Source: http://www.google.com/patents/US8178350?ie=ISO-8859-1&dq=7,054,745
Timestamp: 2015-03-02 17:17:03
Document Index: 143930978

Matched Legal Cases: ['Application No. 60', 'Application No. 60', 'Application No. 60', 'Application No. 200680022409', 'Application No. 200680022409', 'Application No. 200680022409', 'Application No. 200680022554', 'Application No. 06', 'Application No. 06']

Patent US8178350 - Method and apparatus for automated rapid immunohistochemistry - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inAdvanced Patent SearchPatentsA method of biochemical processing may, in certain embodiments, involve the steps of use of a consumable biochemical process element and a consumable biochemical process alterable information memory element associated therewith, such as a substance withdrawal consumable biochemical process alterable...http://www.google.com/patents/US8178350?utm_source=gb-gplus-sharePatent US8178350 - Method and apparatus for automated rapid immunohistochemistryAdvanced Patent SearchPublication numberUS8178350 B2Publication typeGrantApplication numberUS 11/911,801PCT numberPCT/US2006/015023Publication dateMay 15, 2012Filing dateApr 21, 2006Priority dateApr 21, 2005Also published asCA2623199A1, CA2623235A1, CA2623241A1, CA2623251A1, CN101203596A, CN101203597A, CN101203598A, CN101203762A, EP1877787A2, EP1877788A2, EP1880223A2, EP1880239A2, US7838283, US8034610, US8058010, US20080194034, US20080213804, US20080286753, US20090004691, WO2006116035A2, WO2006116035A3, WO2006116037A2, WO2006116037A3, WO2006116039A2, WO2006116039A3, WO2006116199A2, WO2006116199A3Publication number11911801, 911801, PCT/2006/15023, PCT/US/2006/015023, PCT/US/2006/15023, PCT/US/6/015023, PCT/US/6/15023, PCT/US2006/015023, PCT/US2006/15023, PCT/US2006015023, PCT/US200615023, PCT/US6/015023, PCT/US6/15023, PCT/US6015023, PCT/US615023, US 8178350 B2, US 8178350B2, US-B2-8178350, US8178350 B2, US8178350B2InventorsPage A. Erickson, Michael R. Everman, Michael S. Bell, Kevin S. Edberg, Brian D. Sawatzky, Matthew M. BotkeOriginal AssigneeCelerus Diagnostics, Inc.Export CitationBiBTeX, EndNote, RefManPatent Citations (104), Non-Patent Citations (30), Referenced by (1), Classifications (8), Legal Events (2) External Links: USPTO, USPTO Assignment, EspacenetMethod and apparatus for automated rapid immunohistochemistry
US 8178350 B2Abstract
A method of biochemical processing may, in certain embodiments, involve the steps of use of a consumable biochemical process element and a consumable biochemical process alterable information memory element associated therewith, such as a substance withdrawal consumable biochemical process alterable information memory element, that may be queried and at least some of whose information may be changed as a result of actions conducted during processing of a biochemical test sequence. Accordingly, advantages relative to knowing how much of a consumable biochemical process element has been used, and how much may be available during a biochemical test sequence, may be achieved.
1. A method of biochemical processing comprising the steps of:
a. obtaining at least one sample;
b. selecting a biochemical test sequence for said at least one sample;
c. establishing said at least one sample on a proximally paired sample holder;
d. snapping in at least one source in a sample processing system;
e. establishing at least one consumable biochemical process element consumably responsive to said biochemical test sequence;
f. establishing at least one consumable biochemical process alterable information memory element associated with said consumable biochemical process element;
g. detachably electrically connecting said consumable biochemical process alterable information memory element to said sample processing system;
h. querying said consumable biochemical process alterable information memory element;
i. subjecting at least a portion of an exterior sample area of said at least one sample to an appropriate fluidic substance for said biochemical test sequence;
j. establishing a firmly bounded fluidic environment in the vicinity of said exterior sample area at least in part through the presence of said fluidic substance;
k. causing hinged movement between a first surface relative to a second surface;
l. automatically affirmatively initiating a fluid wave in said firmly bounded fluidic environment as a result of said hinged movement between a first surface relative to a second surface;
m. automatically substantially stopping said fluid wave in said firmly bounded fluidic environment;
n. automatically moving an absorbent material to a position in the vicinity of said sample holder;
o. contacting said absorbent material and said fluidic substance;
p. automatically withdrawing said fluidic substance from proximity to said sample upon completion of at least a portion of said process;
q. automatically processing said biochemical test sequence;
r. changing at least some information on said consumable biochemical process alterable information memory element as a result of actions conducted in said step of automatically processing said biochemical test sequence; and
s. accomplishing desired results through said biochemical test sequence.
2. A method of biochemical processing as described in claim 1 wherein said step of snapping in at least one source comprises the step of snapping in at least one source having substances selected from a group consisting of:
a chromogen substance,
a counterstain substance, and
a buffer substance.
3. A method of biochemical processing as described in claim 2 wherein said step of snapping in at least one source comprises the step of snapping in at least two sources.
4. A method of biochemical processing as described in claim 3 wherein said step of snapping in at least two sources comprises the step of:
a. snapping in a primary antibody substance cartridge; and
b. snapping in a linear multiple reagent magazine.
5. A method of biochemical processing as described in claim 1 wherein said step of snapping in at least one source comprises the step of utilizing at least one location specific relative substance use sized source.
6. A method of biochemical processing as described in claim 1, further comprising the step of interfacing with a laboratory information system.
