CA1179868A

CA1179868A - Rotor unit with insert elements for a centrifugal analyser

Info

Publication number: CA1179868A
Application number: CA000455618A
Authority: CA
Inventors: Hermann Edelmann; Manfred Pasch; Sigmar Klose; Hans-Peter Haar; Karlheinz Mann
Original assignee: Boehringer Mannheim GmbH
Current assignee: Roche Diagnostics GmbH
Priority date: 1980-11-25
Filing date: 1984-05-31
Publication date: 1984-12-27

Abstract

ABSTRACT

An insert element for use in a rotor unit of a centrifugal analyser for the analytical deter-mincation of at least one component of a sample fluid comprises a housing containing at least one sample chamber for the reception of a sample liquid, at least one measuring chamber for the measurement of characteristic parameters for the detection of com-ponents of the sample, while the element rotates with the rotor unit, and a fluid connecting channel communicating each sample chamber with an opposed measuring chamber; the housing has retaining means adapted to cooperate with a rotor base of the rotor unit such that the housing is adapted to be held positionally stable on the rotor base when the centrifugal analyser is in operation, with the at least one measuring chamber disposed radially out-wardly of the at least one sample chamber; at least one analysis reagent is disposed in the channel between the sample chamber and its opposed measuring chamber, such that in operation a sample liquid in a sample chamber is brought into contact with, and mixed with, the analysis reagent in the channel, under the action of centrifugal force before it reaches the opposed measuring chamber; the insert element in conjunction with the rotor unit of a centrifugal analyser provides a unit of simple operation with flexible and wide use.

Description

1~79868 The present invention is concerned with an insert element, more especial:Ly an insert element for use with a rotor unit for a centrifugal analyser.
This application is a division of Canadian Patent Application S.N. 390,835, filed ~ovember 24, 1981.
A rotor unit for a centrifugal analyser is described having a rotor base connected with a drive and a rotor head which, in operation, is connected with the rotor base, the rotor head including chambers for the reception of a sample liquid and, radially outwardly from the associated sample chambers, measuring chambers for the measurement of character-istic parameters for the detection of components of the sample, as well as liquid channels for connecting the sample chambers with the measuring chambers.
The present invention is concerned with insert elements for use with a centrifugal analyser adapted for use with such a rotor unit.
Centrifugal analysers with a rotor unit of the above-mentioned type have been conventional for a number of years for the purposes of chemical analysis, especially in clinical chemistry. They have circularly symmetrically constructed rotor units with a plurality ., ~
~ .

~1~9868 - la -of radial analysis channels. Usually, each analysis channel has, from the inside towards the outside, a trough-shaped reagent space, a sample space and a measuring space which,` in the case of the known devices, is constructed as an optical cuvette. The rotor unit can be arranged in a rotor base and a rotor head mounted non-rotatably on the rotor base.
The rotor base is usually constructed as a plate or frame and ~179868 securely attached to the axis of the rotor drive. The term "rotor head" designates the remaining part of the rotor unit which, in particular, includes the above-mentioned analysis channels. In the case of more recent centrifugal analysers, the rotor head is, as a unit, exchangeable and is, in operation, non-rotatably connected with the rotor base. The rotor head and the rotor base can, in each case, be constructed in a large variety of ways and can also differ substantially, especially in the diameter of their outer boundary, Thus, the rotor base can, for example, con5ist of only a holder for the rotor head connected in one piece with the rotor drive axis, which holder is, in operation, completely superimposed by the rotor head.
In the case of the known devices, the rotor head is, while stationary, filled with reagents and samples.
A device which can be used for this purpose is described in Federal Republic of Germany ~atent Specification No.

2,626,810, which also describes the construction of a typical rotor. As is to be seen from this German Patent Specification, a complicated mechanical device is needed for automatically filling the rotor.
After filling, the known rotor heads are placed in the centrifugal analyser and connected with the rotor base. The rotor is set in rapid rotation and, in the case of some devices of this kind, alternating speeds of rotation are used for mixing. Due to the centrifugal 1~79868 acceleration during rotation of the rotor, the reagent passes from its chamber into the sample chamber and then the two together are passed ~nto the measuring chamber, measurement there being carried out with the rotor running. In the case of the known devices, the measurement consists of a detèrmination of the optical density of the liquid in the measuring chambers, which are constructed as optical cuvettes. Thanks to modern electronic evaluation devices, the absorption can be measured in each cuvette at each rotation of the rotor.
In this way, the absorption in all cuvettes can be observed almost continuously. In the case of a typical rotational speed of 1000 rotations per minute, 1000 measurements are carried out per minute for each cuvette. On the basis of this process, there is obtained a precision of measurement which, in the case of comparable analysis frequency, can scarcely be achieved with conventional analysis devices, especially in the case of so-called kinetic analysis determinations in which the speed of the course of the reaction permits conclusions to be made regarding the concentration of a particular component.
The known centrifugal analysers have a number of important advantages but also considerable disadvantages.
A summary of the most important requirements for an optimum analysi~ device can be found in one of the first public:ations concerning centrifugal analysers ~17~1~68 (see Norman G. Anderson in "Analytical Biochemistry", 28, 545-562/1969) One of thes~ requirements is the practically simultaneous measurement of several reactions which, as described above, make possible a bette,r monitoring of the individual courses of reaction. Another requiremen~ i3 that the volumes of the reagents and samples should be as small as possible.
This requirement is also substantially fulfilled by the known centrifugal analysers but an improvement is still desirable. Centrifugal analysers readily permit the attachment of modern data evaluation systems for the evaluation of the measurement results, i.e. not only for the conversion of the absorption values into the desired concentration values but also the statistical evaluation of these concentrations in order to give the physician information which is prepared as far as possible.
Other requirements already mentioned in this early article by Anderson are not fulfilled to a desirable extent by the centrifugal analysers which are at the moment conventional. The known devices still require a large amount of attention from personnel, they are not sufficiently simple to enable them also to be used by untrained personnel and they are not yet sufficiently flexible and variable in order to be able to fulfil very different requirements, especially in the operation of a clinical laboratory.

~79t36~3 These deficiencies have, in the course of time, given rise to a large number of developments of the original concept, which have led to increasingly com-plicated rotor constructions. Thus, these rotors were expensive to produce but are still not able to fulfil all the various requirements of the different analytical determinations which are usual in clinical chemistry.
In particular, the known rotors can only be used for carrying out one analytical determination for a number of samples in one run of the rotor. As a rule, however, in the clinical laboratory a series of differ-ent analytical determinations must be carrie-d out on a sample, for example blood from a patient, which, in toto, are also called the profile. In the case of the known analysers, this necessitates a considerable amount of organisation. mus, the individually nec-essary analytical determinations, communicated, for example, by the physician to the clinical laboratory, must be carried out gradually in separate rotor runnings on one or more centrifugal analysers. Thereafter, the separately determined data must ~e collated and passed on to the physician. This complicated procedure not only requires a considerable amount of organisation but - is, unfortunately, not infrequently the cause of errors of communication which can possibly result in false therapeutic measures being carried out by the physician.
Thus, there is a need for centrifugal analysers which , 98ti~

can be adapted more variably and flexi~ly to various tasks and which, in particular, can be used for pro-file analyses or at least for several different analytical determinations in one rotor running. This is especially necessary for emergency analyses where, under certain circumstances, several different analytical determinations must be carried out in the shortest possible time for one sample, i.e. for one patient.
Another problem of clinical chemistry which is not only typical for centrifugal analysers is that, in the case of the known devices, obtaining the sample, i.e. especially obtaining serum or plasma from blood, and preparing the sample, i.e. especially diluting serum or plasma to the concentrations necessary for the analysis, take place in separate working steps away from the analysis device. It is readily apparent that, in this way, additional manual working steps and, in particular, decanting steps are necessary. These can, in turn, again result in mistakes being made or can, for example, also result in contamination of the samples.
There is herein described a rotor unit for a centrifugal analyser of the initially described type llt7~868 - 6a -tllat, with avoidance of the disadvantages of known centrifugal analysers, the simplest possible operating is possible, together with a most flexible and wide use as possible of the device.
The present invention seeks to provide insert elements particularly for use in such a rotor unit and in conjunction with an appropriately constructed centrifugal analyser.
Thus according to the invention, there is provided an insert element for use in a rotor unit of a centrifugal analyser for the analytical deter-mination of at least one component of a sample fluid comprising:
a housing containing at least one sample chamber for the reception of a sample liquid, at least one measuring chamber for the measurement of characteristic parameters f~r the detection of components of the sample, while the element rotates with the rotor unit, a fluid connecting channel communicating each sample chamber with an opposed measuring chamber, - said housing having retaining means adapted to cooperate with a rotor base of the rotor unit such that said housing is adapted to be held 117~61~

