WO2025237757A1

WO2025237757A1 - System for evaluating tissue health

Info

Publication number: WO2025237757A1
Application number: PCT/EP2025/062434
Authority: WO
Inventors: Elvira Johanna Maria Paulussen; Loes Henrica Martina VAN DE KAMP-PEETERS; Matthias Born; Pieter HORSTMAN; Monique STOFFELS
Original assignee: Koninklijke Philips NV
Current assignee: Koninklijke Philips NV
Priority date: 2024-05-14
Filing date: 2025-05-07
Publication date: 2025-11-20
Anticipated expiration: 2026-11-14

Abstract

A system and method for evaluating health of a tissue is disclosed. The system includes a light source adapted to transmit light having an excitation wavelength to the tissue. The system also includes a device comprising a material comprising fluorescing dots (Fdots) disposed therein. The Fdots are adapted to fluoresce at an emission wavelength when the light having the excitation wavelength is incident thereon, and to terminate fluorescing in a presence of nitric oxide (NO). The system also includes a memory that stores instructions; and a processor that executes the instructions. When executed by the processor, the instructions cause the system to: adjust an output of the light source at the excitation wavelength to treat the tissue with the light at the emission wavelength based on a location of the NO and/or a time when the NO is present.

Description

SYSTEM FOR EVALUATING TISSUE HEALTH

Background

[0001] Light therapy is being investigated to treat oral tissue. For example, certain wavelengths of light have been found to inhibit the growth of oral biofilms, thereby reducing dental plaque in a subject. Additionally, certain wavelengths of light have been found to reduce the inflammation response of human gingival cells. Accordingly, application of such light can reduce gingival inflammation (periodontitis).

[0002] While light therapy shows promise for both reducing the growth of undesired films and treating inflammation of gum tissue, certain materials useful in generating light of the desired wavelengths are not safe for use in internal applications.

[0003] What is needed, therefore, is a device adapted to treat tissue that is safe for internal use.

SUMMARY

[0004] In accordance with a representative embodiment, a system for evaluating health of a tissue is disclosed. The system comprises: a light source adapted to transmit light having an excitation wavelength to the tissue. The system also comprises a device comprising a material comprising fluorescing dots (Fdots) disposed therein. The Fdots are adapted to fluoresce at an emission wavelength when the light having the excitation wavelength is incident thereon, and to terminate fluorescing in a presence of nitric oxide (NO). The system also comprises a memory that stores instructions; and a processor that executes the instructions. When executed by the processor, the instructions cause the system to: adjust an output of the light source at the excitation wavelength to treat the tissue with the light at the emission wavelength based on a location of the NO and/or a time when the NO is present.

[0005] In accordance with another representative embodiment, a method of evaluating a tissue is disclosed. The method comprises: transmitting light having an excitation wavelength to the tissue, wherein the excitation wavelength is in the optical spectrum; providing a device comprising a material comprising fluorescing dots (Fdots) disposed therein. The Fdots are adapted to fluoresce at an emission wavelength with the light having the excitation wavelength is incident thereon, and to terminate fluorescing in a presence of nitric oxide (NO). The method also comprises determining a location of the tissue where and/or a time when the NO is present; and adjusting the transmitting the light at the excitation wavelength to treat the tissue with the light at the emission wavelength based on the location and/or the time.

BRIEF DESCRIPTION OF THE DRAWINGS

[0006] The example embodiments are best understood from the following detailed description when read with the accompanying drawing figures. It is emphasized that the various features are not necessarily drawn to scale. In fact, the dimensions may be arbitrarily increased or decreased for clarity of discussion. Wherever applicable and practical, like reference numerals refer to like elements.

[0007] Fig. 1 is a conceptual view showing sources of inflammation, resulting in production of NO, and resulting adverse effects.

[0008] Fig. 2A is a perspective view of a mouthpiece comprising a material comprising fluorescing dots (Fdots) in accordance with a representative embodiment.

[0009] Fig. 2B is a graph showing Fdot size versus emission wavelength.

[0010] Fig. 3 is a graph showing onset of NO production in the presence of blue light having a wavelength of 450 nm versus time.

[0011] Fig. 4 is a simplified block diagram of a system for evaluating and/or treating oral tissue using an inventive mouthpiece, in accordance with a representative embodiment.

[0012] Fig. 5A is a conceptual view of a system for evaluating and/or treating oral tissue using an inventive device in accordance with a representative embodiment.

[0013] Fig. 5B is a flow chart of method for evaluating and/or treating oral tissue using an inventive device in accordance with a representative embodiment.

[0014] Fig. 6A is a conceptual view of a system for evaluating and/or treating oral tissue using an inventive device in accordance with a representative embodiment.

[0015] Fig. 6B is a flow chart of method for evaluating and/or treating oral tissue using an inventive device in accordance with a representative embodiment. DETAILED DESCRIPTION

[0016] In the following detailed description, for the purposes of explanation and not limitation, representative embodiments disclosing specific details are set forth in order to provide a thorough understanding of embodiments according to the present teachings. However, other embodiments consistent with the present disclosure that depart from specific details disclosed herein remain within the scope of the appended claims. Descriptions of known systems, devices, materials, methods of operation and methods of manufacture may be omitted so as to avoid obscuring the description of the representative embodiments. Nonetheless, systems, devices, materials and methods that are within the purview of one of ordinary skill in the art are within the scope of the present teachings and may be used in accordance with the representative embodiments. It is to be understood that the terminology used herein is for purposes of describing particular embodiments only and is not intended to be limiting. Definitions and explanations for terms herein are in addition to the technical and scientific meanings of the terms as commonly understood and accepted in the technical field of the present teachings.

[0017] It will be understood that, although the terms first, second, third etc. may be used herein to describe various elements or components, these elements or components should not be limited by these terms. These terms are only used to distinguish one element or component from another element or component. Thus, a first element or component discussed below could be termed a second element or component without departing from the teachings of the inventive concept. [0018] As used in the specification and appended claims, the singular forms of terms ‘a’, ‘an’ and ‘the’ are intended to include both singular and plural forms, unless the context clearly dictates otherwise. Additionally, the terms "comprises", and/or "comprising," and/or similar terms when used in this specification, specify the presence of stated features, elements, and/or components, but do not preclude the presence or addition of one or more other features, elements, components, and/or groups thereof. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.

