MASS SPECTROMETRY APPARATUS

Abstract

A mass spectrometry apparatus, including a mass spectrometer and a sample plate. The mass spectrometer includes: a sample plate holder configured to hold a sample plate in an engaged position. The mass spectrometer is configured to perform a mass spectrometric analysis of a sample only when the sample is located on a sample plate that is held in the engaged position by the sample plate holder. The mass spectrometer includes one or more engagement features configured to engage with a sample plate so as to prevent the sample plate from being held in the engaged position by the sample plate holder unless the sample plate includes one or more engagement features configured to limit use of the sample plate to a specific analytical technique or a range of analytical techniques to be performed using the mass spectrometer. The sample plate is configured for use in the specific analytical technique or range of analytical techniques, wherein the sample plate includes the one or more engagement features configured to limit use of the sample plate to the specific analytical technique or range of analytical techniques.

Claims

1. A mass spectrometry apparatus, including: a mass spectrometer including: a sample plate holder configured to hold a sample plate in an engaged position; wherein the mass spectrometer is configured to perform a mass spectrometric analysis of a sample only when the sample is located on a sample plate that is held in the engaged position by the sample plate holder; wherein the mass spectrometer includes one or more engagement features configured to engage with a sample plate so as to prevent the sample plate from being held in the engaged position by the sample plate holder unless the sample plate includes one or more engagement features configured to limit use of the sample plate to a specific analytical technique or a range of analytical techniques to be performed using the mass spectrometer; a sample plate configured for use in the specific analytical technique or range of analytical techniques, wherein the sample plate includes the one or more engagement features configured to limit use of the sample plate to the specific analytical technique or range of analytical techniques.

2. A mass spectrometry apparatus according to claim 1, wherein the mass spectrometer is configured for use only in the specific analytical technique or range of analytical techniques.

3. A mass spectrometry apparatus according to claim 1, wherein the one or more engagement features configured to limit use of the sample plate to the specific analytical technique or range of analytical techniques uniquely correspond to the specific analytical technique or range of analytical techniques.

4. A mass spectrometry apparatus according to claim 1, wherein the one or more engagement features of a first one of the mass spectrometer and the sample plate include one or more projections, and the one or more engagement features of a second one of the mass spectrometer and the sample plate include one or more recesses corresponding to the one or more projections.

5. A mass spectrometry apparatus according to claim 4, wherein the one or more engagement features of the mass spectrometer include one or more projections, and the one or more engagement features of the sample plate include one or more recesses corresponding to the one or more projections.

6. A mass spectrometry apparatus according to claim 5, wherein the one or more recesses included in the sample plate extend partially into a rear face of the sample plate, wherein the rear face of the sample plate is on an opposite side of the sample plate from a front face of the sample plate, wherein the front face of the sample plate is configured to have a sample located thereon when the sample plate is in use.

7. A mass spectrometry apparatus according to claim 1, wherein the one or more engagement features of the sample plate are located on a rear face of the sample plate, wherein the rear face of the sample plate is on an opposite side of the sample plate from a front face of the sample plate, wherein the front face of the sample plate is configured to have a sample located thereon when the sample plate is in use.

8. A mass spectrometry apparatus according to claim 1, wherein the one or more engagement features of the mass spectrometer are located on the sample plate holder.

9. A mass spectrometry apparatus according to claim 1, wherein the one or more engagement features of the mass spectrometer include a hinged plate included in the sample plate holder, wherein the hinged plate is configured to prevent the sample plate from being held in the engaged position by the sample plate holder unless the sample plate includes the one or more engagement features configured to limit use of the sample plate to a specific application of the mass spectrometer.