positionally stable on the rotor base when the centrifugal analyser is in ope:ration, with the at least one measuring chamber disposed radially out-wardly of the at least one sample chamber, and at least one analysis reagent disposed in said channel between said sample chamber and its opposed measuring chamber, such that in operation a sample liquid in a sample chamber is brought into contact with, and mixed with, the analysis reagent in the channel, under the action of centrifugal force before it reaches the opposed measuring chamber.
The rotor unit for a centrifugal analyser may comprise a rotor base adapted to be connected with a drive and a rotor head which, in operation, is connected with the rotor base, the rotor head including chambers for the reception of a s~mple liquid and, radially outwardly from the sample chambers, measuring chambers for the measurement of character-is~ic parameters for the detection of components of the sample, as well as channels for connecting the sample chambers with the measuring chambers, wherein the rotor head comprises a plurality of insert elements of the invention, which are ex-changeable and connectable with the rotor base at ~179868 - 7a -different selected positions, the insert elements being positionally stable when the centrifugal analyser is in operation.
In particular each sample chamber com-municates with a radially outward opposed measuring chamber through a channel.
The rotor unit for a centrifugal analyser may comrpise a rotor base adapted to be - 8 - ~179~6~

connected with a drive and a rotor head which, in operation, is connected with the rotor base, said rotor head supporting a plurality of exchangeable insert elements which are connectable with the rotor base at different selectable positions, said insert elements being positionally stable when the centrifugal analyser is in operation, at least some of said plurality comprising analysis elements, each analysis element having at least one sample chamber for the reception of a sample liquid and, radially outwardly from the sample chamber, at least one measuring chamber for the measurement of characteristic para-meters for the detection of components of the sample, and a fluid connecting channel, communicating each sample chamber with a radially outward opposed measuring chamber.
The insert elements may comprise different insert elements including single analysis elements and multiple analysis elements as well as elements for obtaining or preparing a sample.
Each insert element contains devices for carrying out part stages of analytical determination.
The external shape of the insert elements can differ but they can, for example, also only differ in the chemical composition of a part of their components.
It is import,ant that, by means of the present invention, 1~98~;8 g instead of the previously conventional, uniformly constructed rotors, those are used, the rotor head of which can receive a plurality~ of different insert elements, a substantially increased variability thereby being achieved. Whereas the known rotors, as mentioned above, were only capable of fulfilling one particular task, namely, as a rule, the determination of one chemical component of a sample on a plurality of samples in one rotor running (so-called "batch"
10 ` operation), in the case of the rotor unit according to the present invention, each insert element can be optimally adapted for a particular task. Due to the possibility of connecting a plurality of diffarent insert elements with the rotor base, for each rotor running an individually adapted rotor can be assembled which can then be used in a substantially more varied manner. For example, in this manner, determinations of several components of a sample (profile determin-ation) are possible in one rotor running. Furthermore, there are considerable handling simplifications, such as are described hereinafter.
According to a preferred embodiment of the present invention, the insert elements used can be analysis elements of various constructions, such as simple analysis elements which include devices for determining one of the components of a sample and also multiple analysis elements which have devices for :1179868 simultaneously determining several components of one or more samples. These insert elements can now be adapted entirely to a particular analytical task.
Thus, in their construction, they can have different analysis channels which are suppl~ed with liquid reagents. However, they can also contain pre-packed reagents, especially in solid form, which then, as will be described hereinafter, are dissolved ~y the diluted sample and mixed therewith. The term "insert -element" or "analysis element" includes those of every possible shape and size. Especially simple analysis elements can be, for example, papers or fleeces impreg-nated with reagents which can be exchangeably inserted into the rotor head.
According to another preferred embodiment, the insert elements according to the present invention connectable with the rotor base include elements for obtaining and preparing the samples. In this way, a substantial disadvantage of the known centrifugal analysers is also overcome. Thus, hitherto the sample was, in each case, obtained and prepared separately from the analysis device. In the case of blood analysis, the blood must first, for example,-be centri-fuged for obtaining serum or plasma and this then appropriat~ly diluted before it can be introduced into the sample chambers of a centrifugal analyser. For transferring the samples into the rotor head outside ~179136~

'. --11--of the apparatus, use was made, as mentioned herein-~ before, of complicated apparatus or manual pipetting was necessary. With the inslert elements according to the present invention, hereinafter described in more detail, for obtaining and/or preparing the sample, it is now possible to carry out these important steps in the centrifugal analysis device without manual trans-fer procedures or other manual handling steps being necessary. In this way, not only i5 the operating simplified but the prevention of human errors also increases the dependability.
The spatial measurements of the insert elements are preferably supplemented in such a manner that - - larger elements can be connected to the rotor base in place of an inte~er multiple of the smallest elements. This embodiment o~ the present invention can also be expressed in such a manner that the dimensions of the insert elements contain a raster measure. A particular whole number fraction of the rotor surface or of the rotor circumference determines the base unit of the raster. The individual insert elements are then so constructed that their spatial requirement corresponds to a multiple of this raster base unit. In this manner, the rotor unit according to the present invention becomes especially variable because comparatively large insert elements can now, without waste of space, occupy the place of several 11791~613 smaller insert elements. The holders for the insert - elements are, for the same reason, preferably arranged periodically on the rotor base, insofar as t~ey each lie on the same circumference, the periodicity length of the holder arrangement thereby corresponding to the base unit of the raster.
It is to be expressly pointed out that the present invention is not limited to the case in which the insert elements all have about the same radial distance from the centre of the rotor. On the contrary, for certain uses it can be highly desirable to arrange the insert elements on different circumferences of the rotor, for example in order thus to permit different centrifugal accelerations to act upon the different elements at a particular speed of rotation.
In this case, the holders for the insert elements also have a different radial distance from the rotor centre and thus lie on different circumferences~
A construction of the insert elements which, viewed from the top of the rotor, has a circular sector shape is especially preferred because various insert elements thereby jointlessly abut one another and, from the totality of the insert elements, there is obtained an uninterrupted surface of the rotor head when the rotor is completely loaded with insert elements, although thi~ is not essential. The term "circular sector shape" is here to be understood to - 1~798~i8 mean that the bounding lines of the sectors, i.e.
viewed from the top of the rotor, ex-tend essentially along the radii of the rotor circle. of course, the present invention also inclucles solutions to the problem in ~hich the outer edges differ from the course of these radii in a definite manner which repeats itself in the case of the different elements so that the different insert elements, although they do not have straight side surfaces, as a whole give an uninterrupted loading of the rotor base. Such a construction can be especially advantageous in order to hold together the insert elements by a form-locking construction of their side surfaces.
In conventional centrifugal analysis rotors, it is known to construct the rotor head in two parts, i.e. in a ring on the periphery of the rotor head, which contains cuvettes for optical measurements and an inner part, constructed, when viewed from above, in circuiar form which fits the cuvette ring exactly and, on its periphery, has through openings-which, in the assembled state, are in alignment with and tightly close the entry openings of the cuvettes. Upon rotation of the rotor, the analysis liquid then passes from the analysis channels in the circular inner part into the cuvettes of the cuvette ring. Such a construction has the advantage that the cuvette ring can be made from high quality materials and made very precisely so that ~L79~68 the cuvettes have very good optical properties, whereas the circular inner part can be ma~e comparat-ively simply. Consequently, a preferred embodiment of the present invention is also correspondingly con-struc~ted. In this case, the cuvette ring is to be regarded as being a part of the rotor head and is - securely or exchangeably connected with the rotor base.
All the measuring chambers preferably lie on one circumference of the rotor head, i.e. they have the same radial distance from the centre thereof, in order that a single evaluation unit suffices for the determination of the characteristic parameter which must be measured for the detection of components of the sample. As already mentioned, in the case of known centrifugal analysers and preferably also in the case of the device according to the present invention, the optical absorption at one or more wavelengths is determined as the characteristic parameter for the detection of components of the sample. However, the present invention is not limited to such optical measurements. Precisely because of the novel variability of the device according to the present invention, it is also possible to carry out completely d:ifferent determinations in a centrifugal analyser, these including, for example, electrical measurements in conjunction with electrochemical ~7~1~368 analysis processes of the most varied types. In this case, the measuring chambers have electrodes, the signals of which are passed in an appropriate manner to the evaluation apparatus of the device, for example via sliding contacts or without the use of wires. In such cases, bult also in the case of purely optical measurements, the measuring chambers can also lie on different circumferences of the rotor head.
The sample obtaining and/or sample preparing elements have take-off points at which, by means of appropriate devices of the apparatus, for example canulae of automatic measuring devices or so-called dispensers or dilutors, samples can be taken. These take-off points preferably lie on an arc with the same radius as the feed-in openings of the sample chambers of the analysis element. It is thereby possible, for ~he transfer of the samples from the sample obtaining or sample preparing elements to the analysis elements, to use measuring devices which only move in a vertical direction. The rotor is then brought into a position appropriate for the removal or supply procedure by means of a step-by-step switch device integrated into the drive.
According to a further preferred embodiment, the insert elements carry codings with regard to the sample and/or the components of the sample to be determined ~3~7986~3 with the particular element. These codings can be read by a reading means incorporated into the centri-fugal analyser in order, in this way, to impart to the device essential data for the evaluation and, at the same time, to obtain a control for the correct supplying of the rotor with the insert elements by the operating personnel. Furthermore, the insert elements preferably have markings for triggering the measurement procedure. The insert elements have, of course, in their position with regard to the rotor base, certain tolerances, even though these may be small in the case of precision construction of the holder. Since, in general, the measurement procedure must be triggered with regard to the position of the insert element, it is especially advantageous when the markings in question are on the insert element and not, for example, on the rotor base.
The holding parts which, by form-locking cooperation with the insert elements are preferably used for their precise holding on the rotor base, are preferably arranged in the region of the measuring cells. Possible tolerances in the dimensions of the insert elements thereby have especially little effect with regard to the positioning of the measuring cells.
The present invention also provides insert elements for use with the rotor unit according to the present invention, which insert elements are especially ~7g~fi8 adapted for this purpose and make possible further preferred embodiments of the rotor unit.
Preferred insert elements of this kind include the reagents for carrying out analytical determin-ations in a form which is storage-stable and which can be transported with the insert elements. Such analysis insert elements are especially advantageous for use as "once oniy" elements, which can also be called dispos-able elements. They are already provided by the manufacturer with appropriate reagents for particular analyses and are supplied to the user as a unit con-taining the reagents. This obviates the handling of individual and especially of liquid reagents, which is a considerable simplification. Such disposable elements can be made in a large number of versions, - each version being suitable for one or more identical or different analysis methods and includes the approp-riate reagents, as well as appropriately shaped fluid channels and other devices. For carrying out a plurality of different analytical determinations, the user has then only to select the appro~riate insert element and to place it into the rotor unit.
An especially preferred insert element of the invention for use in the rotor unit contains at least one analysis reagent in dry form and - 11798Çi8 a plurality of very small hollow spaces connected with one another, which connect the sample chamber and measuring chamber with one another. Such insert elements are described in Canadian Patent Application S~. 390,834, fil2d ~ovember ~4, 1981, Klose et al.
-Re~erence is m~a~ to the whole cont~nt of this Canadian Patent Application. ~etails of the construction of the insert elements described therein, which are also important components of the present invention and permit an especially advantageous use thereof, are described in detail in this co-pending Canadian Patent Application, reference to which is hereby made without repeating the content of this Canadian Patent Application.
Other preferred insert elements, namely sample obtaining and/or preparing elements, can be used for taking blood from a patient, for obtaining serum or plasma by the action of centrifugal acceleration and as sample vessels. These elements intended for blood analysis save two additional vessels, namely, a syringe for taking blood from a blood vessel of a patient and a centrifuge tube for obtaining serum or plasma. At the same time, transfer procedures from one vessel to another are avoided. However, in con junction with the present invention, it is especially important that the obtaining and preparation of the sample, as already mentioned hereinbefore, can, in the case of using such 1~L79868 insert elements, take place in the analysis apparatus itself and that the sample is then, without manual steps, transferred in a simple way from the sample obtaining and/or preparing vessel in the analysis apparatus itself into the analysis element.
For a thermostatic control of the sample, it is also advantageous when these sample obtaining and/or preparing elements are used in the rotor unit itself according to the present invention. Thermostatic control can be ensured by an appropriately regulated heating of the rotor base and/or of a part of the rotor head which is not exchangeable with the insert elements, be it by a thermostated fluid flow or by direct electrical heating or cooling. In order to achieve a sufficiently precise thermostatic control of the sample, this must be in thermal contact with the ~-thermostatically controlled parts for a certain minimum period of time. If the obtaining and preparation of the sample take place away from the rotor, then, after introducing the sample into the rotor head connected to the rotor base, it is necessary to wait until the time has expired which is necessary for this thermo-stating. In contradistinction thereto, the sample in the device described herein is already thermostated during the centrifuging and possible further process steps, for example during dilution of the s~mple.
Therefore, the analytical procedure can 1~798~

