SENSOR FOR SINGLE PARTICLE DETECTION

Abstract

The invention provides a sensor (100) for sensing a predetermined particle (10) in a fluid (11), wherein the sensor (100) comprises (i) an electrode (110) and (ii) an recognition element (112), wherein the electrode (110) comprises an electrode face (111) configured accessible to the fluid (11), to the predetermined particle (10) in the fluid (11), and to a redox mediator (12) in the fluid (11); and wherein the recognition element (112) is configured to at least temporarily selectively bind with the predetermined particle (10), thereby limiting access of the redox mediator (12) to the electrode face (111) during the binding of the predetermined particle with the recognition element (112).

Claims

1. A sensor (100) for sensing a predetermined particle (10) in a fluid (11), wherein the sensor (100) comprises (i) an electrode (110) and (ii) a recognition element (112); wherein the electrode (110) comprises an electrode face (111) configured accessible to the fluid (11), to the predetermined particle (10) in the fluid (11), and to a redox mediator (12) in the fluid (11); wherein the recognition element (112) is configured for at least temporarily selectively binding with the predetermined particle (10), and configured to limit access of the redox mediator (12) to the electrode face (111) during the binding of the predetermined particle (10) with the recognition element (112), wherein: the predetermined particle (10) comprises a biological particle selected from the group consisting of an extracellular vesicle (EV), a tumor-derived extracellular vesicle (tdEV), a virus, a DNA-containing particle, a particle modified with DNA, an RNA-containing particle, a particle modified with RNA, a platelet, an allergen, a bacterium, a peptide, a polypeptide, a protein, a lipoprotein, a hormone, a biopolymer, and an enzyme; the recognition element (112) comprises a biological recognition element (112) for the predetermined particle (10); the recognition element (112) is configured at the electrode face (111); and a characteristic dimension (d) of the electrode face (111) is selected from a range of 30-1500 nm.

2. The sensor (100) according to claim 1, wherein the recognition element (112) is selected from the group consisting of an antibody, a single-domain antibody, a nanobody, a knottin, a protein, an enzyme, a polypeptide, a peptide, an aptamer and a nucleic acid.

3. The sensor (100) according to claim 1, wherein the sensor (100) is configured for detecting the predetermined particle (10) on a single particle level, wherein the characteristic dimension (d) of the electrode face (111) is selected to match the predetermined particle (10), and wherein the characteristic dimension (d) is selected from the group consisting of a length, a width, and an equivalent circular diameter.

4. The sensor (100) according to claim 1, wherein the sensor (100) comprises an electrically insulating base (120) enclosing at least part of the electrode (110), wherein the electrically insulating base (120) comprises an insulating base face (126), configured parallel to or protruding from the electrode face (111).

5. The sensor (100) according to claim 4, wherein the electrode face (111) is configured recessed in the base (120).

6. The sensor (100) according to claim 1, wherein the electrode (110) comprises a coating (113) configured at the electrode face (111), wherein the coating (113) is configured not to block an electron transfer between the electrode face (111) and the redox mediator (12), wherein the coating (113) is configured for reducing or preventing fouling of the electrode face (111), and wherein the coating (113) further comprises the recognition element (112).

7. The sensor (100) according to claim 1, further comprising an array (200) of electrodes (110), wherein optionally at least one of the electrodes (110) of the array (200) has an electrode characteristic (119) being different from the electrode characteristic (119) of the other electrodes (110) of the array (200), wherein the electrode characteristic (119) is selected from the group consisting of a dimension (d) of the electrode face (111), the coating (113), the recognition element (112), and an electrically conductive material of the electrode (110), and wherein each of the electrodes (110) is configured for individually sensing a predetermined particle (10).

8. A device (1000) for analyzing a fluid (11), wherein the device (1000) comprises an analyzing space (350) comprising the sensor (100) according to claim 1, wherein the electrode face (111) is configured in fluid contact with the analyzing space (350).

9. The device (1000) according to claim 8, further comprising a channel (300) with a channel wall (310), wherein the channel (300) defines the analyzing space (350), and wherein the channel wall (310) comprises the electrode (110), wherein the channel (300) is a flow through channel.

