodiment of a sample-transporting arrangement;
FIG. 6 is an elevation of an arrangement especially adapted for the transport of blood samples;
FIGS. 7 and 8 are two sections of the same arrangement on the lines DD and EE of FIG. 6;
FIG. 9 is a perspective view of the machine for taking specimens;
FIG. 10 shows a sample identification card;
FIG. 11 is a perspective view of a detail of the identification machine shown in FIG. 9;
FIG. 12 is a diagrammatic view of the arrival identification station of the central laboratory;
FIG. 12a is a partial view on an enlarged scale of the aforesaid station;
FIGS. 13 to 17 show diagrammatically the various phases of cutting and sticking the films containing the specimens;
FIG. 18 is a schematic view of an analysis line;
FIG. 19 is a perspective view of the same line;
FIG. 20 shows diagrammatically a machine for the production of analysis film;
FIG. 21 is a perspective view of a cell of the analysis film;
FIG. 22 explains the principle of operation of a pipette device for taking samples and giving injections with which an analysis line is equipped;
FIG. 23 is a perspective view of a sampling and injecting arrangement according to one preferred embodiment;
FIG. 24 is a perspective view of a device for limiting the travel of the injection needle of the aforesaid arrangement;
FIG. 25 shows a photocolorimeter analysis arrangement with which an analysis line is equipped;
FIG. 26 is a detailed view of FIG. 25;
FIG. 27 shows the appearance of the cell in the arrangement according to FIG. 26.
The side elevation shown in FIG. 1 represents a strip or band 1 carrying a series of identical receptacles 3 and consisting of transparent and deformable material. In the embodiment illustrated, the strip is formed of two films consisting of flexible, transparent and heat-scalable thermoplastic material, which are superimposed and heat-sealed on a part of their surface so as to form a sheath, the heat-sealed portions 2 being disposed in such manner that the parts which are not heatsealed define a series of identical receptacles of capsules 3.
In the embodiment shown in FIGS. 1 and 2, the capsules have at least one opening 4, which is preferably flared upwardly in order to permit the introduction of a needle of a sampling apparatus.
The heat-sealing or welding of the two films forming the sheath can be arranged in such a way that the two films are not welded along their upper edge over a height of a few millimeters, thus forming the groove in which the needle of the sampling apparatus remains engaged during the movement of the sheath, this facilitating the introduction of the needle into the capsules.
The capsules can be of any desired form. The volume thereof can be as reduced as desired and can in particular be smaller than 1 cubic centimeter. It is, for example, possible, but not necessary, to provide for a volume almost twice that of the sample to be taken.
In the case where the sheath has a thickness which limits its deformability slots 5 are cut between each capsule.
In the modified embodiment of FIGS. 3 and 4, the transport or conveying arrangement is made from two sheets 10 and 12 of heat-scalable flexible material which are partly heat-sealed. The receptacles l3 and 15 are formed by appropriate reliefs of the film 15.
The double chambers of FIG. 5 are used when the products introduced into chamber 16 produce a precipitate. The duct 19 is lined with an appropriate porous material 20. By compressing the chamber 16, for example by means of rollers, it is possible to send all the liquid into the chamber 18, the solid precipitate remaining in the chamber 16.
As a modification, it is possible to give any desired form to the reliefs constituting the chambers, for example, the shape of a semispherical cap.
If it should be desired to obtain a chamber with a larger capacity, it is moreover possible for reliefs to be formed on the two sheets and for the sheets to be welded at the undeformed regions, the reliefs being disposed facing one another.
The films, such as those shown in FIGS. 1 to 5, are provided with perforations before the formation and welding thereof, these perforations permitting the films to be driven by means similar to those used in the cinematographic art.
FIGS. 6 to 8 are respectively a perspective view and two different cross sections of an embodiment of a means for conveying specimen materials, said means being particularly adapted for use with blood samples. This conveying means will hereinafter be referred to as the elementary specimen film.
The container is formed of two chambers 30 and 31 of different sizes which communicate by way of a duct or passage 32. The larger of the chambers is for example adapted to receive the blood specimen intended for a chemical analysis section of the central analysis laboratory, while the smaller chamber is intended for a hematology section.
Each chamber contains a certain reagent or anticoagulant, either in the form of liquids injected into each of the chambers before the blood sample is taken, or in the form of thin layers of soluble solids which are deposited in the chambers at the time these latter are formed.