commence shortly after transferring the sample into the analysis insert element. The saving of time thereby resulting results in a greater analysis capacity of the apparatus or in an increased exacti-tude due to the improved thermostating.
The rotor unit described herein is pre-ferably employed in a specially constructed centri-fugal analyser which, in particular, includes evaluation devices for the determination of several 10 different components of a sample in one rotor running.
As mentioned hereinbefore, the present invention makes possible, in a simple manner, the determination of several different components of a physiological liquid in one rotor running. The determination consists of a chemical reaction and the subsequent measurement of a parameter, the value of which is characteristic for the concentration of the component to be determined.
There is a number of known and proven specific chemical reactions for various components of a sample, especially in clinical chemistry, w~ich result in a change of the same parameter characteristic for the concentration, for example the optical absorption of the solution at a particular wavelength. By way of example, mention is made of the numerous reactions which result in a change of the concentration relation-ship of ~AD ,and ~ADH, the absorption of the solution at 340 nm being characteristically influenced. Such 1~9~6~3 determinations, which result in a change of only one characteristic parameter, can be evaluated with con-ventional centrifugal analysers. However, in order fully to utilise the versatility of the novel analysis device according to the present invention, it is advantageous when the centrifugal analyser employed can evaluate several parameters in one rotor running.
In principle, these can also be of a different nature, for example, the measurement of the optical absorption and of the fluorescence and, under certain circumstances, of electrical values. However, a centrifugal analyser is especially preferred which can be used for the determination of the optical absorption at several different wavelengths in one rotor running, for which purpose it has a poLychromic photometer. The term "polychromic" is here not to be understood to mean that the photometer operates with multicoloured light but that it must be a photometer which can measure at a number of different wavelengths, the change of the wavelength being so coordinated with the course of the measuring cuvettes of the rotor that the absorption of each cuvette can be measured at any desired wave-length.
Furthermore, a centrifugal analyser de-scribed herein preferably also has a rotor drive which not only, as in the case of the known apparatus, is suitable for driving the rotor at a speed ~79~