10. A system (2000) for analyzing a fluid (11), comprising the device (1000) according to claim 8, the system (2000) further comprising a further electrode (17), wherein the further electrode (17) is configured to functionally connect to the fluid (11) in the analyzing space (350) during operation of the system (2000), the system (2000) further comprising a control system (1500), wherein the control system (1500) is configured to execute a measuring routine, wherein the measuring routine comprises: measuring during an analyzing period an electric current through the electrode (110) caused by a potential difference between the further electrode (17) and the electrode face (111), wherein the system (2000) further comprises an electric current measuring device (16) configured to measure the electric current through the electrode (110).

11. The system (2000) according to claim 10, wherein the system (2000) further comprises an electric power supply (15) configured for providing the potential difference between the further electrode (17) and the electrode face (111).

12. The system (2000) according to claim 10, wherein the device (1000) comprises the channel (300) according to claim 9, wherein the system (2000) further comprises a fluid transport device (400) functionally connected to the channel (300), wherein the fluid transport device (400) is configured to (i) provide the fluid (11) to the analyzing space (350) and to (ii) remove the fluid (11) from the analyzing space (350) after maintaining the fluid (11) in the analyzing space (350) during the analyzing period.

13. The system (2000) according to claim 12, wherein the system (2000) is configured for providing a series of volumes (V) of the fluid (11) to the channel (300), wherein the volumes (V) of the fluid (11) are separated from each other by a separation fluid (19), wherein the system (2000) is further configured to successively execute the measuring routine for each volume (V) of the fluid (11), wherein successively (i) each volume (V) of the series of volumes (V) of the fluid (11) is provided to the analyzing space (350) and (ii) removed from the analyzing space (350) after maintaining each volume (V) in the analyzing space (350) during the analyzing period.

14. A method for analyzing a fluid (11), the method comprising: providing the system (2000) according to claim 10, wherein the system (2000) comprises the electric power supply (15) according to claim 11, wherein the electrode face (111) is functionally connected to the further electrode (17), and during a measuring stage: (i) providing the fluid (11) comprising a redox mediator (12) to the analyzing space (350), (ii) executing a measuring routine during an analyzing period, wherein the fluid is maintained in the analyzing space during the analyzing period, and (iii) removing the fluid from the analyzing space again; wherein the measuring routine comprises: providing a potential difference between the further electrode (17) and the electrode face (111) and measuring an electric current through the electrode (110), as a function of time; and wherein analyzing the fluid (11) comprises determining a presence of a predetermined particle (10) in the fluid (11), wherein the presence of the predetermined particle (10) is determined based on a minimal duration of a determined change in the measured electric current as a function of time.

15. The method according to claim 14, wherein analyzing the fluid (11) further comprises determining a concentration of the predetermined particle (10) in the fluid (11), wherein the concentration of the predetermined particle (10) is determined based on a number of determined changes over at least the minimal duration in the measured current as a function of time, relative to the analyzing period, wherein the fluid (11) comprises a fluid (11) selected from the group consisting of blood, urine, saliva, sweat, seminal fluid, cerebrospinal fluid, ascites, lymph, milk, gastric acid, lacrimal fluid, and bile.

16. The method according to claim 13, for analyzing a series of volumes (V) of fluid (11), wherein the system (2000) comprises the channel (300) with the channel wall (310), wherein the channel (300) defines the analyzing space (350), wherein the method comprises: providing a series of volumes (V) of fluid (11) comprising the redox mediator (12) to the channel (300), wherein the volumes (V) of the fluid (11) are separated from each other by a separation fluid (19), and wherein the measuring stage comprises: flowing the series of volumes (V) of fluid (11) comprising the redox mediator (12) through the analyzing space (350), thereby sequentially, (i) providing one of the volumes (V) of the series of volumes (V) to the analyzing space (350), (ii) executing the measuring routine during the analyzing period, wherein the respective volume (V) of fluid (11) is maintained in the analyzing space during the analyzing period, and (iii) removing the respective volume (V) of fluid (11) from the analyzing space (350) again, thereby providing the separation fluid (19) to the analyzing space (350); wherein the respective volumes (V) of fluid are analyzed sequentially.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0087] Embodiments of the invention will now be described, by way of example only, with reference to the accompanying schematic drawings in which corresponding reference symbols indicate corresponding parts, and in which:

[0088] FIGS. 1 and 2 schematically depict some aspects of the sensor;

[0089] FIGS. 3 and 5 schematically depicts some aspects of the device and system;

[0090] FIG. 4 schematically depicts some further aspects of the invention.

