NON-INVASIVE ION RESPONSIVE URINE SENSOR

Abstract

Provided is a semiconductor-based ion-responsive urine sensor (IRUS) capable of detecting an analyte in urine by a non-invasive method. When a urine sensor according to an aspect is used, it is possible to diagnose a patient accurately in a comfortable condition and to use the urine sensor for point-of-care (POC) diagnosis.

Claims

1. A sensor for urinalysis, the sensor comprising: an electrochemical sensing unit for detecting an analyte in urine and a signal processor for amplifying signals generated from the sensing unit, the signal processor comprising an ion-sensitive field-effect transistor (ISFET) electrically connected to the sensing unit, wherein the sensing unit is separable from the signal processor, the ISFET comprises a lower gate electrode; a lower insulating layer on the lower gate electrode; a source and a drain on the lower insulating layer and separated from each other; a channel layer on the lower insulating layer and between the source and the drain; an upper insulating layer on the source, the drain, and the channel layer; and an upper gate electrode on the upper insulating layer, and an electrode of the sensing unit is electrically connected to the upper gate electrode of the ISFET.

2. The sensor of claim 1 further comprising a connecting portion for connecting the sensing unit to the signal processor.

3. The sensor of claim 1 further comprising a display unit for displaying results.

4. The sensor of claim 1, wherein the sensing unit comprises: a substrate; a working electrode and a reference electrode both on the substrate; immobilized analyte binding materials on the working electrode; and a test cell for accommodating the electrodes, the analyte binding materials, and an analyte.

5. The sensor of claim 4, wherein the sensing unit comprises a probe coupled to the analyte binding materials via the analyte in a sample and having a negative charge or a positive charge, wherein signals of the analyte are amplified by capacitive coupling of the probe to electrons in the channel layer of the ISFET.

6. The sensor of claim 4, wherein the analyte binding materials comprise deoxyribonucleic acids (DNA), ribonucleic acids (RNA), nucleotides, nucleosides, proteins, polypeptides, peptides, amino acids, carbohydrates, enzymes, antibodies, antigens, receptors, substrates, ligands, membranes, or a combination thereof.

7. The sensor of claim 4, wherein the analyte binding materials are antibodies that specifically bind to prostate-specific antigen (PSA), Annexin A3, or prostate-specific membrane antigen (PSMA), which are prostate cancer markers.

8. The sensor of claim 5, wherein the probe comprises metal nanoparticles.

9. The sensor of claim 1, wherein a thickness of an equivalent oxide layer of the upper insulating layer is smaller than a thickness of an equivalent oxide layer of the lower insulating layer.

10. The sensor of claim 1, wherein a thickness of the channel layer is 10 nanometers (nm) or less.

11. The sensor of claim 1, wherein the channel layer comprises any one selected from the group consisting of an oxide semiconductor, an organic semiconductor, polycrystalline silicon, and monocrystalline silicon.

12. The sensor of claim 1, wherein the sensor comprises a plurality of the sensing units and a plurality of the ISFETs, wherein the plurality of the sensing units are electrically connected to the plurality of the ISFETs, respectively.

13. The sensor of claim 12, wherein, in the plurality of the ISFETs, a plurality of sources are commonly grounded, a plurality of upper gate electrodes are commonly grounded, and a common voltage is applied to a plurality of lower gate electrodes.

14. The sensor of claim 12, wherein each of the plurality of sensing units independently comprises different immobilized analyte binding materials.

15. The sensor of claim 1, wherein the signal processor further comprises a calculation module electrically connected to the ISFET, the calculation module determining an amount of the analyte in urine from a potential difference measured by the ISFET.

16. The sensor of claim 15, wherein the calculation module determines an amount of a prostate cancer marker in the urine according to a graph shown in FIG. 7A, 7B, or 7C.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0033] These and/or other aspects will become apparent and more readily appreciated from the following description of the embodiments, taken in conjunction with the accompanying drawings in which:

[0034] FIG. 1 is a schematic diagram illustrating a sensor according to an embodiment;

[0035] FIG. 2 is a cross-sectional diagram illustrating a sensing unit of a sensor according to an embodiment;

[0036] FIG. 3 is a cross-sectional diagram illustrating a dual-gate ion-sensitive field-effect transistor (ISFET) of a sensor according to an embodiment;

[0037] FIG. 4 is a schematic diagram illustrating a sensor using a probe, according to an embodiment;

