Patent Application
20130084647
The application relates to the field of clinical testing and in particular to an immunological test element having at least one test chamber and covered by a pierceable foil layer. Clinical testing includes immunohematology, immunodiagnostic and other clinical testing. The foil layer is defined by at least one portion that permits puncture in order to facilitate access to the contents of the test chamber.
Predispensed reagents, in particular for immunohematology (“IH”) testing, are often provided in sealed chambers that are accessed when needed in a testing environment. For instance, BIOVUE™ cassettes and MTS Gel Cards™ utilize a foil seal over the Reaction Chamber to maintain the integrity of the pre-dispensed reagent within each column. Other comparable systems use similar test elements for IH testing. It's possible through mishandling of the card/cassette that the inside of the foil seal can come into contact with the pre-dispensed reagent.
Immunological agglutination reactions are typically used for identifying various kinds of blood types as well as for detecting various kinds of antibodies and antigens in blood samples and other aqueous solutions. In such procedures, a sample of red blood cells is mixed with serum or plasma in either test tubes or microplates, wherein the mixture is incubated and then centrifuged. Various reactions then occur or do not occur depending on, for example, the blood types of the red blood cells or whether certain antibodies are present within the blood sample. These reactions manifest themselves as clumps of cells or as particles with antigens or antibodies on their surfaces, referred to as agglutinates. The failure of any agglutinates to appear indicates no reaction has occurred, while the presence of agglutinates, depending on the size and amount of the clumps formed, indicates the presence of a reaction and the level of concentration of cells and antibodies in the sample and reaction strength.
Many such reactions are included in the slate of reactions run on clinical diagnostic analyzers and other analyzers. A clinical laboratory testing and diagnostic system typically includes a Scheduler, which controls and specifies operations in the analyzer by allocating resources at various time points to ensure the desired tests are carried out in a timely and orderly manner. A system clock determines which of the steps are carried out in various parts of the analyzer. Thus, the position of samples, dispensing of reagents, signal detection and the like by various part of the analyzer are specified relative to the common clock to ensure they march to the same beat. The Scheduler ensures that samples are accepted from an input queue as resources are reserved for the various expected tests relevant to a particular sample. Unless the required resources are available, a sample continues to be in the input queue. Samples are further batched into trays (or slots). In a preferred analyzer, the sample is aspirated and then sub-samples are taken from this aspirated volume for various tests. The operation of the Scheduler together with the types of tests supported by the analyzer provides a reasonably accurate description of exemplary analyzers.
Reagents for various tests are preferably provided in sterile packs. Examples of such packs are BioVue Cassettes and MTS Gel Cards, which utilize a foil seal to maintain the integrity of the pre-dispensed reagent within. Further, using very small aliquots of sealed reagents increases the cost and potential bio-hazardous waste while larger quantities of reagents packaged for use in multiple reactions invites cross contamination risk since it is possible through mishandling of the card/cassette that the inside of the foil seal can come into contact with the pre-dispensed reagent. Transfer of the reagent from one well to the next resulting in a false positive response for either a blood type or a screen is a problem that is not addressed well by current systems.
Some components that help run a clinical analyzer as directed and expected by the Scheduler include stepper motors. Control of stepper motors, and hence probe and mechanism movement, is accomplished by techniques well known in the art such as those described in U.S. Pat. No. 5,646,049 which is incorporated herein by reference.