[0091] The schematic drawings are not necessarily to scale.

DETAILED DESCRIPTION OF THE EMBODIMENTS

[0092] FIG. 1 schematically depicts and embodiment of the sensor 100 for sensing a predetermined particle 10 in a fluid 11. The sensor 100 comprises an electrode 110 and a recognition element 112. The electrode face 111 is configured accessible to the fluid 11, to the predetermined particle 10 in the fluid 11, and to a redox mediator 12 in the fluid 11. The recognition element 112 may especially (at least temporarily) selectively bind with the predetermined particle 10 thereby limiting access of a transport T of the redox mediator 12 to the electrode face 111 as is indicated in the figure. Hence, the figure depicts a status during binding of the particle 10 with the recognition element 12, herein also indicated as the engagement period P.

[0093] The fluid 11 may e.g. comprise a bodily fluid, such as of blood, urine, saliva, sweat, seminal fluid, cerebrospinal fluid, ascites, lymph, milk, gastric acid, lacrimal fluid, and bile. Herein, the invention is especially explained based on a biological particle, especially tdEV, in a bodily fluid. Yet, the fluid 11 not necessarily is a bodily fluid, but may e.g. in embodiments comprise (environmental) water. Also, the particle 10 may comprise a non-biological (inorganic) particle 10. The invention may e.g. also be used for determining a (specific) pollution in water. The predetermined particle 10 may e.g. comprise a biological particle 10 such as selected from the group consisting of a (tumor-derived) extracellular vesicle ((td)EV), a virus, a DNA-containing particle, an RNA-containing particle, a (poly)peptide, a protein (including a lipoprotein), and an enzyme. The biological particle 10 may in further embodiments comprise a particle modified with DNA (a DNA-functionalized particle) or a particle modified with RNA (an RNA-functionalized particle). In yet further embodiments, the biological particle 10 may comprise a particle selected from the group consisting of a platelet, an allergen, a bacterium, a hormone, and a biopolymer. The recognition element 112 may thus comprise a biological recognition element 112 for the predetermined particle 10 and may for instance be one or more of an antibody, a single-domain antibody, a nanobody, a knottin, a peptide, an aptamer or a nucleic acid. Herein terms like “a biological recognition element for the biological particle”, etc. are used indicating that the particle 10 has a high (chemical) affinity for biological recognition element 112. At least a part of the particle 10 (herein said part may also be indicated as “marker”) may especially bind to recognition element 112 as is schematically indicated in FIG. 1 by means of matching shapes of the particle 10 and the recognition element 112.

[0094] The electrode face 111 especially comprises the recognition element 112. In the depicted embodiment is the recognition element 112 configured at the electrode face 111. In other embodiments, the element 112 may be configured at a location near the electrode face 111 allowing to block the electrode face 111 for the redox mediator 12.

[0095] The sensor 100 especially comprises an electrically insulating base 120 enclosing at least part of the electrode 110. To minimize an edge effect, the insulating base face 126 of the electrically insulating base 120 may especially be configured parallel to the electrode face 111. In specific embodiments, e.g. depicted in FIG. 1, the insulating base face 126 is configured protruding from the electrode face 111, and a cavity 20 is defined by the electrode face 111 and (the passivation layer 125 of) the insulating base 120. This may also be indicated as a recessed electrode face 111. In the depicted embodiment, the electrode face 111 is configured recessed in the base 120 and the passivation layer 125 encloses the electrode 110. The base 120 further comprises a substrate layer 121 comprising a substrate layer face 122. The passivation layer 125 is configured covering at least part of the substrate layer face 122. Furthermore, the electrode face 111 protrudes from the substrate layer face 122.