10. A mass spectrometry apparatus according to claim 1, wherein the one or more engagement features of the mass spectrometer may include a latch mechanism included in the sample plate holder, and the one or more engagement features of the sample plate may include one or more magnets or magnetic areas, the/each magnet or magnetic area being respectively located in a specific position on or within the sample plate, wherein the latch mechanism is configured to prevent the sample plate from being held in the engaged position by the sample plate holder unless the sample plate includes the one or more magnets or magnetic areas located in the one or more specific positions, the one or more magnets or magnetic areas being configured to move a member of the latch mechanism to allow the sample plate to reach the engaged position.

11. A mass spectrometry apparatus according to claim 1, wherein the mass spectrometer is configured to perform a mass spectrometric analysis of a sample only when the sample is located on a sample plate that is held in the engaged position by the sample plate holder by: the mass spectrometer having a slot into which the sample plate needs to be fully inserted in order to be held in the engaged position by the sample plate holder; the one or more engagement features of the mass spectrometer being configured to prevent a sample plate from being inserted fully into the mass spectrometer unless the sample plate includes the one or more engagement features configured to limit use of the sample plate to a specific application of the mass spectrometer; the mass spectrometer being configured to perform a mass spectrometric analysis of a sample only when a door of the mass spectrometer is closed, wherein the door is configured not to close if a sample plate is only partially, and not fully, inserted into the slot.

12. A mass spectrometry apparatus according to claim 1, wherein the mass spectrometer is configured to perform a mass spectrometric analysis of a sample only when the sample is located on a sample plate that is held in the engaged position by the sample plate holder by: the mass spectrometer having a sample plate position sensor configured to used to detect if a sample plate is held in the engaged position by the sample plate holder; wherein the mass spectrometer is configured to perform a mass spectrometric analysis of a sample only when the mass spectrometer determines, based on an output of the sample plate position sensor, that a sample plate is held in the engaged position by the sample plate holder.

13. A mass spectrometry apparatus according to claim 1, wherein the mass spectrometer has an engagement feature sensor configured to be used to detect whether a sample plate put in the mass spectrometer has the one or more engagement features configured to limit use of the sample plate to a specific analytical technique, wherein the mass spectrometer is configured to perform a mass spectrometric analysis of a sample only when the mass spectrometer determines, based on an output of the engagement feature sensor, that the sample plate put in the mass spectrometer includes the one or more engagement features configured to limit use of the sample plate to a specific analytical technique.

14. A mass spectrometry apparatus according to claim 1, wherein the mass spectrometer is a MALDI TOF mass spectrometer.

15. A mass spectrometry apparatus according to claim 14, wherein: the specific analytical technique or range of analytical techniques is analysis of intact microorganisms, wherein bacteria cultured on an Agar gel are applied intact onto the sample plate, wherein mass spectra produced by the mass spectrometer are used for identification of microorganisms by comparing the mass spectra with databases containing mass spectra of peptides and proteins extracted from microorganisms of interest; wherein the sample plate configured for use in analysis of intact microorganisms has a lipid coating.

16. A mass spectrometry apparatus according to claim 14, wherein: the specific analytical technique or range of analytical techniques is analysis of lipids extracted from the cells of microorganisms, wherein bacteria cultured on an Agar gel are processed to extract characteristic lipids from the cells of the bacteria which are then applied to the sample plate, wherein mass spectra produced by the mass spectrometer are used for identification of microorganisms by comparing the mass spectra with databases containing mass spectra of lipids extracted from microorganisms of interest; wherein the sample plate configured for use in analysis of lipids extracted from the cells of microorganisms does not have a lipid coating.

17. A mass spectrometry apparatus according to claim 1, wherein the mass spectrometry apparatus includes one or more sample plates configured for use in another specific analytical technique or range of analytical techniques to be performed by a mass spectrometer, wherein each sample plate configured for use in the other specific analytical technique or range of analytical techniques includes one or more engagement features configured to limit use of the sample plate to the other analytical technique or range of analytical techniques.