[0019] Unless otherwise noted, when an element or component is said to be “connected to”, or “coupled to” another element or component, it will be understood that the element or component can be directly connected or coupled to the other element or component, or intervening elements or components may be present. That is, these and similar terms encompass cases where one or more intermediate elements or components may be employed to connect two elements or components. However, when an element or component is said to be “directly connected” to another element or component, this encompasses only cases where the two elements or components are connected or disposed immediately adjacent to each other without any intermediate or intervening elements or components.

[0020] As described herein, a system for detecting the presence of RNS or ROS emanating from tissue is described. As will become clearer as the present description continues, many of the representative embodiments are directed to detection of NO. It is emphasized that this is merely illustrative, and other RNS and ROS components are contemplated for detection by the device of the various representative embodiments. Notably, variation of the presently described embodiments to more generally detect RNS or ROS component, including the selection of material for the Fdots may be needed.

[0021] In certain representative embodiments, the system is adapted to treat regions where inflammation exists in the tissue. As such, by the present teachings, the system is adapted to not only detect the presence of inflammation in tissue, but also is adapted to provide treatment to the inflamed area and/or detect the effect of the treatment. As described more fully herein, the devices of the various representative embodiments comprise fluorescent dot (Fdots) including so-called polymer dots (Pdots) and quantum dots (Qdots). The materials selected for the Fdots is adapted to emit fluorescent light when light of a certain wavelength is incident on the Fdots. The light that causes the fluorescent emission from the Fdots is referred to herein as an excitation light having an excitation wavelength. The light emitted from the Fdots during fluorescence is referred to herein as emission light and has an emission wavelength. Notably, the excitation wavelength is selected to provide treatment to inflamed tissue. Moreover, in certain representative embodiments, Fdots are selected so that in the presence of RNS including NO, and ROS, the fluorescent emission terminates. These Fdots may be referred to herein as “turn-off’ Fdots. In other representative embodiment, the Fdots are selected to fluoresce in the presence of RNS or ROS. These Fdots may be referred to herein as “turn-on” Fdots. As such, according to various representative embodiments, the systems of the various representative embodiments function to detect RNS and ROS, which, as described more fully below, is indicative of such inflammation.

[0022] In certain representative embodiments, this detection provides not only the location of inflammation, but also the time of the detection. In other representative embodiments the emission light is used not only to detect RNS or ROS, but also to treat the inflamed tissue. Moreover, based on the detection of inflamed tissue, the output of the light source used for treating the inflamed tissue may be altered to better treat the inflammation. In addition, and as described more fully below, the Fdots may be used to monitor the progress of treatment of a condition. Specifically, as the treated tissue heals, the inflammation is reduced, and the production of NO decreases. In a representative embodiment, as the presence of NO decreases, and the fluorescent emission caused by the excitation light source increases providing a measure of the progress of the treatment. Accordingly, and among other improvements to the field of medical diagnosis and treatment, the present teachings enable the detection and monitoring of inflammation in tissue including internal and external tissue, monitoring of the progress of a treatment, and adaptation of treatment of tissue based on the monitoring.

[0023] Fig. 1 is a conceptual view showing sources of inflammation 101 in a region of tissue, resulting in production of NO, and resulting adverse effects. Notably, in many of the representative embodiments described herein, the tissue that is inflamed is gingivival tissue (e.g., gums), and the indicator of inflammation is NO. However, this is merely for ease of description. More generally, the tissue is not limited to the gums, and other tissue, such as skin, which is susceptible to inflammation, emits RNS or ROS when inflamed, and is beneficially treated with light are contemplated. In other applications, the progress of treatment of tissue can be monitored using Fdots of various representative embodiments. As described more fully below, as the treated area heals, inflammation is reduced, and the emission of NO from the inflamed tissue is accordingly reduced. When the Fdots turn off in the presence of NO, reduced NO caused by the healing of tissue results in an increase in fluorescent emission, and indicates the progress of healing by a particular treatment. Alternatively, when the Fdots turn on (fluoresce) in the presence of NO, and the NO is reduced as a result of the healing of tissue. In this case, a decrease in fluorescent emission is realized.

[0024] As shown in Fig. 1, the inflammation 101, which can result in different layers of tissue, may be caused by infection 102 or injury 104. The sources of injury are diverse, including but not limited to exposure to UVA radiation, UV-induced erythema, wound healing or other injury. As a result, the inflamed layers of skin can release NO. NO exists in vivo as a dissolved free radical gas comprising an unpaired electron on the Nitrogen that can inflict cellular damage under prolonged inflammation. For example, NO can cause DNA damage 106, protein modification 108 and apoptosis 110, as well as other possible deleterious effects on the body. As such, excessive NO levels during inflammation can lead to detrimental effects like protein nitration, DNA damage and programmed cell death.

[0025] The presence of NO in tissue signals inflammation, and as described more fully below, is detected not only to determine the location and/or time of inflammation, but also to determine the location and dose of treatment of the inflamed tissue useful given the condition of the tissue. Moreover, because light treatment of the tissue can result in the production of NO, the devices of the various representative embodiments may be used to monitor the light treatment in real-time. For example, the devices of the various representative embodiments can be used to determine when the light treatment is too intense and/or applied for too long. In this case, the light treatment can be reduced to avoid tissue damage.

[0026] Fig. 2A is a perspective view of a mouthpiece 201 comprising a material 204 comprising fluorescing dots (Fdots) 202 in accordance with a representative embodiment. It is again emphasized that the use of Fdots in a mouthpiece for oral use is merely illustrative, and applications to other tissue are contemplated with appropriate safeguards as described more fully below.

[0027] Once detected, the areas of the tissue where inflammation exists can be treated with light of a particular wavelength useful in treating the underlying condition. Alternatively, or additionally, and again, as described more fully below, the Fdots may be used to monitor the progress of treatment of a condition. Specifically, as the treated tissue heals, the inflammation is reduced, and the production of NO decreases. As the presence of NO decreases, and the fluorescent emission caused by the excitation light source increases providing a measure of the progress of the treatment. Accordingly, in oral applications Fdot signal response to light- induced NO production provides a measure of light treatment status of the oral tissue (e.g., gum) that can be used to determine both the treatment and the progress of the treatment. In such way, severe inflammation (e.g., periodontitis) in the mouth can effectively be treated locally and the light treatment can be adapted and targeted to aim for better safety and effectiveness in a personalized way.