[0096] The electrode 110 of the depicted embodiment comprises a coating 113 at the electrode face 111 comprising a plurality of recognition elements 112. The coating 113 is not necessarily made of a conductive material but is configured to allow an electron transfer between the electrode face 111 and the redox mediator 12, e.g., because of channels or pores in the coating 113. The coating 113 may further be configured for reducing or preventing fouling of the electrode face 111.

[0097] FIG. 1 may further depict a part of a sensor 100 comprising an array 200 of electrodes 110, such as depicted in FIG. 2. In embodiments, all electrodes 110 of the array 200 may be the same. Yet, in further embodiments at least one of the electrodes 110 of the array 200 has an electrode characteristic 119 being different from the electrode characteristic 119 of the other electrodes 110 of the array 200. Examples of the electrode characteristic 119 are depicted and may e.g. be the dimension d, especially the equivalent diameter, of the electrode face 111, the (type of) coating 113, the (type of) recognition element 112, and the conductive material of the electrode 110.

[0098] FIG. 2, especially in combination with FIG. 4, further depicts the difference between selectively binding of a predetermined particle 10 to the recognition element 12 thereby limiting the transfer T of the redox mediator 12 and a determination of another (random) particle 13 that does not bind to the recognition element 12, but still may block the electrode face 111 for the redox mediator 12 for a small period of time. At the top, at t=t.sub.0, no particle is present near the electrodes 110 of the array 200. At t=t.sub.1 a predetermined particle 10, depicted by the unshaded particle 10, is bound to the recognition element 112 of one of the sensors 100, and a random (not predetermined) particle 13, depicted as the shaded (hatched) particle 13, is located in front of another electrode 110 of the array 200. Because of the presence of both particles 10, 13, a transport T of the redox mediator 12 is limited to the respective electrode 110. Hence, when measuring the current I over time t (see FIG. 4), the current I may drop at t=t.sub.1, relative to the current I at t=t.sub.0. Yet a little later, at t=t.sub.2, the random particle 13 is diffused away again, but the predetermined particle 10 is still located at the electrode 110 because it is bound to the recognition element 12. Because of this difference, during measuring the electric current I through the respective electrodes 110 as a function of time t for the electrode 110 with the random particle 13 (top line in FIG. 4) only a current drop is observed over a small period, whereas for the electrode 110 with the predetermined particle 10 (bottom line in FIG. 4) a current drop over a much longer period, especially over the engagement period P is observed. The engagement period P is not necessarily a fixed period and may depend on many parameters as discussed before. Therefore, statistical analysis may help discriminating between a change in current I as a result of a bound particle 10 or e.g. as a result of a particle 13 that moves over the electrode face 111. Based on data analysis e.g. a minimal relevant period (a minimal engagement period P) may be determined that may be indicative for the bound (predetermined) particle 10.

[0099] The sensor 100 may be part of the device 1000 for analyzing a fluid 11 as depicted in FIG. 3. The device 1000 comprises an analyzing space 350 comprising the sensor 100, and the electrode face 111 is in fluid contact with the analyzing space 350. In the device 1000 in FIG. 3, a channel 300 defines the analyzing space 350 and the channel wall 310 of the channel 300 comprises the electrode 110. The channel 300 of depicted embodiment may be named a flow through channel, configured for providing the fluid 11 at a first end 301 of the channel 300 and having the fluid 11 exit at another end 309 of the channel 300. In FIG. 5 another type of flow through channel is depicted. The channel 300 comprises openings (through holes) 320 or, e.g., pores 320 configured in the wall 310 of the channel 300. It is noted in embodiments, the openings 320 may be configured in the wall 310 or the part of the wall 310 configured parallel to the longitudinal axis of the channel 300. Additionally or alternatively, the openings 320 may be configured in a part of the wall 310 of the channel 300, especially arranged perpendicular or traverse to the longitudinal channel axis 1000, as is depicted in FIG. 5. The sensor 100 may be configured in the opening(s) 320. In such embodiment, the fluid 11 including the particle 10 may flow through the opening 320, wherein the predetermined particle 10 may be facilitated to encounter the electrode 110 with the recognition element 112. Using such embodiment, it may be advantageous to continuously provide and remove fluid 11 to the channel 300, without maintaining the fluid in the analyzing space 350 during a discrete analyzing period. In further embodiments, the analyzing space 350 may also be configured at a closed end of a channel 300, wherein the fluid 11 may have to enter and leave the channel at the same location. In such embodiment, the characteristic dimension d may especially be the length (or the width) of the electrode 100, especially defining the exposure of the electrode 100 to the particle 10. The electrode 100 in the embodiment is especially rectangular. In further embodiments (not shown), the electrode 100 may be (a section of) a ring-shaped (cylindrical) (comprising an annulus), e.g. (a section of) a cylinder surrounding the opening 320. Such electrode may herein also be referred to as flow-through electrode.