Description

SUMMARY OF THE FIGURES

[0116] Examples and experiments illustrating the principles of the invention will now be discussed with reference to the accompanying figures in which:

[0117] FIG. 1 shows the method of insertion of a compact sample plate into the sample plate holder of a benchtop mass spectrometer.

[0118] FIG. 2 shows a standard sample plate with 384 sample locations.

[0119] FIG. 3 shows a compact sample plate with 48 sample locations.

[0120] FIG. 4(a) shows a compact sample plate according to example 1.

[0121] FIG. 4(b) shows the compact sample plate of FIG. 4(a) and a sample plate holder configured to engage with the compact sample plate, where the compact sample plate is in held in an engaged position by the sample plate holder.

[0122] FIG. 5 shows a compact sample plate and the sample plate holder of FIG. 4(b), where the sample plate lacks the engagement features required to allow the sample plate to be held in the engaged position by the sample plate holder and such that the sample plate is left protruding from the sample plate holder by several millimetres.

[0123] FIG. 6(a) shows the underside of a compact sample plate according to example 2.

[0124] FIG. 6(b) shows the compact sample plate of FIG. 6(a) and sample plate holder configured to engage with the compact sample plate, where the compact sample plate is in held in an engaged position by the sample plate holder. In this figure, the sample plate holder is drawn semi-transparently so that the engagement features can be seen.

[0125] FIG. 7(a) shows the underside of a compact sample plate according to example 3.

[0126] FIG. 7(b) shows the compact sample plate of FIG. 7(a) and a sample plate holder configured to engage with the compact sample plate. In this figure, the compact sample plate is drawn semi-transparently so that the engagement features can be seen.

[0127] FIG. 8(a) shows a compact sample plate according to example 4.

[0128] FIG. 8(b) shows the compact sample plate of FIG. 8(a) and a hinged plate configured to engage with the compact sample plate. As shown, a portion of the compact sample plate has been cut-away so that the hinged plate and projections thereon can more clearly be seen.

[0129] FIG. 8(c) shows a view of the underside of a compact sample plate and hinged plate as shown in FIG. 8(b).

[0130] FIG. 9(a) shows the back of a compact sample plate according to example 5.

[0131] FIG. 9(b) shows the front of the compact sample plate of FIG. 9(a) as well as a magnetic latch according to example 5.

[0132] FIG. 10(a) shows a standard sample plate according to example 6.

[0133] FIG. 10(b) shows the standard sample plate and a sample plate holder configured to engage with the standard sample plate.

[0134] FIG. 11 shows a sample plate holder adaptor according to example 7, wherein the sample plate holder adaptor has the form of a standard sample plate as described in relation to FIG. 10(a), and is configured to hold four compact sample plates.

[0135] FIG. 12 shows a negative ion MALDI-TOF MS spectrum for a lipid sample where peaks from lipids in the coating on the sample plate are also present

DETAILED DESCRIPTION OF THE INVENTION

[0136] Aspects and embodiments of the present invention will now be discussed with reference to the accompanying figures. Further aspects and embodiments will be apparent to those skilled in the art. All documents mentioned in this text are incorporated herein by reference.

[0137] The following examples concern sample plates for use in mass spectrometers and more preferably, for use in MALDI TOF mass spectrometers.

[0138] In the following description, various sample plates are described for use for example in a MALDI TOF mass spectrometer whereby one or more engagement features, e.g. in the form of a mechanical key, are incorporated into the sample plate to limit use of the sample plate to the specific analytical technique or range of analytical techniques, which may for example help to ensure that only a certain type of sample plate can be used for a specific type of sample. Thus in a regulated environment, the one or more engagement features may help to prevent the wrong sample plate from being used for the wrong analytical technique. For example with an analytical technique involved with in vitro diagnostics a misdiagnosis due to using the incorrect type of sample plate may be avoided.

[0139] Thus, a mass spectrometer can be locked down for use with a particular type of sample plate to be used in a particular analytical technique corresponding to the environment (e.g. lab) in which it is installed.