7. A method of biochemical processing comprising the steps of:
c. establishing at least one substance withdrawal consumable biochemical process element consumably responsive to said biochemical test sequence;
d. establishing at least one consumable biochemical process alterable information memory element associated with said substance withdrawal consumable biochemical process element;
e. detachably electrically connecting said consumable biochemical process alterable information memory element to a sample processing system;
f. querying said consumable biochemical process alterable information memory element:
g. subjecting at least a portion of an exterior sample area of said at least one sample to an appropriate substance for said biochemical test sequence;
h. automatically processing said biochemical test sequence;
i. changing at least some information on said consumable biochemical process alterable information memory element as a result of actions conducted in said step of automatically processing said biochemical test sequence; and
j. accomplishing desired results through said biochemical test sequence
8. A method of biochemical processing as described in claim 7 wherein said step of establishing at least one substance withdrawal consumable biochemical process element comprises the step of encasing an absorbent material in a confinement enclosure.
9. A method of biochemical processing as described in claim 8 and further comprising the step of automatically sequencing said absorbent material to establish an unused portion of absorbent material in an exposed position as part of said biochemical test sequence.
This application is the United States National Stage of International Application No. PCT/US2006/015023, filed Apr. 21, 2006, published as WO 2006/116039 on 2 Nov. 2006, and claiming the benefit of U.S. Provisional Patent Application No. 60/673,486, filed Apr. 21, 2005, each hereby incorporated by reference herein.
This invention relates to the field of automated sample testing such as may be used in biochemistry, perhaps including cytochemistry, histochemistry, and the like. Specifically, it relates to systems and devices that have particular mechanical arrangements and attributes. Such systems and devices may be particularly appropriate for use in a surgical or operative environment, where rapids results may be necessary. Furthermore, this application addresses only certain aspects of the technology disclosed. Other aspects are addressed in the concurrently filed applications entitled: �Enhanced Fluidic Method and Apparatus for Automated Rapid Immunohistochemistry� filed this same day and accorded serial number PCT/US2006/015020, �Parallel Processing Fluidic Method and Apparatus for Automated Rapid Immunohistochemistry� filed this same day and accorded serial number PCT/US2006/015269, and �Wicking Cassette Method and Apparatus for Automated Rapid Immunohistochemistry� filed this same day and accorded serial number PCT/US06/15017. Each of these are hereby incorporated by reference as well as the priority filing (which this filing claims the benefit of), US Provisional Application No. 60/673,486 entitled �Method and Apparatus for Automated Rapid Immunohistochemistry�.
A problem may be that current automated IHC may require 60 to 120 minutes, which may be too long to be useful during intraoperative procedures. Intraoperative guidelines, such as those provided by the College of American Pathologists, may typically recommend reporting pathology data to the surgeon within approximately 20 minutes. Another concern is the economics of manufacture, as well as the ease of use. Operators can sometimes make mistakes and so a simplified manner of operation is desired.
However, existing automatic staining devices may not be simple to use and their internal workings in the complex. Such existing automatic staining devices may required arcane programming commands and complicated procedures, which may require extensive user training before such devices can be operated effectively. Waste material can also require special handling. It therefore may be desirable to simplify the operation of an automatic staining device as well as its manufacture.
Furthermore, the entire process may be fairly involved. For example, a biochemical process can sometimes involve steps including: subjecting a sample to a first antibody substance, perhaps driving the antibody substance around with an air knife to blow air across the surface of the sample, withdrawing the antibody substance, rinsing the sample with a buffer, subjecting the sample to a second antibody substance, perhaps again driving the antibody substance around with an air knife, withdrawing the second antibody substance, again rinsing the sample with a buffer, subjecting the sample to a chromogen substance, withdrawing the first chromogen substance, again rinsing the sample with a buffer, withdrawing the second chromogen substance, subjecting the sample to a counterstain, withdrawing it counterstain, and then perhaps again rinsing the sample with a buffer. Each of these steps may take a significant amount of time in and of themselves, and may result in the sum of the entire procedure taking an inordinate amount of time. In fact, it may not be uncommon for such involved procedures to take 90 minutes or more. Although there may have been efforts to shorten this time period, the simple fact of the chemistry involved may have focused these efforts to some degree on speeding up the mechanical processes involved.
In embodiments, the present invention involves a self contained rapid sample processing system such as shown in FIG. 1. This system can be economical to manufacture and may be easily used within an operator environment. Embodiments can overcome problems that have seemed insurmountable perhaps by approaching the problem from a very different perspective. The present invention presents systems in a variety of embodiments through which sample processing can be accomplished in a variety of biochemical contexts and in a dramatically shorter time period and in a manner that is easier for the operator. In fact, the present invention shortens tests that have previously taken 60 or 90 or even 120 minutes to an intraoperative time frame such as 20 minutes or the like. Embodiments of the invention overcome what may have been previously considered a physical requirement, namely, that many particular biochemistries involved simply required a long time. Embodiments of the invention also permit coincidental processing of all samples at once. Furthermore, by creating particular conditions within the system, the desired amount of chemical interactions can be accomplished in a far shortened timeframe. In embodiments, the invention acts to replenish a microenvironment on an exterior sample area of a sample so that binding or more generally, other interaction, can occur more rapidly. Embodiments of the present invention overcome the longer binding times previously perhaps taken as a physical constant. Embodiments realize that by acting in a manner to replenish a microenvironment, not just move fluid on a sample, can significantly shorten the time needed for a particular amount of interaction. Rather than using a completely new application of reagents or the like, the present invention acts in a manner where the microenvironment is replenished and a shortened interaction is achieved. Some embodiments of the invention achieve this by removing, perhaps mixing, and reapplying the same fluid so that the fluid and the substance in the microenvironment immediately adjacent the sample is not depleted. Embodiments also provide systems for reading and storing consumable information such as many insist from reagents, wicking elements, and the like.
FIGS. 4A-4D show a depiction of surface movement sequences such as in one embodiment that act to eliminate and replenish a fluidic substance.
