阅读说明：本技术 针对基于漫反射光谱法的牙龈炎检测的波长和带宽选择 (Wavelength and bandwidth selection for gingivitis detection based on diffuse reflectance spectroscopy ) 是由 O·T·J·A·弗梅尤伦 S·C·迪恩 L·P·H·舍费尔斯 E·J·D·贝尔纳-菲谢 A· 于 2019-09-09 设计创作，主要内容包括：一种用于检测组织炎症和特别是牙龈炎的系统(100)包括：光发射器(102)；具有在300μm-2000μm之间的源-检测器距离的漫反射光谱探头(107)；以及多个检测器(106、108、110、112),被配置为检测：小于615nm且具有第一带宽的第一波长；以及等于或大于615nm并且分别具有第二带宽和第三带宽的第二波长和第三波长,其中第二带宽或第三带宽大于第一带宽。(A system (100) for detecting tissue inflammation and in particular gingivitis comprising: a light emitter (102); a diffuse reflectance spectroscopy probe (107) having a source-detector distance between 300 μm-2000 μm; and a plurality of detectors (106, 108, 110, 112) configured to detect: a first wavelength less than 615nm and having a first bandwidth; and a second wavelength and a third wavelength equal to or greater than 615nm and having a second bandwidth and a third bandwidth, respectively, wherein the second bandwidth or the third bandwidth is greater than the first bandwidth.)

1. A system (100) for detecting inflammation in tissue (104), comprising:

a light emitter (102);

a diffuse reflectance spectroscopy probe (107) having a source-detector distance between 300 μm-2000 μm; and

a plurality of detectors (106, 108, 110, 112) configured to detect:

a first wavelength, less than 615nm and having a first bandwidth; and

at least a second wavelength and a third wavelength equal to or greater than 615nm and having a second bandwidth and a third bandwidth, respectively, wherein at least the second bandwidth or the third bandwidth is greater than the first bandwidth.

2. The system of claim 1, wherein the light emitter is configured to deliver light to gingival tissue and the plurality of detectors are configured to detect diffusely reflected light from the gingival tissue.

3. The system of claim 1, further comprising:

a spectral analysis unit (105) configured to receive and analyze the detected diffuse reflected light, the spectral analysis unit comprising a splitter configured to distribute the detected light over the plurality of detectors (106, 108, 110, 112).

4. The system of claim 3, further comprising:

a controller (113) comprising an inflammation detection unit (114), the controller being configured to receive an input for detecting tissue inflammation from each detector of the plurality of detectors.

5. The system of claim 1, wherein at least the second bandwidth or the third bandwidth is at least 50% greater than the first bandwidth.

6. The system of claim 1, wherein at least the second bandwidth or the third bandwidth is 100% greater than the first bandwidth.

7. The system of claim 1, wherein at least the second bandwidth or the third bandwidth is 100% -400% greater than the first bandwidth.

8. The system of claim 1, wherein the plurality of detectors are configured to detect at least a fourth wavelength having a bandwidth, at least the fourth wavelength being greater than 615nm, wherein a bandwidth of at least the fourth wavelength is greater than the first bandwidth, the second bandwidth, and the third bandwidth.

9. A system (200) for detecting tissue inflammation, comprising:

a plurality of light emitters (202, 204, 206, 208);

a diffuse reflectance spectroscopy probe (107) having a source-detector distance between 300 μm-2000 μm; and

a detector (210) configured to detect:

a first wavelength, less than 615nm and having a first bandwidth; and

at least a second wavelength and a third wavelength equal to or greater than 615nm and having a second bandwidth and a third bandwidth, respectively, wherein the second bandwidth or the third bandwidth is greater than the first bandwidth.

10. The system of claim 9, wherein the plurality of light emitters are configured to deliver light to gingival tissue and the detector is configured to detect diffusely reflected light from the gingival tissue.

11. The system of claim 9, wherein the plurality of light emitters are configured to deliver light to a light combiner (205) configured to combine the emitted light and deliver the combined light to gingival tissue.

12. The system of claim 9, wherein at least the second bandwidth or the third bandwidth is at least 50% greater than the first bandwidth.

13. The system of claim 9, wherein at least the second bandwidth or the third bandwidth is 100% greater than the first bandwidth.