[0038] FIG. 5 is a diagram illustrating a multiplexing detection system of a sensor according to an embodiment;

[0039] FIG. 6 is a graph of reference voltage (volts, V) versus time (minutes), illustrating the result of an evaluation of stability of a sensor according to an embodiment;

[0040] FIG. 7A is a graph of threshold voltage difference (ΔVth, V) versus analyte molar concentration (molar, M), illustrating the result of measurements of a potential difference according to a known concentration of prostate-specific antigen (PSA), the measurements obtained by a sensor according to an embodiment;

[0041] FIG. 7B is a graph of ΔVth (V) versus analyte molar concentration (M), illustrating the result of measurements of a potential difference according to a known concentration of Annexin A3 (ANX A3), the measurements obtained by a sensor according to an embodiment;

[0042] FIG. 7C is a graph of ΔVth (V) versus analyte molar concentration (M), illustrating the result of measurements of a potential difference according to a known concentration of prostate-specific membrane antigen (PSMA), the measurements obtained by a sensor according to an embodiment;

[0043] FIG. 8 is a series of graphs of ΔVth (V) versus analyte molar concentration (M), illustrating the results of measurements of PSA, ANX A3, and PSMA in patients' urine, the measurements obtained by a sensor according to an embodiment;

[0044] FIG. 9 is a histogram of sensing sigma (voltage difference, ΔV) according to methods of collecting urine from a patient, illustrating the result of measurements of ANX A3, the measurements obtained by a sensor according to an embodiment; and

[0045] FIG. 10 shows tables illustrating the results of measurements of PSA, ANX A3, and PSMA in patients' urine, the measurements obtained by a sensor according to an embodiment.

DETAILED DESCRIPTION

[0046] Reference will now be made in detail to embodiments, examples of which are illustrated in the accompanying drawings, wherein like reference numerals refer to like elements throughout. In this regard, the present embodiments may have different forms and should not be construed as being limited to the descriptions set forth herein. Accordingly, the embodiments are merely described below, by referring to the figures, to explain aspects of the present description.

[0047] Most of the terms used herein are general terms that have been widely used in the technical art to which the present invention pertains. However, some of the terms used herein may be created reflecting intentions of technicians in this art, precedents, or new technologies. Also, some of the terms used herein may be arbitrarily chosen by the present applicant. In this case, these terms are defined in detail below. Accordingly, the specific terms used herein should be understood based on the unique meanings thereof and the whole context of the present invention.

[0048] Throughout the specification, it will be understood that when an element is referred to as being “connected” to another element, it may be “directly connected” to the other element or “electrically connected” to the other element with intervening elements therebetween. The terms, such as “including” or “having”, are intended to indicate the existence of the elements disclosed in the specification, and are not intended to preclude the possibility that one or more other elements may exist or may be added. Also, the terms “unit” or “module” as used herein should be understood as a unit that processes at least one function or operation and that may be embodied in a hardware manner, a software manner, or a combination of the hardware manner and the software manner.

[0049] The terms “configured” or “included” as used herein should not be construed to include all of various elements or steps described in the specification, and should be construed to not include some of the various elements or steps or to further include additional elements or steps.

[0050] The following description of the embodiments should not be construed as limiting the scope of the present invention, and modifications that those of skilled in the art can readily infer from the present invention should be construed as being within the scope of the present invention. Hereinafter, exemplary embodiments for descriptive sense only will be described in detail with reference to the accompanying drawings.

[0051] FIG. 1 is a schematic diagram illustrating a sensor according to an embodiment. Referring to FIG. 1, a sensor 100 according to an embodiment may include a sensing unit 110 for detecting an analyte in urine and an ion-sensitive field-effect transistor (ISFET) 130 electrically connected to the sensing unit 110. In an embodiment, the sensor 100 may include the electrochemical sensing unit 110 for detecting an analyte in urine and a signal processor 130 for amplifying signals generated from the sensing unit 110, wherein the signal processor 130 may include the ISFET 130 electrically connected to the sensing unit 110, the sensing unit 110 may be separable from the signal processor 130, and an electrode of the sensing unit 110 may be electrically connected to an upper gate electrode of the ISFET 130. In another embodiment, the sensor 100 may further include a connecting portion 120 for connecting the sensing unit 110 to the signal processor 130. The connecting portion 120 may be configured to be separable from the sensing unit 110 and, for example, the connecting portion 120 have the form of a plug. In still another embodiment, the sensor 100 may further include a display unit 140 for displaying results obtained by the sensor 100. The display unit 140 may further include a display showing the results and a frame including at least one control interface (e.g., a power button, scroll wheel, or the like). The frame may include a slot for into which a sensor may be inserted. The frame may include a circuit, and thus, when the frame is provided with a sample, the frame may apply an electrical potential or current to an electrode of the sensor 100. A suitable circuit that may be used in the meter may be, for example, an appropriate voltage meter capable of measuring the potential across the electrode. A switch may also be provided which may be open when the electrical potential is measured or closed for measuring the current.