[0140] Preferably, the one or more engagement features included in a sample plate (e.g. to provide the sample plate with a mechanical ‘key’) are configured so that the sample plate will only fit into a mass spectrometer with one or more corresponding engagement features (e.g. the correct ‘lock’). Sample plates configured for use in different analytical techniques can thus have different engagement features, e.g. so as to restrict use of different sample plates to different analytical techniques. The one or more engagement features on a sample plate can be designed so that the sample plate does not fit correctly into the sample plate holder. Preferably the mass spectrometer is configured so that it does not operate if the sample plate does not fit correctly in the sample plate holder. For example, the mass spectrometer may be configured so that a door of the instrument will not close unless the sample plate fits correctly in the sample plate holder. Alternatively, the one or more engagement features on the sample plate can be designed so that the instrument can recognise when the wrong sample plate is fitted and will not operate until a correctly fitting sample plate is present.

EXAMPLES

Example 1

[0141] In this example, as shown in FIGS. 4(a) and 4(b), a sample plate 40 has engagement features in the form of slots which provide a shaped cut-out 41 in an end of the sample plate 40 (the end which is configured to be inserted into the sample plate holder of the mass spectrometer). These engagement features are configured to limit use of the sample plate to (and preferably uniquely correspond to) a specific analytical technique or range of analytical techniques, e.g. ‘Analysis of intact microorganisms’ or ‘Analysis of lipids extracted from the cells of microorganisms’ as described above.

[0142] The slots which provide the cut-out 41 may have a square cornered profile or round cornered profile. The profile of the slots/cut-out 41 may take other forms, but preferably uniquely correspond to the specific analytical technique or range of analytical techniques.

[0143] A sample plate holder 42 of a mass spectrometer (not shown) is configured to hold the sample plate 40 in an engaged position as shown in FIG. 4(b). To this end, the sample plate holder has engagement features, in this case provided by projections which form a ‘key’ 43, which are configured to engage with the engagement features of the sample plate 40 to allow the sample plate 40 to be held in the engaged position as shown in FIG. 4(b). To this end, the projections which form the key 43 are shaped to provide the exact negative of the cut-out 41 in the sample plate 40.

[0144] In this way, only a sample plate with matching engagement features will fit correctly into the sample plate holder 42. Thus, the sample plate holder 42 is configured to prevent a sample plate from being held in the engaged position unless the sample plate includes the cut-out 41.

[0145] A sample plate with engagement features that do not match the cut-out 41 (or with no engagement features) will not fit correctly into the sample plate holder 42. This preferably prevents operation of a mass spectrometer incorporating the sample plate holder 42, e.g. by stopping the door of the mass spectrometer from being closed or by the mass spectrometer detecting the incorrectly fitting sample plate.

[0146] For example, FIG. 5 shows how a compact sample plate 30 that lacks the engagement features of the sample plate 40 is prevented from being held in the engaged position by the key 43 on the sample plate holder 42. Here, the sample plate 30 is left protruding from the sample plate holder 42 by several millimetres. This may prevent the operation of the mass spectrometer because a door of the mass spectrometer cannot be closed whilst the sample plate 30 protrudes from the sample plate holder 42. Alternatively, operation of the mass spectrometer may be prevented in the scenario shown in FIG. 5 by configuring the mass spectrometer to operate only if it detects that the sample plate is being held in the engaged position (not the case in the scenario shown in FIG. 5), for example using an optical sensor 44, .