[0100] FIG. 3 also depicts aspects of the system 2000 for analyzing the fluid 11. The system 2000 comprises the device 1000, a further electrode 17 functionally connected to electrode 110 (face 111), and an electric current measuring device 16 configured to measure the electric current I through the electrode 110, caused by a potential difference between the fluid 11 and the electrode face 111/electrode 110. The embodiment further comprises an electric power supply 15, configured for providing the potential difference between the further electrode 17 and the electrode face 111. The further electrode 17 is functionally connected to the fluid 11 in the analyzing space 350. The system 2000 further comprises a control system 1500 configured to execute the measuring routine (at least comprising measuring during an analyzing period an electric current I through the electrode 110 caused by a potential difference provided between the further electrode 17 and the electrode face 111). The control system 1500 is especially functionally connected to the electric current measuring device 16 and may further be connected to the electric power supply 15. For further automation, the control system 1500 may also be functionally connected to a transport device 400 that is functionally coupled to the channel 300 and that is especially configured to provide the fluid 11 to the analyzing space 350 and to remove the fluid 11 again from the analyzing space 350 (after having maintained the fluid 11 in the analyzing space 350 during the analyzing period). In the embodiment of FIG. 3, the system 2000 comprises the fluid transport device 400.

[0101] In embodiments, the system 2000 is configured for measuring only one sample of the fluid 11. Yet, in specific embodiments, as depicted in the figure, the system 2000 is configured for providing a series of volumes V of the fluid 11 to the channel 300, wherein the volumes V are separated from each other by a separation fluid 19. The system 2000 is further especially configured to successively execute the measuring routine for each volume V of the fluid 11 by flowing the series of volumes V of the fluid 11 through the analyzing space 350. As such, successively (i) each volume V is provided to the analyzing space 350 and again removed from the analyzing space 350 after having been maintained in the analyzing space 350 during the analyzing period. Hence, in such embodiment, the control system 1500 may be functionally connected to the fluid transport device 400, and the control system 1500 may especially be configured to sequentially execute the measuring routine for each volume V of the series of volumes V of the fluid 11.

[0102] The method of the invention may be applied in the system 2000 having the electric power supply 15 functionally connected to the further electrode 17 and the electrode face 111. Yet, the method may also be applied without the power supply 15. In the method, the fluid 11 comprising a redox mediator 12 is provided to the analyzing space 350. Successively, while maintaining the fluid 11 in the analyzing space 350, a measuring routine is executed during an analyzing period. And next, the fluid 11 is removed again from the analyzing space 350. In embodiments, a potential difference between the fluid 11 and the electrode face 111 may already intrinsically be present. However, during the measuring routine, also an external potential difference may be provided between the further electrode 17 and the electrode face 111 by the power supply 15. During the measuring routine, an electric current I through the electrode 110 may be measured as a function of time t. The results (based on a system 2000 comprising two electrodes 110) may for instance be like the graphs depicted in FIG. 4. That graph shows the presence of two particles 10, depicted by a change in the measured electric current I (a current drop) as a function of time t for both electrodes 110. Based on the duration of the two graphs it may be concluded that a predetermined particle 10 was present. Furthermore, in embodiments a concentration of the predetermined particle 10 in the fluid 11 may be determined based on a number of determined current drops lasting at least during a minimal relevant duration. In embodiments, multiple particles may be bound to the electrode, which may be shown by discrete steps (drops when binding a particle and increases when releasing a particle) in such graphs. Based on the amplitude of the change in the current I, in embodiments (also) a size of the particle 10 in the fluid 11 may be determined. The change in the current I especially depicts discrete (interaction) events, each event depicting the presence of a each (single) particle. In embodiments of the method, sequentially a series of volumes V of the fluid is provided to the analyzing space and analyzed.