[0052] In another embodiment, the signal processor 130 may further include a calculation module (not shown), which may be electrically connected to the ISFET 130, for determining the amount of the analyte in urine from a potential difference measured by the ISFET 130. The calculation module may determine an analyte. The calculation module may determine the analyte by measuring a potential difference according to a known concentration of the analyte. For example, the calculation module may determine the amount of a prostate cancer marker in urine according to a graph shown in FIG. 7A, 7B, or 7C. In still another embodiment, the sensor 100 may include a communicator (not shown) which may provide the sensor 100 with the capability to transmit/receive information to/from an external server or a terminal unit. The communicator may employ a wired or wireless communicator.

[0053] FIG. 2 is a cross-sectional diagram illustrating a sensing unit of a sensor according to an embodiment. Referring to FIG. 2, the sensing unit 110 may include a substrate 111; a working electrode 112 and a reference electrode 115 on the substrate; immobilized analyte binding materials on the working electrode 112; and a test cell 114 for accommodating the electrodes 112 and 115, the analyte binding materials, and an analyte. The sensing unit 110 may be disposable. For example, the substrate may be include a material selected from the group consisting of silicon, glass, metal, plastic, and ceramic. The electrodes 112 and 115 may include, for example, silver, silver epoxy, palladium, copper, gold, platinum, silver/silver chloride, silver/silver ion, or mercury/mercuric oxide. The sensing unit 110 may also include an insulating electrode 113 provided on the substrate 111 or on the working electrode 112. The insulating electrode 113 may include a natural or artificially formed oxide film. Examples of the oxide film include Si.sub.xO.sub.y, H.sub.xfO.sub.y, Al.sub.xO.sub.y, Ta.sub.xO.sub.y, and Ti.sub.xO.sub.y (wherein x and y may each be an integer from 1 to 5). The oxide film may be formed by a known method. For example, an oxide may be deposited on a substrate by liquid phase deposition, evaporation, or sputtering. The analyte binding materials may include deoxyribonucleic acids (DNA), ribonucleic acids (RNA), nucleotides, nucleosides, proteins, polypeptides, peptides, amino acids, carbohydrates, enzymes, antibodies, antigens, receptors, substrates, ligands, membranes, or a combination thereof. For example, the analyte binding materials may be antibodies that specifically bind to prostate-specific antigen (PSA), Annexin A3 (ANX A3), or prostate-specific membrane antigen (PSMA), which are prostate cancer markers. Examples of the analyte may include an antigen such as a peptide (e.g., a hormone), a heptene, a protein (e.g., an enzyme), a carbohydrate, a protein, a drug, a pesticide, a microorganism, an antibody, and a nucleic acid that may participate in a sequence-specific hybridization reaction with a complementary sequence. For example, the analyte may include PSA, Annexin A3, or PSMA, which are prostate cancer markers. When the sensing unit 110 is provided with a sample through the test cell 114 accommodating the electrodes 112 and 115, the analyte binding materials, and an analyte, an analyte present in the sample may bind to the analyte binding materials to thereby cause a chemical potential gradient in the test cell 114.