As described, for example, in U.S. Pat. No. 5,512,432 to LaPierre et al., and rather than using microplates or test tubes, another form of agglutination test method has been developed and successfully commercialized. According to this method, gel or glass bead microparticles are contained within a small column, referred to as a microcolumn or a microtube. A reagent, such as anti-A, is dispensed in a diluent in the microcolumn and test red blood cells are placed in the reaction chamber above the column. The column, which is typically one of a plurality of columns formed in a transparent card or cassette, is then centrifuged. The centrifugation accelerates the reaction, if any, between the red blood cells and the reagent, and also urges any cells toward the bottom of the column. In the meantime, the glass beads or the gel material acts as a filter, and resists or impedes downward movement of the particles in the column. As a result, the nature and distribution of the particles in the micro-column provides a visual indication of whether any agglutination reaction has occurred, and if such a reaction has occurred, the strength of the reaction based on the relative position of the agglutinates in the column. If no agglutination reaction has occurred, then all or virtually all of the red blood cells in the micro-tube will pass downward during the centrifugation procedure, to the bottom of the column in the form of a pellet. Conversely and if there is a strong reaction between the reagent and the red blood cells, then virtually all of the red blood cells will agglutinate, and large groupings will form at the top of the microtube above the gel or bead matrix in that the matrix is sized not to let these clumps pass through. Reactions falling between these latter two extremes are possible in which some but not all of the red blood cells will have agglutinated. The percentage of red blood cells that agglutinate and the size of the agglutinated particles each have a relationship with the strength of the reaction. Following the centrifugation process and after all processing steps have been completed, the microtube is visually examined by either a human operator or by machine vision and the reaction between the red blood cells and the reagent is then classified. The reaction is classified as being either positive or negative, and if positive, the reaction is further classified into one of four classes depending on the strength of the reaction.
Gel cards and/or bead cassettes are test elements that employ a plurality of microtubes for purposes of creating agglutination reactions as described above for purposes of blood grouping, blood typing, antigen or antibody detection and other related applications and uses. These test elements commonly include a planar substrate that supports a plurality of transparent columns or microtubes, each of the columns containing a quantity of an inert material, such as a gel material or a plurality of glass beads, respectively, that is coated with an antigen or antibody or material or is provided with a carrier-bound antibody or antigen, each of the foregoing being provided by the manufacturer. A pierceable wrap completes the assembly of the test element, the wrap, which may be, for example, in the form of an adhesively or otherwise-attached foil wrap, covering the top side of the test element, in order to cover the contents of each column. Once pierced, aliquots of patient sample and possibly reagents (e.g., if reagents are not first added by the manufacturer or additional reagents, depending on the test) can be added to the columns, either manually or using automated apparatus. The test element thus containing patient sample (e.g., red blood cells and sera) is then incubated and following incubation, the test element is spun down by centrifugation, as noted above, in order to accelerate an agglutination reaction that can be graded either based on the position of agglutinates within each transparent column of the test element or cassette or due to a lack of agglutination based on the cells settling at the bottom of the test column.
As noted, each of these test elements typically include a foil wrap disposed at the top of the card or cassette covering the columns wherein the wrap can be pierced prior to the dispensing of the patient sample, reagents, or other material into at least one microtube of the test element. The foil wrap forms a seal relative to the contents of the columns to prevent contamination and also prevents the contents of the columns from drying out or degrading.
A number of automated or semi-automated apparatus, such as those manufactured by Ortho-Clinical Diagnostics, Inc., DiaMed A. G., and Grifols, are known that utilize plurality of gel cards or bead cassettes, such as those manufactured and sold by Micro Typing Systems™, Inc., DiaMed™ A. G., and Bio-Rad™, among others. Typically, these apparatus employ separate assemblies to accomplish the piercing function. In one known version, a pipette assembly probe is used to directly puncture the foil wrap. Using the metering probe for puncture wherein contact is made with the contents of the test columns means that this probe must undergo a separate washing operation following the piercing step before use thereof can be resumed to avoid contamination. In addition to potential contamination issues, there are also related issues dealing with spillage as well as fluidic carryover. In addition, washing operations add levels of complexity to the size and manufacture of the apparatus as well as hinder potential throughput time. In another known apparatus, AUTOVUE™, a piercing assembly is provided having a plurality of dedicated punches (gang punch) for puncturing the seals for each of the test chambers of a test element. This dedicated apparatus also adds a level of complexity, including an increase to the size of the overall footprint of the apparatus. The latter assembly also requires washing operations of the punches themselves, albeit on a limited basis, during re-use thereof and includes a large number of punches to accommodate the needs of many different tests.
