US 3477821 A
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Description (OCR text may contain errors)
1969 0. A. HAMILTON 3,477,821
CHEMICAL PACKAGE Filed Dec. 26, 1967 DETECTION INVENTOR. DONALD A. HAMILTON ATTORNEYS United States Patent 3,477,821 CHEMICAL PACKAGE Donald Arthur Hamilton, Pasadena, Calif., assignor to Xerox Corporation, Rochester, N.Y., a corporation of New York Filed Dec. 26, 1967, Ser. No. 693,400
Int. Cl. B01l 3/00 U.S. Cl. 23253 21 Claims ABSTRACT OF THE DISCLOSURE BACKGROUND OF THE INVENTION This invention relates to automatic chemical analysis and, more particularly, to the automatic chemical analysis of body fluids, such as blood, urine, etc.
In copending application Ser. No. 602,025 filed Dec. 15, 1966, there is disclosed an automated chemical analytical system including a plurality of different disposable reaction containers, a magazine for the storage of the plurality of different reaction containers, a station for the addition of sample material to the reaction container, a mixing and incubation station wherein the reaction mixture is maintained in the disposable container for a period of time sufficient to culminate the chemical reaction, a detection station wherein the analytical data is obtained by monitoring one or more of the physical properties of the reaction mixture, a disposal station wherein the dis posable reaction container is eliminated from the system, and means to transport the disposable reaction container from its storage area in the magazine through the system to the disposal station. The heart of the system is the disposable reaction container which, in its broad aspects, has at least one lower compartment for the admixing and reaction of reagents and sample, and an upper section having a plurality of reagent storage chambers in communication with each reaction compartment. At least one wall or end portion of the reaction compartment may be optically transparent so that upon completion of the desired chemical reaction the compartment can be utilized as a cuvette for optical analysis. Optionally, none of the walls need be optically transparent as a probe photometer such as the one disclosed in Gale 3,164,663, may be inserted into the reaction mixture and electromagnetic radiation from a source passed through a radiation conductor, the reaction mixture and back through the radiation conductor to a detection means, without the necessity of passing through the compartment walls.
In copending application Ser. No. 602,018 (also filed Dec. 15, 1966) there is disclosed a similar, though conceptually and structurally different, analytical apparatus and system. The disposable reaction container in this application has a flexible lower compartment, i.e. one having at least one flexible wall, so that during analysis a light source and a detection means pressed against the flexible wall or walls defining the lower cuvette(s) will cause the walls to yield a distance sufficient to define a fixed optical path between the light source and the detection means through the reaction mixture. The automatic ana- 3,477,821 Patented Nov. 11, 1969 'ice lytical apparatus includes monitoring means including a light source and a means responsive to the variations in light transmittance caused by different concentrations of a known constituent in the reaction mixture. The light source and the responsive means are pressed against opposite sides of the reaction compartment or cuvette during analysis to define a fixed optical path through the reaction mixture. Thus, there is provided an automatic analytical apparatus having the optical path defining means built into a detection station. Production requirements for the disposable reaction container are less severe than when the fixed optical path is defined by the rigid walls of the reaction compartment. The reaction container can be mass produced and disposed of after use without significant cost.
In copending application Ser. No. 645,665, filed June 13, 1967, there is disclosed a disposable reaction container of improved design. Specifically, the lower section of the disposable reaction container comprises positioned walls adapted to channel the material added thereto to a portiori of the lower compartment defined by a substantially rectangular volume. Optionally, a still lower compartment can be provided for the storage therein of a magnetic stirring bar so that thorough mixing of added materials can be achieved through use of urging means magnetically coupled to said magnetic stirring bar.
SUMMARY OF THE INVENTION Now in accordance with the present invention, there is "provided a further improved disposable reaction container for use with the aforementioned analytical apparatus and systems. As with prior designs, the improved disposable reaction container has a plurality of lower compartments for the admixing and reaction of reagents and sample material added thereo, and an upper section having a plurality of reagent storage chambers in communication with each reaction compartment. At least two walls on opposite sides of each reaction compartment are inclined to the vertical whereby material added to the reaction compartment is caused to flow into the bottom portion thereof. The inclined walls terminate at a point intermediate the open top portion of the lower section and the bottom wall of the reaction compartment, the walls continuing in a plane perpendicular to a plane passing through the flange portion extending around the outer perimeter of the lower section to define a substantially rectangular volume having substantially perpendicular and parallel sides, said volume adapted for use as a cuvette for optical analysis of the material held therein.
