WO2007146378A2 - Diagnostic apparatus - Google Patents

Abstract

An antigen or antibody test cassette comprises an outer housing incorporating at least one test-set. Each test-set comprises at least a pair of reaction sites. Each reaction site further comprises an immuno-reactive testing strip maintained inside the housing, a sample well for introducing a sample through the housing and onto the testing strip, and a viewing area for observing the reactive area of the testing strip. Each reaction site is isolated from any adjacent reaction site and is marked with conspicuous ordering indicia on an outer surface of the housing adjacent the sample well, whereby clear guidance is provided in a single means for administering multiple samples collected and applied non-contemporaneously in testing for specific antibodies or antigens such as Hgbh in fecal occult blood, transferrin, LH, FSH, therapeutic drug level or viral antibody titer.

Description

DIAGNOSTIC APPARATUS

CROSS REFERENCE TO RELATED APPLICATIONS

[001] The present application claims the priority of US Provisional Application Serial No. 60/813,785, filed June 13, 2006, the specification of which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

[002] The present invention relates generally to diagnostic tests. More particularly, the present invention relates to test cassettes for detecting threshold levels of a physiological substance, which are particularly well-suited to multiple-sample testing where significant time intervals elapse between sampling. The test cassettes are particularly applicable to diagnostic tests for fecal occult blood and/or transferrin.

BACKGROUND OF THE INVENTION

[003] Kits, such as those utilizing immunological lateral flow, are used to detect the presence at some minimum threshold of a substance in a body fluid. The substance tested for may be one or more of an antibody or antigen, for example, a metabolic or digestive byproduct. These generally comprise one sample well for administration of a sample fluid directed onto a test strip borne on a reaction strip bearing at least one antigen- or antibody- reactive immunoassay indicator. Various studies have shown that certain immunological tests, for example immunological fecal occult blood tests (hereinafter "IFOB"), are most accurate and have the most probative value when administered on two or more samples collected at times separated by some significant time period (for example, intervals as short as 1 hour, but often as long as 6 hours, 12 hours, 24 hours, 36 hours, 48 hours or more). By significant time period, it is meant that the time period is one during which some change might reasonably be detected in the level of a physiological substance in a sample of blood, urine or feces. Multiple sampling for IFOB addresses to some extent the risk of obtaining a false negative due to administering only a single sample test. Intermittent polyp bleeding may present the circumstances in which a single test may give a false negative. Additionally, upper GI tract bleeding may lead to a false positive.

[004] Currently, a health professional must administer the sample/s to a diagnostic slide, i.e. there is no test currently approved for over-the-counter distribution. Therefore, the patient must remain in the clinical setting (e.g. doctor's office, clinic, etc.) for some or all of the testing period, sometimes most or all of a day. Alternatively, the patient could leave between sample collections but must keep returning until the test series is completed. Alternatively, the patient is given multiple vials, one per sample collected at clinically significant time intervals. In a series of such qualitative (minimum threshold) tests, the order in which the samples are taken can have diagnostic value and hence needs to be recorded properly. However, when collection of multiple samples is stretched over the relatively long, clinically significant time intervals mentioned, it introduces the risk element of confusing or even totally ignoring the order in which samples were taken.

[005] Therefore, there is a need for a lower cost alternative, that is simpler and more convenient to use, yet provides a better diagnostic result in a single kit. Additionally, there is an unmet need for a test kit that is simple, yet accurate enough for a patient to self-administer samples onto a diagnostic cassette.

SUMMARY OF THE INVENTION

[006] It is therefore one object of the present invention to provide a diagnostic cassette or slide for testing multiple samples that have been consecutively collected, on a non-contemporaneous time schedule, from a single subject which reduces the risk of error caused by losing track of the order in which the samples were obtained. [007] It is yet another object of the present invention to provide an immunological diagnostic cassette or slide which permits a patient to accurately collect multiple samples, the sample collections being separated by some selected time interval.

[008] It is a further object of the present invention to provide an immunological diagnostic cassette or slide which permits a patient to accurately test multiple samples, the sample collections being separated by some selected time interval. [009] It is still another object of the present invention to provide an immunological diagnostic cassette or slide which permits a patient to accurately collect and test multiple samples, the sample collections being separated by some selected time interval and with reduced risk of commingling the samples.