Referring to FIGS. 1, 2, and 10-19, it can be understood that embodiments of the invention may present a self contained system (56) perhaps with a system enclosure (60) that can achieve a method of rapid sample processing. In general, the system may involve obtaining a sample (1), placing that sample in a sample processing system (2), and then automatically processing that sample (1) by operation of the system. The system operator or other person can select an appropriate biochemical test sequence perhaps through a computer or perhaps touch screen display (57) or the like and the sample processing system (2) can be configured as or can include an automatically sequenced test processor (3). The system operator or other person can easily insert multiple reagent magazines and perhaps single primary antibody cartridges for the selected sequences. In embodiments, the sample processing system (2) can include an automatically sequenced biochemical test processor (3), an automatically sequenced histochemical test processor, an automatically sequenced cytochemical test processor, or the like so that it may act to accomplish a particular type of test not previously able to be accomplished in or perhaps merely desired to be accomplished in a rapid manner.
Naturally, the amount of incubation can vary. Significant in some embodiments of the present invention is the possibility that incubation can be greatly shortened as compared to prior techniques. Incubation may also be conducted in a sequence of partial incubation events. In some such partial incubation events it may be arranged such that the automatically sequenced test processor (3) may act to partially incubate a substance for less than or equal to a variety of times. These times may range from 90 seconds to zero seconds. Partial incubation events which may be such as 90, 60, 35, 30, 22, 20, 15, 10, 5, 3, and even zero seconds maybe applied. In such events the sample (1) may also be subjected to the substance (5) without significant disturbance. In this undisturbed timeframe, an appropriate interaction, reaction, or other process can occur in a more traditional sense. In embodiments of the present invention, the amount of interaction can be far greater than would have normally occurred in the selected timeframe. Perhaps even more significantly, partial incubation can occur in time frames that are now dramatically shorter than previously understood as possible for the desired amount of interaction. Combining the partial incubation sequences, a total incubation time can thus be dramatically shortened. Again, through action of embodiments of the invention, the total incubation of a particular chosen substance can even be for a total time of less than or equal to about 300, 250, 200, 150, 20, 16, or even 10 seconds as part of a selected biochemical, histochemical, cytochemical, or other appropriate sample process.
In embodiments of the invention, the system may be configured to act to firmly confine and perhaps restrain the fluidic substance in the vicinity of a sample (1). This may create a bounded fluidic environment (15) or a restrictively confined fluidic environment (17). By firmly confining the environment, a fluid or other substance may be confined by something exhibiting a significantly greater resistance to movement than fluid itself. This may be a rigid material or perhaps something that is pliable. In some arrangements a sample processing system (2) may be configured so that it establishes a bounded fluidic environment (15) in the vicinity of the exterior sample area (4). This bounded fluidic environment (15) may be established through some type of fluidic boundary element (16). A fluidic boundary element (16) may actually be arranged and configured to permit the bounded fluidic environment (15) to exist in the vicinity of the sample (1). By acting to establish a bounded fluidic environment (15) in the vicinity of the exterior sample area (4), the system may serve to provide an environment within which an appropriate reactive substance (5) may be placed. Furthermore, the bounded fluidic environment (15) may serve a variety of purposes. First, it may act to limit the amount of fluidic substance (10) that is used from a source such as the fluidic substance source (11). This may serve to conserve what may prove to be a very expensive substance. In addition, the bounded fluidic environment (15) may serve to facilitate an appropriate action on the fluidic substance (10).
In embodiments, the bounded fluidic environment (15) may be configured to cause or permit a firmly or otherwise restrictively confined fluidic environment (17) in the vicinity of at least a portion of the sample (1). By presenting a restrictively confined fluidic environment (17), the sample processing system (2) may present a fluidic environment that enhances processing. In some embodiments a sample processing system (2) may include a multidirectional fluidic confinement element (18) that can act in more than one direction. It should be understood that this may not be merely a multidimensional confinement element, but rather multidirectional in that the directions may even be within the same dimensional context such as when binding on a top and a bottom, perhaps considered a single dimension, the Z-axis.
In some embodiments, the multidirectional fluidic confinement element (18) may be rigid surfaces, and perhaps even a pair of rigid surfaces. It may also be configured as an opposing surface multidirectional fluidic confinement element (19). This opposing surface multidirectional fluidic confinement element (19) may have two surfaces that oppose each other and thus confine a fluidic environment. In one embodiment, opposing microscopic slides (8) can be used to confine the fluidic environment. As shown, configurations may arrange samples in opposing pairs. These opposing pairs made me think of adjacent opposing pairs as shown in a lined arrangement in the figures. As shown in FIGS. 4A-4D, opposing microscopic slides (8) may act so that a small dimensioned area may be present between the two microscopic slides (8). In this one embodiment it can be understood how the restrictively confined fluidic environment (17) may serve to establish a multidirectional restrictively confined fluidic environment in the vicinity of at least a portion of an exterior sample area (4). By establishing an opposing surface multidirectional restrictively confined fluidic environment in the vicinity of at least a portion of the exterior sample area (4), that exterior sample area (4) may be preferentially subjected to an appropriate fluidic substance (10).
In some embodiments, the multidirectional fluidic confinement element (18) may be configured as an at least three directionally confined fluidic confinement element (20). This may be achieved through the use of an opposing surface multidirectional fluidic confinement element (19) such as shown with two microscopic slides (8) and an additional confinement direction, perhaps at the end of a microscopic slide (8) or at its label element, hydrophobic element, hydrophobic label, or the like. Naturally additional directional confinement can be provided. Confinement can also be accomplished through the use of appropriate materials such as by using a hydrophobic material or the like. As but one example, it can be understood that by using a label that is hydrophobic, certain fluidic substances (10) may actually become confined in yet another direction. Confinement can cause at least three directions of confinement and thus can present an at least three directionally confined fluidic confinement element (20). Naturally it should be understood that a multidirectional fluidic confinement element (18) may act to establish a restrictively confined liquid environment or maybe even a restrictively confined gaseous environment.