of rotation appropriate for the mixing and measuring procedures (usually about 1000 r.p.m.) but, in addition, has a higher speed ~f rotation for centri-fuging samples. Furthermore, the drive is preferably to be capable of moving the rotor stepwise into certain positions, which is of especial advàntage for the preparation and distribution of the samples.
The present invention will now be described in more detail, with reference to the accompanying drawings, which illustrate several specific embodiments and in which:
Fig.l is a perspective schematic illustration of a rotor unit;
Fig.2 is a cross-section through a rotor unit according to Fig. 1, Fig.3 is a top view of a rotor unit from which, in particular, the raster division can be seen;
Fig.4 is a schematic illustration of a view of a com-bined sample obtaining and preparing element;
Fig.5 is a cross-section through an analysis insert element for use with liquid reagents;
Fig.~ is a schematic illustration of a top view of a preferred construction of an analysis channel;
and Figs.7a and 7b are cross-sectional views through a part of an analysis channel present in an 7~8~8 -~3-analysis element according to the present invention, with additional mixing devices.
Figs.l and 2 illustrate-a rotor unit, indicated as a whole by 10, with a rotor base 12 and a rotor head 14. The term "rotor head" includes all the con-structional parts which can be connected with the rotor base for the operation of the centrifugal analyser. In particular, it includes the constructional-elements necessary for the actual analysis. These include, according to the present invention, in the first place various analysis insert elements, for example simple analysis elements 16 and multiple analysis elements, such as the illustrated triple analysis element 18, the sevenfold analysis element 20 and the elevenfold analysis element 21.
Furthermore, a combined sample obtaining and preparing element i~ indicated by 22. Not only on the rotor base 12 but also on the insert elements 16, 18, 20, 21 and 22, there are provided mechanically readable codings 24 and 26, respectively. The analysis elements have inlet openings 28 for the introduction of a sample into the sample chambers 29, cuvette windows 30 and bores 32 which serve as trigger marks for the initiation of the measuring procedure. In Fig.2`there is schemat-ically illustrated a trigger signal emitter 33 which contains a source of light and an optical receiver in order to produce a trigger signal each time upon ~179~68 passing a trigger bore. The path of light for the optical absorption measurement passes along the line S-S in Fig.2 but, for the purpose of clarity, it is not shown in detaii. It is of conventional construct-ion, a polychromic photometer preferably being used.
In the case of the embocliment of the present invention illustrated in the ~'igures, an optical absorption measurement i9 employed as characteristic parameter for the detection of components in a sample.
-10 This is the most conventional analysis process in clinical chemistry but the present invention can also be applied to other analytical principles in which, as characteristic parameter, for example the fluorescence, the luminescence, the reflection, the radioactivity or electrical data of the reagent mixture are measured in the measuring chamber in order to determine therefrom the concentration of certain components of a sample, for example of enzymes or substrates in a physiological liquid.
In Fig.l, there can be seen two measuring devices 34 and 36 which serve for measuring, diluting and distributing the samples. There is preferably used a sample-reagent measurer 34 which, in general, can also be called a diluter, and a sample distributor 36 which, in general~ can be called a dispenser. Both of them are arranged to be movable vertically in the centrifugal analyser according to the present invention, - 1~798~8 as is indicated by the double arrows 38 and 40.
The insert elements 16, 18, 20, 21 and 22 can be connected by holding pins 42 to the rotor base 12, which has corresponding holding slots 43 (see Fig.2).
The shapes of the holding slots 43 and of the holding pins 42 are so adapted with regard to one another that they fit into one another and ensure a position-stable arrangement of the insert elements 16, 18, 20, 21 and 22. For fixing the insert elements, there is also provided a central locking member 44 which, by means of a thread 46, can be screwed on to the rotor base 12 and which lies upon seatings 48 of the insert elements 16, 18, 20, 21 and 22. The rotor base 12 is connected via a driving axis 50 to a rotor drive for the centri-fugal analyser. The quality of the mounting of the driving axis and the weight of the rotor base are important for a low vibration running of the rotor.
Furthermore, the weight distribution of the insert eiements is preferably such that, even in the case of different loading of the rotor, not too great an imbalance results. Insofar as the rotor is not completely loaded, it can be necessar~ to apply appropriate weights to the rotor base in order to avoid too great an imbalance.
Fig.3 shows a top view of a centrifugal analyser according to the present invention which differs from that illustrated in Figs.l and 2 in that it has place ~798~8 ~or a larger number of insert elements. Fig.3 clearly shows, in particular, the advantageous rastering according to the present invention of the fixin~ means and thus of the arrangement of the insert elements 16, 17, 19, 21 and 22, which can ~e changed as desired.
It can be seen that the circular surface of the rotor base 12 is divided up into a plurality of whole seg-ments B of the same size. In the illustrated embodi-ment, these segments are sectors of a circle which -10 are cut off on a radius corresponding to the inner boundary 52 of the seating 48. Each sector corres-ponds to a definite angular measurement of the circle which is characterised as the basic unit of the raster of the insert element arrangement and is indicated in the Figure by reference G.
As can be seen from Fig.3, in the case of a preferred embodiment, all the holding slots 43 for the insert elements are arranged on the same circum-ference ~. The arrangement is periodic with the periodicity length a. It is important for the present invention that the periodicity length a corresponds to the basic unit G of the raster. It is thereby possible to combine with this insert elements of different sizes, for example elements 17, 19 and 21, as desired and without waste of space on the various places of the rotor base.
In contradistinction to Fig.l, Fig.3 shows 11~79~8 ~;

analysis elements with five, eleven and seventeen analysis channels, indicated by 17, 21 and 19, respectively. The illustrated elevenfold analysis element 21 corresponds in size to two base units of the raster G and has two holding pins 42 on its under side. The seventeenfold analysis element 19 has a size corresponding to three raster base units G and three holding pins 42. It can easily be seen that, due to this construction according to the present invention, an especially advantageous arrangement of various insert elements on the rotor base is possible.
The illustrated embodim~nt is especially simple in that the insert elements have, per raster unit of their size, only one holder and are constructed as simple sectors with straight side edges. Howèver, the present invention includes a number of more com-plicated constructions of the insert elements. Thus, several holders per raster base unit bring about an improved positioning of the elements. A construction of the side edges 54 deviating from a straight line can also improve the engagement from element to element and thus the exactitude of the arrangement thereof on the rotor base 12. Insert elements which do not touch one another and are fixed spaced apart on the rotor base can`be of advantage in certain cases.
The insert elements do not all have to be arranged with the same radial distance from the centre of the rotor~

98~;8 In this case, not all of the holders are present on the same circumference but, in this case, too, it is advantageous when the periodicity length of the holders present approximately on the same circumference corres-pond tp the base unit of the particular associated insert element raster. In all cases, it is important that the spatial measurements of the insert elements and the arrangement thereof are so adapted with regard to one another that larger elements can be accommodated in place of a number of the smallest elements. The rastering according to the present invention can thereby be used in a number of variations.
As can also be seen from the number of inlet openings 28 and measurement chambers 30 of the analysis elements in Fig.3, the multiple analysis elements 17, 19 and 21 each have a number of analysis channels which is a multiple of six less one. In general, it can be said that multiple analysis elements of the type accord-ing to the present invention preferably have a number of analysis channels which corresponds to a whole number multiple of a base number less one, the base number being the maximum number of analysis channels of the smallest analysis element plus one. The des-cribed preferred number of analysis channels of the multiple analysis elements gives, in the case of the above-described raster division, an optimal utilisation of the elements but it should be borne in mind that the ~98~8 side edges of the insert elements have a certain spatial requirement which, in each case, corresponds approximately to the spatial requirement of one analysis channel.
All the cuvette windows 30 are on a common measurement circle which is s~own by a broken line and indicated by M. In this way, a single photometer suffices for all the measurements. According to the present invention, the inlet openings 28 of the sample chambers 29 in the analysis elements are also present on the same circumfer~nce as the removal opening 56 of the combined sample obtaining and preparing element 22.
This sample circle P is also illustrated by a broken line.
On the left side of Fig.2 there can be seen the combined sample obtaining and preparing element 22 in cross-section. In Fig.4 it is again illustrated in top view with the associated components. It preferably has a cyiindrically-shaped inner chamber 58, the circular cross-section of the cylinder lying in a plane at right-angles to the plane of the paper in Fig.2~ On the lower end of the insert element 22 on the left side in Fig.2, there is a piston 60 in the inner chamber 58. On the end opposite to the piston, the inner chamber 58 is closed by an elastic stopper 62 made of rubber-elastic material which, according to Fig.2, has a IU-shaped cross-section. On the same end, 986~3 there ~s a connecting part 64 for an injection needle which can be connected with the insert element via a connecting piece 68 cooperating with the connecting part 64. The rear pointed encl 70 of the injection needle 66 thereby penetrates into the closure stopper 62 of the insert element, an outwardly sealed off fluid connection thereby being produced between the hollow space of the needle 66 and the inner chamber 58 of the insert element 22.

In the assembled state, there is found upwardly, in the region-of the closure stopper 62, the take-off opening 56 of the combined sample obtaining and pre-paring element 22. It opens in the middle chamber of three dilution chambers 72, 74 and 76 (see Figs.3 and 4~. Similarly to the connection of the injection needle 66, the take-off opening 56 is penetrated ~y a needle-like canula of the corresponding diluter and is again closed when the canula 78 of the diluter 34 is pulled out.

On the radial outer end of the insert element 22, there can be connected a piston rod 80 which, passing through bore 81, engages in a recess 82 of the piston 60 and can be positively connected therewith.
The combined samplè obtaining and preparing element 22 according to the present invention is used as follows:

~7~868 First it is provided at the intended places with the injection needle 65 and the piston rod 80 and the piston 60 is brought into the radially inner-lying position (in Fig.2 on the rig~lt). The needle can then be inserted into the blood vessel of a patient in order, in conventional manner, to rernove blood, as with a syringe, by pulling back the piston 60. The piston is drawn back completely, the piston rod 80 and the injection needle 66 are removed and the insert element 22 is placed into the analyser. After the rotor unit 10 has been loaded to the necessary extent for a particular measurement, a centrifuging run is carried out in the manner described hereinafter in more detail.
The solid components of the blood thereby collect on the radially outer end of the insert element 22, whereas radially more towards the interior of the inner space 58 it is filled with serum or, if an appropriate coagulation agent has been added, with plasma. The further analysis steps are described in more detailhereinafter in connection with the descrip-tion of the total function of the apparatus.
Details of the construction of the analysis elements are to be seen, in particular, in Figs. 2, 5, 6 and 7. In Fig. 2, the analysis channel of an es-pecially preferred analysis element can be seen in cross-section. This is indicated in the Figure with 16 as being a ~7986~