[0028] Another beneficial aspect of the various representative embodiments includes the improved ability to monitor the temperature of the tissue. Notably, in certain known medical measurements, the temperature is used to identify areas where tissue damage is imminent. These known methods provide only a course measure, with a threshold of 43 °C being the benchmark above which damage can occur. It is noted that one source of inflammation can be the applied radiation (light) used in the treatment of the tissue. Beneficially, the devices and systems of the various representative embodiments are adapted to provide a more accurate measure of the change in the temperature of the tissue undergoing treatment and more promptly. Specifically, by monitoring the rise in the temperature, the applied light dose could be altered before the temperature reaches a dangerous level. So, in addition to monitoring existing inflammation and adapting the light treatment using devices and systems of various representative embodiments, the present teachings contemplate monitoring the change in temperature caused by the treatment, and adjusting the treatment to avoid deleterious impact on the tissue.

[0029] As alluded to above, the Fdots 202 are selected from a number of materials adapted to cause fluorescent emission at a particular wavelength, and to terminate emission in the presence of a particular RNS or ROS. As will be appreciated, depending on the material chosen for the Fdots, the “termination” of emission may vary. For example, in some representative embodiments, emission stops completely and the Fdots function as an on-off switch. In other representative embodiments, the emission reduces gradually or partly for example by including Fdots comprising different materials that can impact the spectra, sensitivity and specificity to provide a gradual output signal from the Fdots. More generally, the degree of termination of fluorescent emission is related linearly or non-linearly to the concentration of NO. Notably, the correlation between output (emission) signal and NO concentration may not always be initially obvious, and certain transformations and calculations may be required to get to relation between fluorescent emission signal and NO concentration.

[0030] Moreover, in other representative embodiments, depending on the material chosen, the Fdots are chosen to fluoresce in the presence of RNS or ROS. Again, depending on the material chosen for the Fdots, the initiation of emission will vary. For example, in some representative embodiments, emission starts immediately and the Fdots function as an on-off switch. In other representative embodiments, the emission starts gradually. More generally, the degree of commencement of fluorescent emission may also be related to the concentration of NO. As such, by the selection of materials used for the Fdots, NO concentration can be made to gradually change fluorescence (emission) intensity, but also other factors including reaction time may play a role. In many applications such as described more fully below, the excitation wavelength or the emission can be selected for treating tissue with light therapy.

[0031] In certain applications, the Fdots comprise Qdots. Quantum dots are nanoscale crystals with optical and electric properties. They can emit or absorb specific wavelengths. Qdot biosensors are developed as fluorescence sensor for NO. The sensor emits fluorescent light when excited by visible (e.g., blue) light and turns off fluorescence when NO is present meaning the Qdots will code for a visual signal response in the presence of NO. Like other types of Fdots, Qdots comprise a material having a valence band and a conduction band separated by an energy gap that depends on the nature and the size of the material. After the absorption of light having a particular wavelength/energy, the electrons are excited to the conduction band, leaving a hole in the valence band. The photo-generated electron-hole pair is known as an exciton, which, upon recombination, gives rise to the fluorescence emission.

[0032] One drawback to certain known Qdot materials is their inclusion of heavy metals. Heavy metals can be toxic, and as such may not be useful in applications to internal tissues (e.g., the gums). As such, in certain applications, Qdots materials comprising heavy metals cannot be used. However, in other applications, the material 204 is selected to encapsulate the Qdot material comprising the heavy metal in a biocompatible material (e.g., polymer or silicone) that are beneficially permeable to NO to render its use safe in internal applications.

[0033] Qdots comprising heavy metals may, however, be used in applications that are not internal, such as the skin. In such applications, the Qdots usefully provide an indication of the presence and concentration of NO, which in turn is indicative of inflammation caused by a skin disease or injury.

[0034] Qdots that do not comprise heavy metals are also contemplated. These Qdots are generally not toxic and therefore may be used in internal applications, such as mouthpiece 201. Qdots contemplated for use in such internal applications comprise, but are not limited to Silicon Qdots, Carbon Qdots and Graphene Qdots. These materials are nanocrystals embedded in a polymer matrix (e.g., material 204)

[0035] Silicon Qdots lend greater biocompatibility and provide certain optical properties, such as long-lived excited states, large Stokes shift and tunable luminescence that can be beneficial in certain applications.

[0036] Carbon Qdots also lend greater biocompatibility due to their nontoxicity, while providing comparatively greater optical absorptivity, chemical stability and comparatively easy synthesis. Like Silicon Qdots, the fluorescence of Carbon Qdots is more efficient than many other materials, and thus lends itself to improved detection of NO, treatment of inflamed tissue, and monitoring of the progress of treatment of tissue.

[0037] Graphene Qdots when properly treated can also be used in vivo. Graphene Qdots comprise a layer of graphene and are chemically and physically comparatively stable. Graphene Qdots exhibit fluorescence emission across a comparatively large spectral range, including UV radiation, visible light an infrared (IR) radiation.

[0038] Just by way of illustration and not limitation, the Qdots may comprise a fluorescent molecularly engineered material comprising with iron(III) dithiocarbamates; Cadmium Selenium-Zinc Sulfur (CdSe-ZnS) nanocrystals; and surface bound tris(/V- (dithiocarboxy)sarcosine)iron(III).

[0039] By way of illustration and not limitation, “turn-on” Qdots may comprise CdSe-ZnS nanocrystals as fluorophores and surface bound tris(N-(dithiocarboxy)sarcosine)iron(III) as reactive centers for NO.

[0040] In certain representative embodiments, both Qdots that emit light in the presence of NO and Qdots that terminate emission in the presence of NO are contemplated. These Qdots are referred to as “turn-on/turn-off ’ Qdots. By way of illustration and not limitation, the following materials are contemplated for use as “turn-on/turn-off’ Qdots useful in the detection of NO: Fe⁺³; group II materials (alkyl metals, metal oxides or organic salts) with the use of an inorganic shell (e.g., ZnS); and group VI materials (Se, S and Te) with the use of an inorganic shell (e.g., ZnS).