The specimen conveying arrangements shown in FIGS. 3 to 8 are provided with a magnetic track '35 disposed parallel to the edge of the film, the purpose of which will be explained later. This track is either formed by a deposit of magnetic ink disposed on the film or by a strip of magnetic adhesive stuck on the film.
Furthermore, the chambers are disposed on the film in such a way as to leave between them, or between each of them and the edge of the film, a space sufficient to stick on the film a label for identifying the sample contained in the chamber.
FIG. 9 is a perspective view of a machine for taking samples, each sample-taking center being equipped with such a machine in accordance with the invention.
The elementary specimen films of the type such as shown in FIG.'6 contain a certain number of double chambers, such as '30 and 31. The number of double chambers may for example The sample-taking machine comprises essentially two spools 40 and 41, arranged in the manner shown in connection with the spools of a magnetic tape recorder. The supply spool 40 contains a virgin elementary film 42. The machine contains a motor (not shown), which is of the step-by-step type. By the film being driven in the direction of the arrow 75, this motor permits the double chambers to be positioned in front of a sample-taking member.
The patient rests his ann 44 on an arm-rest 43. The sample is taken by means of a needle 45, which the operator forces into the vein of the patient, the needle being connected by a thin tube 46 to a needle 47 which is to be inserted into one of the chambers forming a doublechamber, in the present case, into the chamber 30. At the same time'as the needle '47 is pushed into the chamber 30, a second needle 49 fast with the needle 47 is pushed into the chamber 30, as shown in the figure, or in a modified form, into the chamber 31, so as to bring the double chamber into communication with the atmosphere and thus to facilitate the filling, which is effected by gravity. The arrangement of the needles is shown-to a larger scale in FIG. 11. The member for imparting movement to the needles 47 and 49 is not shown. This can be effected by any known means.
The identification of each specimen or sample is effected in the following manner:
On arrival, the patient is given a card of the type shown in FIG. 10. This card 61 comprises at least one detachable slip 62.
The card and the slips 62 carry'all the numbers of'the sample-taking center, in the present case 2,400, and the register number of the patient, in the present case 9104.
The patient writs his particulars on the card 61 and his name on at least one slip. A duplicate of this card, necessary for the archives of the sample-taking center, can be obtained by any known means, as for example by a carbon copy, a photocopy or by filling a counterfoil bearing the same reference numbers as the card.
The card 61 is introduced, before the sample of blood is taken, into a slot 65 in the machine. A notch 60 cut in the card permits the vertical travel of this latter in the slot 65 to be limited. The effect of this operation is to displace the end of a flap 66 which is'interposed on the path of the needles 47 and 49. The taking of the sample is then made possible.
The end of the operation of filling the double chamber is signalled, either by visual observation of the level in the chamber 30, or automatically by a level detector of known type (not shown), which rings a hell or illuminates a lamp. A member then cuts off the slip 62 and sticks it on the film adjacent the chamber 31. This cutting member comprises a die 67 which is actuated by a jack 68 cooperating with a bearing plate 69 pressed against the film by a jack 70.
The sticking operation is effected by any known means, for example, by a deposit of adhesive on one of the faces of the slip. When the sticking operation is completed, the film is advanced by one'step, so as to bring the chamber 30 up to a device-designated to close the holes made by the needles 47 and 49 when taking the sample. This latter device comprises particularly a heating die 71, pressed by a jack 72 against the upper part of the chamber which is to be closed.
The machine is equipped with a control device (not shown) comprising means for detecting the presence of the identification slip (this detector is, for example, a phototransistor or a magnetic reading head cooperating with a magnetic mark placed on the slip). If the detector does not confirm the presence of the identification slip, the device prevents the film from being advanced. In the contrary case, it is possible for the motor to be started, and the motor to beadvanced by one step in such a way as to bring another double chamber in front of the sample-taking member. The flap 66 is then returned by a spring 73 into the position for preventing samples from being taken.
The advancing of the film is effected by the operator by means of a button (not shown), which is accessible from the front of the machine.
When the elementary specimen film is completely used up (in the aforementioned case, when the twenty-five samples have been taken), the supply spool 40 is empty while the takeup spool 41 is full. It can then be sent to the central laboratory in an appropriate container.