Thus, the extent systems and supplies require either a tolerance for false positive results, which may result in retesting or erroneous tests, or packaging of reagents in single use packs, which results in increased generation of waste as well as inefficiency.
For each test intended to be performed on a clinical analyzer, there would be available one or more disposable punches compatible with the reagents to be used in tests implemented on the clinical analyzer. Preferably such a clinical analyzer is an immunohematology analyzer, but other uses, such as in a immunodiagnostic analyzer are also within the scope of this disclosure. By way of an example duration, all of the disposable punches may be replaced once every six months unless an earlier replacement is warranted. According to one aspect, an exemplary embodiment of an immunodiagnostic test analyzer has a disposable punch in a repositionable punch holder, at least one set of sealed elements, each sealed element sealed with a puncturable seal, for holding at least one member of the group consisting of a reagent, a sample and a reaction mix. Preferably, the puncturable seal is a foil seal. Further, the foil seal may be pre-stressed, although this is not a requirement. Each element may comprise a substrate, at least one test column supported by said substrate, each said test column containing a test material, and a wrap adhesively or otherwise-attached wrap covering the top of said at least one element to form the sealed element. A disposable punch is defined to have any suitable shape for punching an opening in an element provided it is not used for aspirating fluids into or out of the element. It is noteworthy that through even chance mishandling of the card/cassette the inside of the foil seal can come into contact with the pre-dispensed reagent or a tip. Then, transfer of the reagent from one well to the next can result in a false positive response for either a blood type or a screen in an immunodiagnostic analyzer or immunohematology testing.
According to one aspect, an exemplary method for reducing cross contamination in an immunodiagnostic testing apparatus comprises multiple steps. In one such step, a time, say T, for using an element having a puncturable seal in the performance of a specified test is estimated, typically by a scheduler. A disposable punch may take any suitable shape, but it is not used for aspirating fluids from one element to another. The disposable punch may be held singly or, more preferably, in an array or collection of disposable punches. The prior use of each disposable punch is tracked by the system to ensure its future use does not compromise testing by introducing the possibility of unacceptable cross-contamination or otherwise compromising test results. To this end it is expected that replacing the disposable punches is desirable if one or more of the conditions selected from exceeding a specified number of uses of a punch, exceeding a time duration for which a punch is expected to be in use, and an increase in variability of control test results above a threshold is met. A disposable punch is used to punch an opening in a seal on the element to enable a fluid carrying tip to aspirate fluids therefrom or to dispense fluids therein. An element may be a particular chamber in an MTS Gel-Card, a reagent holding vessel, a patient sample holding tube, bead cassette, a microtube, a test tube and the like.
If a disposable punch could be used for more than one assay then it would reduce the number of punches for all of the assays on the system. According to one aspect, the exemplary method for reducing cross contamination in an immunodiagnostic testing apparatus includes determining whether a previous use of the disposable punch provisionally assigned/available for a specified test is compatible with the specified test. Such a disposable punch may be provisionally marked as the ‘current’ disposable punch. In a preferred embodiment the ‘current’ disposable punch is associated with an actuator. If the current disposable punch is not compatible, i.e., it has been used with a test or reagent that will introduce unacceptable risk of cross-contamination, then another disposable punch is made the ‘current’ disposable punch and evaluated in a like manner. It should be noted that there may be multiple actuators in other implementations. In a preferred embodiment, one or a few actuators operate a greater number of punches. Further, while there are multiple punches, the number of punches is less than the distinct type of elements that need to be accessed with the help of a punch. The use of multiple punches allows for more efficient use of punches with replacement of punches becoming relatively infrequent without the requirement that each type of element have its own dedicated punch. Returning to the exemplary method, if there are no disposable punches that pass the evaluation, then a new disposable punch is loaded. This may require scheduling and/or executing a routine to load a new punch. In a related aspect, a disposable punch may be replaced by a new disposable punch for reasons other than compatibility such as time for which it has been in use, or the number of seals it has been used to punch. When a new punch is introduced, its use with different types of elements is tracked to ensure it is only used with other compatible elements.