single analysis element. However, it is to be stressed that the here-described const~lction of an analysis channel, as well as a number of other constructions adapted to a particular analytical purpose, can, if desired, also be used in a multiple analysis element, for example the elements 18, 20 and 21. For the variability achieved by the present invention, it is important that various analysis insert elements are constructed in different ways, whereby not only the io chemicals provided but also the physical construction of the analysis channels can differ from one element to another and, in the case of multiple analysis elements, also within one element, depending upon the purpose of the element, this depending upon the analytical determinations to be carried out with the element.
The analysis element illustrated in cross-section in Fig.2 has a sample chamber 29, a measuring chamber 84 and a fluid channel 86 joining the two which, in the present case, has, in the plane of the drawing of Fig.2, a substantially rectangular cross-section and, at rightangles to the plane of the drawing, only has a comparatively small lumen. In a practical case, the height of the fluid channel 86 is 6 mm. and the breadth 1 mm. The capacity of the sample space 29 is, in the case of this embodiment, about 20 ~1. In the fluid channel 86, t:here are fleece papers 88, 90 and 92 ~IL179868 containing appropriate dry reagents for a particular analysis. They have a plurality of small hollow spaces connected with one another in which are present the reagent and in which, at the same time, a distri-bution and mixing up of the diluted sample takes in or with the reagents, as is described in the above-mentioned co-pending Canadian Pa~ent Application.
Radially in an out-ward direction, the fluid channel has a connecting channel 94 which opens into the measurement chamber 84. Radially inwardly, this is bounded by a barrier 96. The measurement chamber 84 is so dimensioned that the sample-reagent mixture fills it, in the case of centrifuging, to such an extent that the cuvette window 30 is completely in the region of the fluid.
In principle, the analysis procedure takes place in such a manner that the sample, i.e. the serum or plasma in the necessary dilution, passes through the ~pening 28 and into the sample-chamber 29. The rotor is then set into motion and the sample f~uid penetrates into the fleece papers 88, 90, 92, dissolves t~e reagents and, together with these, passes into the measurement chamber. There, during the centrifuging, in principle similarly to the case of the known centri-fugal analysers, a determination is carried out of the optical absorption in order to obtain therefrom the desired concentration of a component of the sample.

1~79868 Further details are described in the above-mentioned co-pending Canadian Patent Application and herein-after in a specific Example.
High requirements are demanded of the materialused ~or making the insert elements and especially for the analysis elements. It must be inert towards the physiological fluids and reagents which come into con-tact with it and yet must be capable of being worked into the necessary shapes in an economic manner.

Furthermore, the cuvette windows 30 must be transparent in the necessary spectral range. This is something of a problem, especially in the case of the low wave-lengths employed for analytical purposes (for examplè
340 nm.). Although, in the described embodiment, the cuvette windows 30 are illustrated as elements inserted into an injection moulded part, it can be desirable to produce a larger part or even the whole of the upper and lower sides of the analysis element from an approp-riate transparent synthetic resin. Between these transparent synthetic resin surfaces there is then present, in a sandwich-like manner, a middle part which laterally bounds the analysis channel with the sample chamber 29 and the measuring chamber 84. The whole insert element can, of course, also be made of trans-parent material. Preferred optically transparent ~ materials include, for example, polymethyl methacrylate and polystyrene.

11798~3 .

As already mentioned hereinbefore, the trigger bores are preferably provided in the analysis elements 16 to 21 and not, for example, in the rotor base in order to ensure a precise arrangement of their position with regard to the cuvette openings 30. A further advantage of this arrangement i5 that a measurement procedure is actually only triggered off at rotor positions at which it is also necessary. Thus, for example, the sample obtaining and preparing element 22 has an uninterrupted shutter surface 35 and a single analysis element 16 only one trigger mark whereas the equally large triple analysis element 18 and the five-fold analysis element 17 have three and five marks, respectively. If the trigger marks were provided on the rotor base and thus were not exchangeable with the insert elements, the measurement procedures would also be triggered off on those positions at which no measurement is necessary. Especially in the case of the use of a flashlamp for the photometer of the centrifugal analyser, a considerable saving of energy and increase of life result if no unnecessary measure-ment ~rocedures and thus flashes are initiated by the triggering.
It can also be seen from Fig.2 that, in the previously described manner, the holders for the insert elements, i.e. here the holding pins ~2, are present in the region of the cuvette. Possible measurement - ~7~868 deviations in the production of the insert elements or due to thermal expansion act, due to this measure, to a comparatively small extent on the distance of the element holders 42, 43 to the cuvette windows 30.
As already mentioned, the analysis elements preferably contain the reagents in a dry form already pre-packed by the manufacturer because an especially simple operating of the apparatus is thereby possible, with a simultaneously high degree of flexibility.

However, for special reactions, it can also be desirable to use liquid reagents, these preferably being first introduced into the apparatus in the analysis channel. Fig.5 shows an appropriate analysis element 97 in radial cross-section through the middle of its analysis channel. It can be seen that the fluid channel 86 here forms an appropriate hollow chamber for the reception of a reagent which is limited by the barriers 100 and 101. The cover 102 of the liquid analysis element 97 contains a filling opening 98 for the reagent. The sample chamber 29 ! fluid channel 85, measuring chamber 84 and holding pin 42 are formed on the lower part 104 of the liquid analysis element 97, which is welded to the covering part 102.
For the operation of the liquid analysis element, an appropriate reagent is introduced through the open-ing 98 manually or with the help of a measuring device 1~'7~

not shown in Fig.l and arrangea on an appropriate circumference of the centrifugal analyser. The subsequent analysis procedure takes place analogously to that in the known centrifugal analysers, the advantage of the device according to the present invention being that, as insert elements in a rotor unit, there can be used thos~e filled with various reagents and possibly differently shaped liquid analysis elements 97.

Fig.6 shows a special embodiment of an analysis channel of an analysis element 16, 17, 18, 19, 20 or 21. There is illustrated a cross-section roughly in the middle of the height of the fleece paper contain-ing reagents according to Fig.2, the cross-section running parallel to the rotor surface. There can be seen the sample chamber 29 and the fluid channel 86, as well as the fleece papers 88, 90 and 92 containing the reagents. The particular feature of the illustrated embodiment is that, radially inwardly towards the measurement chamber 84, two antechambers 106 are connected which serve for a supplementary mixing of the reagents dissolved out of the fleece papers 88, 90 and 92 with the sample solution.
In order to achieve this additional mixing action, the centrifugal analyser is, in one mixing run, accelerated and braked several times before the measurement, the reaction mixture thereby alternatingly ~17~

penetrating at least partly into the antechambers 106 and then, when the acceleration in the peripheral direction (tangential acceleration) stops, again flowing back into the measuring chamber 84. A very good mixing up is achieved by means of this procedure.
A mixing device based on the same principle can also have a construction other than that here described, all that is necessary being that the antechambers 106 lie radially inwardly from the measuring chamber 84 and, via appropriate small barriers 108, are in connection therewith, the barriers having a height such that they can be at least partly overcome by the fluid in the case of accelerating or braking the rotor and, on the other hand, do not hinder the flow-bac~ of the fluid when there is no tangential acceleration.
In a preferred embodiment of the present invention, the walls 107 of the antechambers 106 are provided with a curvature which, in the illustrated cross-section, corresponds to an arc about a point which, on the connecting line between the measuring chamber 84 and the centre of the analysis rotor, lies between these two points. Thi~ is indicated in Fig.6 by dotted lines, the middle point of the curvature being indicated by K and the rotor centre by Z.
Figs.7a and 7b show other devices which can be used for the additional mixing up of the reaction 791~68 mixture. These are static mixing devices which can be arranged in the analysis elements in the fluid channel before the measuriny chamber 84. The illus-tration is a cross-section in the plane as in Figs.~
and 5. The direction of flcw of the reaction mixture is indicated by arrows. The mixing action is, in the case of Fig.7a, achieved by baffles 110 which divide up the flow of fluid and again bring it together in order thereby to achieve a mixing action. These baffles can be cast in one piece on the appropriate constructional parts of the analysis element. Anothèr embodiment is illustrated in Fig.7b, in which case a mesh structure 112 is introduced into the analysis element and fixed at an appropriate part in the fluid channel 86 and serves to divide up the reagent mixture current, again to bring it together and thus to mix it up.
In the following, there is explained the method of operating the device according to the present invention, the intermediate steps already previously explained in detail here being only briefly mentioned.
For programming the whole device, it is prefer-able to use a requirement card which can be completed by the investigating physician. A coding for the sample is contained therein in a mechanically readable form, with which is associated the name of the patient.
This info~ation-is referred to as the sample identi-1~ 7g~8 fication. By means of appropriate mechanically read-able marking, the so-called requirement profile is determined, i e. the physician stipulates which com-ponents o~ the sample are to be analytically deter-mine,d. The information ~s, in the following, called the analysis identification.
With the help of the previously described sample taking and preparing element, usable as a syringe, a blood sample is taken from the patient.

