Classifications

• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
  • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
  • G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
  • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
  • G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
  • G01N2021/7769—Measurement method of reaction-produced change in sensor
  • G01N2021/7786—Fluorescence

Definitions

• Oxygen is a key metabolite in cellular respiration and is required for adenosine triphosphate (ATP) synthesis. As insufficient oxygen delivery may result in irreversible tissue damage, early detection of compromised tissue oxygenation is of great importance.
• ATP adenosine triphosphate
• oxygen-interactive luminescent organic dyes have been developed for a variety of imaging and monitoring applications.
• the field of oxygen measurement via phosphorescence quenching is a particularly important and growing field.
• oxygen sensitive phosphors incorporated into wearable devices are hindered by low emission intensity and require the use of expensive optics and detectors.
• BRIEF SUMMARY OF THE DISCLOSURE [4] Accordingly, embodiments of the technology disclosed herein address one or more of the issues identified above by incorporating light scattering or reflective particles into a polymer-luminescent material matrix to improve emission intensity by redirecting photons, which are initially emitted by the luminescent material in directions away from the detector, back towards the detector.
• this technology and method may be used to improve 1 Q B ⁇ 84790144.1 MGH 2022-051-02 QB 125141.04363 luminescence intensity in applications outside of oxygen sensing and may act as both an enhancer of luminescence intensity as well as indicator of changing conditions in the underlying sample (e.g. a wound) via material changes in optical scatterer properties.
• this approach is broadly applicable and is not limited to a particular luminescent material chemistry or mechanism of photoemission.
• Embodiments of the sensing material include a light emitting material responsive to an analyte of interest (also referred to simply as an "analyte"), a plurality of signal enhancing particles, and one or more polymer matrices in which the light emitting material and signal enhancing/scattering particles are disposed.
• the light emitting material that is responsive to an analyte of interest includes a light emitting material that undergoes at least one of a change in intensity or a change of spectral properties based on exposure to the analyte of interest.
• the analyte of interest includes oxygen and the light emitting material includes a metalloporphyrin.
• the plurality of signal enhancing particles include light scattering or reflective particles.
• the signal enhancing particles include at least one of glass (e.g. solid or hollow particles such as spheres), titanium dioxide, zinc, barium sulfate, diamond, polystyrene, or polypropylene.
• the material is constructed in two or more independently tunable layers.
• a first tunable layer includes the light emitting material responsive to an analyte of interest along with a polymer
• a second tunable layer includes a plurality of signal enhancing particles.
• the second tunable layer including a plurality of signal enhancing particles is positioned between, and in contact with, both of a sample of interest (such as a wound such as a skin lesion) and the first tunable layer including the light emitting material responsive to analyte of interest.
• a sample of interest such as a wound such as a skin lesion
• the first tunable layer including the light emitting material responsive to analyte of interest there may also be an optional adhesive layer, between the scattering layer and the sample, however in some embodiments the scattering layer itself may include an adhesive, instead of or in addition to the separate adhesive layer.
• the single layer of material may also include adhesive or there may be a separate adhesive layer between the single layer of material and the sample.
• the polymer matrix may be or include an adhesive.
• the light emitting material may or may not be responsive to the analyte of interest and instead the scattering or reflective particles may be responsive to the analyte of interest.
• the scattering or reflective particles may undergo an interaction with 2 Q B ⁇ 84790144.1 MGH 2022-051-02 QB 125141.04363 underlying sample conditions, such as absorption of an analyte or release of a drug, that may change the optical scattering or reflective properties of the signal enhancing scattering or reflective particles.
• the interaction may cause changes in at least one of index of refraction, absorptive properties, scattering angle, size, shape, orientation, or number of scatterers.
• the excitation source is a flash (e.g. a flash source such as an electronic source) and the detector is a camera.
• the excitation source is a laser or an LED and the detector is a photodiode.
• the system for measuring the analyte of interest includes exposing the sensing material to conditions where the analyte may be present and, following illumination, monitoring at least one of the luminescence intensity, scattering angle, or luminescence lifetime of the light emitting material responsive to the analyte of interest.
• FIG. 1A demonstrates a construction wherein only a semitransparent luminescent layer is present with no scattering or backscattering layer, demonstrating how photons are lost when they are emitted in directions away from photodetectors.
• FIG. 1B shows a construction according to the present disclosure wherein the luminescent layer and scattering layer are separate layers positioned so that the luminescent layer is between the scattering layer and the excitation source and photodetectors. In one construction, the matrix of the scattering layer and the matrix of the luminescent layer are made from different materials.