[0041] As described more fully below, once detected, the areas of the skin where inflammation exists can be treated with light of a particular wavelength useful in treating the underlying condition. Alternatively, or additionally, and again, as described more fully below, the Fdots may be used to monitor the progress of treatment of a condition. Specifically, as the treated tissue heals, the inflammation is reduced, and the resulting production of NO decreases. As the presence of NO decreases, when the Fdots are “turn-off’ Fdots, the fluorescent emission caused by the excitation light source increases. By contrast, when “turn-on” Fdots are used, as the treated tissue heals, the inflammation is reduced, and the production of NO decreases. As the presence of NO decreases, when the Fdots are “turn-on”, the fluorescent emission caused by the excitation light source decreases. Moreover, in certain representative embodiments such as described below in connection with Figs. 5A-5B, the Fdots emit light of one wavelength when light of an excitation wavelength is incident thereon, and emits light of a different wavelength in the presence of NO.

[0042] In accordance with other representative embodiments, the Fdots 202 are polymer dots (Pdots). Just by way of illustration, sub fluorophore groups (groups such as C = O, C = N, N = O) are contemplated for use as Pdots in accordance with various representative embodiments. Unlike Qdots that may comprise toxic materials, Pdots comprise organic nanoparticles (e.g., semiconducting polymer nanoparticles (SPNs)) assembled from polymer chains with - conjugated systems. Pdots may consist of hydrophobic semiconducting polymers with a volume or weight fraction more than 50% and a diameter generally less than 50 nm, sometimes the particles size can be less than 30 nm. Pdots have shown characteristics of large absorption cross section, high brightness, good photostability, low toxicity. Moreover, Pdots provide comparatively high fluorescence brightness under both one photon and two-photon stimulation, and therefore are useful in biosensing and treatment applications such as those described in connection with various representative embodiments described herein.

[0043] As described more fully below, certain Pdots emit fluorescent light when excited by visible blue or violet light and turn off fluorescence when nitric oxide (NO) is present. Moreover, certain Pdots emit fluorescent light when excited by visible blue or violet light and emit fluorescent light of a different wavelength (e.g., near infra-red (NIR) when nitric oxide (NO) is present. As such, Pdots will code for a visual signal response in the presence of NO. [0044] As described more fully below, once detected, the areas of the skin where inflammation exists can be treated with light of a particular wavelength useful in treating the underlying condition. Alternatively, or additionally, and again, as described more fully below, the Pdots may be used to monitor the progress of treatment of a condition. Specifically, as the treated tissue heals, the inflammation is reduced, and the production of NO decreases. As the presence of NO decreases, the fluorescent emission caused by the excitation light source increases. Alternatively, in certain other representative embodiments, when the presence of NO decreases, the fluorescent emission decreases.

[0045] Fig. 2B is a graph showing Fdot size versus emission wavelength. As alluded to above, different Fdot materials have different excitation and emission wavelengths. Moreover, the size of the Fdots varies depending on the material selected. As shown in Fig 2B, the emission wavelength increases with increasing Fdot size (volume). As described more fully below, in certain applications it is useful to select the wavelength used for treatment, and/or the excitation wavelength, and/or the emission wavelength. As such, by the present teachings, the size of the Fdot as a function of emission wavelength is useful. Just by way of illustration, when the same treatment wavelength for tissue is assumed, the size of the Fdots used in the representative embodiments of Figs. 5A-5B are smaller than the size of the Fdots used in the representative embodiments of Figs. 6A-6B.

[0046] Furthermore, and as will be appreciated from a review of Fig. 2B, the size of the Fdots contemplated for use in accordance with devices of the various representative embodiments are comparatively small. The Fdot sensors size lend easily for adaptation into mouthpieces or other devices for medical diagnosis and treatment. As such, the level of response can be collected by integrated sensors that are small enough to be captured by the mouthpiece comprising a plurality of Fdots is improved compared to certain known devices and systems.

[0047] Fig. 3 is a graph showing onset of NO production in the presence of blue light having a wavelength of 450 nm versus time. Specifically, the blue light is applied to the tissue for a period of time, and the resultant peaks of NO are detected. First curve 302, second curve 304, third curve 306 and fourth curve 308 are measures of the concentration of NO at times of sampling with the fourth curve 308 indicative of the cessation of illumination has stopped, and shows that NO is still released from skin for a time after illumination is terminated.

Consequently, as described more fully below, light-induced NO production can serve as a ‘memory system’ of treated positions of tissue and according to various representative embodiments, light treatment can be adapted and targeted to aim for better safety and effectiveness.

[0048] Fig. 4 is a simplified block diagram of a system 400 for evaluating and/or treating oral tissue using an inventive mouthpiece, in accordance with a representative embodiment. Various aspects and details of presently described system may be common to those described in connection with representative embodiments above, and may be used in systems of representative embodiments described below. These common aspects and details may not be repeated in order to avoid obscuring the presently described representative embodiments.

[0049] The system 400 comprises a mouthpiece 401, which comprises a plurality of Fdots disposed in a suitable material. It is emphasized the mouthpiece 401 is merely an illustrative device, and other devices are contemplated for use in connection with the system 400. Moreover, these alternative devices are contemplated for both internal and external use with appropriate materials and devices based on the application. Just by way of illustration, and as noted below, instead of the mouthpiece 401, the device may be adapted to monitor and/or treat skin conditions that are responsive to light treatment including, for example inflammatory skin diseases or injuries such as overexposure to UV radiation.

[0050] The system 400 comprises a detector 402. As will be appreciated, the detector 402 is selected to detect the presence of RNS or ROS. In certain embodiments, the detector 402 is adapted to detect the presence of NO. In certain embodiments, the detector 402 is adapted to determine the location and time of the presence of NO. As described more fully below in connection with various representative embodiments, different types of detectors are contemplated. For example, in certain representative embodiments, the detector 402 comprises a pixelated (ID, 2D or 3D) charge coupled device (CCD) or a complementary metal oxide semiconductor (CCD) device. In other representative embodiments, the detector 402 detects NO by monitoring the chemiluminescence of the reaction of NO with ozone. In this reaction, NO2 is formed in an excited state, which upon decay to the ground state emits a photon of blue light. In yet other representative embodiments, the detector 402 may comprise electrochemical sensors, including for example, but not limited to differential pulse voltametric (DPV) or diphenyl phosphate (DPP) electrochemical sensors. In yet other embodiments, the detector 402 may comprise a photoacoustic sensor.