It is to be noted that the machine can optionally be provided with a device preventing rotation in the direction opposite to that indicated by the arrow 75.
The central analysis laboratory, described here by way of example, comprises in two principle sections, namely, a section for chemical analysis and a section known as the hematology section. An identification station for the specimens contained in the elementary specimen films has been provided common to both sections and associated with an electronic data processor.
The identification station is shown diagrammatically in FIGS. 12 and 120.
At the identification station, the elementary specimen film arriving from a sample-taking center becomes the supply spool 81 of a device which unwinds in the direction of the arrow 83 toward a takeup spool 82. The displacement is effected intermittently so as to position each double chamber in succession in front of a fixed index 79. When a double chamber is stopped in front of the index 79, the identification slip 62, which is stuck on the film in the vicinity of this double chamber, is read through a magnifying device 84 by an operator, who has a keyboard machine 85 at his disposal. The operator types the information read on the slip on to theleft part of a sheet 86. Simultaneously, the information is sent in coded form into a memory 87. As soon as the information in memorized, it is transferred in nondestructible manner into a data processor 88. This latter transmits the information which it has received by telepn'nting through the keyboard 85, to the right part of the sheet 86. If the bits of information carried by a single line of the sheet coincide, the information received by the data processor is correct and the operator makes the application by means of a strip-advance key, for example, the key 91, so that the film advances by one step.
During the displacement of the film the transfer of the contents of the local memory is made on to the magnetic tape 35 carried by the film by means of a recording head 89 similar to that of a data processor magnetic memory. A the same time, a checking of the identification signal relating to the double chamber which has preceded the double chamber 80 by one step is effected by reading by means of a magnetic reading head 90 and nondestructible transfer to the data processor 88; this latter effects the comparison with the information which has previously been transmitted to it by the memory 87.
If the bits of information are identical, it is then certain that the coded information carried by the magnetic track facing the specimen is in accordance with that carried by the corresponding slip. In the contrary case, a warning signal is given.
In FIG. 12, the arrows symbolize the various transfers of information. The use of a local memory 87 is necessary because of the difference between the working rhythm of the operator and the working rhythm of the data processor.
When the supply spool is empty, the takeup spool is transferred to the following station. A new supply spool is placed in position manually by the operator, who starts up the arrangement until he has exhausted the stock of spools which have to be identified.
By means of this arrangement, the specimens are identified on magnetic tape, and a complete list of the specimens to be analyzed remains recorded.
As already previously explained, the elementary specimen film comprises a plurality of double chambers, the two chambers of a double chamber communicating with one another through a passage. Each of the chambers contains a separate anticoagulant.
At the moment when the sequence of closing the holes made by the sample-taking needles is initiated at the station for taking blood samples, there is efi'ected the closing of the communication passage between the chambers. One of the chambers (the chamber with the smaller volume) will serve to supply the blood for the hematology section.-
The blood contained in each small chamber of the elementary specimen film is transferred into the respective cells of an auxiliary film; the process and the machine serving to carry out this operation will be hereinafter described.
The spools of elementary specimen films, once emptied or partially empty of the blood contained in the small chambers and intended for the chemical investigation are sent to a centrifuging station. The blood contained in the chambers is separated into a solid phase remaining at the bottom of the chamber and a liquid phase or serum, which is above the solid phase and on which the analysis operations will be carried out.
The auxiliary films intended for the hematology section are not centrifuged.
At the departure from the centrifuging station, the spools of elementary specimen films are sent to a station for sticking the said films to form reels. This sticking station is semiautomatic and is placed under the control of an operator throughout the time of operation thereof. At this station, a plurality of elementary specimen films are assembled end-to-end in order to form a single film, known as the large specimen film, the purpose of which will be hereinafter explained.
On leaving the centrifuge machines, each spool of elementary specimen film is placed on a continuously rotating table so that the operator who is seated at the sticking station can easily reach at any instant the spool which he has to put in position. The sticking device makes it possible to obtain a con tinuous sti'ip from the different spools which have been centrifuged.
The operations of cutting and sticking or cementing the films are set out by reference to FIGS. 13 to 17.