The sample identification is, as coding 26, simult-aneously applied to the insert element 22. This can take place, for example, by transferring an approp-riate adhesive label present on the requirement card with a bar icoding on to the appropriate surface of the sample obtaining and preparing element 22.
In the clinical laboratory with the device according to the present invention, the requirement cards of several patients are successively introduced into an appropriate reading device of the apparatus.

In this way, the device obtains not only the sample identification but also the analysis identification.
From these data, a calculator incorporated into the device determines the necessary loading of the rotor with the insert elements for the analyses to be carried out. Corresponding directions for the rotor loading are indicated on a picture screen device or by print out. The :Loading can also take place fully automatic-ally. The loading of the rotors is carried out according to these instructions. This takes place, in the case of the previously described embodiment of the apparatus, in that, according to the directions, sample obtaining and preparing elem~nt 22 and analysis elements 16 to 21 are placed on the rotor base 12.
After the rotor base 12 is loàded, the central closure 44 is closed. The loading of the rotor takes place in a manner which depends entirely upon the individual case. If, for example, only one analysis is needed, then, in addition to the sample obtaining and prepar-ing element 22, there is merely placed on a single analysis element 16. The next sample can thereafter be placed on. In other cases, a particular, frequently repeating profile is required, i.e. a series of analyses important for a particular disease picture.
For other purposes, corresponding multiple analysis elements 18, 20, 21 can be provided which, in their individual analysis channels, contain various reagents and in which the analysis channels can possibly also be constructed with different shapes. Such profile analysis elements make possible a particularly economic determination of frequently recurring profiles. If, in other cases, the same analysis is necessary for a number of samples, other multiple analysis elements can again be used which, in several analysis channels, contain reagents for the same determination. In this 798~8 case, the appropriate sample obtaining and preparing elements filled with the sam~les are successively loaded on and subsequently the appropriate multiple analysis element. Finally, compendious and special anaLysis profiles can be fulfilled by a combination of single and multiple analysis elements. It can be seen that, by means of the device according tc the present invention, a great flexibility is possible.
Handling is particularly simple because, especially in the case of the use of prepacked dry reagents, complicated manual steps are no longer necessary.
If a large sample throughput is required, it can be desirable to load the rotor unit with the - insert elements away from the centrifugal analyser.
For this purpose, it is desirable to provide inter-mediate discs which are incorporated between the rotor base and the insert elements in the apparatus and thereby to load the insert elements away from the apparatus in an appropriate manner. The unit com-prising the intermediate disc and the insert elements which, in this case, forms the rotor head, is then, in its totality, placed in the centrifugal analyser.
The intermediate discs permit several rotor heads to be loaded with insert elements and thus to prepare them for the measurement while the centrifugal analyser is, for exa!~ple, being used to carry out other analyses.

1~L798~i8 After the rotor head, equipped with the insert elements, has been placed in the apparatus and connected to the rotor base, there follows the sample obtaining run of the rotor in which, in the sample obtaining and preparing elements, the sample, i.e.
serum or plasma, can be obtained in the above described manner by centrifuging.
Thereafter follows the sample preparation which includes, in particular, the appropriate diluting, the stepwise functioning of the rotor drive according to the present invention thereby being used. The rotor is brought into a position in which the dilutor 34 stands precisely above the take-off opening of a sample obtaining and preparing element 22. There-after, the dilutor 34 moves down vertically, penetrates the closure stopper 62, removes the sample by suction and again moves upwardly in order to introduce various diluted samples into the dilution chambers 72, 74 and 76 in the manner known for dilutors. By means of the stepwise drive of the rotor, it is thereby, in each case, brought into the correct position under the dilutor 34. The precise positioning of the rotor is simplified by the codings 24 provided on the rotor base, which can be read off by a reading device present on the apparatus and, in this manner, makes possible a precise c:ontrol of the rotor.
The pre-diluting in the dilution chambers 72, - 1~ 798~;B

74 and 76 (see Figs.3 and 4) has the advantage that a comparatively large amount of sample can be diluted relatively exactly. The amount of sample transferred to the inlet openings 28 of the analysis elements is, on ~he other hand, very small~ The dispenser 36 is provided for sucking out an amount of diluted sample sufficient for all the analyses to be carried out on a particular dilution of a particular sample and for dispensing it to the appropriate inlet openings of the sample chambers. Of course, the functions of the dilutor 34 and of the dispenser 36 can be ful-filled by a single unit but the use of two separate units is advantageous because a quicker loading of the analysis elements is thus obtained.
During the sample diluting and dispensing, the rotor moves stepwise back and forth, corresponding to the coding 24, under the control of the central unit of the centrifugal analyser. The dosing units 34 and 36 thereby only have to perform vertical movements.
Due to the thereby resulting mechanical simplicity of the drive making this move~ent possible, an economic construction and a great dependability of the apparatus is achieved.
Before the following mixing and measuring, any liquid analysis elements 97 present are provided with reagents.
After completion of the sample dilution and iL~79~8 .

dispensing, there follows the mixing and measuring in which the centrifugal analyser is brought to the speed of rotation necessary for the mixing and sub-sequent measuring. During this running, the codings 26 on the insert elements 16, 18, 20, 21 and 22 are - read by the apparatus and compared with the ~ed-in sample identification and analysis identification.
Should a discrepancy be obsexved, error indications are immediately given. In this way, an erroneous analysis due to false loading of the rotor with the insext elements is excluded with certainty. This control can, of course, also take place after load-ing or during the course of obtaining the sample.
For the various rotor runnings, in general different speeds of rotation are necessary. Of course, the necessary speeds of rotation depend upon the diameter of the rotor used. The highest speeds of rotation are, in normal cases, needed for centri-fuging for obtaining serum or plasma samples. They are of the order of several thousand rotations per minute in the case of an effective rotor diameter of about 25 cm.
The speed of rotation during the mixing and measuring of the apparatus according to the present invention must be adjusted to the particular analysis insert elements employed. In the case of the use of liquid analysis elements, the experience gained from ~17~8~8 - 4~ -the use of conventional centriEugal analysers can be used. Insofar as, use is made of the insert elements according to the above-mentioned Canadian Patent Application, the speeds of rotation in the mlxlng and measuring runs of the apparatus are also to be chosen accordiny to the instructions given in such Canadian Patent Application. In one example o the above mentioned Canadian Patent Application, use is made of a comparatively small rotor of 33 mm. diameter in which the measurement circle diameter is 28 mm. The analysis channel is constructed according to the em-bodiment illustrated in Fig. 6, the fluid channel 86 thereby having a breadth of 1 mm. and a height of 6 mm.
The fluid channel 86 contains fleece papers provided with dry reagents, the radial distance of which from the centre of the rotor is from about 4 to 10 mm.
Further details regarding the chemical composition of the dry reagents and further constructional details are given in the above-mentioned Canadian Patent Application. The course of measurement consists, in the case of the described measurements for example for the determination of glucose described in the above-mentioned Canadian Patent Application, of the following steps:
1. Centrifuging at 2880 r.p.m. for 1 to 25 seconds.
The dilut:ed sample thereby penetrates into the ~ il7~8S8 first 1eece paper and dissolves out the reagent.
2. Centrifuging at 12000 r.p.m. for 5 seconds. The solution is hereby driven out of the fleece into the cuvette, only a minima]l amount of solution remaining behind on the fleece.

3. A one second acceleration ~o 1200 r.p.m. and-stopping of tha rotor for a further second. This procedure is repeated 6 to 20 times, whereby, due to the tangential acceleration, the solution is driven into the antechambers 106 and a mixing effect is thereby achieved.

4. ~ seconds centrifuging at 12000 r.p.m. for sediment-ing impurities and for driving out air bubbles.

5. Measuring at 28~0 r.p.m.
If rotors of a different diameter are used or the insert elements with the analysis reagents have a different radial distance from the centre of the rotor, corresponding speeds of rotation are to be used which lead to the same values for the centrifugal acceleration.

Depending upon the dimensions and the analytical process used, however, an empirical determination of the most appropriate speeds of rotation is also necessary.
Since all insert elements which, in the case of a particular rotor running, are connected with the rotor are subjected to the same speed of rotation programme, the analytical determinations simultaneously used must be so coordinated with one another that they can be ,8 - carried out with the same speea of rotation programme.
As mentioned above, it is thereby possible also to make use of the fact that the centrifugal acceleration increases from the centre to the periphery of the rotor. The radial arrange,ment, for example, of the fleece papers or other reagent carriers within the insert elements and/or the radial positioning of the insert element itself are thus, for example, determin-ing for the centrifugal forces to which the dilute sample fluid or the reagent solution are subject in such a reagent carrier.
Further measures for the adaptation to the various analytical determinations to the given con-ditions are described in the above-mentioned Canadian Patent Application. By appropriate coordination of the various measures mentioned, it is possible to provide insert elements for a series of analytical determinations which can be measured with the same mixing and measuring run of the centrifugal analyser.