[0051] The system 400 also comprises a light source 404. The light source 404 is selected to provide an excitation wavelength to cause fluorescent emission from the Fdots as described above, or to provide light of a selected wavelength for treatment of the tissue as alluded to above and as described more fully below. The light source 404 is also adapted to modify the intensity of light incident on the mouthpiece 401 and/or the tissue undergoing treatment, and/or the time of the application of light to the tissue, as described below.

[0052] The modification of the applied light from the light source 404 may carried out in a number of ways based on data the output from the detector 402. For example, in certain representative embodiments, data from the detector 402 is adapted enable measurements of NO concentration relative to a threshold. Illustratively, in accordance with a representative embodiment, based on data from the detector 402, the instructions cause the system 400 to determine the location where and/or the time when, a concentration of the NO is greater than a threshold. Based on this predetermined threshold, the instructions may cause the system 400 to adjust the intensity and/or duration of light from the light source.

Just by way of illustration, the threshold may be in a range of approximately 30 parts-per-billion (ppb) and approximately 300 ppb NO. Moreover, the threshold may be set to indicate the level of NO is not existent. For example, the NO may be deemed not present when the concentration of the NO is below approximately 20 ppb.

Furthermore, the adjustment of the light source 404 may be iterative in accordance with certain representative embodiments. For example, after an adjustment of the light source 404 based on the data from the detector, the location is a first location, the time is a first time, and the instructions further cause the system to determine a second location where and/or a second time when the concentration of the NO is greater than the threshold; and further adjust the output of the light source at the excitation wavelength based on the second location and/or the second time. [0053] Data from the detector 402 are provided to a controller 403. The controller 403 comprises a processor 405, and a memory 407, which stores computer-executable instructions (code). In accordance with representative embodiments described more fully below, these instructions, when executed by the processor 405 carry out various functions of representative embodiments described herein. As such, the memory 407 may store a set of software instructions that can be executed by the processor 405 to cause the system 400 to perform some or all aspects of certain methods or computer-based functions described herein.

[0054] The controller 403 may be implemented by a computer that includes more elements than the controller 403 and memory 407 of Fig. 4. Notably, in accordance with a representative embodiment, the controller 403 may be remote to the system 400, and is adapted to control various aspects of the system 400 remotely via connections including both wired and wireless connections and protocols. In this sense, the controller 403, at least in part is a specialty or particular computer useful in controlling the system 400.

[0055] The controller 403 may operate as a standalone device or may be connected, for example, using a network to other computer systems or peripheral devices. In representative embodiments, the system 400 performs logical processing based on digital signals received via an analog-to- digital converter. The controller 403 can also be implemented as or incorporated into various devices, such as a workstation that includes a controller, a stationary computer, a mobile computer, a personal computer (PC), a laptop computer, a tablet computer, or any other machine capable of executing a set of software instructions (sequential or otherwise) that specify actions to be taken by that machine. The controller 403 can be incorporated as or in a device that in turn is in an integrated system that includes additional devices. In an embodiment, the controller 403 can be implemented in a device that also provides video or data communication. Moreover, the controller 403 may be connected to components of the system via a local wired interface such as an Ethernet cable or via a local wireless interface such as a Wi-Fi connection.

[0056] The processor 405 may be considered a representative example of a processor of the controller 403 and executes instructions to implement some or all aspects of methods and processes described herein. The processor 405 is tangible and non-transitory. As used herein, the term “non-transitory” is to be interpreted not as an eternal characteristic of a state, but as a characteristic of a state that will last for a period. The term “non-transitory” specifically disavows fleeting characteristics such as characteristics of a carrier wave or signal or other forms that exist only transitorily in any place at any time. The processor 405 is an article of manufacture and/or a machine component.

[0057] The processor 405 is configured to execute software instructions to perform functions as described in the various embodiments herein. The processor may be a general-purpose processor or may be part of an application specific integrated circuit (ASIC). The processor may also be a microprocessor, a microcomputer, a processor chip, a controller, a microcontroller, a digital signal processor (DSP), a state machine, or a programmable logic device. The processor may also be a logical circuit, including a programmable gate array (PGA), such as a field programmable gate array (FPGA), or another type of circuit that includes discrete gate and/or transistor logic. The processor may be a central processing unit (CPU), a graphics processing unit (GPU), or both. Additionally, any processor described herein may include multiple processors, parallel processors, or both. Multiple processors may be included in, or coupled to, a single device or multiple devices.

[0058] The term “processor” as used herein encompasses an electronic component able to execute a program or machine executable instruction. References to a processor should be interpreted to include more than one processor or processing core, as in a multi-core processor. A processor may also refer to a collection of processors within a single computer system or distributed among multiple computer systems, such as in a cloud-based or other multi-site application.

[0059] “Memory” is an example of computer-readable storage media, and should be interpreted as possibly being multiple memories or databases. The memory or database may for instance be multiple memories or databases local to the computer, and/or distributed amongst multiple computer systems or computing devices. A computer readable storage medium is defined to be any medium that constitutes patentable subject matter under 35 U.S.C. §101 and excludes any medium that does not constitute patentable subject matter under 35 U.S.C. §101. Examples of such media include non-transitory media such as computer memory devices that store information in a format that is readable by a computer or data processing system. More specific examples of non-transitory media include computer disks and non-volatile memories.

[0060] The memory 407 may include a main memory and/or a static memory, where memories in the system 400 communicate with each other and the processor via a bus (not shown). The memory may be considered a representative example of a memory of the controller 403, and store instructions used to implement some or all aspects of methods and processes described herein. Memories described herein are tangible storage mediums for storing data and executable software instructions and are non-transitory during the time software instructions are stored therein. As used herein, the term “non-transitory” is to be interpreted not as an eternal characteristic of a state, but as a characteristic of a state that will last for a period. The term “non- transitory” specifically disavows fleeting characteristics such as characteristics of a carrier wave or signal or other forms that exist only transitorily in any place at any time. The memory is an article of manufacture and/or machine components. The memory is a computer-readable medium from which data and executable software instructions can be read by a computer (e.g., by the processor of the controller 403). The memory may be implemented as one or more of randomaccess memory (RAM), read only memory (ROM), flash memory, electrically programmable read only memory (EPROM), electrically erasable programmable read-only memory (EEPROM), registers, a hard disk, a removable disk, tape, compact disk read only memory (CD- ROM), digital versatile disk (DVD), floppy disk, Blu-ray disk, or any other form of storage medium known in the art. The memory may be volatile or non-volatile, secure and/or encrypted, unsecure and/or unencrypted. The inventive concepts also encompass a computer readable medium that stores instructions that cause the processor to execute the methods described herein. Finally, a computer readable medium is defined herein to be any medium that constitutes patentable subject matter under 35 U.S. C. §101 and excludes any medium that does not constitute patentable subject matter under 35 U.S. C. §101. Examples of such media include non- transitory media such as computer memory devices that store information in a format that is readable by a computer or data processing system. More specific examples of non-transitory media include computer disks and non-volatile memories.