In the improved design of the present invention, each storage chamber in the upper section has a plurality of longitudinal ribs extending from the lower portion of the upper section to the top wall of the storage chamber. Reagent tablets are snapped into place and snugly held thereby to prevent premature movement of the pro-packaged reagents from their respective storage chambers. By this design, the previously required. restraining layer (for example, layer 16 as shown in FIGURE 1 of Ser. No. 645,665) can be omitted without undesirable eflects. As an additional advantage, less force is necessary to dislodge the reagent tablet from its storage chamber as only small distortions of the storage chamber are necessary to drop the tablet into the lower compartment. Further, no force is necessary to break the restraining layer as such layer is omitted.
In a further embodiment, the longitudinal ribs are provided with a reverse taper (i.e. the tapered wall is closer to the center of the storage chamber at its boundary with the lower portion of the upper section than at its boundary with the top wall of the storage chamber), said reverse taper operating to securely hold a reagent tablet inserted into the storage chamber in place. This reverse taper protects against accidental jarring of the disposable reaction container which might otherwise dislodge the reagent tablet from its storage location. Only slight additional force is necessary to dislodge the reagent tablet upon appropriate command but this is not undesirable in view of the added protection against accidental dislodging.
The walls of the reaction compartment can be transparent and rigid, the distance between one pair of opposite walls defining a fixed optical path through the reaction mixture. This fixed optical path or fixed distance between the pair of opposite walls is equal, within certain tolerances, for each disposable reaction container representing a single chemical analysis whereby uniformity and reliability of analytical data and results can be achieved.
In a different design, at least one pair of opposite walls are flexible so that a fixed optical path to the reaction mixture can be defined by pressing a light source against one wall and a detection means against the other wall. The walls yield a distance sufiicient to define a fixed optical path between the light sources and the detection means through the reaction mixture. Alternately, higher than atmospheric pressure means can be positioned over the upper storage section so that a relatively inert gas, such as nitrogen, can be admitted to the reaction compartments through holes made in the upper section during sample addition. The side walls will be bowed outwardly and can be made to press up against acurately positioned optical path defining means. Thus, in each instance, there is provided within each detection station means to define an optical path which will be maintained constant for each disposable reaction container representing like chemical testing units.
Optionally, a small circular compartment can be provided in the lower portion of each reaction compartment for the storage of a magnetic stirring bar which can be rotated during incubation, by means magnetically coupled thereto, to thoroughly mix the materials added to the reaction compartment.
BRIEF DESCRIPTION OF THE DRAWINGS The nature of the invention will be more easily understood when it is considered in conjunction with the accompanying drawings wherein:
FIGURE 1 is an exploded side view of an exemplary disposable reaction container of the present invention;
FIGURE 2 is a top view of the disposable container of FIGURE 1;
FIGURE 3 is an end view of the disposable container of FIGURE 1;
FIGURE 4 is a top view of the lower section of the disposable container of FIGURE 1;
FIGURE 5 is a side sectional view of an upper section storage chamber showing longitudinal ribs with a reverse taper, the section in this embodiment being taken on a line which would correspond to line 5-5 in FIGURE 2; and
FIGURE 6 is an end view of a disposable container of the present invention during one form of optical analysis.