A preferred immunohematology analyzer includes means for aligning the specified element, which may be a chamber a cassettes with a disposable punch in the repositionable punch holder. Means for aligning are implemented by programming a processor to determine the suitable punch for the specified element followed by aligning the punch in question with an actuator and the element such that upon command the actuator moves the punch to pierce the seal on the element. Means for aligning generate instructions for moving the disposable punch or the specified element adjacent to each other prior to the time for the next use of the specified element. This ensures that at the time for the next use, the disposable punch is positioned correctly relative to the specified element for operating the disposable punch, if needed. In a preferred embodiment, the element is moved to a different location for aspiration of fluids from it or for dispensing of fluids into it. Preferably, a fluid-carrying tip is selected from a disposable metering tip, a washable metering tip, and a reusable metering tip.
According to one aspect there is provided a linear path suitable for the repositionable punch holder to move a disposable punch along it. In another aspect, in another preferred embodiment, the repositionable punch holder may move the disposable punch along a closed path, an exemplary closed path being a circular path.
According to one aspect, there is provided a means for compatibility testing to determine if the disposable punch is compatible with the next planned use of the disposable punch. Means for compatibility testing are implemented by programming a processor to determine whether the disposable punch in question, the current disposable punch, is compatible with the element in need of having its seal pierced, and if there is no other compatible disposable punch available, then the disposable punch is replaced with a new punch. Further, the number of times the disposable punch has been used is evaluated to decide whether to replace the disposable punch. In a preferred exemplary embodiment, a lookup table is used to identify a disposable punch corresponding to a test or a reagent. Then, the means for compatibility testing further determine if a new disposable punch is needed—such as due to the time for which the disposable punch has been in use, or the number of times the disposable punch has been used. Other possible criteria include incidence of suspected cross-contamination. When disposable punches are replaced, in the interest of efficiency, preferably all or most of the punches in the punch nest are replaced.
In another preferred embodiment, an immunodiagnostic testing apparatus includes an incubator or a card/cassette preparation station holding a cassette or a card with a plurality of chambers and at least one disposable punch held in a manipulable configuration of disposable punches; software for estimating or assigning a time for using a particular element sealed with a wrap in a test to be performed by the immunodiagnostic testing apparatus; a means for aligning the at least one disposable punch element with the particular element; and an actuator for punching a sufficiently large opening using at least one disposable punch in the wrap on the particular element to enable a fluid-carrying tip to aspirate or dispense fluids without touching the wrap.
Without loss of generality, in the immunodiagnostic testing apparatus the fluid-carrying tip is selected from a disposable metering tip, a washable metering tip, and a reusable metering tip. The wrap may be a foil seal. In an embodiment, the foil seal may even be pre-stressed.
According to one aspect, there is provided an immunodiagnostic test element comprising a substrate, at least one test column supported by said substrate, each said test column containing a test material, and a wrap adhesively or otherwise-attached wrap covering the top of said at least one test element, such as, for example, an adhesively-attached foil wrap wherein said foil wrap includes a weakened portion directly above each said at least one test column, each said weakened portion being formed by pre-stressing said portion, but not to the point of puncturing the foil wrap. Further details for such elements are found in US Patent Publication No. 20090246877.
By providing at least one pre-stressed portion, the foil wrap is drastically weakened locally, thereby enabling each pre-stressed portion to be easily punctured, for example, using a disposable fluid aspirating dispensing member, such as a metering tip. Moreover, the pre-stressed portions are also locally deformed and assume a bowl-like concave shape. Alternatively, the pre-stressing can be performed on the wrap prior to covering of the test element with the wrap.
The pre-stressing of the foil wrap results in local deformation of the foil wrap, creating an indentation that is inwardly curved, forming a substantially bowl-like appearance. This portion can then be easily punctured in a distinct operation.
These and other features and advantages will become readily apparent from the following Detailed Description, which should be read in conjunction with the accompanying drawings.