[0061] Additionally, the memory 407 is an example of a computer-readable storage medium. Computer memory is any memory which is directly accessible to a processor. Examples of computer memory include, registers, and register files. References to “memory” should be interpreted as possibly being multiple memories. The memory may for instance be multiple memories within the same computer system. The memory may also be multiple memories distributed amongst multiple computer systems or computing devices. Software instructions, when executed by the processor, perform one or more steps of the methods and processes as described herein. In an embodiment, the software instructions may reside all or in part within the memory and/or the processor during execution by the controller 403.

[0062] The system 400 may also comprise a display 406 connected to the controller 403. In certain representative embodiments, the display 406 comprises a graphic user interface (GUI) and is connected to the controller 403 via a local wired interface such as an Ethernet cable or via a local wireless interface such as a Wi-Fi connection. The display 406 may be a monitor such as a computer monitor, a display on a mobile device, an augmented reality display, a television, an electronic whiteboard, or another screen configured to display electronic imagery.

[0063] The controller 403 may be interfaced with other user input devices by which users can input instructions, including mouses, keyboards, thumbwheels and so on. The controller 403 may also include one or more input interface(s) such as those noted above that may connect to other elements or components, as well as an interactive touch screen configured to display prompts to users and collect touch input from users. These interfaces may also be icons (not shown) on a display (not shown in Fig. 4 via the GUI.

[0064] As described more fully below, the display 406 enables the user to determine the presence and/or levels of RNS (e.g., NO) based on data from the detector 402, and enables the user (e.g., using the GUI or other interface) to provide inputs from the controller 403 to the light source 404. Just by way of illustration, and as described more fully below, the inputs provided to the light source may alter the duration, or location, or intensity, or a combination thereof, of light applied by the light source 404 based on data from the detector 402. Moreover, and again as described more fully below, based on the data received from the detector 402, the instructions in the memory 407 may cause the processor to alter the duration, or location, or intensity, or a combination thereof, of light applied by the light source based on data from the detector.

[0065] Fig. 5A is a conceptual view of a system 500 for evaluating and/or treating oral tissue using an inventive device in accordance with a representative embodiment. Various aspects and details of presently described system may be common to those described in connection with representative embodiments above, and may be used in systems of representative embodiments described below. These common aspects and details may not be repeated in order to avoid obscuring the presently described representative embodiments.

[0066] Turning to Fig. 5A, a mouthpiece 501 is shown for reference, and is used to monitor and/or treat gums 506 of a subject’s mouth. A portion of the mouthpiece is enlarged to show the Fdots 502 disposed in a material 504 as shown. It is again emphasized that application of the teachings to oral healthcare is merely illustrative, and other applications are contemplated. Just by way of example, rather than gums 506 of a subject’s mouth, the portion comprising Fdots 502 in material 504 may be crafted to be used to monitor other internal tissue, or external tissue, such as skin tissue.

[0067] As shown, light 512 is incident from a light source (not shown in Fig. 5A) on a wavelength dependent beamsplitter 516. The beamsplitter 516 is adapted to reflect the light 512 towards the portion. In the presently described representative embodiment, the light 512 has a first wavelength selected to treat the tissue by transmission through the material 504, and to cause fluorescent emission 514 from the Fdots at second wavelength, which is different from the first wavelength. As such, in the present example, the first wavelength is the excitation wavelength because it causes fluorescent emission, and is selected to treat the inflammation in the tissue as described above. In certain representative embodiments, the excitation wavelength of the light 512 is violet or blue visible light, although other wavelengths are contemplated to carry out the excitation of the Fdots while at the same time providing the therapeutic light treatment of the particular tissue and the particular cause of the inflammation.

[0068] As shown, NO 510 emanates from the tissue (e.g., gums 506) and traverses the portion comprising the Fdots 502 disposed in the material 504. As described above, in the presence of NO, the fluorescent emission 514 by the Fdots 502 terminates, and as described below, this termination of fluorescent emission 514 by the Fdots 502 allows the locations of NO production resulting from inflammation and/or non-inflammatory processes such as from light therapy on the tissue to be determined, and the time at which the inflammation exists, as may be desired. [0069] The wavelength of the fluorescent emission 514 traverses the beamsplitter 516 unimpeded, and is incident on a charge-coupled device (CCD) camera 518. As such, in the present example, the second wavelength is the emission wavelength. As noted above, the Fdots 502 are selected to comprise a material that emits fluorescent radiation having a first wavelength when light of the excitation wavelength is incident thereon, and emits fluorescent radiation of a second (different) wavelength in the presence of NO. In certain representative embodiments, the emission wavelength of the fluorescent emission 514 is near-infrared (NIR), although other wavelengths are contemplated to carry out the excitation of the Fdots.

[0070] As shown, the fluorescent emission 514 is incident on the CCD camera, which identifies the regions where and when NO is present, but also by where and when NO is absent. Specifically, the CCD camera records areas/times of the gums 506/tissue where light of the emission wavelength is present, and by absence where areas/times where the light of the emission wavelength is absent. Stated somewhat differently, light 512 is adapted to be incident on particular portion of the gums 506/tissue being monitored and/or treated. In regions of the portion of the gums 506 where NO is present, the fluorescent emission 514 terminates, and in regions where NO is not present, the fluorescent emission 514 continues caused by the light 512. These data are recorded, and provided to the controller 403 so the processor 405 can alter the output of the light source to provide light 512 to treat regions where the inflammation of the tissue exists. Moreover, and as alluded, these data from the CCD camera 508 can also be used to monitor the progress of treatment of the tissue by the light 512. Based on these data, the processor 405 can alter the output of the light source so that light of a particular intensity is applied for a particular time to provide the needed light treatment. Finally, thesemay also be used to monitor the temperature of the tissue under treatment based on.