• FIG. 1C shows a construction according to the present disclosure wherein the luminescent layer and scattering layer are one layer. In one construction, the matrix of the scattering layer and the matrix of the luminescent layer are the same material. 3 Q B ⁇ 84790144.1 MGH 2022-051-02 QB 125141.04363 [12] FIG.
• FIG. 2A shows a construction according to the present disclosure wherein photons emitted by an excitation source impinge upon the disclosed sensing material, which in this construction includes separate semi-transparent luminescent and scattering layers, where the luminescent layer includes a light emitting material (which may or may not be responsive to an analyte of interest).
• the interaction of the scatterers with the analyte of interest which may include absorption of an analyte or release of a drug, may cause an increase or decrease in one or more wavelengths of light emitted and scattered by the scattering layer due to changes to the scatterers such as a change in index of refraction.
• FIG. 2B shows a construction according to the present disclosure wherein photons emitted by an excitation source impinge upon the disclosed sensing material, which includes a semi-transparent luminescent layer and a scattering layer.
• the interaction of the matrix surrounding the scatterers with an analyte of interest can cause a change to the material surrounding the scatterers (e.g. a change in index of refraction or absorptive properties) which in turn can cause an increase (or decrease) in one or more wavelengths of light scattered by the scattering particles.
• FIG.3 shows a construction according to the present disclosure wherein photons emitted by an excitation source impinge upon the disclosed sensing material, which includes a semi-transparent luminescent layer and a scattering layer.
• the interaction of the scattering layer with the analyte of interest e.g. absorption of an analyte or release of a drug
• the interaction may cause a change in the scattering layer, such as a change, increase, or decrease in one or more scattering angles of one or more wavelengths of scattered light.
• FIG.4 shows a construction according to the present disclosure wherein photons emitted by an excitation source impinge upon the disclosed sensing material, which includes a semi-transparent luminescent layer and a scattering layer.
• the interaction of the scattering layer with the analyte of interest e.g. absorption of an analyte or release of a drug
• can cause a change in the scattering layer such as a change in the size, shape, or orientation of the scatterers.
• the change in scatterer size, shape, or orientation results in an increase or decrease in one or more scattering angles of one or more wavelengths of scattered light or an increase or decrease in intensity of one or more wavelengths of scattered photons.
• FIG.5 shows a construction according to the present disclosure wherein photons emitted by an excitation source impinge upon the disclosed sensing material, which includes a semi-transparent luminescent layer and a scattering layer.
• the interaction of the scattering layer 4 Q B ⁇ 84790144.1 MGH 2022-051-02 QB 125141.04363 with the analyte of interest (absorption of an analyte or release of a drug) can cause a change in change in scatterer number, such as an increase or decrease in the number of scatterers.
• the change in scatterer number results in an increase or decrease of in one or more scattering angles of one or more wavelengths of scattered light or an increase or decrease in intensity of one or more wavelengths of scattered photons.
• FIG. 6 shows a construction according to the present disclosure wherein Mie scattering is leveraged by incorporating Mie scatterers into a scattering layer. Mie scatterers scatter photons directionally forward and backward relative to the direction of the incident photon. In one construction, the Mie scattering layer is positioned between the excitation source and an additional reflective layer that is configured to reflect the forward scattered light towards the photodetector. [18] FIG.
• FIG. 7 shows a construction according to the present disclosure wherein distributed rod-shaped particles serve as light scatterers in addition to scale bars for automating camera image processing and analysis through incorporation of techniques, including machine learning, to compensate for variables such as camera distance and orientation.
• FIG. 8 shows luminescence intensity and luminescence decay time of air- exposed and N2-exposed samples of isooctyl acrylate (IOA)-based adhesive embedded with cyclohexenyl pivaloyl Pt-porphyrin.
• IOA isooctyl acrylate
• Panel A shows a control sample of only the matrix polymer and the cyclohexenyl pivaloyl Pt-porphyrin on the substrate.
• Panel B shows the cyclohexenyl pivaloyl Pt-porphyrin in IOA-based adhesive embedded with hollow glass spheres.
• Panel C shows cyclohexenyl pivaloyl Pt-porphyrin in in IOA-based adhesive embedded with TiO2 particles.
• Emission intensity was assessed using a Nikon D3400 DSLR camera equipped with 60 mm lens and two bilaterally mounted Vivitar flash units.
• a blue/UV bandpass filters (385/70 nm, Chroma Technologies) was mounted on the lens and red-green dual bandpass filters (525/30 nm+650/40 nm) were mounted on the flash units.
• the distance between the lens and the oxygen-sensing film was ⁇ 35 cm.
• Exposure time and aperture number were 0.01 s and f/11, respectively.