[0054] FIG. 3 is a cross-sectional diagram illustrating a dual-gate ISFET of a sensor according to an embodiment. Referring to FIG. 3, regarding the dual-gate ISFET, the ISFET 130 may include a lower gate electrode 131; a lower insulating layer 132 on the lower gate electrode 131; a source 134 and a drain 133 on the lower insulating layer 132 and separated from each other; a channel layer 135 on the lower insulating layer 132 and between the source 134 and the drain 133; an upper insulating layer 136 on the source 134, the drain 133, and the channel layer 135; and an upper gate electrode 137 on the upper insulating layer 136. Due to super capacitive coupling generated in the dual-gate ISFET 130 including the channel layer 135, a small surface potential voltage difference that occurs in the sensing unit may significantly amplify a threshold voltage variation of a lower field-effect transistor. In this regard, an amplification factor may be determined according to a thickness of the lower insulating layer 132, a thickness of the channel layer 135, a thickness of the upper insulating layer 136. As the thickness of the lower insulating layer 132 increases, and as the thickness of the upper insulating layer 136 and the thickness of the channel layer 135 decreases, the amplification factor may become larger. The channel layer 135 may be an ultra-thin film layer having a thickness, for example, of 10 nanometers (nm) or less, 9 nm or less, 8 nm or less, 7 nm or less, 6 nm or less, 5 nm or less, or 4 nm or less. The channel layer 135 may include any one selected from the group consisting of an oxide semiconductor, an organic semiconductor, polycrystalline silicon, and monocrystalline silicon. Also, in the sensor, a thickness of an equivalent oxide layer of the upper insulating layer 136 may be less than a thickness of an equivalent oxide layer of the lower insulating layer 132. For example, the thickness of an equivalent oxide layer of the upper insulating layer 136 may be about 25 nm or less, and the thickness of an equivalent oxide layer of the lower insulating layer 132 may be about 50 nm or greater. When the thickness of an equivalent oxide layer of the upper insulating layer 136 is less than the thickness of an equivalent oxide layer of the lower insulating layer 132, amplification of signal sensitivity may occur. A dual-gate ISFET 130 according to an embodiment may include both an upper field-effect transistor including an upper insulating layer 136 and a lower field-effect transistor including a lower insulating layer 132 in one device. Depending on respective modes of operation, each gate of the dual-gate ISFET may independently be operated as an upper gate or a lower gate. When upper and lower gates of a device are used simultaneously, capacitive coupling may be observed due to the structural specificity of the dual-gate structure, and thus, the correlation between upper and lower field-effect transistors may be established. In a dual operation mode, a lower gate may be used as a main gate. Thus, a transistor according to an embodiment may be operated in a dual-gate mode.

[0055] FIG. 4 is a schematic diagram illustrating a sensor using a probe according to an embodiment. Referring to FIG. 4, the sensing unit may further include a probe 30 coupled to analyte binding materials 10 via an analyte in a sample and having a negative charge or a positive charge. Signals of the analyte 20 may be amplified by capacitive coupling of the probe 30 to electrons in the channel layer 135 of the transistor.

[0056] FIG. 5 is a diagram illustrating a multiplexing detection system of a sensor according to an embodiment. Referring to FIG. 5, regarding a multiplexing detection system of a sensor, the sensor may include a plurality of transistors 130 and a plurality of sensing units 110 for detecting an analyte. The sensor may include the plurality of sensing units 110 and the plurality of ISFETs 130, wherein the plurality of sensing units 110 may respectively be electrically connected to the plurality of ISFETs 130. In the plurality of transistors 130, a plurality of sources may commonly be grounded, a plurality of upper-gate electrodes may commonly be grounded, and a common voltage may be applied to a plurality of lower-gate electrodes. In addition, a plurality of drains in the plurality of transistors 130 may have a parallel structure. The plurality of sensing units 110 may each independently include different immobilized analyte binding materials. The plurality of transistors 130 may sense the same or different analyte signals from the plurality of sensing units 110, amplify the signals, and output the signals through a semiconductor parameter analyzer.

[0057] Example Manufacture of Sensor and Analysis of Characteristics

[0058] (1) Manufacture of Sensor for Urinalysis

[0059] (1.1) Manufacture of Dual-Gate ISFET

[0060] A silicon-on-insulator (SOI) substrate having resistivity of about 10 ohm-centimeter (Ω-cm) to 20 Ωcm was prepared, a thickness of silicon as a lower-gate electrode was about 107 nm, and a thickness of a buried SiO.sub.2 oxide film as a lower insulating film was about 224 nm. After performing standard RCA cleaning, the upper silicon was etched with about 2.38 percent by weight (wt %) of a tetramethylammonium hydroxide (TMAH) solution to form an ultra-thin film, and a channel region was formed by photolithography. In this case, a length, a width, and a thickness of the channel were respectively about 20 micrometers (μm), 20 μm, and 4.3 nm. Subsequently, n-type polycrystalline silicon was deposited using a chemical vapor deposition (CVD) apparatus to form a source and a drain. Then, an upper insulating layer was formed by oxidizing silicon dioxide of a thickness of about 23 nm on the source and the drain. Next, to form an upper gate electrode, an Al thin layer having a thickness of about 150 nm was deposited on the upper insulating layer using an electron beam (e-beam) evaporator. Next, to remove defects and improve an interfacial state therebetween, heat treatment was performed at a temperature of about 450° C. in a gas atmosphere including N.sub.2 and H.sub.2, thereby completing the manufacture of a dual-gate ISFET.