Referring to FIGURES 1-4, there is seen a disposable reaction container 10 having a lower section 12 and an upper section 14 having a plurality of reagent storage chambers 18, 20, 22, etc. Lower section 12 has two separate lower compartments 24 and 26. Each lower compartment has a bottom wall 28, exterior side walls 30, 32, and 34 and interior wall 36. The wall portions of compartments 24 and 26 terminate in a horizontal flange 38 which encircles the outer perimeter of the two compartments and holds them together as a distinct unit. Bottom wall 28 is parallel with horizontal flange 38 with walls 30, 32, 34 and 36 being perpendicular thereto, the five walls thus defining a rectangular volume having slightly rounded edges and corners. The rectangular volume does not extend all the way from bottom wall 28 to flange 38 but terminates intermediate these two elementsv The lines of termination of the rectangular solid along each wall define a plane which is parallel to the plane of horizontal flange 38. From this plane the walls diverge upwardly and outwardly as at 30, 32', and 34 and 36 until they intersect with horizontal flange 38 to define a rectangular opening beneath the plurality of reagent storage chambers when upper section 14 is in position on flange 38. As shown walls 32 terminate in a short leg 32 just prior to its intersection with flange 38, leg 32" being perpendicular to flange 38. If desired this leg can be omitted whereby walls 32 will diverge upwardly and outwardly from the plane at the top of the rectangular volume until they intersect with flange 38. The shape of the opening is not critical as long as it will not interfere with the introduction of sample and reagents into the lower compartment. The sloping walls channel all materials downward toward the bottom of the reaction compartment. Interior walls 36 extend to the plane of horizontal flange 38 and are connected to each other at line 40 thereby forming a distinct barrier between compartments 24 and 26.
Resting on flange 38 and barrier line 40 is an upper storage section 14 which comprises an upper layer 42 defining a plurality of reagent storage chambers 18, 20, 22, etc. in the form of top-hats. Each of the storage chambers has a plurality of longitudinal ribs R for holding the reagent tablets in place. The ribs extend from flange 44 around the perimeter of the plurality of reagent storage chambers to the top thereof as designated by layer 42. A cut-away view of storage chamber 20- is shown in FIGURE 1 wherein reagent tablet T can be seen as it is held in place by the longitudinal ribs. A plurality of tablets can be stored in each storage chamber if desired. Application of force on the top of the chambers will cause inversion of the top-hat with the resultant deposition of the storage tablet or tablets into the lower compartment.
One side of flange 44 which extends the length of the disposable reaction container is slightly wider than the border which encircles the remainder of the upper storage section 14. This wider portion is indicated at 45. Flange 38 which encircles the upper perimeter of the lower section is also wider along this side. Thus, the rectangles with slightly rounded edges formed by flange 38 encircling the upper perimeter of lower section 12 and flange 44 encircling the lower perimeter of upper section 14 are of equal size and dimension so that the two members can be suitably joined to provide a unitary disposable container. Preferably, each member is formed out of a plastic material which can be heat sealed to the other member to provide an exceptionally strong bond which cannot be broken under normal use. Flanges 38 and 44 are sufficiently wide along the wider portions 45 so that a code area 46 can be provided between inner bond 48 and outer bond 50. Any suitable type of coding can be placed on this code area to indicate or record any information which desirably should be known during a chemical analysis, such as the actual test which has been prestored in the particular disposable reaction container, patient number, instructions for the associated automatic analytical apparatus and system, analytical results, etc. Typical codes include binary coding in the form of light and dark areas, magnetic coding, etc.
In operation, container 10 is taken from a supply magazine and passed to a sample addition station where the proper amount of sample diluted with distilled water is aliquoted into compartment 24. This addition is accomplished by injecting the sample solution through a needle which has been inserted through upper section 14. Preferably, this insertion is made at a point which will not cause undue rotation of the supported container. For example, with a container as shown in the figures, the insertion for each compartment can be made at a point approximately equidistant from the centers of the four storage chambers 18, etc. The sample-holding container is then passed to a reagent addition sta ion where. h PP .cation of a pushing force on each storage chamber causes the reagent stored therein to be emptied into the appropriate compartments. Reagent addition can be done in one operation or it can be done sequentially as is necessary to complete the analytical procedure. If done sequentially, the addition can be done during or after incubation. In essence, reagents can be added any time prior to final detection as determined by the particular analytical procedure utilized. Container is passed to a mixing station where it is maintained for a time sufiicient to ensure thesdissolution of all solid materials in the liquid contained in the lower compartments. The container next passes to an incubation station where appropriate reaction conditions are imposed upon the materials within the container for a time sufiicient to complete the desired reaction which is then measured at a detection station. It is not necessary that the mixing and incubation stations be separate and distinct at it is contemplated that these operations may be performed in a single station.