• ISO was set to 100. Afterwards, images were separated in red, green, and blue channels to assess the red and green signal intensity.
• Luminescent organic dyes have been developed for a variety of imaging and monitoring applications.
• the field of oxygen measurement via phosphorescence quenching is a particularly important and growing field.
• Oxygen sensing through phosphorescence quenching dates back to the 1930s and has been developed into an established technique. Measuring oxygen concentration through phosphorescence quenching has ample of benefits compared to traditional techniques. First, this approach provides a direct measurement of tissue oxygenation, while other techniques only provide indirect measurements (e.g. blood oxygenation).
• Pulse oximetry a common tool to measure blood oxygen saturation, relies on pulsatile blood flow, is affected by varying skin color and competing molecules, and is prone to error if the subject is not still.
• Current transcutaneous oxygen monitoring (TCOM) tools as well as blood gas analysis require bulky devices and trained personnel.
• oxygen sensors based on luminescence quenching can be made small and are easy to operate.
• the method of oxygen measurement through luminescence quenching relies on measuring the change in luminescence intensity or lifetime of certain molecules when exposed to oxygen. The collision of molecular oxygen with the excited-state probe results in energy transfer from the probe to the oxygen molecule via triplet-triplet-interaction.
• This energy transfer causes a decrease in intensity and lifetime; in this way both lifetime and intensity are inversely proportionally to oxygen concentration.
• the limit of detection of the probe depends on the lifetime of the excited state of the oxygen-sensing material.
• These oxygen-sensing molecules can be incorporated into a polymer matrix for stabilization and easy handling. Since detection sensitivity can be related to the lifetime of the of the excited state of the oxygen-sensitive molecule, concentrations of the oxygen-sensitive molecule should be kept as low as possible to avoid aggregation. Aggregation of the probe can result in energy transfer between the molecules with a subsequently reduction in luminescence lifetime and limit of detection.
• the light scattering material may be used to indicate features of the material or of the tissue it is in contact with.
• the scattering property could be modulated by the amount of a drug released from a film or bandage, such that the measured scattered light, in combination with oxygen sensing, could indicate drug release quantitatively or semi-quantitatively.
• the scattering material can be made to change in response to tissue properties, such as water content, amount of exudate/transudate released, or the presence of bacteria or specific species of bacteria. Scattering changes could be used to detect or distinguish diseased vs healthy tissue, such as for example, determining the margins of a wound beneath the bandage.
• the scattering material can also be set so that it could act as a "timer" or indicator of the film or bandage lifetime or wear time, such that a change in scattering could act as a personalized indicator that a bandage change or replacement is necessary, for example.
• a change in scattering could act as a personalized indicator that a bandage change or replacement is necessary, for example.
• the size of the scatterer influences the spectrum of light scattered, such changes as listed above could also be encoded in changes to the light scattering spectrum and read out by measurement of the spectrum or chosen spectral regions. These changes in scattering can arise from changes or modifications to individual scattering elements, such as scatter size and shape, as well as the aggregate status of the scatterers, such as proximity. [25] It is also worth noting that such changes in these scatters could also be set so that an intervention could change or tune the scattering properties.
• the scatters could be exposed to light which could be used to increase or decrease the scattering efficiency; such an approach could be used for manual or automatic "tuning" of the material property to maximize function of films and bandages such as signal to noise ratio or total signal intensity.
• Chemical treatment of the scatters could also be used to modulate scattering properties, where chemical treatments could be compounds typically used in clinical care, such as but not limited to isopropanol or iodide antiseptics. Chemical treatments could also be specifically selected or compounded formulations or solutions that react with or alter the scatterers to achieve similar changes. 7 Q B ⁇ 84790144.1 MGH 2022-051-02 QB 125141.04363 [26] The approach used in current devices to increase signal intensity has been the application of multi-layer architecture.
• the luminescent formulation is usually cast onto a reflective substrate, e.g. polytetrafluoroethylene.
• a reflective substrate e.g. polytetrafluoroethylene.
• a distinguishing feature of the present innovation is the combination of the luminescent formulation and a reflective or scattering layer by using reflective or scattering particles. These scattering or reflecting particles may be dispersed within the formulation (or in a polymer matrix which includes the formulation) resulting in a single layer that contains both components, including the luminescent formulation as well as the scattering material. Combining the luminescent layer with the reflective layer into a single layer would allow for a smaller and simpler architecture as well as the reduction of materials and costs. Such an approach may also for more facile manufacturing of materials.
• the luminescent formulation may be present in a separate layer from the scattering or reflective elements.