[0010] It is yet a further object of the present invention to provide a kit for a patient to collect her/his own non-contemporaneous multiple samples, and even to conduct multiple individual IFOB and/or IFOT (transferrin) tests where each of the multiple samples are placed on one of at least two segregated reaction sites in a single cassette or slide.

[0011] It is yet a further object of the present invention to provide a multi-sample cassette or slide appropriately marked with indicia to facilitate a tester's correct application in the desired order multiple, non-contemporaneously, consecutively obtained samples to one of at least two segregated reaction sites.

[0012] It is still a further object of the present invention to provide a multi-sample cassette, for testing samples collected at clinically significant time intervals of an hour or more.

[0013] It is an additional object of the present invention to provide a multi-sample cassette which is particularly well-suited for testing samples of body fluids (e.g. feces, urine or blood) collected at times separated by clinically significant intervals for one or more of an analyte selected from the group consisting of hemoglobin (Hgb), transferrin (TFN), follicle stimulating hormone (FSH), luteinizing hormone (LH) and therapeutic drug levels.

[0014] Finally, it is an object of the present invention to provide a multiple strip cassette which becomes a graph guiding the tester as to the fluctuating levels or trend of a biological marker or therapeutic drug.

[0015] These objects and others not specifically enumerated here are achieved by providing an apparatus which provides multiple single-use wells, each individually leading to a separate test site and having clear markings indicating the appropriate well to use for a particular interval's sample. As an example, such indicia may include letters or numbers; color-change tabs; or by repositioning or applying stamps or seals either alone or in conjunction with indicia. [0016] More specifically, an immunological fecal occult antigen test cassette comprises an outer housing incorporating at least one test-set. Each test-set comprises at least a pair of reaction sites. Each reaction site further comprises an immunoreactive testing strip maintained inside the housing, a sample well for introducing a sample through the housing and onto the testing strip, and a viewing area for observing the reactive area of the testing strip. Each reaction site is isolated from any adjacent reaction site and is marked with conspicuous ordering indicia on an outer surface of the housing adjacent the sample well, whereby clear guidance is provided in a single means for administering multiple non- contemporaneous fecal sample testing.

[0017] An immunoreactive test cassette of the invention, further comprises a displaceable cover film covering at least the sample well of each reaction site when not displaced.

[0018] An immunological fecal occult blood test cassette of the invention is useful to detect human Hgb. Alternatively, an immunoreactive cassette of the invention is useful to detect transferrin.

[0019] The immunological test cassettes described could further comprise at least two test-sets, wherein each test-set further comprises a set of testing strips that are reactive to a different antigen than the testing strips of the at least one other test-set. For example, in a single cassette two test-sets of different testing strips could distinguish the presence of human Hgb, transferrin, both or neither. At least one test-set would have testing strips for detecting human Hgb, and at least one other test-set could have testing strips for detecting transferrin. For each test-set, the testing strips are segregated to permit their individual use separated by a clinically significant time interval.

[0020] A kit for administering an immunological fecal occult blood test, comprises the fecal occult test cassette described hereinabove and further comprises at least one covering decal for application over each reaction site after the reaction site has been used. Additionally, decals could be provided for indicating the order of samples tested and a positive or negative test result, to be applied to each reaction site. Furthermore, indicia on each decal would match the indicia on each reaction site. [0021] A kit for administering an immunological test using the immunological fecal occult antigen test cassette having pre-attached, repositionable displaceable cover films further may comprise a seal for sealing the portion of displaceable cover film covering a used reaction site, whereby accidental re-use of the used reaction site is prevented by sealing the used lane immediately after the sample is applied.

[0022] Decals indicating a positive or negative test result for application to each reaction site could also be provided for physically labeling each testing strip result. In a preferred embodiment, indicia on each backing sheet of decals would be clearly associated with the indicia on one of the reaction sites.

[0023] The decals for each reaction site are provided in a separate location such as on separate backing sheets not having decals for any other reaction site, in order to minimize the risk of mislabeling. Alternatively, decals for each cassette could be removably attached to the underside of the test cassette.