[0071] Fig. 5B is a flow chart of method for evaluating and/or treating oral tissue using an inventive device in accordance with a representative embodiment. Various aspects and details of presently described system may be common to those described in connection with representative embodiments above, and may be used in systems of representative embodiments described below. These common aspects and details may not be repeated in order to avoid obscuring the presently described representative embodiments.

[0072] The method begins at 520 with the application of light 512 from the light source. At 522 NO production exists. As noted above, the NO production may arise not only from inflammation in the tissue being treated, but also from the applied light. At 524 fluorescence initiates due to the presence of the NO.

[0073] At 526, data from the CCD camera are used to determine spatial (and if desired) temporal aspects of the inflammation. As noted above, based on these data, through execution of instructions stored in memory 407, the processor 405 can alter the output of the light source so that light of a particular intensity is applied for a particular time to provide the appropriate light treatment. Moreover, these data from the CCD camera 508 can also be used to monitor the progress of treatment of the tissue by the light 512. Finally, these data may also be used to monitor the temperature of the tissue under treatment as noted above. [0074] Table 530 lists various parameters that can be stored in memory 407 to select the appropriate intensity and duration of the treatment. These factors include, but are not limited to, skin tone/baseline levels, inflammation level and boundary conditions. In accordance with a representative embodiment, these parameters stored in a look-up table in memory, and based on the NO levels and locations, adjustments of the treatment light are carried out. So, just by way of illustration, in accordance with a representative embodiment, for a given set of skin tone/inflammation/boundary conditions stored in memory (e.g., in a look-up table), a light intensity level and duration are assigned, and through execution of instructions stored in memory, the processor 405 causes the light source to adjust the location, and/or intensity, and/or duration of the treatment light applied. In accordance with another representative embodiment, locations where a subject indicates a location a certain symptom (e.g., sore or swollen gums) may be provided (e.g., via the GUI or other interface). Based on this information, the processor 405 causes the light source to adapt the location and/or intensity to ensure a particular treatment is carried out at a particular. Moreover, subject-specific data (e.g., pain threshold) can be stored in memory, and execution of instructions by the processor 405 can cause the adaptation of the light source to carry out a treatment having an appropriate intensity and duration based on the subject-specific data.

[0075] Fig. 6A is a conceptual view of a system for evaluating and/or treating oral tissue using an inventive device in accordance with a representative embodiment. Various aspects and details of presently described system may be common to those described in connection with representative embodiments above, and may be used in systems of representative embodiments described below. These common aspects and details may not be repeated in order to avoid obscuring the presently described representative embodiments.

[0076] Turning to Fig. 6A, a mouthpiece 601 is shown for reference, and is used to monitor and/or treat gums 606 of a subject’s mouth. A portion of the mouthpiece is enlarged to show the Fdots 602 disposed in a material 604 as shown. It is again emphasized that application of the teachings to oral healthcare is merely illustrative, and other applications are contemplated. Just by way of example, rather than gums 606 of a subject’s mouth, the portion comprising Fdots 602 in material 604 may be crafted to be used to monitor other internal tissue, or external tissue, such as skin tissue. [0077] As shown, light 612 is incident from a light source (not shown in Fig. 6A) on Fdots 602 disposed in material 604. The light 612 has a wavelength selected to cause fluorescent emission 614 from the Fdots 602. As such, in the present example, the light 612 is the excitation wavelength because it causes fluorescent emission 614. In this representative embodiment, the wavelength of light of the fluorescent emission 614 is blue and is selected to treat the inflammation in the tissue as described above. In certain representative embodiments, the excitation wavelength of the light 612 is violet, although other wavelengths are contemplated to carry out the excitation of the Fdots 602 while at the same time providing the therapeutic light treatment of the particular tissue and the particular cause of the inflammation.

[0078] As shown, NO 610 emanates from the tissue (e.g., gums 606 and traverses the portion comprising the Fdots 602 disposed in the material 604. As noted above, the Fdots 602 are selected to comprise a material that not only fluoresces when light of the excitation wavelength is incident thereon, but also to terminate fluorescent emission by the Fdots 602 in the presence of NO when turn-off Fdots are implemented, or initiate fluorescent emission in when turn-on Fdots are implemented.

[0079] In accordance with a representative embodiment, the detector 402 is adapted to determine the level of NO in the region around the tissue. These data are recorded, and provided to the controller 403 so the processor 405 can alter the output of the light source to provide light 612 to treat regions where the inflammation of the tissue exists. Moreover, and as alluded, these data can also be used to monitor the progress of treatment of the tissue by the light 612. Based on these data, the processor 405 can alter the output of the light source so that light of a particular intensity is applied for a particular time to provide the needed light treatment. Finally, these data may also be used to monitor the temperature of the tissue under treatment as noted above.

[0080] Fig. 6B is a flow chart of method for evaluating and/or treating oral tissue using an inventive device in accordance with a representative embodiment. Various aspects and details of presently described system may be common to those described in connection with representative embodiments above, and may be used in systems of representative embodiments described below. These common aspects and details may not be repeated in order to avoid obscuring the presently described representative embodiments.

[0081] The method begins at 620 with the application of light 612 from the light source. At 622 NO production exists. As noted above, the NO production may arise not only from inflammation in the tissue being treated, but also from the applied light. At 624 fluorescence terminates due to the presence of the NO caused by inflammation and/or absorption of blue light. [0082] At 626, data from the detector 402 are used to determine concentration of NO near the tissue being treated, and based on these data, the degree of inflammation can be determined. As noted above, based on these data, through execution of instructions stored in memory 407, the processor 405 can alter the output of the light source so that light of a particular intensity is applied for a particular time to provide the appropriate light treatment. Moreover, these data from the detector can also be used to monitor the progress of treatment of the tissue by the light 612. Finally, these data may also be used to monitor the temperature of the tissue under treatment as noted above.

[0083] Table 630 lists various parameters than can be stored in memory 407 to select the appropriate intensity and duration of the treatment. These factors include, but are not limited to, skin tone/baseline levels, inflammation level and boundary conditions. In accordance with a representative embodiment, these parameters stored in a look-up table in memory, and based on the NO levels and locations, adjustments of the treatment light are carried out. So, just by way of illustration, in accordance with a representative embodiment, for a given set of skin tone/inflammation/boundary conditions stored in memory (e.g., in a look-up table), a light intensity level and duration are assigned, and through execution of instructions stored in memory, the processor 405 causes the light source to adjust the location, and/or intensity, and/or duration of the treatment light applied. In accordance with another representative embodiment, locations where a subject indicates a location a certain symptom (e.g., sore or swollen gums) may be provided in the GUI or other interface. Based on this information, the processor 405 causes the light source to adapt the location and/or intensity to ensure a particular treatment is carried out. Moreover, subject-specific data (e.g., pain threshold) can be stored in memory, and execution of instructions by the processor 405 can cause the adaptation of the light source to carry out a treatment having an appropriate intensity and duration.