• the scattering or reflective elements can also be created such that their scattering/reflective properties are tunable to both internal or external stimuli, including the presence of water or bacteria, or such as the detection of healthy tissue from diseased tissue.
• the procedures of the present disclosure can find application not only in oxygen-sensing devices, such as wearable devices or paint-on bandages but also in any type of application that requires luminescent thin-films that suffer from a low emission intensity.
• the system is designed such that a sensing material is placed close to a sample of interest (e.g.
• a film or bandage which includes the sensing material might be placed adjacent to a wound such as a skin lesion) and properties of the sample are monitored using the sensing material.
• the sample may release a material (e.g. oxygen) that is monitored by the sensing material, or the sensing material may release a material into the sample (e.g. a drug) whose release levels or remaining amounts are monitored by the sensing material.
• the sensing material may include a light emitting material responsive to an analyte of interest, where the properties of the light emitting material are affected by the presence or absence of the analyte of interest, as discussed further below.
• the light emitting material may or may not be responsive to an analyte of interest and the sensitivity of the sensing material to the analyte of interest may be conferred by other components in the sensing material such as scattering particles and/or a matrix which contains the scattering particles, as discussed further below.
• the sensing material such as scattering particles and/or a matrix which contains the scattering particles, as discussed further below.
• Embodiments of the present disclosure are provided which address this problem by redirecting at least a portion of the light that is emitted in a direction away from the detector toward the detector to improve the overall signal that is obtained.
• the light may be redirected by reflection and/or scattering of emitted photons by the scattering particles towards the detectors.
• FIG. 1B shows an embodiment in which the scattering particles are disposed within a semi-transparent luminescent layer along with a light emitting material, such that the sensing material is made of a single layer of material; while the scattering particles are shown in the embodiment of FIG.1B as being on one side of the layer, in other embodiments the scattering particles may be distributed throughout the layer.
• the sensing material may be placed on or near a sample such as a wound (e.g. a skin lesion) on a subject (e.g. a human or animal subject).
• FIG.1C shows another embodiment which includes separate luminescent and scattering layers.
• Various examples disclosed herein which are presented as having a single layer may also be implemented using two or more layers, with components distributed between the layers in different proportions.
• examples disclosed herein which are presented as having two or more layers may also be implemented using a single layer. Accordingly, both the single-layer and the multi-layer embodiments are encompassed with the scope of the present disclosure.
• FIG. 1C depicts a sample against which the sensing material is placed, the sample has been omitted from the remaining images for the sake of clarity.
• FIG. 1C includes an optional adhesive layer, between the scattering layer and the sample, however in some embodiments the scattering layer itself may include an adhesive, instead of or in addition to the separate adhesive layer.
• the single layer of material may also include adhesive or there may be a separate adhesive layer between the single layer of material and the sample.
• the polymer matrix may be or include an adhesive.
• FIG. 2A shows an embodiment according to the present disclosure wherein photons emitted by an excitation source impinge upon the disclosed sensing material, which in this embodiment includes separate semi-transparent luminescent and scattering layers, where the luminescent layer includes a light emitting material (which may or may not be responsive to an analyte of interest).
• the interaction of the scatterers with the analyte of interest which may include absorption of an analyte or release of a drug, may cause an increase or decrease 9 Q B ⁇ 84790144.1 MGH 2022-051-02 QB 125141.04363 in one or more wavelengths of light emitted and scattered by the scattering layer due to changes to the scatterers such as a change in index of refraction.
• FIG. 2B shows an embodiment according to the present disclosure wherein photons emitted by an excitation source impinge upon the disclosed sensing material, which includes a semi-transparent luminescent layer and a scattering layer.
• the interaction of the matrix surrounding the scatterers with an analyte of interest can cause a change to the material surrounding the scatterers (e.g. a change in index of refraction or absorptive properties) which in turn can cause an increase (or decrease) in one or more wavelengths of light scattered by the scattering particles.
• changes in the optical properties of the scatterers or the surrounding matrix, or both, due to interaction with an analyte of interest can lead to changes in the light-scattering properties of the scatterers that can be detected by the photo detector.
• materials that undergo changes in refractive index when absorbing water may be used as the scattering particles, including hydrogels or swellable polymer block co-polymers.
• the refractive index of hydrogels decreases.
• the scattering particles may include PVA, Polyacrylic acid, PDMS, polystyrene, or polystyrene block-co-polymers.
• the matrix may include PDMS, PVA, PEG, alginate, colloidal hydrogel, collagen, or hyaluronan.
• any combination of scattering particle materials may be used with any combination of matrix materials, provided that there is a sufficient difference in refractive index between the scattering particle materials and the matrix materials.