BRIEF DESCRIPTION OF THE DRAWINGS

[0024] The invention is herein described, by way of example only, with reference to the accompanying drawings, wherein:

[0025] Figs, la-c are top plan views of exemplary embodiments of immunological multi- sample test cassettes for samples whose collection are separated by one clinically significant time interval, two time intervals, and three intervals, in accordance with teachings of the disclosure;

[0026] Fig. 2 is a top plan view of the lower portion of an exemplary embodiment of a cassette, in accordance with teachings of the disclosure;

[0027] Fig. 3 is a bottom plan view of the cassette upper portion seen in Fig. 2 and complementarily designed to mate with the lower portion, according to teachings the disclosure;

[0028] Fig. 4 is a top plan view of an immunological triple-interval, single-analyte test cassette, constructed in accordance with an exemplary embodiment of the teachings of the disclosure; [0029] Fig. 5 is a top plan view of an immunological single-interval, dual-analyte test cassette, constructed in accordance with an exemplary embodiment of the teachings of the disclosure;

[0030] Fig. 6 is a top plan view of an immunological triple-interval, single-analyte test cassette, constructed in accordance with another exemplary embodiment of the teachings of the disclosure;

[0031] Fig. 7 is a top plan view of an exemplary embodiment of a decal sheet for use with the triple-interval, single-analyte test cassettes of the present invention;

[0032] Fig. 8 is a top plan view of an immunological triple-interval, single-analyte test cassette, constructed in accordance with another exemplary embodiment of the teachings of the disclosure;

[0033] Fig. 9 is a top plan view of another exemplary embodiment of a decal sheet and test cassette constructed in accordance with an_. exemplary embodiment of the present invention; and

[0034] Fig. 10 is a perspective view taken from above the front side showing cover shield placement on a multiple sample, multiple interval test cassette constructed in accordance with the present invention.

DETAILED DESCRIPTION OF THE INVENTION

[0035] An immunological test cassette consists of a support structure such as a protective outer housing or semi-rigid backing card (e.g. plastic film, such as PETE) incorporating at least one test-set. Each test-set comprises at least a pair of reaction sites. Each reaction site further comprises an immunoreactive testing strip, a sample well for directing a sample through the support structure onto the testing strip, and a viewing area for observing at least the reactive area of the testing strip. Each reaction site is separated from adjacent reaction sites and is conspicuously marked with order and/or time interval indicia visible to a user and adjacent the sample well, whereby clear guidance is provided in a single means for separately testing samples collected at specified time intervals. The indicia can designate some time period for each reaction site, e.g. Day 1, Day 2, Day 3, etc., Test 1, Test 2, and so on. Alternatively, Arabic or Roman numerals alone could be used to designate the preferred order in which the reaction sites should be used. Further distinguishing marking indicia could be using different geometric shapes, symbols or colors for each reaction site or strip set.

[0036] Various mechanisms are employed to limit unintentional exposure of test-strip lanes and to increase reporting accuracy. For instance, a test cassette may be provided with one or more displaceable cover films covering each sample well, if not the whole used reaction site or even the whole cassette, when not displaced. In one embodiment, lifting the displaceable cover could reveal some previously hidden indicia, indicating the well has been used and preventing its re-use. Alternatively, each reaction site may be accompanied in a kit by similarly identified adhesive-backed decals for [a] covering the well or entire strip lane, and [b] for indicating the particular result of a reaction site. For example, reaction sites marked for use in the first testing round would have a devoted set of similarly marked decals or stickers for labeling after use. A kit for a test conducted at one week intervals might have one set of decals that indicate the day of the week on which the first sample was taken, and numeral decals to apply to each subsequent sample well on the subsequent week or weeks. [0037] The cassettes of the invention are particularly useful for easy discrimination between human hemoglobin and a false positive caused by transferrin, which is indicative of upper GI bleeding. An immunological fecal occult antigen test cassette could have at least two test-sets, wherein one set of testing strips are immuno-reactive to human hemoglobin, and the testing strips of the other test-set are immuno-reactive to transferrin. The kit includes at least one decal for application to each reaction site after the reaction site has been used. In reading the following description, the reader should bear in mind that although the embodiments show longitudinal strips and reaction strips, the reaction site might be provided on a reaction strip which is some other geometric shape, for example, circular, and hence be provided in strip-sets or a housing having corresponding circular motif. [0038] Where the test cassette comprises a displaceable cover film, a seal is provided for sealing that portion of displaceable cover film covering the used reaction site, whereby accidental re-use of the used reaction site is prevented. [0039] The multiple-well cassettes of the invention are also particularly useful for testing levels of reproductive hormones, such as LH for predicting ovulation, FSH for confirming menopause, and any other physiological substance, therapeutic drug level, or viral antibody titer, which may fluctuate over time, intervals of an hour or more, and particularly intervals of from one day to the next to as much as one or more weeks. [0040] Referring to Figs. Ia, Ib and Ic, three examples of immunological diagnostic test cassettes 10, 12 and 14 comprise a support structure 16 having in the upper surface 17 thereof at least one test-set 11, 13 and 15 comprising two or more parallel reaction sites 20. Each reaction site 20 comprises an inlet, port or sample well 19 through which a physiological sample is introduced onto a testing strip 18 below, and a viewing port 20 for viewing the testing strip 18 during the test. Support structure 16 is primarily a protective and support structure for the reaction sites 20. Rigid shells and semi-rigid plastic films can be adapted to serve the same purpose.