An important aspect of embodiments of the present invention may be its use with particularly challenging substances such as low affinity antibody substances or perhaps low temperature antibody substances. In this manner, embodiments of the invention can serve to achieve results where previously they may not have been practically possible. As one example, a low affinity antibody substance, such as any antibody substance that typically does not exhibit an acceptable percentage of binding within the previously understood time frames, can be used. As such, the sample processing system (2) may serve through its programming or the like to subjects the sample (1) to a low affinity antibody substance. A type of low affinity antibody substance may even be a substance that has not previously been effectively usable in automated staining devices. In addition to low affinity antibody substances, a heat sensitive antibody substance might also be used. While in some systems such antibody substances may not have been used in the past, now they might be used to a greater degree. While some systems utilized heat to cause accelerated interaction within the previously acceptable time frames, the present system may be able to be used with antibody substances that are heat sensitive. Thus some substances that may not have been able to be used may now be usable. This may exist even if the accelerated time frames are not available due to their intolerance to elevated temperatures and their low affinities. In some instances, an antibody that typically and traditionally bound less than about half of its typical eventual amount in about 150, 180, or 240 seconds might be used. All this, of course, may even take place under normal temperature conditions and thus the system may be used with an antibody substance that traditionally takes longer than the mentioned time frames to bind about one half of their typical eventual amount under normal temperature conditions.
In some embodiments, the amount of interaction may be an appropriate amount. In situations such as the binding of an antibody to a sample (1), embodiments of the invention may accomplish a significant percentage of a traditionally accepted total amount of unelevated temperature antibody binding in a reduced time period. These significant percentages may be percentages such as greater than or equal to about 70, 80, 90, 95, 98, perhaps substantially all, or even 100% of a traditionally accepted total amount of unelevated temperature antibody binding. A qualitative amount and time frame can also be provided such as embodiments which provide a detection indication in less than or equal to about a visiting outpatient, an intraoperative procedure time limit, or perhaps even the College of American Pathologists Intraoperative Guideline amount of times. By achieving results in these more general contexts, the present invention can offer systems that can be used more effectively by doctors and more effectively for patients. The present invention may thus be appropriate for use in an operating room time constraint environment or the like. It may even permit use in a surgery time constraint environment or the like. Quantitatively, embodiments of the invention may provide a detection indication in less than about the aforementioned 60, 45, 30, 20, 15, 12, and even 10 minute time frames. Aspects of the system such as the automatically sequenced test processor (3) and such may be configured to serve as a reduced histochemical detection time period process completion element. These may be configured to provide a detection indication in less than any of the previously mentioned time frames. A system may also be configured to use interaction times that are less than about 75%, 50%, 30%, 23%, or even 18% of a traditional unelevated temperature interaction time frame. This may also apply in situations with elevated temperatures as well. A system may also provide a completion element configured to provide the aforementioned detection indication time frames and made provide a histochemically time shortened interaction element with the aforementioned time frames. As mentioned earlier, the system may provide an indication in less than or equal to about 500, 400, 300, 240, 180, 150, or perhaps even less than or equal to about 120 seconds times. This may occur for substances that cause about 50% or perhaps 80% of their traditionally accepted total amount of unelevated temperature interaction in longer than about 90 for the 50% amount or perhaps 660 seconds for the 80% amount.
As mentioned earlier, one of the aspects of an embodiment of the invention may counter a depletion of a substance (5) as it interacts with the sample (1). As shown in FIG. 12, a sample can be subjected to the substance (5) through some type of fluidic environment. This fluidic environment may be a restrictively confined fluidic environment (17). Within any type of fluidic environment, restricted or not, there may be contained a microenvironment (28) which may exist immediately next to the sample (1). This microenvironment (28) may also be immediately adjacent or next to the sample (1). A microenvironment many contain elements of the substance (5) which actually interact with the sample (1). When elements of substance (5) become depleted, the amount of interaction may slow down. An aspect of embodiments of the present invention may be the fact that this microenvironment (28) can be replenished without replacing the entire fluid. Specifically, as can be understood from FIGS. 4A-4D, by eliminating the fluidic substance (1) from within the microenvironment (28), the fluidic substance source (11) can be replenished and subsequently replaced. Through appropriate arrangements, the sample processing system (2) can include a sample interface microenvironment affirmative depletion avoidance element (29). This sample interface microenvironment affirmative depletion avoidance element (29) may be a combination of programming and perhaps hardware that acts to achieve the appropriate activity. This action may be as simple as merely accomplishing substantial mixing within the sample interface microenvironment (29). Interestingly, while air knifes and the like have been used, these appear to have not achieved the level of mixing necessary in the microenvironment (28) in order to afford substantially reduced process times as embodiments of the present invention can now achieve. In fact, existing systems (which may even use air knife systems) still retain the old processing times of an hour or perhaps even 90 or 120 minutes whereas the present invention affords significantly shorter process times�times that are less than an intraoperative 20 minute guideline.
To minimize substance usage, and to efficiently achieve the goal of rapid processing, embodiments of the invention can act to non-replacingly substantially refresh the substance (1) in the microenvironment (28) adjacent the sample (1). This can occur in the sample interface microenvironment, by acting to transiently eliminate the substance (5) from within the vicinity of the sample (1) and then acting to reapply that same substance. As mentioned, substantial refreshing can occur. Even in other systems that move a fluidic substance (10), such does not appear to occur as evidence by the fact that even those systems still have the slow process times and do not act to rapidly process the sample as in embodiments of the present invention. As shown in FIGS. 4A-4D, this can occur by moving the perhaps firm surfaces (7) that define the bounded fluidic environment (15) or perhaps a firmly restrictively confined fluidic environment. By the term firm, it should be understood to encompass both rigid or even pliable boundary elements. It can also occur by taking advantage of the effects of capillary action as shown. Through such activity, the sample processing system (2) or perhaps the automatically sequenced test processor (3) through the inclusion of a subroutine or programming or the like can be considered as having a sample interface microenvironment substance refresher element (30). This can achieve refreshing the fluidic substance (10) without replacing it.