FIG. 13 shows a first end of an elementary specimen film of the double chamber type. The elementary specimen film is formed in such a way that the portion 90 of the flexible strip provided with double chambers and extending beyond the last chamber 91 on the side of the end of the film has a well established length, in the present case V4 ;4designates the space between two consecutive double chambers; the other strip 93 forming the film extends in the same direction over a length much larger than A FIG. 14 shows a second end of an elementary specimen film of the double chamber type, in which the strip 93 is extended beyond the last small chamber 94 over a length equal to AA, while the strip provided with the double chamber is extended for a length much greater than .4
I The end portions of film which extend beyond the extreme chambers for a length greater thanarethe inactive parts of the film, which serve for the fastening on the spools.
The operation of cutting the ends of the film, illustrated in FIGS. 15 and 16, is effected in such a way that the aforesaid inactive parts are reduced to a length equal to 3/4Abeyondthe corresponding chambers.
The sticking or cementing is carried out in accordance with FIG. 17, the second end of a first elementary film being placed in contact with the first end of a second elementary film so as to obtain a continuous strip in which the various double chambers are equidistant from one another by a length 4 This cementing method keeps the large specimen film from having discontinuities in its thickness at the cementing zones.
A cementing and cutting operation is carried out in the same manner on the auxiliary films.
On leaving this heat-setting tool, by means of another driving mechanism, the heat-set strip enters a heat-sealing tool 126.
The strip carrying the magnetic track enters the same heatsealing tool 126 at the level of the driving mechanism. The lateral perforations permit a perfect synchronism of the two strips to be obtained.
By another alternating rectilinear movement, the two strips thus brought face to face are heat-sealed. The analysis film 122 is thus formed on leaving this tool.
On leaving the heat-sealing arrangement, the analysis film 122 crosses the large specimen film 121.
Situated close to the crossing or intersection point is a station 127, known as the transfer station, where the following operations are carried out:
the taking from each chamber of the large specimen film of a calibrated volume of the liquid phase which it contains by a pipette device 128;
injection of this volume into a cell of the analysis film by means of an injection device 129;
transfer of the identification information carried by the strip portion of the large specimen film corresponding to a given chamber on that film to the magnetic strip portion of the analysis film in a position corresponding to the cell receiving the liquid.
These transfers necessitate step-by-step and synchronized displacements of the measuring film and of the large specimen film.
The analysis film, of which the cells contain the aforesaid calibrated volumes, is displaced in such a way that the cells arrive and are stopped for an instant at a certain number of reagent addition stations such as 131, 133, 135. Between the reagent addition stations are roller type members 132, 134, and 136 for mixing the contents of the cells.
The film then reaches a station 137, at which is carried out an operation for the heat-sealing the holes left by the needles. After this station, the film enters a thermostatically controlled chamber 138 in which the chemical reaction is able to be developed.
By way of example, the residence time in this chamber common to all the analysis operations, except the enzymatic analyses, is of the order of eight minutes. The film, moving forward step-by-step, is thus stopped in the chamber or oven, and each cell remains therein for the time necessary for the development of the reaction.
Immediately on leaving the oven, a reaction is stopped by sudden cooling produced in a member 140.
Situated on the outlet side of the cooling member 140 is an analysis device 141, such as a photocolorimeter.
The results of the analysis of the contents of each cell are transmitted, with the corresponding identification information, to a central memory for the purpose of numerical treatment by the data processor with which the laboratory is equipped.
The film is then destroyed by an appropriate device 142 and the debris collected in a receptacle 143.
FIG. 19 is a perspective view of an analysis line which comprises only a single station 127 for addition of reagent. The references used in FIG. 19 indicate the elements corresponding to FIG. 18.
FIG. 20 represents a preferred embodiment of a machine for the production of analysis film. g
This machine comprises essentially two supply spools 123 and 124 for heat-scalable flexible strips provided with lateral perforations of cinematographic type.
The strip from the spool 124 carries a magnetic track.
The spools 123 and 124 are simultaneously set in motion by means of a step-by-step motor 150 on the shaft 152. Several secondary shafts 153 to 156 for driving toothed wheels 157 to 160 are arranged on shaft 152. V
The strip fed by the spool 123 unwinds in front of a member for the heat-forming of cells and comprising a die, of which the heated active elements 161 and 162 are moved by a jack 163. The element 162 is guided by fixed rods 164 and 165. After the formation of cells, such as 168, the two strips are arranged facing one another and are heat-sealed. The heat-sealing operation is advantageously effected by means of a heating block 169 cooperating with the aforesaid element 162, in which has been formed a cavity 170 corresponding to the relief of the cells. The aforesaid analysis film 122 is obtained on leaving the apparatus.