[0147] This same optical sensor 44 could be used to detect whether a sample plate put in the mass spectrometer has the cut-out 41, with the mass spectrometer being configured to operate only if it determines, based on the output of the optical sensor 44, that the sample plate put in the mass spectrometer includes the cut-out 41. In this way, the mass spectrometer could be able to prevent use of sample plate 30 (which lacks the required cut-out 41), even if a user removed the key 43 of the mass spectrometer in an attempt to enable the sample plate 30 to be held in the engaged position by the sample plate holder. To do this, the sensor could be a multi-channel (or stacked single channel) reflective device that detects the shape of the engagement features on the sample plate by the correct combination of reflected and non-reflected light. Alternatively, the sensor can be an imaging device which images the engagement features and compares the features with a reference image. The imaging device could be the camera used to view the samples as held on the sample plates in the mass spectrometer.

Example 2

[0148] In this example, as shown in FIGS. 6(a) and 6(b), the sample plate 60 has a shaped recess 61 which extends partially into a back surface of the sample plate 60. The recess 61 can be formed of individual grooves or formed from a cut-out with a square cornered profile or a round cornered profile or the profile can have a different shape. This differs from example 1 in that the recess 61 extends only partially into the back surface of the sample plate 60.

[0149] The recess 61 is configured to limit use of the sample plate 60 to (and preferably uniquely correspond to) a specific analytical technique or range of analytical techniques, e.g. ‘Analysis of intact microorganisms’ or ‘Analysis of lipids extracted from the cells of microorganisms’ as described above.

[0150] Similar to example 1, a sample plate holder 62 has corresponding engagement features provided in this case by a projection 63 that is designed to be the negative of the recess 61 in the sample plate so that it can fit exactly.

[0151] If the sample plate has engagement features which do not match the engagement features of the sample plate holder, it will not fit properly into the sample plate holder such that incorrect operation of the mass spectrometer will be prevented.

Example 3

[0152] In this example, as shown in FIGS. 7(a) and 7(b), a sample plate 70 has engagement features provided by a number of slots 71 of a certain size and spacing in the back face of the sample plate 70 that run the full length of the sample plate 70.

[0153] The slots 71 are configured to limit use of the sample plate 70 to (and preferably uniquely correspond to) a specific analytical technique or range of analytical techniques, e.g. ‘Analysis of intact microorganisms’ or ‘Analysis of lipids extracted from the cells of microorganisms’ as described above.

[0154] Similar to example 1, a sample plate holder 72 has corresponding engagement features provided in this case by a corresponding array of pegs or dowels or ridges 73 which slide in the slots when the sample plate is inserted into the sample plate holder.

[0155] If the pattern of slots in a sample plate does not match the pattern of pegs or dowels or ridges in the sample plate holder 72, it will not be possible to insert the sample plate into the sample plate holder 72 and therefore into the mass spectrometer.

[0156] Although in this example the pegs or dowels or ridges are described as being part of the sample plate holder 72, they may in other examples be included in another part of the mass spectrometer, e.g. as part of a slot through which the sample plate needs to be pushed in order to go into the sample plate holder.

Example 4

[0157] In this example, as shown in FIGS. 8(a), 8(b) and 8(c), a sample plate 80 has engagement features provided by a series of grooves 81 in a back face of the sample plate 80.

[0158] The grooves are configured to limit use of the sample plate 80 to (and preferably uniquely correspond to) a specific analytical technique or range of analytical techniques, e.g. ‘Analysis of intact microorganisms’ or ‘Analysis of lipids extracted from the cells of microorganisms’ as described above.

[0159] Similar to example 1, a sample plate holder (not shown) has corresponding engagement features provided in this case by projections in the form of pegs or dowels 83 on a hinged plate 82 fitted such that the hinged plate 82 will only tilt out of the way of the sample plate 80 if the engagement features of the sample plate and sample plate holder match, i.e. if the projections on the hinged plate 82 fit into the grooves 81 on the back face of the sample plate 80.

[0160] When a sample plate lacks the grooves 81 in the back face of the sample plate, the hinged plate 82 is configured to stop the sample plate from being fitted into the sample plate holder and it will not be possible to insert the sample plate correctly into the mass spectrometer.