Chemically, by refreshing the substance a high level of the desired activity can continually occur. As shown in FIG. 5 with respect to a representative substance, in this can a particular antibody substance, this can be understood. In this graphic depiction of what a traditional accelerated/heated antibody substance binding profile may be (58) slow binding activity may likely be due to depletion of the antibody substance in the microenvironment (28). Thus the typical binding of an antibody substance can take in excess of 14 minuets to achieve 95% of its eventual amount of binding. By acting, perhaps through the five waves or the like as shown to repeatedly refresh the substance (5), embodiments of the system can achieve the refreshed antibody substance binding profile (59) shown. Through this refreshing, the curve can be repeatedly on its steeper portion and thus a higher rate of binding or other interaction can be achieved.
As can be seen in FIGS. 4A-4D, collected fluidic substance (36) may be available within some proximity of the exterior sample area (4). This collected fluidic substance (36) may then be reapplied to the sample (1) perhaps through action of a substance reapplication element (37). This substance reapplication element (37) may act upon at least a portion of the transiently eliminated substance, perhaps most or all of that indicated as the collected fluidic substance (36). By reapplying at least a portion of the transiently substantially eliminated appropriate fluidic reactive substance, the sample processing system (2) act to replenish the microenvironment (28) caused by a fluidic substance (10) so that this microenvironment (28) is no longer depleted of the particular substance (5) of interest.
By referring to FIGS. 11 through 14, it can be understood that a variety of mechanical arrangements can be used to achieve the mentioned rapid sample processing. In one type of mechanical embodiment, multiple samples (1) can be configured in an aligned arrangement. FIG. 11 shows that an upper glass microscope slide (43) can be connected to an upper slide holder (44). Similarly, a lower glass microscope slide (45) can be held by a lower slide holder (46). Both the upper slide holder (44) and the lower slide holder (46) can be connected through some type of hinged movement element (47). The hinged movement element (47) may act to permit some sort of angular movement between slide holders and thus the upper glass microscope slide (43) and the lower glass microscope slide (45). In a general sense, the hinged movement element (47) may simply cause some angular movement component between a first and a second surface, such as the microscope slides (8) or other types of surfaces. This movement can occur through use of a motor, perhaps a stepper motor under computer control such as lower slide holder motor (48) and upper slide holder motor (49). As can be understood from the drawings, the upper and lower lance microscope slides (43 and 45) he serve as a movable firm fluidic boundary element. When some type of motive force element acts on these movable firm fluidic boundary elements, fluid motion can occur and this may be considered as causing fluid movement of the movable firm fluidic boundary element. The hinged movement element (47) may thus serve as a hinged fluid wave element. Furthermore, the pair of slides (43 and 45) may be a proximally paired sample holder.
A hinged movement element (47) may serve as a first and second surface movement element. While the surfaces shown in the figures are actually microscopic slides, it should be understood that the surfaces need not be planar. They may be substantially planar or flat; they can be curved as well. The surfaces may also be rigid surfaces, a pair of rigid surfaces, or a pair of substantially planar rigid surfaces. In FIGS. 14 and 4C, when the hinged movement element (47) is in a closed position, the upper glass microscope slide (43) may be in close proximity to the lower glass microscope slide (45). Through some operation whether it be through software, hardware, or perhaps firmware, the sample processing system (2) may be considered to include a close proximity surface displacement element. This close proximity surface displacement element can serve to permit movement or displacement of one surface relative to another while also permitting positioning at some point where the surfaces are in close proximity to one another. In one embodiment, the invention can be configured to displace the first surface relative to and in close proximity to the second surface, The surfaces of course may be, but need not be, microscopic slides (8).
As mentioned earlier, a motive force element (23) can cause angular or other movement between a first surface relative to its second surface. Angular movement can be seen by comparing the movements shown in FIGS. 11 through 14 and FIGS. 4A-4D. It can be seen that the sample processing system (2) may be considered to include first and second surface angular movement element. This element can act to displace a first surface relative to and in close proximity to a second surface. While different aspects of these movements are shown in FIGS. 11 through 14 and 4A-4D, it should be understood that the ultimate sequencing achieved by an automatically sequenced test processor (3) can include many variations of these movements. As shown in FIG. 6 a specialized sequence of movements can be achieved to accomplish a particular application that subjects the sample to a substance, transiently eliminates that substance, mixes the substance, reapplies the substance, and ultimately withdraws the substance from a sample (1). As indicated, various step timings and sequences can be achieved. For example as shown in step three and four, an initial sequence of ways to mix a primary antibody can be achieved followed by a wave sequence that may permit significant incubation time periods in general. It can also be noticed through FIG. 6 that an entire detection sequence can be achieved in less than 15 minutes�a significantly reduced time period as compared to most existing systems.
As shown in FIGS. 4A-4D it can be seen how the angular movement element can actually achieve elimination and reapplication of a fluidic substance (10). Viewing the sequence shown in FIGS. 4A-4C in the order A-B-C as but one example of a sequence, it can be seen how closing the slides together can cause the sample (1) to be subjected to a fluidic substance (10). FIG. 4A shows how the two surfaces, in this case microscopic slides (8) can be in an open position. In this arrangement, the fluidic substance (10) is eliminated from in the vicinity of, and is eliminated from, an exterior sample area (4) of the sample (1). As shown, this may occur through capillary action whereby the fluidic substance (10) is pulled back from the sample (1) perhaps by the natural tendency of the fluid in such an arrangement.