• the scattering particles may be no lower than 10 nanometers and no lower than 100 micrometers.
• FIG. 3 shows an embodiment according to the present disclosure wherein photons emitted by an excitation source impinge upon the disclosed sensing material, which includes a semi-transparent luminescent layer and a scattering layer. The interaction of the scattering layer with the analyte of interest (e.g.
• absorption of an analyte or release of a drug can cause a change in scattering angle of the photons scattered by the scattering layer.
• the interaction may cause a change in the scattering layer (e.g. a change in the scattering particles and/or the matrix), such as a change, increase, or decrease in one or more scattering angles of one or more wavelengths of scattered light.
• the angular scattering pattern is altered by changes induced in scattering particle aspect ratio.
• the scattering particle shape may change from or to rods, discs, or spheres.
• 10 Q B ⁇ 84790144.1 MGH 2022-051-02 QB 125141.04363 changes in scattering angle may be monitored, e.g.
• the scattering particles may include PVA, PDMS, polystyrene, polystyrene block-co-polymers.
• the matrix may include PVA, PDMS, polystyrene, polystyrene block-co-polymers.
• any combination of scattering particle materials may be used with any combination of matrix materials, provided that there is a sufficient difference in refractive index between the scattering particle materials and the matrix materials.
• the scattering particles may be no lower than 10 nanometers and no lower than 100 micrometers.
• FIG. 4 shows an embodiment according to the present disclosure wherein photons emitted by an excitation source impinge upon the disclosed sensing material, which includes a semi-transparent luminescent layer and a scattering layer.
• the interaction of the scattering layer with the analyte of interest e.g. absorption of an analyte or release of a drug
• can cause a change in the scattering layer such as a change in the size, shape, or orientation of the scatterers.
• the change in scatterer size, shape, or orientation results in an increase or decrease in one or more scattering angles of one or more wavelengths of scattered light or an increase or decrease in intensity of one or more wavelengths of scattered photons.
• interaction with an analyte may cause changes in the size and/or aspect ratio of the particles, as well as their orientation.
• scattering particles may include rods or stacked disks that alter their shape (e.g. size, aspect ratio) upon analyte interaction.
• scattering particles can be enmeshed in a matrix that, upon interaction, escape the mesh.
• Particles that contain a drug e.g. PS, PMMA, PDMS
• the scattering particles may include PVA, PDMS, polystyrene, polystyrene block-co-polymers.
• the matrix may include PVA, PDMS, polystyrene, polystyrene block-co- polymers.
• any combination of scattering particle materials may be used with any combination of matrix materials, provided that there is a sufficient difference in refractive index between the scattering particle materials and the matrix materials.
• the interaction of the scattering layer with the analyte of interest can 11 Q B ⁇ 84790144.1 MGH 2022-051-02 QB 125141.04363 cause a change in change in scatterer number, such as an increase or decrease in the number of scatterers.
• the number of scatterers may change due to an increase or decrease in aggregation of the scattering particles which is influenced by the presence of the analyte of interest; while the number of actual particles may not change, the changes in aggregation would lead to changes in how the particles (or clumps of particles) behave for the purpose of scattering, creating a higher or lower effective number of scatterers.
• the change in scatterer number results in an increase or decrease of in one or more scattering angles of one or more wavelengths of scattered light or an increase or decrease in intensity of one or more wavelengths of scattered photons.
• a change in scattering particle number may occur if particles dissolve or breakdown in the presence of an analyte. In this embodiment, only a fraction of the particles may need to either be interacting or interact for this effect.
• scattering particles may be made of multiple scattering particles linked together and the analyte may cause the break of the linkage, and may result in a decrease in particle size but increase in particle number, changing light scattering properties.
• the scattering particles may include PVA, PDMS, polystyrene, polystyrene block-co-polymers.
• the matrix may include PVA, PDMS, polystyrene, polystyrene block-co-polymers.
• any combination of scattering particle materials may be used with any combination of matrix materials, provided that there is a sufficient difference in refractive index between the scattering particle materials and the matrix materials.
• Mie scattering is leveraged by incorporating Mie scatterers into a scattering layer, although in some embodiments the Mie scatters may be incorporated into the luminescent layer and do not necessarily have to be disposed in a separate layer.
• Mie scatterers scatter photons directionally forward and backward relative to the direction of the incident photon.
• the Mie scattering layer is positioned between the excitation source and an additional mirror layer that is configured to reflect the forward scattered light towards the photodetector.
• the matrix itself may change upon interaction with an analyte. For example, water absorption may change the surrounding index of refraction which may alter scattering intensity and angle.