[0041] Referring to Figs 2 and 3, support structure 16 comprises a lower shell 24 and upper shell 26. Testing strip 18 is an absorbent strip that has been treated, for example, with antibodies to be reactive to a human physiological substance, such as human hemoglobin (hHgb) or transferrin (Tfh) in the case of tests for IFOB or IFOT, or with antigen in the case of a test for detecting viral antibody titer. Lower shell 24 has formed on its upper, inner, surface a plurality of lower strip guide pegs 22 and lower strip guide walls 23 which cooperate with upper strip retaining pegs 28 on the lower or inner surface of upper shell 26 to immobilize a testing strip 20 in a specific location under a well 19 and viewing port 18 of upper shell 26 when lower shell 24 and upper shell 26 are mated and interlocked. Lower shell 24 is shown as being substantially planar with a roughly rectangular periphery, surmounted by a low outer wall 32. Lower shell 24 is trisected by isolation and support walls 34. [0042] Upper shell 26 has a general conformation highly complementary to that of lower shell 24. Upper shell 26 is also substantially planar and has outer periphery dimensions surmounted by its outer wall 36 to match lower shell 24 with which it mates. Upper shell 26 has formed on its lower (inner when assembled) surface a series of pins 38 adjacent to its peripheral wall 36 which project upward from the planar surface and are of the length and cross-sectional dimension to be inserted into and held by friction or some other positive lock mechanism by hollow posts 40 to a depth that brings peripheral walls 32 and 36 into complete contact. Upper shell 16 is similarly trisected by isolation and support walls 44 which are also brought into contact with their lower counterparts support walls 34 when the shells 24 and 26 are interlocked. Parallel to and positioned on either side of support walls 44 are positioning and isolation ridges 42. Isolation ridges 42 ensure that the lower and upper support walls 34 and 44, respectively, are properly aligned to reduce the possibility of sample migration from one reaction site to another.

[0043] Finally, the outer surface of upper shell 26 has conspicuous indicia associated with each of wells 19 to easily differentiate between them either by assigning an order (numeric, alphabetic, day, date, time of day, time' interval, etc.) to match numbered samples, or an easily discerned sample/well relationship. Several examples of useful indicia systems will be discussed further hereinbelow. The viewing ports 18 may be open, but preferably are protected by a transparent window or film. Furthermore, the indicia, "C" and "T" are used to denote the locations on the testing strip 20 of a control bar indicator and a test bar positive result indicator which appear in appropriate test conditions.

[0044] Assembly of the components in Figs 2 and 3, results in the exemplary embodiment illustrated by Fig. Ib, having three test lanes 50, 52 and 52 in test set 13. Each test lane 50, 52, and 54 is an independent (but attached) unit for the testing of samples collected from an individual with reduced risk of confusion between and cross-contamination from one lane to the next, the collection times being separated by two intervals. Embodiments of test cassettes with test sets 11 having two reaction sites 20 each, as in Fig. Ia, are for testing where two samples are collected, separated by a single clinically significant time interval. Where each test set comprises four reaction sites, as in Fig. Ic, sample collection times are separated by three clinically significant time intervals. The clinically significant time interval may be as short as one or more hours, and as long as several days or even a week.