At a detection station, light of appropriate wavelength is passed from a light source through the reaction mixture to detection means situated on the opposite side of the reaction mixture from the light source. The amount of light transmitted (or, conversely, the amount of light absorbed) at the testing wavelength will be representative of the amount of the constituent under analysis in the test solution.
Preferably, the disposable container as shown in the drawings is used in conjunction with a double-beam detectionmechanism. In one compartment there is provided a solution of the material being tested with all the reagents which will bring the reaction mixture to the desired point for analysis. The other compartment contains a solution of the material being tested in the absence of reagents. In certain instances, one or more reagents can be added to this latter solution, provided the reagents do not carry the reaction to completion or do not adversely affect, in any other way, the optical analysis. This latter solution is called a critically incomplete blank and will enable the analytical system to compensate for the effects of the sample and the reagents added thereto. To maintain the detection mechanism in calibration, standard solutions are passed through the detection mechanism at intervals so that the latter can adjust for deviations which occur during operation.
Optionally, light from the light source and light which has passed through the reaction mixture can be conducted to the disposable container and the detection means, respectively, through light conduits which are pressed against an opposite pair of rigid walls which comprise a portion of the lower compartment. In this embodiment, the optical path is defined by the distance between the opposite walls of the lower compartment against which the light conduits are pressed. Since it is preferred to maintain this optical path constant for all like analytical procedures, strict production requirements must be met in the production of disposable containers having rigid lower compartment walls.
Referring to FIGURE 5, there is seen a side-sectional view of an alternate embodiment of an upper section storage chamber wherein the longitudinal ribs R have a reversed taper which operates to more securely hold the reagent tablet within the storage chamber. The diameter of the tablet can be chosen so that it will not move about in the chamber during storage. Normally, only one tablet would be stored in each compartment with this particular design though, if desired, tablets of varying diameter can be chosen so that more than one can be snapped into place and securely held by the longitudinal ribs. As with prior designs, application of force on the top of the storage chamber will result in the inversion thereof with the resultant deposition of the stored materials into the lower reaction compartments. Relatively greater force will be required with this design, as compared to the force necessary with the design of FIGURES 1-4, since the tablet must be forced through the constriction at the lower end of the storage chamber. The advantage of more secured storage of the reagent tablet more than compensates for this very minor disadvantage. Additionally, the longitudinal ribs are not subjected to continual stress and thus the danger of cold flow, with the possible premature release of the tablet(s) is eliminated.
An optional form of optical analysis is shown in FIG- URE 6 wherein a disposable reaction container 10 having flexible walls 30 and 34 has light source means and detection means pressed against opposite walls of the lower reaction compartment. Thus, in the detection station as illustrated in FIGURE 6, light conduits 60 and 62 are pressed against walls 30 and 34, respectively, of each lower compartment. Conduit 60 is connected at the opposite end to a light source (not shown) which can be filtered to provide light of a desired wavelength or wavelengths. Conduit 62, directly opposite conduit 60, is connected to an appropriate detection means (not shown) for monitoring the intensity of the light passed through the liquid mixture in the lower compartment. During the actual analysis, conduits 60 and 62 are moved toward each other whereby the flexible walls of the compartment Will deform and assume the position as shown by the dotted lines thus defining a fixed optical path L between the interior sides of deformed walls 30 and 34 and through the reaction mixture. As previously indicated, higher than atmospheric pressure means can be positioned over the upper storage section so that a relatively inert gas can be admitted to the reaction compartments through holes made in the upper section during: sample addition. The side walls will be bowed outwardly and can be made to press up against accurately positioned optical path defining means. This technique requires no moving optical components and has less danger of scratching the side walls or optical windows of the reaction compartments. Additionally, there is greater assurance in this technique that the side walls will be fiat rather than concave or convex. These latter two features will assist in achieving more accurate and reliable data. By providing a fixed optical path L in this manner, it is easier to mass produce the disposable container as a certain critical feature, the optical path, has been eliminated as a strict production requirement. The optical path defining means is now built into the detection station and, as would be expected, significantly less detection stations should be produced than disposable containers. Since a fixed optical path is dcfined by the detection station and will be the same for each container passing therethrough, highly accurate and reliable data can be obtained with this system.