FIG. 4B shows the microscopic slides (8) in an intermediate position. As can be understood, the fluidic substance (10) may be pulled along the area in between a microscopic slide (8) and may pass across the exterior sample area (4). FIG. 4C shows how in one embodiment the microscopic slides (8) may be moved to a closed position and are in close proximity to each other. First, it can be understood that the fluidic substance (10) may now be fully covering all appropriate areas between the microscopic slides (8). Furthermore, in FIG. 4C it can be seen that the microscopic slides may not actually be perfectly parallel to each other when they are in the closed position. The microscopic slides (8) may have attached to themselves some type of identifier. This identifier, shown in FIG. 4A as labels (50) can cause spacing through their own thickness. Shim elements (81) can also be used. These shim elements (81) may be interleaved so that each does not impinge upon an adjacent one and thus double spacing if not desired. Thus the holders can serve as interleaved proximally paired sample holders and may be interleaved about a shim element. Furthermore, the shim element (81) or even the labels themselves may also be a hydrophobic element to aid in firmly confining the fluidic environment. In instances where the identifiers or perhaps labels (50) are relatively thick, it is possible that the microscopic slides (8) do not become fully parallel and the spacing may even be narrower at the other end. This is shown in FIG. 4C as one possibility. Minimizing spacing can serve not only to reduce fluid but also to permit the use of existing label arrangements�even if not optimum.
The reverse sequence should also be understood. Considering FIGS. 4A-4C in the order C-B-A, it can be understood how the fluid movement element (42) can act to not only apply fluid to the sample (1) (as in the A-B-C case) but also to eliminate the fluid from a sample (1) (as in the C-B-A case). Again, with FIG. 4C depicting two surfaces in close proximity to each other, when the surfaces are moved apart in an angular fashion, they may ask to eliminate fluid from the exterior sample area (4) of the sample (1). As shown in FIG. 4B as the surfaces or perhaps the microscopic slides (8) are moved apart, the fluidic substance (10) may start moving back toward the hinged movement element (47). As the two surfaces continue to increase their angular movement, a full elimination of fluid can occur. Ultimately it may be sufficient that the fluidic substance (10) is moved beyond the exterior surface area (4) of the sample (1) and is ultimately collected in some other location. Thus, as can be understood how to FIG. 4A, collected fluidic substance (36) may exist as a result of the motive force element (23) acting upon the fluidic substance (10). Once eliminated from an exterior sample area (4), the collected fluidic substance (36) can become mixed to some degree and can be ready for reapplication.
Referring to FIGS. 8 and 16-18, it can be seen that a plurality of samples (1) may be held by a plurality of sample holders. In such an arrangement, it can be seen that the microscopic slides (8) may be held in place by some sort of slide retention element, perhaps such as a slide retention spring (51). Of course, other arrangement are possible. In such an arrangement, multiple samples can be processed coincidentally. For convenience, these multiple samples may be placed adjacent to each other and moved as one. In this configuration, the sample processing system (2) may have a sample holder that serves as a multiple, close proximity, substantially parallel or perhaps planar holder for a particular type of sample, a microscopic slide, or perhaps merely surfaces.
The sample holder may also serve as a multiple, close proximity, substantially parallelly-oriented sample surface pair or perhaps even a proximally paired sample or surface as shown in FIGS. 10-18. As mentioned with reference to FIGS. 4A-4D, it is possible to vary the spacing in order to alter the amount of fluid involved. As shown in FIGS. 3 and 4A-4D, this microenvironment (28) may be within a volume immediately adjacent a sample (1). By capillary or other action causing the elimination or at least substantial elimination of the fluidic substance (10) (some fluidic substance may remain on a sample) the system can act to cause an adequate or even total removal of the microenvironment (28). By eliminating the fluidic substance (10) and pulling it back into a collected fluid substance fluidic substance (36) the fluidic substance (10) may be refreshed and mixed.
FIG. 6 is a table that shows that a variety of repetitious actions that can be accomplished in one example of a sequence. As shown, the automatically sequenced test processor (3) can repeatedly mix or otherwise act upon a substance (5) or perhaps a sample (1). Referring to step three, it can be noticed that a sequence may be used to initially mix a primary antibody. Such mixing may involve, as but one example, three sequences where the fluidic substance (10) he pooled as a collected fluidic substance (36) and eliminated from the exterior sample area (4). This may be held for a relative short time period (or no time period at all) such as approximately 1.5 seconds. Similarly, during the initial mix action the fluidic substance (10) may be held exposed to and reapplied to the sample (1) for some time (or again, or no time period at all) such as in one example, two seconds.
As mentioned, the system may act to automatically withdrawal a substance such as a fluidic substance from within proximity to sample. This can occur by using an absorbent material (72). This absorbent material may be a wicking material. A substance withdrawal element (53) may be configured to withdraw substance from one or more samples. It may act to come in transient contact at a location where fluidic substance exists. This transient contact location may be selected as a particularly desirable location from which to withdraw a fluidic substance. As mentioned the withdrawal of the spent substance may be through a wicking element (73). The wicking element (73) can act to pick away a substance from it proximity of the sample. This wicking can exist by or because of capillary action and thus the wicking element may present a capillary action substance withdrawal element. Withdrawal of this substance from a sample can be enhanced in some fashions. In embodiments, the system may be configured to provide an enhanced withdrawal orientation element. This element may be an enhanced withdrawal orientation sample tilt element (74). By establishing a substance withdrawal enhancement condition for the sample (1), the system may facilitate withdrawal while the substance withdrawal enhancement condition is established. This substance withdrawal enhancement element (74) can be both programming and mechanical operation. In one embodiment, the system may act to tilt sample to an enhanced withdrawal orientation. This may involve orienting a surface to facilitate wicking of a substance, establishing a tilted surface, establishing an untilted surface, and establishing surfaces at at least about 22.5� , 30� , 45� , and perhaps 67.5� . Furthermore when surfaces are angled with respect to each other a bisected angle between the two surfaces, may be tilted. Again, this can occur at various angles perhaps at least about 22.5� , 45� , and 90� .