In the figure, the form of the cell has been indicated diagrammatically as a parallelepiped for the sake of simplicity. This form is not in any way limitative, and the cell can have any form which is appropriate to the nature of the sample and the type of analysis.
FIG. 21 shows in perspective a portion of an analysis film 174, in which the cells 175 have a shape which is particularly adapted to the chemical analyses such as those usually carried out on blood samples. The cell 175 is substantially in the form of a cup having at its upper end a flattened portion 176 intended for the introduction of needles, the sample contained in the cell and formed by a mixture of serum and additive bears the reference 177 The different specimens of calibrated volumes effected either at the station where the auxiliary film is formed from the specimen film or at the transfer station 127 or at various reagent injection stations are produced by means of an apparatus for taking and measuring the samples, formed by a movable sample-taking pipette equipped with a level gauge and extended by a tube in which the liquid flows under the action of a gas under pressure.
FIG. 22 explains the principle of the operation of the apparatus.
The apparatus comprises a container 201 provided with a cover 202 through which extends a pipe 203 fitted with a cock 214 and an expansion valve 217. and a flexible tube 204 connected to a pipette 205 which is movable under the action of an electromagnet 206 The pipette 205 and the electromagnet 206 are carried by a float 207 which is above the liquid 208 in the container The tube 204 is extended by a tube 215 to above a second container 209. Positioned along the path of the tube is a level gauge 210 formed by a radiation gauge comprising a radiation source 211 and a cell 212. An electronic relay 213 transmits the current of the cell to the electromagnet The operation of the apparatus is as follows;
The substance 208 to be sampled is placed in the container 201, and the float 207 and the cover 202 closing in fluidtight manner are placed in position. A container 209 for receiving the sample is positioned beneath the end of the tube 215.
The tube 203 is connected to a source of gas, the pressure of which exceeds atmospheric pressure by a value equal at least to the weight of the liquid column, the height of which is the distance between the surface of the liquid and the highest point of the tube 204. The sampling pipette 205isin the low position, that is to say, dipping into the liquid.
As soon as the cock 214 is opened, the gas pressure which is applied to the surface of the liquid causes the matter to rise in the pipette and the flexible and transparent tube 204. As soon as the. liquid reaches the level gauge 210, the cell is no longer excited by the radiation, and, by means of therelay 213. it acts on the electromagnet 206, which lifts the pipette out of the liquid. The volume of liquid drawn in is thus. equal to the volume of the piping between the end of the pipette and the level gauge.
The gas pressure continuing to be exerted on the open end of the pipette drives all the liquid contained in the tube 204 toward the container 209. As soon as the liquid column has passed completely in front of the gauge 210, the cell is once again energized and transmits to the relay 213 the order for the descent of the pipette. This order can be delayed to wait until the apparatus is completely empty and the container 209 is replaced by a new container.
It is quite obvious that several elements given in this description in order to illustrate the operation can be replaced by equivalent elements without departing from the scope of the invention.
Thus, the electromagnet 206 can be replaced by a hydraulic or pneumatic jack.
The level gauge can be of any type, for example, a photoelectric cell gauge; a radiation gauge; or a gauge with electric contacts, between which the liquid to be analyzed establishes the flow of an electric current.
The tube 204is described as a flexible and transparent tube in the case where a radiation gauge is used. For a contact-type gauge, it is unnecessary for the tube to be transparent.
The tube can also be rigid and provided with a connection with the pipette 205 which permits the alternating movement of the pipette, following the movement of the float when the liquid level falls, for example, a connection by an elastic bellows.
The arrangement of the pipette on a float has advantages as regards ease in positioning and permits the travel of the pipette to be limited to a few millimeters. Such a reduced travel is desirable for high rates of sample-taking, for example, one sample per second, which is easily attained by the apparatus. Furthermore, an alternating movement of such small amplitude is easily obtained by means of an electromagnet of low power and small volume. The receptacle is placed under pressure by means of any gas of which the pressure is higher than atmospheric pressure. The gas is generally compressed air. A neutral gas, for example nitrogen, can be used. The effective pressure of the gas is regulated by the expansion valve 217, this making it possible to cause the speed of progression of the liquid in the pipette and in the tube 204 to vary. This ex pansion valve can be an expansion valve which automatically regulates pressure ,and which maintains a constant pressure in the container 201 When the pipette is moved out of the liquid 208, the pressure of the gas drives the sample towards the container 209 and the gas continues to escape through the tube 204 until the pipette is once again immersed in the liquid. This gas circulation taken place at a high speed and produces a good cleaning of the walls, which avoids the contamination of a sample by traces of preceding samples.