It is also contemplated that the disposable reaction container 10 as shown in FIGURE 6 can be used in conjunction with a double-beam detection mechanism, as described above in relation to FIGURES 1-4.
A more complete discussion of further modifications in the disposable container design, reagent storage techniques, the automatic analytical apparatus and system with which the disposable reaction containers of the present invention are to be utilized, etc., is given in Ser. Nos. 602,018 and 602,025. Reference is made thereto for said complete discussion. Portions of those applications which are necessary to a complete understanding of the present invention are incorporated herein by reference.
As previously indicated, a magnetic stirring bar may be disposed Within the reaction compartment for thorough mixing of materials added thereto through magnetic coupling with properly positioned urging means. Optionally, a cylindrical recess can be provided below the bottom wall 28 of each lower compartment and in communication with each reaction compartment for the storage of such a magnetic stirring bar. The shape of the storage recess is not critical as long as the magnetic stirring bar can easily drop into the recess when the bar is not in use. With the reaction mixture in the lower compartment, the disposable container is moved to a mixing station where an external magnetic field is applied, such as by a rotating magnetic bar. The rotation of the magnetic bar within the disposable container creates a vortex and by regulating the rotational speed of the magnetic stirring bar it is possible to thoroughly mix all the reagents with the sample as well as to clean the walls of the reaction compartment and the storage chambers of undissolved reagents. This insures that all reagents are present in the reaction mixture in proper amounts. Upon completion of the mixing operation, the stirring bar will settle into its storage recess out of the way of optical analysis which proceeds through the side walls forming the rectangular volume of each reaction compartment. An exemplary stirring bar comprises a small cylindrical section of stainless steel wire. Should the magnetic material have a deleterious effect on the assay, then the stirring bar should be entirely covered with a material which will not interfere in the analytical procedure, such as a complete coating of glass or inert plastic.
The side-sectional view as shown in FIGURE 1 indicates that there is a slight buckle to the longitudinal rib below the area of contact with the tablet T. The degree to which this takes place will depend, among other things, upon the diameter or size of the tablet as well as the particular material chosen for the upper storage section. For relatively rigid materials, the buckle will be less pronounced though by properly sizing the reagent tablet it can be securely held in place. For the relatively more flexible materials, the slight buckle obtained will be helpful in more securely holding the reagent tablet within the storage chamber.
While the invention has been described with reference to its preferred embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teaching of the invention without departing from its essential teachings. For example, only a portion of the storage chamber may be cylindrical with the lower portion thereof being in the form of a cone-shaped funnel which will not impede the deposition of the reagent tablet into the lower admixing compartment.
What is claimed is:
1. A disposable reaction container comprising a lower section having at least one compartment for the admixing of materials added thereto, an upper section securely mounted on said lower section and having a plurality of separate reagent storage chambers adjacent each of said compartments, and restraining means to prevent the premature movement of prepackaged reagents from said plurality of storage chambers, said'restraining means comprising at least one rib extending into each storage chamber and adapted to securely hold at least one reagent tablet in place therein.
2. The disposable reaction container of claim l'wherein each storage chamber has a plurality of ribs therein.
3. The disposable reaction container of claim 1 wherein each storage chamber is substantially cylindrical has three ribs disposed about the periphery thereof, said ribs being substantially equidistant from each other.
4. The disposable reaction container of claim 1 wherein the lower section has a plurality of separate admixing compartments.
'5. The disposable reaction container of claim 1 wherein at least one set of opposite walls defining a portion of each compartment is optically transparent so that upon completion of the desired chemical reaction each compartment can be utilized as a cuvette for optical analysis.
6. The disposable reaction container of claim 5 wherein each set of optically transparent opposite walls is parallel to the longitudinal axis of said container.