• scattering particles could be one or any combination of TiO 2 , SiO 2 , BaSO 4 , ZnO, gold, silver, tin.
• the scattering particles may include PVA, PDMS, polystyrene, polystyrene block-co-polymers.
• the matrix may include PVA, PDMS, polystyrene, polystyrene block- 12 Q B ⁇ 84790144.1 MGH 2022-051-02 QB 125141.04363 co-polymers.
• any combination of scattering particle materials may be used with any combination of matrix materials, provided that there is a sufficient difference in refractive index between the scattering particle materials and the matrix materials.
• FIG. 7 shows a construction according to the present disclosure wherein distributed particles can serve as light scatterers.
• the distributed particles may be homogenously sized or may vary in size.
• the rod- shaped particles comprised of materials including metals such as silver and gold may range in size from 10 nm to 100 ⁇ m, with all of the particles within a particular sensing material sample being substantially uniform in length, e.g. within at least 10% of the nominal length.
• FIG. 8 provides proof-of-concept results for the disclosed procedures.
• FIG. 8 shows luminescence intensity and luminescence decay time of air-exposed and N 2 -exposed samples of isooctyl acrylate (IOA)-based adhesive embedded with cyclohexenyl pivaloyl Pt- porphyrin.
• IOA isooctyl acrylate
• Panel A shows a control sample of only the matrix polymer and the cyclohexenyl pivaloyl Pt-porphyrin on the substrate.
• Panel B shows the cyclohexenyl pivaloyl Pt-porphyrin in IOA-based adhesive embedded with hollow glass spheres.
• Panel C shows cyclohexenyl pivaloyl Pt-porphyrin in in IOA-based adhesive embedded with TiO2 particles.
• Emission intensity was assessed using a Nikon D3400 DSLR camera equipped with 60 mm lens and two bilaterally mounted Vivitar flash units.
• a blue/UV bandpass filters (385/70 nm, Chroma Technologies) was mounted on the lens and red-green dual bandpass filters (525/30 nm+650/40 nm) were mounted on the flash units.
• the distance between the lens and the oxygen-sensing film was ⁇ 35 cm.
• Exposure time and aperture number were 0.01 s and 13 Q B ⁇ 84790144.1 MGH 2022-051-02 QB 125141.04363 f/11, respectively.
• ISO was set to 100. Afterwards, images were separated in red, green, and blue channels to assess the red and green signal intensity.
• the materials include a light emitting material responsive to an analyte of interest, a plurality of signal enhancing particles, and a polymer matrix.
• the light emitting material responsive to analyte of interest includes a light emitting material that undergoes at least one of a change in intensity or a change of spectral properties based on exposure to the analyte of interest.
• a system for measuring an analyte of interest comprising the sensing material described above which may further include an excitation source and a detector.
• the excitation source and detector are generally orthogonal to the sensing material (e.g. see FIGS.1-6).
• a sample may be positioned in close proximity to the sensing material and the sensing material may be positioned between the sample and the excitation source and detector.
• the sample may be a wound or healthy skin.
• the signal enhancing particles may enhance the intensity of the light emitting material responsive to an analyte of interest by redirecting photons that are emitted in directions away from the detector back toward the detector through reflection or scattering.
• the photons being scattered or reflected in various embodiments of the present disclosure originate from luminescence of a light emitting material.
• the light emitting material may luminesce via electronic relaxations from triplet to singlet states, resulting in isotropically emitted photons.
• the detected signal is an emission property or a change in emission property.
• the emission property is luminescence intensity.
• the emission property is luminescence lifetime.
• the emission property is scattering angle.
• an increase or decrease in luminescence intensity, lifetime, or scattering angle for one or more scattered wavelengths is related to the presence or absence of an analyte of interest.
• the detected 14 Q B ⁇ 84790144.1 MGH 2022-051-02 QB 125141.04363 signal correlates to an analyte that may be an indicator of a biological sample, for example the progress of wound healing or the presence or absence of bacterial infection.
• the analyte may be oxygen.
• the levels of light from the light emitting material that are measured by the detectors may be a function of the influence of the analyte on the light emitting material, on the scattering or reflective particles, and/or on the polymer matrix in which the scattering or reflective particles are embedded.
• the sensing material includes the light emitting material responsive to an analyte of interest and the plurality of signal enhancing particles are constructed in two or more independently tunable layers, as exemplified in FIGS.1C-6.
• the layers may have a thickness between 10-1000 micrometers, in another embodiment the layers may have a thickness between 100-500 micrometers.
• each of these independently tunable layers includes the same polymer matrix.
• these tunable layers include different polymer matrices.