Although the level gauge can be of any known type, a radiation-type level gauge using radiation emitted by a radioactive body has advantages, because it permits detecting the passage of even a colorless liquid circulating in a capillary tube; a level gauge using electric contacts has the same advantage.
Provision is made for the level gauge to be able to be displaced along the tube 204 so as to cause the extracted volume to vary.
The foregoing description shows that one of the major advantages of the sampling apparatus resides in the fact that it is adapted to measure very small volumes which are of the order of fractions of a cubic centimeter, and at a high rate, of the order of one sample per second.
FIG. 23 is a perspective view of an arrangement for taking samples and for injecting a calibrated volume of a liquid, in accordance with a preferred embodiment. This arrangement operates in accordance with the previously described principle; it forms part of the stations for adding reagents to the analysis sequences, and also the stations for filling analysis films and auxiliary films with serum.
The example shown in the figure relates to an arrangement for withdrawing from a vessel a certain quantity of reagent and for injecting the said reagent into the respective cells of an analysis film.
The vessel 230, containing the reagent 231, is a sealed consta'nt level vessel; the vessel contains a float 232 pivoted about ahorizontal axis and formed by a plurality of plates, such as 233; the float serves to close a conduit 234 for supply of reagent when the liquid rises above a certain upper limit and to open it if the level falls too low. In accordance with the principle described above, a compressed gas is injected through a conduit 235 situated above the reagent level.
The analysis film 236 is displaced in the direction of the arrow 237 in such a way that each cell 238 is successively stopped for a certain time in front of the sampling and injecting arrangement.
This arrangement comprises a tube 240 capable of being immersed in the liquid of the vessel 231 and, for this purpose, it is fast with the plunger of an electromagnet 241. The aforesaid tube is connected by a flexible pipe 242 to an injection needle 243 capable of piercing the cell 238 at its upper par. This needle is fast with a jack 244. A second needle 245, fast with the jack 244, serves to place the interior of the cell under atmospheric pressure. An electronic device comprising two probes 246 and 247 serves to control the movement of various movable parts and to ensure the injection of a calibrated volume of reagent.
The operation of the arrangement is as follows:
As soon as a cell 238 arrives in front of the arrangement, the electromagnet 241 controls the descent of the tube 240 into the liquid of the vessel 230. The pressure exerted by the gas above the liquid causes this latter to rise in the tube. The probe 247, as soon as it detects passage of the liquid, controls the descent of the needles 243 and 245 into the cell 238. The probe 246, the position of which is adjustable along the conduit 242, so as to be able to adjust the volume to be injected, detects the arrival of the liquid and controls the ascent of the tube 240 out of the liquid. The pressure obtaining in the vessel then drives ofi the extracted quantity through the needle towards the cell placed under atmospheric pressure. After extracting the needles, the film advances by one step, and the following cell comes in front of the arrangement.
This arrangement can be adapted to the extraction from the chamber of a large specimen film of a given quantity of blood and the injection of the said given quantity of blood into the corresponding cell of an auxiliary film, such as that shown in FIG. 18 and 19.
In this arrangement, which is shown in perspective in FIG. 24. the chamber of a large specimen film replaces the aforesaid vessel 230. In addition, the tube 240 is replaced by a needle, the movements of which are controlled in such a way as to enter the liquid phase of each chamber without ever coming into contact with the solid phase. One embodiment is shown in FIG. 24. The large film 250 is arranged to be displaced step by step in accordance with the arrow 251, so that the large chambers such as 252, arrive and are stopped for a certain time facing a sample-taking needle 253. This needle is fast with a piston 254 which is movable inside the cylinder 255. The piston is normally held in the raised position by a gas under pressure arriving through a conduit 256. The detection of the level 257 of separation of the liquid phase 258 from the solid phase 259 is effected by means of an electronic device comprising a plurality of optical cells such as 261, disposed vertically behind the film 250 and illuminated through it by means of light sources such as 262.