[0061] (1.2) Manufacture of an Electrochemical Sensing Unit

[0062] In order to prepare an electrochemical sensing unit, SiO.sub.2 having a thickness of about 300 nm was grown to form p-type silicon which was used as a substrate. After standard RCA cleaning was performed thereon, a working electrode of titanium (Ti) was deposited on the substrate at a thickness of about 100 nm using an e-beam evaporator to measure the electrical potential difference. Next, as an insulating electrode, a SnO.sub.2 film was deposited on the Ti layer to a thickness of about 45 nm using an RF sputtering method with power of about 50 watts (W). Thereafter, a sputtering process was performed under an Ar gas atmosphere with a flow rate of about 20 standard cubic centimeters (sccm) and a pressure of about 3 milliTorr (mTorr). Next, a test cell for accommodating a sample was prepared from polydimethylsiloxane (PDMS) and attached onto the insulating electrode to prepare a sensing unit. In addition, a silver/silver chloride electrode was used as a reference electrode.

[0063] (1.3) Manufacture of Sensor

[0064] A sensor for urinalysis was prepared by connecting the upper gate electrode of the transistor prepared in (1.1) to the working electrode of the sensing unit prepared in (1.2) by a plug-in method.

[0065] (2) Analysis of Characteristics of Sensor

[0066] (2.1) Evaluation of Sensor Stability

[0067] In order to evaluate stability of the sensor prepared in (1.3), a signal was measured while alternately applying human urine and a pH 10 solution.

[0068] Specifically, human urine was obtained from Asan Medical Center, Seoul, Korea. The pH 10 solution was prepared by adding NaOH to distilled water while using a pH meter. First, a human urine sample was injected into the sensor and reacted for 10 minutes, and then the human urine sample was removed therefrom. Subsequently, the pH 10 solution was injected thereto for 10 minutes of reaction, and after the pH 10 solution was removed therefrom, the human urine sample was injected again thereto for 10 minutes of reaction. This process was repeated so as to analyze how the signals of the sensor varied. The evaluation results are shown in FIG. 6.

[0069] FIG. 6 is a graph illustrating the result of an evaluation of stability of the sensor according to an embodiment.

[0070] As shown in FIG. 6, it can be seen that even though different solutions were alternately injected into the sensor according to an embodiment, the reference voltage measured was consistent for each solution. Accordingly, the sensor according to an embodiment was found to measure electrical signals stably.

[0071] (2.2) Detection of Prostate Cancer Markers PSA, ANX A3, PSMA

[0072] To detect prostate cancer markers PSA, ANX A3, and PSMA (i.e., analyte), respective analyte binding materials such as antibodies for each analyte of PSA (available from Biorbyt), ANX A3 (available from Abnova), and PSMA (available from Abcam) were immobilized. An EDC/Sulfo-NHS reaction was performed to form —COOH groups on a surface of the insulating electrode of the sensor, and thus, —NH.sub.2 groups of the antibodies were bound thereto such that the antibodies were immobilized. Urine samples from healthy adults and patients clinically diagnosed with prostate cancer were obtained from Asan Medical Center, Seoul, Korea.

[0073] First, the minimum signal of the sensor was normalized using a phosphate buffered saline (PBS) solution. In an experimental group, to stabilize the initial electrical signal, the PBS solution was injected into the sensing unit having an immobilized antibody against a specific prostate cancer marker. Thereafter, a urine sample of an actual clinical patient was injected into the sensing unit and reacted for 20 minutes and, subsequently, measurement was performed under a urine condition. In the control group, the signal of the urine itself was measured, which was performed to remove the background noise from the experimental group results. After the initial signal was stabilized by injecting the PBS solution into the sensing unit in which an antibody against a specific prostate cancer marker was not immobilized, the same urine used in the experimental group was injected and reacted for 20 minutes. Thereafter, measurement was performed. The final result was obtained by removing the control group signal from the experimental group signal.