• the layer embedded with light emitting material is hydrophobic while the layer with the plurality of signal enhancing particles is hydrophilic.
• Particles disclosed in this work ideally have a difference in index of reflection from the surrounding polymer matrix. In one embodiment, the difference in index may be no lower than 0.01 and no lower than 1.
• the particles may include bare metallic, glass-coated metallic, polymeric, or glass particles.
• the particles are solid, core-shell, or hollow in structure.
• the particles are glass (e.g. solid or hollow particles such as spheres), titanium dioxide, zinc oxide, barium sulfate, or diamond.
• Particles may also include polymeric materials such as polystyrene or polyethylene. Other types of particles could be metallic particles including but not limited to gold, silver, tin, and nickel. Additionally, particles can be a combination thereof, such as core- shell particles. [45] In some embodiments the particles are spherical, faceted, rod, oblate spheroid, or disc shaped. In one embodiment, exemplified in FIG. 8, the particles are rod-shaped and with well-characterized dimensions which can be used as an internal distance calibration registration tool or fiduciary marker for image-based analysis. [46] In some embodiments the signal enhancing particles have at least one dimension larger than the wavelength of light being scattered or reflected by the particles.
• the particles are smaller than 1/10 th of the wavelength of light being scattered by 15 Q B ⁇ 84790144.1 MGH 2022-051-02 QB 125141.04363 them. More specifically, the particles may be no smaller than 0.001 ⁇ m (1 nm) and no greater than 100 ⁇ m.
• there may be an additional reflecting layer e.g. a white or mirrored layer positioned between the sample and the sensing material.
• the reflecting layer may be a glass microfiber filter paper.
• the reflecting layer may be white silicone.
• the sample is a wound and a clinician can observe the wound through the sensing material.
• an oxygen occlusive layer is positioned over the sensing material and sample.
• the occlusive layer is Tegaderm (about 3,000 cc O2/m 2 /day).
• the occlusive layer may include materials with lower oxygen transmission rates, such as 3M Medical Tape 1524 or 3M Medical Tape 9834.
• the occlusive layer 3M medical tape 1513 and 3M medical transfer adhesive.
• the polymer matrix provides structure to the sensing material.
• the materials may possess an oxygen permeability to ensure rapid exchange of the analyte (e.g., oxygen) but a low permeability for water vapor (e.g., be hydrophobic). Absorbance of water by the matrix may result in structural changes and consequently in changes of the optical properties.
• analyte e.g., oxygen
• water vapor e.g., be hydrophobic
• the polymer includes at least one of nitrocellulose, agarose, hydrogel, poly(ethylene glycol) (PEG) hydrogel, poly(methyl methacrylate (PMMA), poly(propyl methacrylate) (PPMA), tetraethyl orthosilicate (TEOS), triethoxy(octyl)silane (Octyl-triEOS), 2,4-diethyl-1,5-pentanediol, poly(ethylmethacrylate) (PEMA), Polystyrene (PS), ethylcellulose, Poly(1-trimethylsilyl-1- propyne) (PTMSP), polyethylene terephthalate (PTFE), low-density polyethylene (LDPE), or polydimethyl siloxane (PDMS).
• PEG poly(ethylene glycol)
• PMMA poly(methyl methacrylate
• PPMA poly(propyl methacrylate)
• TEOS tetraethyl
• FIG. 1C includes an optional adhesive layer, between the scattering layer and the sample, however in some embodiments the scattering layer itself may include an adhesive, instead of or in addition to the separate adhesive layer.
• the single layer of material may also include adhesive or there may be a separate adhesive layer between the single layer of material and the sample.
• the polymer matrix may be or include an adhesive.
• the adhesive layer may be an acrylate adhesive, a cyanoacrylate adhesive, a urethane or urethane polymer adhesive, an albumin-glutaraldehyde adhesive, or a hydrogel-based adhesive.
• the signal enhancing particles may have a different index of refraction than the index of refraction 16 Q B ⁇ 84790144.1 MGH 2022-051-02 QB 125141.04363 of the adhesive or adhesive-containing layer.
• the index of refraction signal enhancing particles is different from the index of refraction of the polymer matrix by at least 0.01. In other embodiments, the index of refraction of the signal enhancing particles is different from the adhesive by approximately 0.4.
• the sensing material additionally includes one or more reference light emitting materials that are not responsive to the presence of the analyte of interest. In one embodiment, the reference light emitting material is not responsive in emission intensity or spectral properties to the presence of oxygen.
• the reference dyes may be pH-independent (e.g., display no degradation and no change in optical properties with pH), soluble in the matrix material, possess emission bands that do not overlap with the emission bands of the sensor dye, be excitable at the same wavelength as the sensor dye, and be photostable (e.g., limited photobleaching of the reference dye).