, The cylinder is equipped internally with nozzles 265 permitting the injection of compressed gas. in addition, addition, a conduit 269 is disposed at the upper part of the cylinder so as to permit the establishment, when it is open, of a pressure higher than that supplied by the conduit 256. The aforesaid nozzles are disposed vertically in such manner that they are representative of the level detected in the chamber 252. The opening and closing of each nozzle can be controlled by a device 266 actuated by a coil 267. One nozzle correspondsto each optical cell. If a cell is energized, which indicates that it is facing the liquid phase, the corresponding nozzle is closed, and vice versa.
The sample-taking sequence is as follows: at the moment that the chamber is stopped, the conduit 269 is opened. The piston descends to a level fixed by that of the first open nozzle which it encounters. The needle 253 then dips into the serum 258. A needle 270, controlled by a jack 271, will pierce the chamber in its upper part so as to place it under a pressure higher than atmospheric pressure. The serum then rises in the sample-taking needle 253 and a calibrated volume is injected, as described above, into one of the cells of the analysis film.
FIG. 25 shows a preferred embodiment of a photocolorimetric analysis arrangement.
The cells of the analysis film 174 are stopped one after the other, for a short instant, generally less than one second, in front of a photocolorimeter comprising a source of light radiation 330, a series of filters and screens 331 to 334 especially adapted to the measurement in question, and a receiving cell 335 of the photoelectric type.
A device comprising a fixed plate 336 and a movable plate 337 moved by a jack 338 encloses the cell as soon as it is stopped on the optical axis of the photocolorimeter and thus makes it possible to guarantee a constant thickness of liquid to be analyzed and interposed on the path of radiation.
While the cell remains between the aforesaid plates, the liquid in the cell passes from a lower level 178 to a high level 179, as shown in FIGS. 21 and 27. The light radiation passes through a limited observation zone 180 of the cell.
The displacement of the measuring film in front of the photometer is assured by a mechanical driving arrangement synchronized with the arrangement used before the different injection heads and in the tool for obtaining the film.
The laboratory can also be equipped with enzymatic lines enabling an evolution curve to be given as a function of time of the enzyme being considered.
An enzymatic line differs from the aforesaid chemical analysis line, in that it comprises several photocolorimeters separated by ovens, in each of which the reaction proceeds for a certain time. The measurements made by the various photocolorimeters are directed to the data processor and treated by the latter.
The laboratory includes a hematology section comprising particularly a section for counting corpuscles and a section for the analysis of hemoglobin.
Starting from the station for distributing the specimens, coming immediately after the entry identification of the spools. several film spools intended for hematology are formed from spools of elementary specimen films.
A cementing station identical with that described in the chemical section assures the formation of a continuous film.
A continuous and identified film is available at the discharge from the hematology cementing station.
Three different analysis lines are found along the travel of this film: a line for counting red corpuscles, a line for counting white corpuscles and an analysis line for hemaglobin.
The red corpuscle counting line permits, by juxtaposition of two counting apparatus, operating on an average at the speed of one count per second. This count is for example carried out on five thousand corpuscles. The sequence operates in the following manner:
Specimens are transferred directly into the counters by two sampling and injection heads which operate simultaneously and from two samples of specimen film.
The entry to the counters is formed by a dilution arrangement especially adapted to this type of very high dilution l/50,000.
The counter operates with the dilute sample and extracts for example 0.5 cc of solution.
The line for counting red corpuscles makes it possible for the average volume of the corpuscles to be supplied by an appropriate system. It also permits the hematocrit reading to be calculated: Mean volume x red corpuscle count Volume of red corpuscles.
The white corpuscle counting line functions in exactly the same manner, the dilution here also being made in the counting apparatus by a mechanism which guarantees'the accuracy for a dilution to 1/500.
The pulses of each counter, both on the red corpuscle line and on the white corpuscle line, can be counted by an electronic counter, the contents of which are read in parallel by the data processor.
As soon as the counting is ended, each counter lets the data processor know that the counting is completed by a'programstopping signal.
The hemoglobin analysis line is a simple chemical dosage line. The combination by data processor of the dosage of hemaglobin and of the number of red corpuscles permits the average hemaglobin density to be supplied.
The laboratory may possibly comprise a section for establishing the leucocyte formula from the examination of colored platelets.