FIG. 15 depicts a perpendicular absorbent wicking roll (52); FIGS. 7, 8, and to some extent 27 through 30 depict systems configured with a parallel substance withdrawal element (53) and having upper and lower slide cameras (63 and 64). When any particular fluidic substance (10) has accomplished its function and is no longer needed, that substance (5) may be withdrawn. This withdrawal can occur in a variety of fashions perhaps such as by automatically moving an absorbent material to a position in the vicinity of the sample. Thus, system may have absorbent material movement element (75). In the embodiments of the system, the absorbent material movement element (75) may be a linear absorbent material movement element that may permit an absorbent material to move along a straight path forward and backward when needed. When extended, the absorbent material may make contact with at least some of the fluidic substance. In embodiments where the absorbent material is contained within it confinement enclosure, the system may act to automatically move the confinement enclosure and achieve the withdrawal of substance. When extended, it absorbent material may even be pressed past a point of initial contact to assure adequate wicking. Thus, the system may contain an absorbent material substance pressure element (76) such as may be contained in programming of or hardware constituting a movement mechanism.
As mentioned earlier, the absorbent material may be encased in confinement enclosure (75). This confinement closure (75) may be configured to substantially encase the absorbent material. Furthermore, in instances where multiple samples and perhaps varying amounts of multiple samples the system may be configured to establish a coordinated exposed area of absorbent material that is appropriate for an anticipated amount of a substance to be withdrawn. By coordinating an absorbent material parameter, be it width, length, type of with material, thickness, or the like, the system can be assured of not reaching a saturation level�especially when adjacent samples are involved. Thus, the absorbent material may have a multiple sample saturation coordinated parameter. The absorbent material exposed area may be coordinated for an anticipated amount of substance.
As mentioned, the substance withdrawal element may be enclosed and may present a cassette. This cassette or other enclosure may be removably engaged by some removable engagement element, perhaps a snap arrangement. The operation may be accomplished by merely extending and then retracting the wicking cassette or other substance withdrawal element. The substance be removed from any further interaction, and it may be appropriate to withdraw the substance by some type of wick element. This wick element may also act to capillarly withdraw the substance from proximity to the sample (1) upon the completion of at least a portion of the process. As shown in FIG. 6, in one representative test sequence, the withdrawal of the fluidic substance (10) can occur multiple times throughout the overall process. For instance, steps 5, 8, 11, 15, 18, 21, etc., indicate that at multiple times a particular substance is withdrawn from the sample (1) as part of the overall test sequence. Withdrawal can also occur at times when no substance is supposed to be on a sample such as that shown in step 1. At this point in time this could be considered unnecessary however it may serve to assure that the sample(s) are dry and ready to begin processing. As shown in FIGS. 7, 8, and 27 through 30, this cassette may be arranged with a parallel major axis that is oriented with a plurality of samples and thus the system may have a parallel major axis orientation element (76). As shown in FIGS. 15, 25, and 26, it may also be oriented in a perpendicular fashion, perhaps with a perpendicular major axis orientation element (77). While FIGS. 15, 25, and 26 show a perpendicular orientation element, FIGS. 7-8 and 27 through 30 indicate a parallel embodiment in which one cassette can be used. As shown, the upper and lower slide holders (49 and 48) may be arranged so that microscopic slides (8) are configured in a row of pairs along a pivot axis of a hinged movement element (47). This holder is one type of linearly arranged plural sample holder. As such, when fluidic substance (10) is transiently eliminated it becomes a collected fluidic substance (36) closest to the pivot axis of the hinged movement element (47). Furthermore to facilitate withdrawal of the substance the upper and lower slide holders (49 and 48) may be tiled. At this point, a parallel wicking cassette can be moved into place to coincidentally withdraw the spent substance from within the vicinity of the samples (1). As shown the substance withdrawal element (53) can be established so that the absorbent material is configured in a median angular orientation relative to the samples. In this arrangement, the major axis of the absorbent material, that is the axis of the long dimension of its exposed material is parallel to a plurality of linearly arranged samples. Furthermore, the cassette itself may be tilted to correspond to any tilt of the samples, perhaps by being aligned with a bisected angle. Thus the mechanical configuration (in this embodiment) may serve as a median angular orientation element which orients the absorbent material appropriately for withdrawal of the collected fluidic substance (36).
Regardless of whether the absorbent material (72) is used in a cassette or other arrangement, embodiments may include multiple amounts of absorbent material (72) that may be sequenced so that in the series of actions in any test or in separate tests, multiple events of withdrawing differing spent substances can occur. Thus, additional amounts of unused portions of a larger amount of absorbent material (72) may be presented to a location such as that of a collected fluidic substance (36) or merely in the vicinity of the sample(1) or the samples (1). To accomplish this, embodiments can include an absorbent material sequence element (78). Through action of the automatically sequenced test processor (3), or more generally, the sample processing system (2), the system may act to automatically sequence the absorbent material so that an unused portion is sequentially presented at appropriate times. This may occur through an absorbent material advance element that establishes an unused portion of absorbent material in an exposed position as part of the biochemical or other test sequence. In addition, embodiments may advance or sequence the material in appropriate amounts perhaps incrementally and so there may be included, perhaps through programming or the like, an absorbent material multiple sample appropriate incremental advance element that acts to only sequence an appropriate amount based on how many samples were processed.