14. The system of claim 9, wherein at least the second bandwidth or the third bandwidth is 100% -400% greater than the first bandwidth.

15. The system of claim 9, wherein the detector is configured to detect at least a fourth wavelength having a bandwidth, at least the fourth wavelength being greater than 615nm, wherein a bandwidth of at least the fourth wavelength is greater than the first bandwidth, the second bandwidth, and the third bandwidth.

Technical Field

The present disclosure is generally directed to an oral care system for detecting the presence of tissue inflammation and particularly gingivitis using optimized wavelength selection for spectroscopic analysis.

Background

Currently, gingivitis detection using Diffuse Reflectance Spectroscopy (DRS) is performed using small, angled probes that are configured around one or more optical fibers that transmit light, due to the limited space in the oral cavity. Such a small probe can be used to measure the interproximal areas where gingivitis usually originates. However, such small probes, when in contact, exert a great pressure on the tissue, thereby pushing blood aside, thus disrupting the DRS measurement of blood properties. Therefore, DRS measurements are preferably performed in a non-contact mode, and the required non-contact mode results in detection of specularly reflected light in addition to the required diffuse reflection component. Since diffuse reflected light (i.e., light propagating through tissue) is highly attenuated, these specular components become relatively large.

Due to the different chromophores in the gingival tissue, the spectral properties of the diffuse reflected light differ from the spectral properties of the source light: the effect of hemoglobin absorption is evident, as is the scattering component, which is the component that enables diffuse reflection (i.e. without it light will not be diffusely reflected/returned), and the absorption component is due to melanin, which is one of the main absorbing chromophores in the gingival tissue. Other major chromophores are carotene and hemoglobin: especially oxidized and deoxygenated.

In principle, the optical properties of all tissues can be extracted from the measured DRS spectra. This can be done using an inverse model or using a look-up table (LUT) generated using a monte carlo simulation. However, these methods are not suitable for consumer products due to the required processing power and time, especially the required number of sampling wavelengths.

To extract hemoglobin concentration from the DRS spectrum, one or more isoabsorption wavelengths are typically used, for example, isoabsorption wavelengths at about 584nm and 800 nm. However, illumination LEDs typically do not generate Near Infrared (NIR) wavelengths because such wavelengths are not visible. Thus, the output at >780nm for a normally illuminated LED is extremely low or zero.

Accordingly, there is a continuing need in the art for inventive oral care systems and methods to enable the use of a minimum number of wavelengths and commercially available Phosphor Converted (PC) Light Emitting Diodes (LEDs) to accurately detect tissue inflammation, particularly gingivitis.

Disclosure of Invention

The present disclosure relates to inventive systems and methods for gingivitis detection based on diffuse reflectance spectroscopy using illuminated light emitting diodes. Various embodiments and implementations herein are directed to a gingivitis detection system that includes an oral care device using commercially available Light Emitting Diodes (LEDs) and an optimized minimum number of wavelengths, which still enables accurate gingivitis detection. The oral care device includes one or more light emitters using commercially available illumination LEDs, a DRS probe, and a detector using an optimized minimum number of wavelengths.

In general, in one aspect, a system for detecting tissue inflammation is provided. The system comprises: a light emitter; a diffuse reflectance spectroscopy probe having a source-detector distance between 300 μm-2000 μm; and a plurality of detectors configured to detect: a first wavelength less than 615nm and having a first bandwidth; and a second wavelength and a third wavelength equal to or greater than 615nm and having a second bandwidth and a third bandwidth, respectively, wherein the second bandwidth or the third bandwidth is greater than the first bandwidth.

In various embodiments, the light emitter is configured to deliver light to the gingival tissue and the plurality of detectors are configured to detect diffusely reflected light from the gingival tissue.

In one embodiment, the system further comprises a spectral analysis unit configured to receive and analyze the detected diffuse reflected light, the spectral analysis unit comprising a splitter configured to distribute the detected light over a plurality of detectors.

In various embodiments, the system further comprises a controller having an inflammation detection unit, the controller configured to receive an input for detecting tissue inflammation from each of the plurality of detectors.

In one embodiment, the second bandwidth or the third bandwidth is at least 50% greater than the first bandwidth.

In one embodiment, the second bandwidth or the third bandwidth is 100% greater than the first bandwidth.