[0074] To obtain a reference result that is used to quantitatively analyze an amount of an analyte in a sample, artificial urine containing a known concentration of the analyte was used (the known concentration: 1.5 L of distilled water (D.I), 36.4 g of urea, 15.0 g of sodium chloride, 9.0 g of potassium chloride, 9.6 g of sodium phosphate, 4.0 g of creatinine, and 100 mg of albumin). In detail, to measure a potential difference, artificial urine containing PSA, ANEX A3, or PSMA in a range of 10.sup.−15 g/mL to 10.sup.−9 g/mL was injected to a sensor having an immobilized antibody corresponding to the selected marker. The measurement results are shown in FIGS. 7A to 7C.

[0075] Each of FIGS. 7A to 7C show a graph illustrating the results of measurements of potential differences according to a known concentration of PSA, ANX A3, and PSMA, respectively, the measurements obtained by using a sensor according to an embodiment. Using the results of FIGS. 7A to 7C as a reference, the amounts of PSA, ANX A3, and PMSA may be quantitatively measured in urine of an actual clinical patient.

[0076] Next, an analyte, that is, PSA, ANX A3, or PMSA, was quantitatively detected in the urine of actual prostate cancer patients. Using the results of FIGS. 7A to 7C as a reference, each analyte (antigen) was quantitatively detected for two patients. The results are shown in FIG. 8.

[0077] FIG. 8 shows graphs illustrating the results of measurements of PSA, ANX A3, and PSMA in patients' urine, the measurements obtained by using a sensor according to an embodiment.

[0078] As shown in FIG. 8, the prostate cancer markers PSA, ANX A3, and PMSA were found to be quantitatively detected in urine of actual clinical patients by using a sensor according to an embodiment. As a result, it was found that diagnosis of diseases including prostate cancer is possible by a non-invasive urine test using a sensor according to an embodiment.

[0079] In general, even urine of the same patient may have different amounts of an analyte in a sample depending on a method of urine collection; in some cases, a marker may not even be detected depending on a method of urine collection. In order to confirm the effectiveness of urinalysis using a sensor according to an embodiment, irrespective of a method of urine sample collection, urine samples from each patient were collected through pre-operative self-voiding, through prostate massage, and through catheter during surgery, and then tested. Quantitative detection of ANX A3 in urine was performed, and urine samples from two healthy adults were used as a control group. The measurement results are shown in FIG. 9.

[0080] FIG. 9 is a histogram illustrating the results of measurement of ANX A3 by using a sensor according to an embodiment.

[0081] As shown in FIG. 9, the sensor according to an embodiment, irrespective of a method of urine sample collection, was found to accurately detect an amount of an analyte in the urine sample. Therefore, a sensor according to an embodiment may be used not only for early diagnosis of diseases such as prostate cancer, but also for monitoring the prognosis of a patient.

[0082] Next, the amounts of prostate cancer markers PSA, PSMA, and ANX A3 in urine samples of 22 prostate cancer patients were quantitatively detected in the same manner as described above. The measurement results are shown in FIG. 10.

[0083] FIG. 10 shows tables illustrating the results of measurements of PSA, ANX A3, and PSMA in patients' urine, the measurements obtained by using a sensor according to an embodiment.

[0084] As shown in FIG. 10, the amount of an analyte in urine samples were quantitatively measured using a sensor according to an embodiment. As a result, it can be seen that urinalysis may be performed accurately and easily by using a sensor according to an embodiment.

[0085] As apparent from the foregoing description, when a sensor according to an aspect is used to analyze urine for diagnosis and testing of a disease, it is possible to minimize patient's stress, clinical stress, and work burden, to accurately diagnose the patient in a comfortable condition, and to use the sensor for point-of-care (POC) diagnosis.

[0086] It should be understood that embodiments described herein should be considered in a descriptive sense only and not for purposes of limitation. Descriptions of features or aspects within each embodiment should typically be considered as available for other similar features or aspects in other embodiments.

[0087] While one or more embodiments have been described with reference to the figures, it will be understood by those of ordinary skill in the art that various changes in form and details may be made therein without departing from the spirit and scope of the disclosure as defined by the following claims.