[0103] Hence, the invention is especially based on a time-resolved electrochemical detection of discrete interaction events of the particle(s) on the electrode. In embodiments, the invention relates to functionalized electrodes.

[0104] An amperometric detection method may be used comprising electrolyzing a redox mediator (e.g., ferrocene) on the (nano)electrode, giving a constant base current. Particles (e.g., tdEVs) that are not electroactive, and are immobilized on the nanoelectrode surface, may block a mass transfer of the redox mediator onto the electrode, especially resulting in a decrease of (the amplitude of) this base current. The electrolysis of the redox mediator on the electrode may jointly generate an electrophoretic force pulling (especially negatively) charged particles onto the electrode, which may allow a low-concentration analyte detection. However, this electrophoretic force essentially applies to all charged entities in the solution. Consequently, a highly effective anti-fouling layer 113 may in embodiments be configured to minimize non-specific binding of (random) particles 13 onto the electrode surface 111. To this aim, the surface 111 of the electrodes 110 may be chemically modified with an anti-fouling layer (e.g., zwitterionic or poly(ethylene glycol) layers) to avoid non-specific binding. The anti-fouling layer may further e.g. be functionalized with tdEV specific antibodies (such as. anti-EpCAM), to facilitate specific binding.

[0105] Microliter samples containing tdEV, e.g. whole blood (unprocessed or e.g. diluted or concentrated) may be introduced in a simple microfluidic channel with dimensions similar to the electrode array. Sample size may be in the microliter or nanoliter range, or may even be tens or hundreds of picoliter. When a tdEV approaches the functionalized (nano)electrode surface, it may interact with antibodies and gets immobilized, which blocks mass transfer of the redox mediator to the electrode, resulting in an abrupt drop in the measured current (also indicated with the term “OFF signal”). A longer OFF signal indicates better specificity of the analyte entity to the probe. If the dissociation rate constant, k.sub.off(K.sub.D×/k.sub.on), is smaller, the tdEV tends to stay longer on the electrode, resulting in longer current blockage. Thus, the OFF signal time duration may give valuable information about the interaction strength of the analyte with the functionalized electrode surface. The amplitude of the current drop can also give information regarding the particle size. Since an interaction between e.g. non tdEV and the recognition element is not specific, non-tdEV may be dissociated faster on average, resulting in a shorter OFF signal period compared to the longer period of tdEVs. After break-up of antibody-antigen complex (in the order of seconds), a new sample can be injected. By introducing the sample at ˜1 μl per step (volume that may contain a few tens of EVs), the total volume may be screened within ˜15 minutes.

[0106] In embodiments, the invention may provide a sensor 100 for the label-free electrochemical detection of particles 10 such as tdEVs with high sensitivity and specificity, down to the single tdEV level. For specific detection, the electrode 110 may be functionalized with antibodies. One of the main challenges at such low concentrations, is the diffusion time of the particles, especially of biomarkers or biological particles, to the electrodes 110, which time for instance is relatively large for EVs. Therefore, in the invention advantage may be taken of the electrophoretic force. Owing to e.g. an oxidation reaction at the electrode, the particles 10 may be attracted onto the electrode 110, making the transport several orders faster. Other biomolecules may also be attracted to the electrode 110. Therefore, in embodiments, an antifouling layer 113 may be configured at the electrode 110 to assist in highly selective detection.