In one embodiment, the second bandwidth or the third bandwidth is 100% -400% greater than the first bandwidth.

In one embodiment, the second bandwidth and the third bandwidth are greater than the first bandwidth.

In general, in another aspect, a system for detecting tissue inflammation is provided. The system comprises a plurality of light emitters; a diffuse reflectance spectroscopy probe having a source-detector distance between 300 μm-2000 μm; and a detector configured to detect: a first wavelength less than 615nm and having a first bandwidth; and a second wavelength and a third wavelength equal to or greater than 615nm and having a second bandwidth and a third bandwidth, respectively, wherein the second bandwidth or the third bandwidth is greater than the first bandwidth.

In various embodiments, the plurality of light emitters are configured to transmit light to the gingival tissue, and the detector is configured to detect diffusely reflected light from the gingival tissue.

In one embodiment, the plurality of light emitters is configured to deliver light to a light combiner configured to combine the emitted light and deliver the combined light to gingival tissue.

In one embodiment, the second bandwidth or the third bandwidth is at least 50% greater than the first bandwidth.

In one embodiment, the second bandwidth or the third bandwidth is 100% greater than the first bandwidth.

In one embodiment, the second bandwidth or the third bandwidth is 100% -400% greater than the first bandwidth.

In one embodiment, the second bandwidth and the third bandwidth are greater than the first bandwidth.

As used herein for purposes of this disclosure, the term "controller" is used generally to describe various devices relating to the operation of an imaging device, system or method. The controller can be implemented in numerous ways (e.g., such as with dedicated hardware) to perform the various functions discussed herein. A "processor" is one example of a controller employing one or more microprocessors that may be programmed using software (e.g., microcode) to perform the various functions discussed herein. The controller may be implemented with or without a processor, and may also be implemented as a combination of dedicated hardware to perform some functions and a processor (e.g., one or more programmed microprocessors and associated circuitry) to perform other functions. Examples of controller components that may be employed in various embodiments of the present disclosure include, but are not limited to, conventional microprocessors, Application Specific Integrated Circuits (ASICs), and Field Programmable Gate Arrays (FPGAs).

It should be understood that all combinations of the foregoing concepts and additional concepts discussed in greater detail below (provided that such concepts do not contradict each other) are considered a part of the inventive subject matter disclosed herein. In particular, all combinations of claimed subject matter appearing at the end of this disclosure are considered part of the inventive subject matter disclosed herein.

These and other aspects of the invention will be apparent from and elucidated with reference to the embodiments described hereinafter.

Drawings

In the drawings, like reference numerals generally refer to like parts throughout the different views. Moreover, the drawings are not necessarily to scale, emphasis instead generally being placed upon illustrating the principles of the invention.

Fig. 1 is a graph showing a diffuse reflection spectrum measured from a healthy gum.

Fig. 2 is a graph showing the absorption spectra of oxidized and deoxygenated hemoglobin.

Fig. 3 is a diagram showing wavelength dependent sampling depths for different source-detector distances using a 200 μm fiber.

Fig. 4 is a schematic diagram of a system for detecting tissue inflammation, according to an embodiment.

Fig. 5 is a schematic diagram of a system for detecting tissue inflammation, according to an embodiment.

FIG. 6 is a schematic diagram of a diffuse reflectance spectroscopy probe according to an embodiment.

Detailed Description

The present disclosure describes various embodiments of systems and methods for improving detection of tissue inflammation and particularly gingivitis using commercially available Light Emitting Diodes (LEDs) and Diffuse Reflectance Spectroscopy (DRS). More generally, applicants have recognized and appreciated that it would be beneficial to provide optimized wavelength selection for DRS-based gingivitis detection using wavelengths within the visible spectrum. Accordingly, the systems and methods described or otherwise contemplated herein provide an oral care device configured to obtain measurements of gingival tissue. The oral care device includes a light emitter using commercially available illumination LEDs, a DRS probe, and a detector for spectral analysis.

The embodiments and implementations disclosed or otherwise envisioned herein may be used with any suitable oral care device. Examples of suitable oral care devices include toothbrushes, flossing devices, oral irrigators, tongue cleaners or other personal care devices. However, the present disclosure is not limited to these oral care devices, and thus the disclosure and embodiments disclosed herein may encompass any oral care device.