7. The disposable reaction container of claim 1 wherein each rib is vertically disposed within its'storage chamber.
8. The disposable reaction container of claim 1 wherein said upper section and said lower section are heat sealed together.
9. The disposable reaction container of claim 1 wherein said lower section has a flange which encircles the upper perimeter thereof, said upper section has a flange which encircles the lower perimeter of said plurality of reagent storage chambers and is wider along one longitudinal portion, the area circumscribed by said upper section flange being substantially rectangular and substantially equal to the area circumscribed by said lower section flange; said upper section and said lower section being securely mounted together; and said wider portion bein adapted for the storage of information.
10. The disposable reaction container of claim 1 wherein said upper section has a flange which encircles the lower perimeter of said upper section and surrounds the plurality of reagent storage chambers, said upper section flange being wider along one longitudinal portion and capable of having information stored thereon.
11. The disposable reaction container of claim 1 wherein the side walls of each admixing compartment are sufficiently flexible so they will yield when pressed against by cooperating members in a detection station to define a fixed optical path between a light source and a detection means through a reaction mixture within each of said admixing compartments.
12. The disposable container of claim 11 wherein said side walls are parallel to the longitudinal axis of said container.
13. The disposable reaction container of claim 1 wherein each rib is provided with a reverse taper such that the tapered rib is closer to the center of the storage chamber at its boundary with the lower portion of the upper section than at its intersection with the top wall of the storage chamber.
14. The disposable reaction container of claim 13 having a plurality of reversely tapered ribs within each storage chamber such that the cross-sectional area of the effective opening between the tapered ribs is less than the cross-sectional area of the top wall of the storage chamber.
15. The disposable reaction container of claim 1 wherein each of said plurality of storage chambers comprises a substantially cylindrical cavity terminating in a coneshaped funnel, the cross-sectional area of the cone being equal at its upper end to the opening at the bottom of said cavity, and the cross-sectional area of the cone being the greatest at the lower portion of the upper section.
16. The disposable reaction container of claim 1 wherein the side walls of each admixing compartment are sufficiently flexible so they can be bowed outwardly when greater than atmospheric pressure is applied to the internal portion of each admixing compartment.
17. A disposable reaction container comprising a lower section having a plurality of separate compartments for the admixing of materials added thereto, said lower sect1on having a flange which encircles the upper perimeter of said plurality of admixing compartments, the lower portion of each compartment comprising a bottom wall and parallel and perpendicular side walls which define a substantially rectangular volume, said rectangular volume terminating in a plane parallel to said flange, each of said parallel and perpendicular side walls diverging upwardly and outwardly from said plane substantially until each of said walls intersect with said flange, an upper storage section securely mounted on said flange, said upper section having a plurality of separate reagent storage chambers in communication with each of said plurality of admixing compartments, and restraining means extending into each of said plurality of separate storage compartments to prevent the premature movement of prepackaged reagents therefrom, said restraining means comprising at least one vertically disposed rib about the periphery of each of said storage chambers.
18. The disposable reaction container of claim 17 having a plurality of verticallydisposed ribs within each of said storage chambers.
19. The disposable reaction container of claim 17 wherein said upper section is of unitary construction and each of said plurality of storage chambers comprises a substantially cylindrical cavity formed therein and open at one end for communication with an adjacent lower compartment in said lower section, said ribs within said storage chamber extending from a point adjacent the open end of said cavity to the closed upper end of said cavity.
20. The disposable reacton container of claim 17 wherein each of said ribs has a slight reverse taper such that the effective cross-sectional area at the open end of said cavity is less than the cross-sectional area at the closed end thereof.
21. The disposable reaction container of claim 17 wherein the side walls of each admixing compartment parallel to the longitudinal axis of the container are suf ficiently flexible so they will yield when pressed against References Cited UNITED STATES PATENTS 3,036,894 5/1962 Forestiere 23-230 3,145,838 8/1964 Van Deusen 20647 3,326,363 6/1967 Bennett et al. 206-47 MORRIS O. WOLK, Primary Examiner R. E. SERWIN, Assistant Examiner U.S. Cl. X.R.