[0084] The illustrations of the embodiments described herein are intended to provide a general understanding of the structure of the various embodiments. The illustrations are not intended to serve as a complete description of all of the elements and features of the disclosure described 1 herein. Many other embodiments may be apparent to those of skill in the art upon reviewing the disclosure. Other embodiments may be utilized and derived from the disclosure, such that structural and logical substitutions and changes may be made without departing from the scope of the disclosure. Additionally, the illustrations are merely representational and may not be drawn to scale. Certain proportions within the illustrations may be exaggerated, while other proportions may be minimized. Accordingly, the disclosure and the figures are to be regarded as illustrative rather than restrictive.

[0085] One or more embodiments of the disclosure may be referred to herein, individually and/or collectively, by the term “invention” merely for convenience and without intending to voluntarily limit the scope of this application to any particular invention or inventive concept. Moreover, although specific embodiments have been illustrated and described herein, it should be appreciated that any subsequent arrangement designed to achieve the same or similar purpose may be substituted for the specific embodiments shown. This disclosure is intended to cover any and all subsequent adaptations or variations of various embodiments. Combinations of the above embodiments, and other embodiments not specifically described herein, will be apparent to those of skill in the art upon reviewing the description.

[0086] The Abstract of the Disclosure is provided to comply with 37 C.F.R. §1.72(b) and is submitted with the understanding that it will not be used to interpret or limit the scope or meaning of the claims. In addition, in the foregoing Detailed Description, various features may be grouped together or described in a single embodiment for the purpose of streamlining the disclosure. This disclosure is not to be interpreted as reflecting an intention that the claimed embodiments require more features than are expressly recited in each claim. Rather, as the following claims reflect, inventive subject matter may be directed to less than all of the features of any of the disclosed embodiments. Thus, the following claims are incorporated into the Detailed Description, with each claim standing on its own as defining separately claimed subject matter.

[0087] The preceding description of the disclosed embodiments is provided to enable any person skilled in the art to practice the concepts described in the present disclosure. As such, the above disclosed subject matter is to be considered illustrative, and not restrictive, and the appended claims are intended to cover all such modifications, enhancements, and other embodiments which fall within the true spirit and scope of the present disclosure. Thus, to the maximum extent allowed by law, the scope of the present disclosure is to be determined by the broadest permissible interpretation of the following claims and their equivalents and shall not be restricted or limited by the foregoing detailed description.

Claims

CLAIMS:

1. A system for evaluating health of a tissue, the system comprising: a light source adapted to transmit light having an excitation wavelength to the tissue; a device comprising a material comprising fluorescing dots (Fdots) disposed therein, wherein the Fdots are adapted to fluoresce at an emission wavelength when the light having the excitation wavelength is incident thereon, and to terminate fluorescing in a presence of nitric oxide (NO); a memory that stores instructions; and a processor that executes the instructions, wherein, when executed by the processor, the instructions cause the system to: adjust an output of the light source at the excitation wavelength to treat the tissue with the light at the emission wavelength based on a location of the NO and/or a time when the NO is present.

2. The system of claim 1, wherein Fdots further comprise polymer dots (Pdots) and the tissue is an internal tissue.

3. The system of claim 2, wherein the internal tissue comprises an oral tissue, tumor cells, fungal infections, inflamed tissue or a bacterial virus.

4. The system of claim 2, wherein the material comprises a polymer matrix structure and the Pdots comprise non-toxic polymer nanocrystals embedded into the polymer matrix structure.

5. The system of claim 1, wherein the when the NO has a concentration in a range of approximately 30 parts-per-billion (ppb) and approximately 300 ppb.

6. The system of claim 1, wherein the NO is not present when a concentration of the NO is below approximately 20 ppb.

7. The system of claim 1, wherein the emission wavelength is selected to treat the tissue.

8. The system of claim 1, wherein instructions further cause the processor to determine a location and/or the time.

9. A method of evaluating a tissue, the method comprising: transmitting light having an excitation wavelength to the tissue, wherein the excitation wavelength is in the optical spectrum; providing a device comprising a material comprising fluorescing dots (Fdots) disposed therein, wherein the Fdots are adapted to fluoresce at an emission wavelength with the light having the excitation wavelength is incident thereon, and to terminate fluorescing in a presence of nitric oxide (NO); determining a location of the tissue where and/or a time when the NO is present; and adjusting the transmitting the light at the excitation wavelength to treat the tissue with the light at the emission wavelength based on the location and/or the time.

10. The method of claim 9, wherein the method further comprises determining the location where and/or the time when a concentration of the NO is greater than a threshold.

11. The method of claim 9, wherein Fdots further comprise polymer dots (Pdots) and the tissue is an internal tissue.

12. The method of claim 11, wherein the internal tissue comprises an oral tissue, tumor cells, fungal infections, inflamed tissue or a bacterial virus.

13. The method of claim 12, wherein the material comprises a polymer matrix structure and the Pdots comprise non-toxic polymer nanocrystals embedded into the polymer matrix structure.

14. The method of claim 10, wherein the transmitting is terminated when the concentration of NO concentration is in a range of approximately 30 parts-per-billion (ppb) and approximately 300 ppb.

15. The method of claim 10, wherein the NO is not present when the concentration of the NO is below approximately 20 ppb.

16. The method of claim 10, wherein the location is a first location, the time is a first time, and the method further comprises: determining a second the tissue where and/or a second time when a concentration of the NO is greater than the threshold; and further adjusting the transmitting the light at the excitation wavelength based on the location and/or the time.

17. A tangible, non-transitory computer readable medium that stores instructions, which when executed by a processor, causes the processor to: determine location of a tissue where and/or a time when a concentration of the NO is greater than a threshold; and adjust an output of a light source at an excitation wavelength based on the location or the time to treat the tissue with the light at an emission wavelength.