Gingivitis is an inflammation of the gums characterized by swelling, edema and redness of the gums, mostly caused by plaque build-up in the gingival sulcus (pocket). Such gum disease is often found in hard-to-reach areas, such as interproximal areas between and around the posterior teeth.

In fact, it is estimated that 50% -70% of the adult population is affected by gingivitis. However, consumers are often unable to detect early signs of gingivitis. Normally, gingivitis develops until the individual finds the gums bleeding easily when brushing their teeth. Therefore, gingivitis can only be detected when the disease has progressed and is apparently difficult to treat. Although improving oral hygiene readily reverses gingivitis, it is important to maintain good oral health and to find the gingivitis as soon as possible, as gingivitis can spread to irreversible periodontitis.

Gingivitis can be visually diagnosed by detecting redness and swelling of the gums. (see RR. Lobene et al, "A modified gingival index for use in clinical trials", Clin. Prev. Dent.8:3-6, (1986) describing non-contact gingivitis index based on redness and inflammation of the gums). However, this has a limited sensitivity and is highly dependent on the color rendering index of the light source used. Thus, modern phosphor converted LEDs may have a lower CRI, resulting in poor visual judgment.

Fig. 1 shows an example of a Diffuse Reflectance Spectroscopy (DRS) spectrum measured from a healthy gum 1, showing the measured values including hemoglobin (blood) and melanin at the bottom (dashed) line of the graph. The top line of the graph also shows a scatter component 2, the scatter component 2 being the component that enables diffuse reflection (i.e. if there is no scatter, no light is diffusely reflected/returned). Line 3 (middle line in the graph) shows the absorption component due to melanin 3, which is one of the main absorbing chromophores in the gingival tissue. The hemoglobin dominated region is best suited to determine DRS signal content originating from blood.

The effect of hemoglobin absorption is apparent when looking at fig. 2. Other major absorbing chromophores are hemoglobin: in particular oxyhemoglobin (HbO2) and deoxyhemoglobin (Hb). The absorption spectra of these two chromophores are clearly shown in figure 2.

Redness of the gum is an acute inflammatory response to bacterial biofilm toxins from plaque in the gingival sulcus or along the gum line area. This inflammatory response causes vasodilation in the short term, relaxing smooth muscle cells in the arterioles and widening the blood vessels, thereby increasing the blood supply to the capillary bed. This can cause the gums to turn red and the temperature to rise slightly, making measurement difficult. Additionally, the capillaries become more permeable, which results in increased fluid loss from the capillaries to the interstitial spaces, resulting in swollen gums. If the inflammation is chronic, additional reddening occurs by increasing vascularization of the tissue, where additional capillaries can be formed to address the additional blood demand of the tissue.

These factors enable detection of gingivitis based on Diffuse Reflectance Spectroscopy (DRS). DRS is an optical method involving, for example, emitting white light toward a target and analyzing the spectral properties of the diffusely reflected (rather than specularly reflected) light. The DRS probe configuration includes: a source fiber adjacent to a detection fiber; a central source fiber surrounded by a plurality of detection fibers; or a single optical fiber that acts as both a source and a detector. An important property of the probe is the source-detection separation, as it affects the sampling depth of the probe (i.e., the depth of the measured light source in the tissue). For gingivitis detection, the average diffuse reflectance spectrum sampling depth is required to be greater than 250 μm. To obtain such an average, a minimum source-detector distance of about 300 μm is required depending on the wavelength. However, such a sampling depth cannot be achieved using blue light due to the high absorption of hemoglobin. Fig. 3 shows wavelength dependent sampling depths (250 to 1000 μm) for different source-detector distances. Furthermore, all gums are not identical, and in some individuals the sampling depth may need to be deeper, thus different wavelength(s) and/or probe design may be needed.

A particular goal with certain embodiments of the present disclosure is to utilize diffuse reflectance spectral signals to achieve accurate gingivitis detection using a minimum number of wavelengths and commercially available Phosphor Converted (PC) Light Emitting Diodes (LEDs).