- 4g - 117~68 With further reference to Figure ~ the fleece papers 88, 90 and 92 may be introduced into rotor head 14 and insert elements 16, 17, 19 and 21 in a simple manner.
In particular as shown in Figure 2 insert element 16 includes a lower part and a cover part, which are identified as 104 and 102 respectively in the similar insert element in Figure 5. The fluid channel 86 is preferably of rectangul~ar cross-section, the internal dimension at right angles tothe plane of the drawing in Figure 2 being relatively small. When the cover part is removed, fleece papers 88, 90 and 92 may be easily inserted into the ~luid channel 86 from above, after which the cover part may be secured to the lower part, for example by gluing or welding in the case of disposable insert elements and by a mechanical connection whereby the cover part can be removed, in the case of reusable insert elements.
As indicated above insert elements which ~0 may be used with or form a part of the.rotor unit are more particularly described in the aforementioned Canadian Patent Application.
The invention in the related co-pending Canadian application is more especially concerned with a process for carrying out analytical determinations by mixing 1179~8 and incubating a sample solution with at least one reagent solution and optical measurement of one para-meter in the incubated reaction solution mixture, mixing, incubating and measuring being carried out during the action of a centrifugal force, wherein, underthe influence of the centrifugal force, the sample solution is brought together with a soluble dry reagent, with at least partial dissolving thereof, and the mixture or the solution is forced centrifugally through a plurality of small hollow spaces, the centrifugal force and the flow resistance of the small hollow spaces being so adapted with regard to one another that a complete dissolving of the removed portions and mixing of the reaction components and possibly incuba-tion takes place before the reaction solution passes from the small hollow spaces into a measuring chamber in which the measurement is carried out.
The process of the aforementioned copending Canadian Patent application enables the previously com-plicated construction of centrifugal analysis rotorsto be avoided and replaced by the simple constructed rotor of the present invention, which is adapted for the reception o exhangeable insert elements and which, in spite of its simple mechanical construction, makes all manipulations superfluous and merely requires the introduction of the sample solution.
The plurality of small hollow spaces provided in the insert element acts counter to the liquid flowing ~i7~8~8 outwardly into the measuring chamber under the influ-ence of the centrifugal force with such a flow resistance and, at the same time, brings about such a complete mixing of the sample solution and of the reagent to be dissolved in the sample solution that special spatial constructions of mixing chambers, con-necting channels and the like become superfluous and, solely by the selection of the measurements of the small hollow spaces, every desired flow velocity and mixing intensity at a given centrifugal force can be achieved.
The plurality of small hollow spaces necessary herefor can be achieved in a very simple way by using a mesh-shaped element, for example an interwoven mesh, a paper strip, fleece or the like, or an open-celled foamed material or a structured surface. The pores and depressions contained therein form the small inter-connected hollow spaces.
Therefore, the size of the hollow space corres-ponds to the size of the open spaces in such mesh-shaped elements and will normally not exceed about 2 mm., preferably 1 mm., the lower limit being determined by the ability of the solution to pass through under the action of the centrifugal force.
In~stead of a mesh-shaped element, use can also be made, for example, of an open-celled foamed material or of a structured surface which is covered with a second surface which can be flat or also - 52 _ 11 7 9 8 6 ~

structured. The structured surface can be not only a roughened surface but also one provided with a plura-lity of small pocket-like depressions. The connection between the individual very small hollow spaces is, in this case, obtained in that the second oppositely-lying surface does not lie closely thereon but at a small distance therefrom which is sufficient for the passage of liquids under the influence of gravity. If two structed surfaces thereby lie against one another, then the structuring on both surfaces can be different so that, depending upon the speed of rotation of the rotor, differing effects can be brought about.
In the direction of flow of the liquid, i.e.
in the direction towards the measuring chamber, ele-ments can also be provided with differing sizes of the small hollow spaces and correspondingly different flow resistances at a given centrifugal force. In this way, it is possible, as desired, to increase or decrease the rate of flow in the individual sections of the flow path from the sample introduction point to the measuring chamber.
It is possible employing such insert elements to provide several different dry reagents with which the sample solution is contacted under the influence of the centrifugal force. Consequently, a multi-step analytical determination can be carried out in which different and successive reactions take place. It is also possible spatially to separate different components ~ _ 53 ~ 7~

of a reagent which are not compatible with one another, i.e. not only within the small hollow spaces but also outside of them.
In a first embodiment employing such insert elements, the sample solution, which can be used more or less prediluted, is allowed to flow along a path pro-vided with the very small hollow spaces in which the average hollow space size ancl the average flow resis-tance has the same value. This embodiment is especially useful for one-step processes. If desired, a path with increased flow resistance can follow as a braking path, for example in order to increase the incubation time until the reaction mixture enters the measuring chamber.
This is explained in more detail in the aforementioned copending application.
In another embodiment employing such insert elements the use of two incubation steps with the use of two different reagents is possible. The sample fluid is hereby first allowed to flow through a first element having a plurality of very small interconnected hollow spaces which contains a first dry reagent. Arranged therebehind in the direction of flow there is a second element with a plurality of very small interconnected hollow spaces with a greater flow resistance than the first element. This second element can be, for example, a mesh-shaped body with denser packing of the fibres than in the first element or can be a foamed material with comparatively small pores. Consec~uently, this _ 54 _ i 1 7198 ~ 8 second element has a greater flow resistance and brakes the fluid so that the first reaction can take place between the sample solution and the first reagent.
Beyond this second element is then arranged a third element with a plurality of small interconnected hollow spaces which, in turn, possessles a lower flow resistance than the second element and which contains a second reagent different from the first one. Thus, in the case of this embodiment, the sample solution flows through two incubation stages, between which is a braking path. If desired, a further braking path can be arranged to follow the third element.
A further preferred embodiment corresponds to the above-described method with two incubation stages and a braking for the fluid therebetween but, between the second and the third element, an additional element is provided in which a separation can be carried out.
In this additional, fourth element, the very small hollow spaces either have a reactive surface or are so constructed that they include a molecular sieve action.
In the case of a reactive surface, this either has g~oups acting as an ion exchanger or contains groups which manifest an affinity chromatography action or contains enzymatically or immunologically active bodies bound covalently or in some other manner. The fixing of substances of the above-mentioned kind i.e.
of substances which are enzymatically active or - 55 - 1 1 7 9 ~ ~ 8 immunologically active or are suitable for affinity chromatography, on surfaces of solid bodies is well known and does not need to be described here in more detail. When the fourth element is, for example, a mesh-shaped body which consists of cellulose or polyamide fibres, then, for the activation of the surface, use can be made, for example, of the processes described in Federal Republic of Germany Patent ~:17~

Specifications Nos.2,708,018 and 2,438,436. The same applies in the case of affinity chromatographically active substances which are fixed on to the fibre surfaces. In the case of surfaces with an ion exchange function, the fourth element can consist of one of the known ion exchange materials, for example can be based upon sulphonated or amidated poly~tyrene resins, celLuLose fibres or cross-linked dextran gels. The fourth element with a chemically reactive surface can also consist of a dense packing of very small granules with reactive surfaces which can be made of substances known for this purpose. Examples of such materials include glass, metals, synthetic resin~, ceramic granules and the like materials which are known to be useful as carriers for chromatographically or biologic-ally active substances.
As mentioned above, the dry reagent is preferably arranged within the very small hollow spaces through which the qample fluid flows. However, it is also possible to place the reagent, for example in granul-ated or tabletted form, before the very small hollow spaces or in an interruption thereof. If, by approp-riate choice of the centrifugal force and of the size of the small hollow spaces, the rate of flow is corre~pondingly small, the contact time between the solid reagenl and the sample solution can be fixed within wide limits so that sufficient time is available ~798~8 for complete dissolving of the reagent into the ~ample solution. However, depending upon the nature of the reagent used, it may suffice when only a part thereof is dissolved out. In these cases, the reagent is preferably used in an excess over the amount necessary for the reaction with the sa~ple solution. The reagent can also contain sparingly soluble or insoluble particles which dissolve into the sample solution only slowly or not at all. Such insoluble particles should have a particle size which lies substantially below the size of the small hollow spaces and their connect-ing openings in order to ensure a satisfactory passage through the small hollow spaces. However, it is also possible, on a part of the path, so to construct the very small hollow spaces that they exert a sieve function on such insoluble particles.
~he described method of working with the arrange-ment of elution and mixing paths, braking and incub-ation paths and reactive surface paths can, of course, also be supplemented by repetition of these process sections, for example by combining the three above-described methods of working in any desired way.
The measurement of the reaction results can be carried out by the methods usual for this purpose, for example, optically with the determination of the reaction end point or by recordal of a kinetic reaction.
Conductivity measurements can also be carried out.