Example 5

[0161] In this example, as shown in FIGS. 9(a) and 9(b), a sample plate 90 has engagement features in the form of small magnets or magnetic areas 91, each being respectively located in a specific position on or within the sample plate 90.

[0162] The magnets or magnetic areas 91 are configured to limit use of the sample plate 90 to (and preferably uniquely correspond to) a specific analytical technique or range of analytical techniques, e.g. ‘Analysis of intact microorganisms’ or ‘Analysis of lipids extracted from the cells of microorganisms’ as described above.

[0163] With reference to FIG. 9(b), a latch mechanism that includes a latch plate 92, which is itself included in a sample plate holder of a mass spectrometer (not shown), is configured to prevent the sample plate 90 from being held in the engaged position by the sample plate holder unless the sample plate 90 includes the magnets or magnetic areas located in the specific positions. Holes 93 in the latch plate carry magnets or magnetic areas 94 that correspond to the magnets or magnetic areas in the sample plate so that, provided the sample plate includes the magnets or magnetic areas located in the specific positions, the latch plate 92 attaches to the sample plate in a manner that permits the latch plate 92 to slide with the sample plate 90 in order to allow the sample plate to be held in the engaged position by the sample plate holder (e.g. by the latch plate sliding to the exact position required to ‘unlock’ the sample holder). Note if the sample plate 90 did not include any magnets or magnetic areas, then the latch plate 92 would preferably not attach to the sample plate 90 and would prevent the sample plate 90 from reaching the engaged position (e.g. by the latch plate not sliding to the exact position required to ‘unlock’ the sample holder). Note that if the sample plate 90 included one or more magnets or magnetic areas, but included them other than in the specific positions, then the latch plate 92 would preferably attach to the sample plate 90 in a manner that prevented the sample plate 90 from reaching the engaged position (e.g. by the latch plate sliding to a position other than the exact position required to ‘unlock’ the sample holder).

[0164] In this way only a sample plate 90 with the correctly located magnets or magnetic areas can be held in the engaged position by the sample plate holder.

[0165] The magnets or magnetic areas in example 5 could be used in combination with the other engagement features described in any of examples 1 to 4 above.

Example 6

[0166] In this example, as shown in FIGS. 10(a) and 10(b) a sample plate 100 has engagement features provided by grooves 101 in the side of the sample plate 100.

[0167] In this example, the sample plate 100 has the form of a standard sample plate (except for the addition of grooves 101), rather than a compact sample plate (as was the case for examples 1-5 discussed above).

[0168] The grooves 101 are configured to limit use of the sample plate 100 to (and preferably uniquely correspond to) a specific analytical technique or range of analytical techniques, e.g. ‘Analysis of intact microorganisms’ or ‘Analysis of lipids extracted from the cells of microorganisms’ as described above.

[0169] Similar to example 1, a sample plate holder 102 has corresponding engagement features provided in this case by projections in the form of blades 103 which fit into the grooves 101 in the sample plate 100 when it is inserted into either the sample plate holder or sample stage.

[0170] If the grooves in the sample plate 101 correspond exactly with the blades 103 in the sample plate holder or sample stage, the sample plate can be held in an engaged position by the sample plate holder 102, though in FIG. 10(b) the sample plate is shown partially inserted so that the engagement features can be seen.

[0171] The sample plate 100 has the form of a modified standard micro-titer sample plate as used in a commercial MALDI mass spectrometer (Shimadzu MALDI-7090TH). This commercial instrument has a load lock where the sample plate is inserted into a cassette type sample plate holder. When the sample plate is to be analysed in the mass spectrometer, the cassette type sample plate holder (with sample plate) is transferred from the load-lock onto the sample stage. This mass spectrometer has a sensor in the load-lock to ensure that the sample plate is correctly inserted into the cassette type sample plate holder (for example to prevent the sample plate being inserted upside down).