[0045] Referring to Fig. 4, a test set 11 comprising four reaction sites 20 reactive to

LH can be used for determining an ovulation curve, to increase chances of successful egg fertilization. [0046] Referring to Fig. 5, a cassette 70 has two test sets 11, one test set for Hgbh and the other for Tfn, each test set 11 comprising two reaction sites 20 reactive to its respective antigen. Lanes 1 and 2 are for detecting human hemoglobin in samples taken 24 hours apart. Two accurate positive test results will tell a physician that the patient has a GI bleed, but since the positive Hgbh result may be a false positive due to the presence of transferrin, samples are simultaneously applied to a transferrin-reactive test strip in the second reaction site to provide immediate determination of whether Hgb_h positives are apparently due to lower or upper GI bleeding. Additionally, to correctly help a physician determine whether two days results indicate bleeding that is waxing, waning or steady, indicia designating the order of samples collection are very important .

[0047] Referring to Fig. 6, a test set 11 has four reaction sites 20, for sampling separated by three clinically significant intervals of about one week, and reactive to a therapeutic drug, metabolite or substance such as FSH, which serves as a guide for a tester to graph the fluctuating levels or trend of a biological substance, marker or therapeutic drug. Since a test for therapeutic drug levels should preferably be quantitative, gauge indicia 72 are provided on the support structure surface 16 adjacent to each viewing port 18. [0048] Fig. 7 shows a sheet of decals, preferably transparent or at least translucent, used herewith to [a] augment the indicia provided on the exemplary embodiments and [b] to reduce the chances of re-applying a sample to a used reaction site and prevent premature exposure of neighboring reaction sites. First, it should be noted that the sheet 82 is shown with a score or fold line 84 facilitating a situation where the tester only sees and works with either the "1" set of decals 86 or the "2" set of decals 88, but not both. If the two halves of sheet 82 are separated into individual sheets, confusion and commingling of number sets and samples is less likely to occur. Of course, preferably the decals could come pre-segregated and the respective sheets separated, rather than merely folded or scored. Each set of decals is designated by having the same or similar indicia to the test lane for which it was intended to be a match, test lanes 1 or 2 in this example. The decals are used as follows: after applying the first sample to the well, the circular "1" decal is removed and applied over the well so it is clear at the next testing period that it has been used, and thus the "2" is clearly the next well to be used in the next round. The "1" elliptical decal is used to cover the "1" sight port. When a result of C or T is registered, the appropriate "1" C or T decal is likewise applied over the sight port of the used test lane. The same procedure is followed for subsequent test runs, "2" decals used for the second day sample, "3" decals for the third day and so on. As a variant, where sight ports are not protected by a cover film, applying both elliptical decals immediately to their respective sight ports may be advisable, as it may reduce the risk of contamination by one day's sample to accidentally run into the sight port which is often just a slot , thereby contaminating another day's/period's testing strip. In order to permit easier reading of the result, the decal may have an adhesive of the sort that permits relatively easy lifting and re-positioning of the decal. For that matter, repositionable well cover decals sight port decals could even be applied by the manufacturer prior to packaging. [0049] Referring to Fig. 8, a test set 11 has four reaction sites 20, for sampling separated by three clinically significant intervals, and reactive to Hgb, Tfh, LH, FSH, therapeutic drug levels, viral antibody titer, etc.