Certain cells of the measuring film may, during the'analysis, receive neither specimen nor reagent; these cells are intended to check the calibration of the photocolorimeters during the measurement. Other cells can be filled with a comparison solution for the purpose of recalibrating the photocolorimetric scale.
The material of the analysis film may with advantage be a colored plastic material serving the purpose of an optical filter.
The multiple and automatic installation according to the invention has the following advantages: error in identification impossible; contamination of the samples with one another is eliminated; minimum consumption of reagents; high rate of measurement; system very well adapted to the possibilities of data processors; very good reliability because of the independence of the measurements relatively to one another and the safety systems which are adopted; very high measurement security, each measuring cell is independent; low production and operating cost and considerable reduction in personnel; number of bits of information supplied greatly increased, and hence possibility of assistance to diagnostics.
The invention is not limited to an installation for blood analysis operation, but is applicable to any problem involving multiple analyses. The taking of blood samples has only been given by way of example. The arrangements described can also be used for the purpose of analyzing materials of different extraction by means of adaptations which are simple to the person skilled in the art.
What is claimed is:
l. A conveyor system for carrying liquid specimens comprising:
a. a supporting web formed with lateral perforations of the type found on cinematographic film and having a magnetic track whereon a coded identification may be recorded; and
b. a flexible and transparent sheath covered by said web and defining therewith a series of regularly spaced liquid sealed chambers, said chambers being adapted to receive said specimens.
2. A conveyor system as defined in claim 1 further comprising first ends of said web and sheath arranged in such manner that one of said first ends is extended beyond the first chamber on the side of the said first ends a length equal to a given fraction of the spacing between said chambers, and the other of said first ends is extended in the same direction a distance equal to the difference between the spacing between said chambers and said length; second ends of said web and sheath arranged in such manner that one of the second ends is extendedbeyond the first chamber on the side of the said second ends over said'length and the other of said second ends is extended over a distance equal to said difference, whereby said conveyor system may be joined to other similar systems endto-end, the first end of one system being brought into contact and stuck to the second end of another system so as not to form any extra thickness.
3. A conveyor system for carrying liquid specimens as claimed in claim 1 further including a device for transferring a given quantity of liquid from said specimen chambers comprising:
a. a tube,
b. means for causing one end of said tube to penetrate in fluidtight manner into said specimen chamber below the level of the liquid to be extracted;
c. a secondspecimen chamber connected to the other end of said tube; I
d. means for exerting a pressure in the said first specimen chamber, whereby the liquid is causedto rise in the said tube;
e. means for causing the rise to stop when the liquid has reached a selected position in the tube; and
f. means for lifting said one end of the tube out of the liquid, whereby the pressure exerted in the first specimen chamber drives the liquid contained in the tube into said second specimen chamber.
4. A conveyor system for carrying liquid specimens as claimed in claim 3 further including:
a. means for detecting the presence of said liquid at a given position in said tube, said last mentioned means activating said means for lifting said one end of the tube out of the liquid;
b. a float in said fluidtight specimen chamber carrying said means forcausing said one end of the tube to penetrate below said liquid level.
5. In an installation for multiple and automatic analysis of a liquid specimen, a device for deposition said specimen on a conveyor system comprising:
a. an intermittently driven web having a series of spaced chambers formed of flexible, transparent material;
b. means for extracting said specimen from the substance being studied;
0. a card adapted to be positioned in relation to said chambers to identify said specimen; and
d. means for disabling said extracting means when said card is not properly positioned.
6. A device for depositing a liquid specimen on a conveyor system as defined in claim 5 wherein said card has at least one detachable slip, and further comprising:
a. means to detach said slip from said card and to stick the slip on said web;
b. an electric sensor for detecting the presence of the slip on said web;
c. stopping means activated by said sensor in the absence of a slip on said web for stopping the advance of said web.
7. Adevice for depositing a liquid specimen on a conveyor system as defined in claim 5, further comprising:
a. a hollow needle connected to said extracting means for injecting said specimen into one of said chambers;
b. a flap having a position interposed between said needle and said chambers; and
c. means responsive'to said card beingpositioned to identify said specimen to move said flap from its interposed position.
8. in an installation for multiple and automatic analysis of a liquid specimen carried in a chamber, an intermittently movable web, a photocolorimeter device comprising:
a. a pair of parallel plates positioned in spaced relation to,
and on opposite sides of said web; and