- 58 _ ~179~

The insert element can consist solely of a mesh-shaped element which defines a plurality of very small interconnected hollow spaces. ~xamples of such mesh-shaped elements include interwoven meshes, fleeces, papers, open-celled foamed materials, tightly packed small bodies and the like. When the insert element consists solely of such an element with very small inter-connecting hollow spaces, then the analysis reagent is contained in the hollow spaces in dry form. In the simplest case, such an insert element can thus consist only of a piece of fleece or paper impregnated with the analysis reagent. Such an insert element can, for example, be employed in such a manner that a centrifugal analysis rotor body is provided which has a number of circularly arranged sample supply chambers and a number of measuring chambers associated therewith and arranged radially outwards therefrom, which are connected to-gether by radial slots, the insert element being tightly and fittingly inserted into these slots, the sample solution is introduced into the smaple supply chamber and, after closure by a rotor cover plate or the-like, a predetermined centrifugal force is produced, under the influence of which the sample fluid is spun out-wardly through the f~e~ce or paper. The fluid hereby flows through the many very small interconnected hollow spaces, dissolves the dry reagent, brings about a com-plete mixing of the reaction components and an incuba-taion due to the deflection of the direction of flow in 9~3~8 the passage from one very small hollow space to the next which is necessary and finally passes into the measuring chamber in which a measurement is carried out in known manner.
However, in a further embodiment of the insert element, this can also have a sample reception chamber and/or a measuring chamber, in addition to the element having the plurality of very small interconnecting hollow spaces. Such an embodiment of the insert element for example, consist of the element having the very small hollow spaces in the form of a longitudinal body, which is outwardly sealed off with a foil, which con-sists, for example, of a synthetic resin, whereby, on at least one narrow side of the longitudinal body, the foil forms a loop which defines a measuring chamber and/or a sample providing chamber. Such an insert element can, for example, be produced in an extremely simple manner by laying a rectangular paper or fleece strip impreg-nated with the dry analysis reagent on to a synthetic resin foil which projects slightly on both sides, for example by 0.5 to 1 mm. On one end, the foil is folded over and, on the other side of the strip laid in such a manner that a small loop is formed on the folded over end. By sealing the projecting edges of the foil, the finished insert element is obtained. Instead of a foil, correspondin~ly shaped bodies of synthetic resin or similar shapable material can, of course, also be employed.

:1179~

The insert element can contain several usually different analysis reagents present spatially separated from one another. As already mentioned, the analysis reagents can be present within the very small hollow spaces. For example, a definite amount of a solution of the analysis reagent is applied to a point of the element having the smal:l hollow spaces, for example a fleece or paper strip, and dried, for example, by lyophilisation or by some other method of drying.
Alternatively, the analysis reagent can also be present, in the insert element according to the present inven-tion, as a formed body, for example, in the form of a granulate, in tabletted form or the like but then, in general, is placed outside of the very small hollow spaces.
The insert element can be made reactive on at least a part of the surface of the small hollow spaces. As already mentioned above, the mesh-shaped body can hereby consist of fibres or filaments, on the surface of which are fixed reactive substances, for example enzymatically or immunologically reactive substances. Reference is made to the above embodiment in the scope of the explanation of the process.
Several elements or bodies, which have a plurality of very small interconnected hollow spaces, can be arranged side by side, or preferably, behind one another forming the insert element, so that it is ~1798~

possible, by means of different sizes of the small hollow spaces, to provide different flow resistances and thus also rates of flow, ~ithout a variation of the centrifugal force being necessary by change of the speed of rotation. In the case of a mesh-shaped element, the flow resistance is, for example, caused by the thickness of the fibres and the nature of their connec-tion. With decreasing fibre diameter, the average diameter of the small hollow spaces becomes smaller and the flow resistance increases correspondingly. Due to ~17~8~8 the nature of the connection of the individual fibres, the size of the openings between the very small hollow spaces is also influenced and, by utilisation of this effect, the flow resistance can be adjusted to a definite desired value. In this way, it is pos~ible, within the insert element, to provide paths with a greater and lesser flow resistance and thus to bring about an acceleration or braking of the rate of flow of the reaction solution.
10A preferred insert element is characterised in ' that, between the sample supplying chamber and the measuring chamber, sections are arranged with differ-ing average hollow space size~ which have differing flow resistances for a throughflowing fluid.
A further preferred insert element is character-ised by a first ~lement, which has a plurality of very small interconnecting hollow spaces and contains a ~ first reagent, a second element, arranged therebehind in the direction of flow, with a plurality of very small interconnecting hollow spaces with a greater flow resistance than the first element and a third element, arranged therebehind in the direction of flow, which has a plurality of very small interconnecting hollow spaces which possess a lower flow resistance than the hollow spaces of the second element and which contains a second reagent.

- 63 _ ~7~&1~8 A further preferred insert element is characterised in that, between the second and third element, it has a further element with a plurality of very small interconnecting hollow spaces which have a reactive surface.
Such an insert element preferably also contains elements which have enzymatically or immunologically active substances bound to the surface thereof.
A further preferred insert element contains elements, the surfaces of which have reactive groups with ion exchange properties.
The insert elements can also be present bundled together to give larger segment-shaped units so that an analysis profile can be determined in a single worXing step since each individual element permits the determination of another parameter of the introduced sample. Such segment-shaped insert element bundles can also be used for the simultaneous measure-ment of a particular parameter in a plurality ofsamples. In this case, each insert element in the insert element bundle contains its own sample intro-duction chamber. It is clear that any desired combinations between these embodiments are possible so that many iclentical and/or different determinations can be carried out simultaneously. The insertelements can be made to be reusable but are preferably disposable.

- 64 ~ g~fi~

The reagents can be present in mixed form or as individual components which, when the sample fluid flows through, are successively dissolved and mixed with one another. In this case, the various mesh-shaped elements arranged in the insert element can consist of individual paper strips each of which contains a definite amount of reagent impregnated therein. Such individual components of a carrier containing an analysis reagent are described, for example, in Federal Republic of Germany Patent Speci-fication No. 2,852,994.
The aforementioned copending Canadian Patent application describes a particular insert element which comprises a fibre fleece which contains 40%
polyamide fibres and 40~/0 regenerated cellulose.
It has a take-up capacity for aqueous solutions of about 500 ml/m in the case of a thickness of 0.5 mm and a weight per unit surface area of 75 g,/m2 (VS 532* of the firm Binzer).

*Suppliers designation

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. An insert element for use in a rotor unit of a centrifugal analyser for the analytical deter-mination of at least one component of a sample fluid comprising:
a housing containing at least one sample chamber for the reception of a sample liquid, at least one measuring chamber for the measurement of characteristic parameters for the detection of components of the sample, while the element rotates with the rotor unit, a fluid connecting channel communicating each sample chamber with an opposed measuring chamber, said housing having retaining means adapted to cooperate with a rotor base of the rotor unit such that said housing is adapted to be held positionally stable on the rotor base when the centrifugal analyser is in operation, with the at least one measuring chamber disposed radially out-wardly of the at least one sample chamber, and at least one analysis reagent disposed in said channel between said sample chamber and its opposed measuring chamber, such that in operation a sample liquid in a sample chamber is brought into contact with, and mixed with, the analysis reagent in the channel, under the action of centrifugal force before it reaches the opposed measuring chamber.

2. An insert element according to claim 1, wherein said channel has a configuration adapted to the relevant purpose of the analysis.

3. An insert element according to claim 1, or 2, wherein said retaining means is disposed in said housing adjacent said at least one measuring chamber.

4. An insert element according to claim 1, or 2 , wherein said housing has marks for triggering of the measurement procedure.

5. An insert element according to claim 1, or 2, wherein said retaining means comprises a form-locking holding part in the region of the at least one measuring chamber adapted to cooperate with a corresponding form-locking holding part on the rotor base.

6. An insert element according to claim 1, wherein it contains at least one analysis reagent in dry form and the fluid channel comprises a plurality of very small interconnected hollow spaces which connect the sample chamber with the measuring chamber.

7. An insert element according to claim 1, wherein it includes a mixing means in the fluid channel between the analysis reagent and the measuring chamber.

8. An insert element according to claim 6, wherein it includes a mixing means in the fluid channel between the analysis reagent and the measuring chamber.

9. An insert element according to claim 7, wherein the mixing means includes at least one ante-chamber into which, upon accelerating or braking the rotor, at least a part of the sample-reagent mixture enters from a measuring space due to tangential acceleration.