[0050] Fig. 9 shows a cassette having a twin reaction site test-site accompanied by a decal sheet. The decals have been applied and cover the well for reaction site marked 1, also indicating a negative test result. The "2" reaction site has been covered with the larger oval decal to preserve the test, and the test result indicated as a positive result. [0051] While, the decal system can also be useful for marking a previously unmarked cassette or pair of cassettes, an exemplary embodiment is shown with reference to Fig. 10, wherein each reaction site 12 and 14 of the cassette 10 is pre-covered by its own plastic cover film that is completely or at least partially (shown) peel-able and re-adherable and that requires separate peeling operations to uncover each test lane. In use, a tester lifts up a portion of the film cover to reveal at least the well 42 of the test lanes underneath, applies the sample to the revealed well 42 and readheres the cover film 62 over the used well 42. Even though a "T" or "C" is applied to the first test result, to make sure the same well 42 is not used twice, one or more method using decals as seals may be used. Alternatively, labeling technology employing indicia revealed by the act of peeling up the decal may be employed. An opaque or otherwise visibly distinguishable decal, for example the large round decal in Fig. 9, can be applied as a seal over the used well 42 before re-adhering the cover film 62. Alternatively, or in addition, one or more decals, preferably easily seen, can be used to seal down the edges of the cover film for that test lane. Of course, the method of using the second test lane is similar to that for the first. A physician can tell which test lane really gave the first result, i.e. was used for the first sample, by noting which well is sealed by the dark round decal.

[0052] Finally, an exemplary embodiment seen in Fig. 11 demonstrates the use of a thin plastic backing film on which test strips are situated. A transparent cover film having one opening per test strip corresponding to sample wells is then placed over the strips and lower film and heat welding or adhesive is used to adhere the upper and lower films and simultaneously compartmentalize each test strip from the adjacent test strips. Once a sample is applied, a decal can be used to cover the used sample well and prevent its re-use. In this embodiment, films take the place of the cassette housing in earlier embodiments. [0053] It is intended that the appended claims cover all such features and advantages of the invention that fall within the spirit and scope of the present invention. As numerous modifications, permutations and changes will readily occur to those skilled in the art, it is intended that the invention not be limited to the limited number of embodiments described herein. Accordingly, it will be appreciated that all suitable variations, modifications and equivalents may be resorted to, falling within the spirit and scope of the present invention.

Claims

What is claimed is:

1. A test cassette, said cassette having an support structure incorporating at least one test-set; each test-set comprising at least a pair of reaction sites; each reaction site comprising a testing strip positioned in the support structure, a sample well for introducing a sample through the support structure and onto the testing strip, and a viewing area in the support structure for observing the reactive area of the testing strip; each reaction site being isolated from any adjacent reaction site; and each reaction site being marked with conspicuous order indicia on an outer surface of the housing adjacent the sample well, whereby clear guidance is provided in a single means for administering multiple non-contemporaneous physiological sample testing.

2. A test cassette according to claim 1, further comprising a displaceable cover film covering at least the sample well of each reaction site when not displaced.

3. A test cassette according to claim 1, wherein the antigen is fecal occult blood.

4. A test cassette according to claim 1, wherein the antigen is transferrin.

5. A test cassette according to claim 1 or claim 2, further comprising at least a first and subsequent test-sets, wherein each subsequent test-set further comprises a set of testing strips that are reactive to a different antigen than the testing strips of the first test-set.

6. A test cassette according to claim 4 further comprising at least one test-set having testing strips for detecting transferrin.

7. A test cassette according to claim 5, further comprising at least one test-set having testing strips for detecting fecal occult blood.

8. A test cassette according to claim 4 further comprising at least one test-set having testing strips for detecting transferrin.

9. A test cassette according to claim 6 further comprising at least one test-set having testing strips for detecting transferrin.

10. A kit for administering an immunological test, comprising the immunological fecal occult antigen test cassette of claim 1 and further comprising at least one decal for application to each reaction site after the reaction site has been used.

11. The kit of claim 9, further comprising decals indicating a positive or negative test result for application to each reaction site.

12. The kit of claim 9 furthering comprising indicia on each decal to match the indicia on each reaction site.

13. A kit for administering an immunological test, comprising the immunological fecal occult antigen test cassette of claim 2 and further comprising a seal for sealing the portion of displaceable cover film covering a used reaction site, whereby accidental re-use of the used reaction site is prevented.

14. The kit of claim 12, further comprising decals indicating a positive or negative test result for application to each reaction site.

15. The kit of claim 12, furthering comprising indicia on each decal to match the indicia on each reaction site.

16. The kits of claims 9-14 wherein decals for each reaction site are on backing sheets not having decals for any other reaction site.