[0172] Thus, if the Shimadzu MALDI-7090™ were modified to include the sample plate holder 102, then operation of the instrument would be prevented if a wrong sample plate (lacking the grooves 101) were inserted into the sample plate holder 102, since the blades 103 would prevent the wrong sample plate from being held in the engaged position by the sample plate holder 102, and the mass spectrometer would detect an incorrectly inserted sample plate.

Example 7

[0173] In this example, as shown in FIG. 11, a sample plate holder adaptor 110 has the form of a standard sample plate as described in relation to FIG. 10(a) (including the grooves 111), and is therefore configured to be held by a sample plate holder of a typical standard floor standing mass spectrometer (lacking any special modifications or engagement features as described herein).

[0174] The sample plate holder adaptor 110 is configured to hold four compact sample plates 40 as described in relation to example 1.

[0175] The sample plate holder adaptor 110 includes, for each of the sample plates it is configured to hold, engagement features in the form of a projections which form a ‘key’ 41, which are configured to engage with the engagement features of the sample plate 40 to allow the sample plate 40 to be held in an engaged position as shown in FIG. 11.

[0176] Thus, in this example, the sample plate holder adaptor 110 plays the role of the sample plate holder 42 described in connection with example 1.

[0177] In this way, a commercial MALDI mass spectrometer (e.g. Shimadzu .sup.MALDI-7090™—described above) can be retrofitted, though use of the sample plate holder adaptor 110, to prevent a sample plate from being held in the engaged position by the sample plate holder adaptor 110 unless the sample plate includes one or more engagement features configured to limit use of the sample plate to a specific analytical technique or a range of analytical techniques to be performed using the mass spectrometer. This may help to “lock down” the mass spectrometer for use only with sample plates 40 configured for use in a specific analytical technique or range of analytical techniques to be performed using the mass spectrometer, without needing to modify the original sample plate holder of the instrument.

[0178] In a possible modification of example 7 (not illustrated), the sample plate holder adaptor 110 of FIG. 11 could be modified to use other forms of engagement features, e.g. such as those described with reference to examples 2-5.

[0179] In another possible modification of example 7 (not illustrated), the sample plate holder adaptor 110 of FIG. 11 could be modified to include the grooves 101 described with reference to example 6, in order to permit use with the sample plate holder 102 described with reference to example 6.

[0180] Final Remarks

[0181] The features disclosed in the foregoing description, or in the following claims, or in the accompanying drawings, expressed in their specific forms or in terms of a means for performing the disclosed function, or a method or process for obtaining the disclosed results, as appropriate, may, separately, or in any combination of such features, be utilised for realising the invention in diverse forms thereof.

[0182] While the invention has been described in conjunction with the exemplary embodiments described above, many equivalent modifications and variations will be apparent to those skilled in the art when given this disclosure. Accordingly, the exemplary embodiments of the invention set forth above are considered to be illustrative and not limiting. Various changes to the described embodiments may be made without departing from the spirit and scope of the invention.

[0183] For the avoidance of any doubt, any theoretical explanations provided herein are provided for the purposes of improving the understanding of a reader. The inventors do not wish to be bound by any of these theoretical explanations.

[0184] Any section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0185] Throughout this specification, including the claims which follow, unless the context requires otherwise, the word “comprise” and “include”, and variations such as “comprises”, “comprising”, and “including” will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

[0186] It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Ranges may be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent “about,” it will be understood that the particular value forms another embodiment. The term “about” in relation to a numerical value is optional and means for example +/−10%.

REFERENCES

[0187] A number of publications are cited above in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Full citations for these references are provided below. The entirety of each of these references is incorporated herein.

[0188] [1] DE19754978C

[0189] [2] U.S. Pat. No. 6,287,872B

[0190] [3] EP2792471 B1

[0191] [4] US2017029587A1

[0192] [5] GB2524854B

[0193] [6] EP3055420B1

[0194] [7] Kaleta and Wolk, Clin Lab News; May 2012