[0107] The terms “upstream” and “downstream” relate to an arrangement of items or features relative to the propagation of an element such as a particle or a fluid in a channel or light in a beam of light (during operation), wherein relative to a first position within the channel or beam, a second position in the channel or beam closer to an inlet (for the element or fluid) of the channel or respectively closer to a light generating means is “upstream”, and a third position within the channel further away from the inlet or respectively further away from the light generating means “downstream”.

[0108] The term “plurality” refers to two or more. Furthermore, the terms “a plurality of” and “a number of” may be used interchangeably. The terms “substantially” or “essentially” herein, and similar terms, will be understood by the person skilled in the art. The terms “substantially” or “essentially” may also include embodiments with “entirely”, “completely”, “all”, etc. Hence, in embodiments the adjective substantially or essentially may also be removed. Where applicable, the term “substantially” or the term “essentially” may also relate to 90% or higher, such as 95% or higher, especially 99% or higher, even more especially 99.5% or higher, including 100%. Moreover, the terms “about” and “approximately” may also relate to 90% or higher, such as 95% or higher, especially 99% or higher, even more especially 99.5% or higher, including 100%. For numerical values it is to be understood that the terms “substantially”, “essentially”, “about”, and “approximately” may also relate to the range of 90%-110%, such as 95%-105%, especially 99%-101% of the values(s) it refers to.

[0109] The term “comprise” includes also embodiments wherein the term “comprises” means “consists of”. The term “and/or” especially relates to one or more of the items mentioned before and after “and/or”. For instance, a phrase “item 1 and/or item 2” and similar phrases may relate to one or more of item 1 and item 2. The term “comprising” may in an embodiment refer to “consisting of” but may in another embodiment also refer to “containing at least the defined species and optionally one or more other species”.

[0110] Furthermore, the terms first, second, third and the like in the description and in the claims, are used for distinguishing between similar elements and not necessarily for describing a sequential or chronological order. It is to be understood that the terms so used are interchangeable under appropriate circumstances and that the embodiments of the invention described herein are capable of operation in other sequences than described or illustrated herein.

[0111] The term “further embodiment” and similar terms may refer to an embodiment comprising the features of the previously discussed embodiment, but may also refer to an alternative embodiment.

[0112] The devices, apparatus, or systems may herein amongst others be described during operation. As will be clear to the person skilled in the art, the invention is not limited to methods of operation, or devices, apparatus, or systems in operation.

[0113] It should be noted that the above-mentioned embodiments illustrate rather than limit the invention, and that those skilled in the art will be able to design many alternative embodiments without departing from the scope of the appended claims.

[0114] In the claims, any reference signs placed between parentheses shall not be construed as limiting the claim.

[0115] Use of the verb “to comprise” and its conjugations does not exclude the presence of elements or steps other than those stated in a claim. Unless the context clearly requires otherwise, throughout the description and the claims, the words “comprise”, “comprising”, “include”, “including”, “contain”, “containing” and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of “including, but not limited to”.

[0116] The article “a” or “an” preceding an element does not exclude the presence of a plurality of such elements.

[0117] The invention may be implemented by means of hardware comprising several distinct elements, and by means of a suitably programmed computer. In a device claim, or an apparatus claim, or a system claim, enumerating several means, several of these means may be embodied by one and the same item of hardware. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage.

[0118] The invention also provides a control system that may control the device, apparatus, or system, or that may execute the herein described method or process. Yet further, the invention also provides a computer program product, when running on a computer which is functionally coupled to or comprised by the device, apparatus, or system, controls one or more controllable elements of such device, apparatus, or system.

[0119] The invention further applies to a device, apparatus, or system comprising one or more of the characterizing features described in the description and/or shown in the attached drawings. The invention further pertains to a method or process comprising one or more of the characterizing features described in the description and/or shown in the attached drawings. Moreover, if a method or an embodiment of the method is described being executed in a device, apparatus, or system, it will be understood that the device, apparatus, or system is suitable for or configured for (executing) the method or the embodiment of the method respectively.

[0120] The various aspects discussed in this patent can be combined in order to provide additional advantages. Further, the person skilled in the art will understand that embodiments can be combined, and that also more than two embodiments can be combined. Furthermore, some of the features can form the basis for one or more divisional applications.