As mentioned, the absorbent material can be advanced in multiple sample appropriate increments. In embodiments such as shown in FIGS. 10 and 16 through 18 that have upper and lower slide holders (49 and 48) arranged in a row as one type of linearly arranged plural sample holder, the sample processing system (2) may be operated in a manner in which not all positions are used in all test runs. In such a manner, or otherwise, it may be appropriate to use an altered amount of absorbent material (72). For example, while a row of eight sample pairs is presented in the embodiment shown in FIGS. 10 and 16 through 18, perhaps only five samples may need to be run with three different tests. In such an instance, three locations (two pairs and one run by itself) may be actioned. If perhaps ten withdrawal events are needed for each of these tests (e.g., primary antibody, rinse, secondary antibody, rinse, chromogen 1, rinse, chromogen 2, rinse, counterstain, rinse) only 30 singular withdrawal spots may be needed. Rather than using withdrawal programming for when a full sample holder is used, where 80 singular withdrawal spots may have been needed, the system may automatically act to advance in multiple sample appropriate increments and thus conserve absorbent material (72). Furthermore, since a cassette or the like may have only a finite amount of total absorbent material, the system can track the multiple sample appropriate increments and perhaps totalize them through programming or the like that may act as a multiple sample appropriate increment tracker element. It may even inform an operator when it may be appropriate to replace an element such as a cassette or the like. Referring to the above example, it may also be understood that a single sample can be run as well. In fact, through proper programming and in conjunction with the mechanical system presented, the automatically sequenced test processor (3) may present a single sample protocol automatically sequenced biochemical test processor.
An aspect of some embodiments may be the fact that the sample process system (2) may act substantially coincidentally on all samples contained. From FIGS. 10, 16, 17, 18, and 19 it may be understood that one appropriate configuration of the system may present a substantially coincident sample treatment element to which multiple samples are responsive. In the configuration shown this may involve the multiple sample holders shown. Such a system may also involve the use of individual or location specific reagent containers (55). These may dispense from a side actuator button (61) as shown in FIG. 19, from a top actuator (62) as shown in FIGS. 20-24, or otherwise. As shown in FIG. 12, the reagent containers (55) can move or otherwise place reagent on each microscopic slide pair. Further, as may be understood from FIGS. 20-24, the reagent containers (55) may be configured to include one or more of a cartridge (65) or a magazine (66). The cartridge (65) may be a container for a single antibody substance or the like, perhaps such as the primary antibody substance. The magazine may be a single container for multiple substances with multiple chambers and thus may present a single container multiple chamber multiple fluidic substance magazine (69). It may also be configured in somewhat of a line and thus present a linear reagent magazine such as is shown in one embodiment. The system may include a single container multiple chamber multiple fluidic substance magazine whereby a single container may have multiple chambers with in it so that multiple fluidic substances can be placed in the chambers. In one arrangement, a dispensement force element (68) may be used to release substance from the single container multiple chamber multiple fluidic substance magazine (69). By having at least two substance chambers, the system can act automatically to determine which substance or interactive fluidic substance is appropriate and can then dispense that substance. All that may be necessary for the operator is the place the single container multiple chamber multiple fluidic substance magazine (69) in the system. In order to facilitate processing that differs by location, the system may be configured to include location specific sources. These location specific sources may even have a correspondence with sample of locations. By including multiple substance source magazines, as one type of a location specific multiple substance source, differing substances can be dispensed on one sample throughout the course of an automated test sequence. In addition, the system may include location specific single substance sources as well. Thus the system may include a single container multiple chamber multiple fluidic substance magazine (69), a linearly disposed multiple substance source (70), or even a primary antibody cartridge (71) as shown in FIGS. 20 through 21. Thus, the system can act to automatically process samples even when differing substances are required.
As may be understood from the detachable reagent cartridges, magazines, and the wicking cassette as but some examples, the system may involve use of at least one consumable biochemical process element. These may be consumably responsive to the automatically sequenced test processor (3). In order to understand substance, material, or, more generally consumable availability, it may be advantageous to know both how much of an item has been used and how much of an item is available. For this and other purposes, embodiments may include a consumable process alterable information memory element perhaps in this embodiment a consumable biochemical process alterable information memory element (82). This consumable biochemical process alterable information memory element (82) may be physically or otherwise associated with one or more consumable biochemical process elements. Upon installing, snapping in or attaching the consumable, a consumable biochemical process alterable information memory element detachable electrical connection may be established such as by a plug, an electrical, or any other type of connection. Through some type of consumable biochemical process alterable information memory element detachable electrical connection direct communication to and from can be established. The automatically sequenced test processor (3) or other aspect of the sample processing system (2) may act through software or the like to query the memory and perhaps even to change it upon consumable usage or the like. As such the system may include a consumable information query element (83) and perhaps even a consumable information change element (84). These are but examples of what may act as a consumable biochemical process element. In one embodiment, the system may include an electrically erasable and programmable memory element attached to a consumable biochemical process element. This consumable biochemical process element may be any items that may be consumed or worn out in use of the system. For instance, using the substance withdrawal consumable biochemical process element such as the wicking cassette as one example, this item may have an electrically erasable and programmable memory element attached to it. In this instance this may be considered a wicking element electrically erasable and programmable memory element (85). Similarly, for a fluidic substance container such as the cartridge (65) or the magazine (66), there may be a fluidic substance container electrically erasable and programmable memory element (86) attached to either or both of these. Thus consumables such as these can be more easily handled and monitored. Finally, whether with or without the memory and information elements just mentioned, the system can be configured with a network connection or other communication modality to interface with a laboratory information system or the like. This can be considered a laboratory information system interface element (87).
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U.S. Provisional Application No. 60/673,468 filed Apr. 21, 2005, Entitled Method and Apparatus for Automated Rapid Immunohistochemistry
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