The following discussion relates to certain exemplary embodiments of an immunodiagnostic analyzer (also referred to as an immunohematology analyzer depending on the context) using disposable punches and sealed elements pierced thereby. In a preferred embodiment, the analyzer uses a gel card or bead cassette. It will be readily apparent to those of skill in the field that the inventive concepts described herein also relate to literally any other form of immunodiagnostic analyzers that include at least one test chamber and a wrap/seal, such as, for example, a foil wrap, which covers the at least one test chamber, which is also referred to as an element or sealed element. In addition, certain terms are used throughout this discussion in an effort to provide a frame of reference with regard to the accompanying drawings. These terms should not be regarded as limiting, except where specifically indicated.
Typically prior to use of a reaction chamber, the foil must be either physically removed or perforated to create an opening that can be accessed by the pipetter. For manual testing, a technician will peel the foil off the reaction chambers that are needed to run a test. Automated Immunohematology systems typically gain access to the reaction chambers by piercing the foil with either the pipetter probe itself or by a sharp metal punch. In the case of AutoVue™, a series of punches are arranged in gangs for opening specific card types. Each punch is dedicated to a specific Reaction Chamber type to mitigate carry-over from one well to the next. Over time these punches become dirty or contaminated and must be cleaned by service person. In the case of ProVue™, the pipetter is cut at an angle on the dispense end and the resulting sharp point is used to perforate the foil before each metering event. This approach requires that the outside of the probe be washed after every fluid dispense into a reaction chamber to avoid carry-over to the next reaction chamber.
For VISION™, the design uses a disposable tip pipetter or a washable probe system. For each fluid dispense into a reaction cell, the foil seal has to be opened in such a way that when the tip enters a reaction cell, there is no contact with foil seal. A large opening in the foil above the test column needs to be created to allow access by the disposable tip. The AutoVue™ “gang punch” approach is large and requires cleaning by service every 6 months. A new smaller foil punch mechanism that addresses carry-over is desirable as a result. It is also desired that the foil opening mechanism open only those test columns scheduled for use and can be serviced by the operator instead of a service person. The prevention of touching the seal is especially important when the same tip is used to pipette fluids/suspensions such as patient red blood cells into multiple column types such as A, B, and D. Table in
The disclosed embodiment uses disposable foil punches that can be replaced by the operator on a periodic basis. The number of such punches required would be dictated by the number of different column types run on the instrument. The Piercing Punch would preferably be an injection molded plastic part, but other materials and manufacturing methods can be use. Each punch can preferably be replaced by an operator on a periodic basis. Approximately 20 punches would be needed to avoid any Cell to Cell Carry-over for most applications.
Further, the inert material is further coated with an antibody or provided with a carrier-bound antigen or antibody, such as anti-A, also typically provided by the manufacturer. A pierceable foil wrap 305 provided at the top side of each test element 310 covers that seals the microtubes in order to protect the contents and also to prevent dehydration or degrading thereof.
The foregoing immunodiagnostic test elements or element holder 225 can be used in an automated testing apparatus 200, such as that shown in
In the testing apparatus 200 shown, for example, a plurality of test elements 310, such as those previously described according to either
Following incubation, for carrying out an agglutination reaction, the element holder 225, 300, 400 is removed from the incubator and then spun down, thereby accelerating an agglutination reaction as red blood cells are clumped together in the presence of coated reagents. The plurality of beads disposed in each element/column 310 includes particles having diameters ranging between about 10 and 100 microns, providing a matrix to let the red blood cells, but not the heavier formed agglutinates to pass through by filtering. The resulting reaction can be imaged within the analysis station (not shown) of the immunodiagnostic analyzer 200 by the illumination assembly and imaging subsystem. Machine vision for grading of the reaction may provide automated data generation. Additional details are provided in the commonly-assigned U.S. Pat. No. 5,578,269 to Yaremko et al., the entire contents of which are incorporated herein by reference.
In a typical analyzer, as shown in
In another aspect, as shown in the exemplary logic of
It will be understood that numerous variations and modifications are possible in this disclosure. Such variations are should be considered as being within the scope of the following claims.