Referring to fig. 4, in one embodiment, fig. 4 is a tissue inflammation detection system 100. The system 100 includes a light emitter 102 that uses commercially available illumination LEDs. The inventive systems described herein use commercially available illumination LEDs because they are inexpensive and efficient. Thus, the useful wavelength range is typically from 500nm to 780 nm. The system 100 also includes a Diffuse Reflectance Spectroscopy (DRS) probe 107 (shown in FIG. 6), the Diffuse Reflectance Spectroscopy (DRS) probe 107 having a source-detector distance d between 300 μm-2000 μm. The source fiber 101 is configured to be provided with light from a light source, such as a phosphor converted LED, and to transmit such light to the tissue 104. The detector fiber 103 is configured to pick up diffusely reflected light from the tissue 104 and transmit the light to the spectral analysis unit 105. As shown in fig. 6, DRS probe 107 is comprised of one source fiber 101 and one detection fiber 103, however, other suitable configurations are contemplated according to embodiments described herein. For example, in embodiments comprising more than one detector fiber, the outputs from each fiber should be combined together and a single resulting signal should be transmitted into the spectral analysis unit 105 where the signal is distributed over the wavelength sensitive detectors.

According to one embodiment, the spectral analysis unit 105 is a splitter configured to distribute the received diffuse reflected light over n wavelength sensitive photodetectors (e.g., band pass filter + photodiodes) 106, 108, 110, and 112. The spectral analysis unit 105 may include a fused fiber splitter, a dispersion splitter (e.g., a prism or grating), a light guide manifold, or any suitable alternative. The detector 106 is configured to be sensitive to λ 1 with a particular full width at half maximum (FWHM 1). The detector 108 is configured to be sensitive to λ 2 with FWHM 2. The detector 110 is configured to be sensitive to λ 3 with FWHM 3. The detector 112 is configured to be sensitive to λ 4 with FWHM 4. The output of each wavelength sensitive photodetector is input to a controller 113 having a inflammation detection unit 114. The inflammation detection unit 114 may include an algorithm that may be based on any mathematical equation of these inputs. According to one embodiment, a spectrometer or tunable filter may also be used as the spectral detector. However, these are currently considered too expensive and/or cumbersome for consumer products.

According to an exemplary embodiment including four wavelengths, the detector 106 is sensitive to λ 1, where λ 1 ═ 575nm-585nm, preferably 580nm, and FWHM1 ═ 10 nm; the detector 108 is sensitive to λ 2, where λ 2 ═ 589nm-599nm, preferably 594nm, and FWHM2 ═ 10 nm; the detector 110 is sensitive to λ 3, where λ 3 is 670-680 nm, preferably 675nm, and FWHM3 ≧ 10 nm; and the detector 112 is sensitive to λ 4, where λ 4 ═ 695nm-705nm, preferably 700nm, and FWHM4 ≧ 15nm, preferably 20nm-50 nm.

According to another exemplary embodiment including five wavelengths, the detector 106 is sensitive to λ 1, where λ 1 ═ 575nm-585nm, preferably 580nm, and FWHM1 ═ 10 nm; the detector 108 is sensitive to λ 2, where λ 2 ═ 589nm-599nm, preferably 594nm, and FWHM2 ═ 10 nm; the detector 110 is sensitive to λ 3, where λ 3 is 670-680 nm, preferably 675nm, and FWHM3 ≧ 10 nm; the detector 112 is sensitive to λ 4, where λ 4 ═ 689nm-699nm, preferably 694nm, and FWHM4 ≧ 10 nm; and an additional detector (not shown) is sensitive to λ 5, where λ 5 ≧ 715nm-725nm, preferably 720nm, and FWHM5 ≧ 15nm, preferably 20nm-50 nm.

According to another exemplary embodiment including five wavelengths, the detector 106 is sensitive to λ 1, where λ 1 ═ 570nm-580nm, preferably 575nm, and FWHM1 ═ 10 nm; the detector 108 is sensitive to λ 2, where λ 2 ═ 625nm-635nm, preferably 630nm, and FWHM2 ═ 10 nm; the detector 110 is sensitive to λ 3, where λ 3 ≧ 669nm-679nm, preferably 674nm, and FWHM3 ≧ 10 nm; the detector 112 is sensitive to λ 4, where λ 4 ≧ 737nm-747nm, preferably 742nm, and FWHM4 ≧ 10 nm; and an additional detector (not shown) is sensitive to λ 5, where λ 5 is 765nm-775nm, preferably 770nm, and FWHM5 ≧ 15nm, preferably 20 nm.

Any of the wavelength-specific selections described above may be incorporated in embodiments where spectral diversity is provided by a wavelength-specific emitter rather than a wavelength-sensitive detector. As shown in fig. 5, an inflammation detection system 200 is shown, the inflammation detection system 200 comprising four wavelength-specific emitters 202, 204, 206 and 208, the four wavelength-specific emitters 202, 204, 206 and 208 being configured to be provided with light from the LEDs having desired spectral and/or modified properties by applying, for example, band-pass filters. The transmitter 202 is associated with λ 1 and FWHM 1. The transmitter 204 is associated with λ 2 and FWHM 2. Emitter 206 is associated with λ 3 and FWHM 3. The transmitter 208 is associated with λ 4 and FWHM 4. Similar to system 100, system 200 may include additional transmitters associated with additional wavelengths and bandwidths. Light from the four wavelength specific emitters is passed to an optical combiner 205 or any suitable alternative. Similar to system 100, system 200 includes a Diffuse Reflectance Spectroscopy (DRS) probe, such as that shown in FIG. 6, having a source-detector distance between 300 μm and 2000 μm. The detector fiber 103 is configured to pick up diffusely reflected light from the tissue 204 and transmit the light to a controller 213 having an inflammation detection unit 214. The inflammation detection unit 214 may include an algorithm that may be based on any mathematical equation of these inputs.

Advantageously, the present system enables accurate gingivitis detection using a minimum number of wavelengths and commercially available Phosphor Converted (PC) Light Emitting Diodes (LEDs).

All definitions, as defined and used herein, should be understood to control dictionary definitions, definitions in documents incorporated by reference, and/or ordinary meanings of the defined terms.

The indefinite articles "a" and "an" used in the specification and claims are to be understood as meaning "at least one" unless explicitly indicated to the contrary.

The phrase "and/or" as used herein in the specification and claims should be understood to mean "one or two" of the elements so combined, that is, the elements are present in combination in some cases and separately in other cases. The use of "and/or" listed elements should be construed in the same way, i.e., "one or more" of the elements so connected. In addition to elements explicitly identified by the "and/or" clause, other elements may optionally be present, whether related or unrelated to those elements specifically identified.

As used herein in the specification and claims, "or" should be understood to have the same meaning as "and/or" as defined above. For example, when an item in a list is separated, "or" and/or "should be interpreted as being inclusive, i.e., including at least one of a plurality of elements or a list of elements, but also including more than one, as well as including (optionally) other unlisted items. To the contrary, terms such as "only one" or "exactly one," or "consisting of," when used in the claims, are intended to mean including only one of the plurality or list of elements. In general, the term "or" as used herein should be interpreted as an exclusive alternative (i.e., "one or the other, but not both") only when preceded by an exclusive term (such as "one of," "only one of," or "exactly one of").

As used herein in the specification and claims, the phrase "at least one," when referring to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each element specifically listed within the list of elements, and not excluding any combinations of elements in the list of elements. This definition also allows that, in addition to elements specifically identified within the list of elements to which the phrase "at least one" refers, other elements may optionally be present, whether related or unrelated to those specifically identified elements.

It is to be understood that, unless explicitly stated to the contrary, in any methods claimed herein, including a plurality of steps or acts, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited.

In the claims, as well as in the specification above, all transitional phrases such as "comprising," "carrying," "having," "containing," "involving," "holding," "consisting of," and the like are to be understood to be open-ended, i.e., to mean including but not limited to. The transition phrases "consisting of …" and "consisting essentially of …" alone should be closed or semi-closed transition phrases, respectively.

While several inventive embodiments have been described and illustrated herein, one of ordinary skill in the art will readily envision a variety of other means and/or structures for performing the function and/or obtaining the results and/or one or more of the advantages described herein, and each of such variations and/or modifications is deemed to be within the scope of the inventive embodiments described herein. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and/or configurations will depend upon the specific application or applications for which the teachings of the present invention is/are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, embodiments of the invention may be practiced otherwise than as specifically described and claimed. Inventive embodiments of the present disclosure are directed to each individual feature, system, article, material, kit, and/or method described herein. Additionally, any combination comprising two or more such features, systems, articles, materials, kits, and/or methods, if such features, systems, articles, materials, kits, and/or methods are not mutually inconsistent, is included within the scope of the present disclosure.