• the reference dye may be chemically inert, non-toxic, or otherwise not impede or negatively affect wound healing.
• the reference light emitting material is coumarin.
• Other reference dyes could be but not limited to fluorescein derivatives, quantum dots, Oregon green, Alexa fluorophores or food dyes.
• the light-emitting material responsive to an analyte of interest is a porphyrin.
• it is a metalloporphyrin.
• it may be a pivaloyl-terminated metalloporphyrin, a silanated porphyrin, or alkynyl porphyrin.
• Additional materials that could be used as oxygen-sensing light emitting dyes include but not limited to polycyclic aromatic hydrocarbons, such as anthracene, 3,4-benzopyrene, and decacyclene, fullerenes, metal-ligand complexes, such as metal porphyrins, Ru(1,10- phenanthroline)3, Ru(bipyridine)3, and Ir(III) polypyridine complexes, lanthanide complexes, such as europium complexes, Terbium(III) complexes (e.g. Tb(acac)3(phen)), and Eu(tta)3 and Gd(tta)3 complexes.
• polycyclic aromatic hydrocarbons such as anthracene, 3,4-benzopyrene, and decacyclene
• metal-ligand complexes such as metal porphyrins, Ru(1,10- phenanthroline)3, Ru(bipyridine)3, and Ir(III) polypyridine
• the signal enhancing particles may be responsive to a change in the conditions of the sample which may produce a corresponding observable change in the scattering or reflectivity of the particles.
• the change in scattering or reflectivity may be a result of particles changing size or shape, aggregating with other particles, or disaggregating from a conglomerate as a result of changing sample conditions, producing an increase or decrease in the effective number of particles which in turn affects the amount or properties of the scattered light.
• One embodiment of this may include particles 17 Q B ⁇ 84790144.1 MGH 2022-051-02 QB 125141.04363 swelling as a result of exposure to water, resulting in a change in scattering directionality and orientation and a corresponding change in detected luminescence intensity.
• Rayleigh scattering dominates when particles are smaller than a tenth of the wavelength of light being scattered.
• Rayleigh scattering is wavelength dependent and is emitted in all directions.
• Mie scattering dominates when particles are the same size or larger than the wavelength of light being scattered. Mie scattering is less wavelength dependent than Rayleigh scattering, is strongly directional, and is stronger than Rayleigh scattering.
• scattering of photons from them may transition from Rayleigh scattering to Mie scattering or from Rayleigh scattering to Mie scattering. This change in dominant scattering mechanism can be leveraged to indicate a change in the sample conditions as a function of particle size.
• the changes in sample conditions that may induce changes in particle scattering may include presence of water, release of drug(s), release of exudate or transudate, detection of healthy or diseased tissue, or duration of contact with sample (e.g. to act as a personalized timer for bandage wear time).
• utilizing Mie scattering is exemplified in FIG. 6 wherein a mirrored surface is positioned between the sample and the signal enhancing particles.
• the detector may include one or more of a camera, photodiode and phototransistors, photomultiplier tubes, CCD, CMOS, or a fiber optically coupled detector.
• the excitation source may include a laser, LED, incandescent lamp or flash source (e.g. an electronic flash source) which may be outfitted with filters to permit only a certain wavelength or range of wavelengths to pass.
• the source may be continuously illuminating or applied to a sample in a single pulse or a series of pulses, or modulated such as via a sine wave or triangle wave.
• the excitation is applied as a pulse to measure luminescence lifetime.
• the excitation source is applied as a pulse to prevent or reduce photobleaching of the light emitting material.
• the wavelengths emitted may be ultraviolet, visible, or infrared wavelengths.
• the excitation source may include incandescent, fluorescent, laser, LED and gas lamps include mercury and Xenon lamps.
• excitation sources may have broad emission bands (covering a broad range of the electromagnetic spectrum) (e.g., incandescent lamps), some may show medium to narrow bands (e.g., LEDs), or some show narrow emission lines (e.g., lasers).
• the excitation source may be 18 Q B ⁇ 84790144.1 MGH 2022-051-02 QB 125141.04363 suitable for single photon excitation or multiphoton excitation.
• the excitation source may be a two-photon excitation source.
• the excitation source and/or detector may be coupled to a controller, e.g. a computing system, which controls emission of light and collection and processing of data as disclosed herein.
• the controller may be part of a single device which includes the excitation source and detector or one or more of these may be provided as separate elements.
• some or all of the actions of the controller may be distributed among multiple devices that are coupled to one another in a wired or wireless manner, including a networked computer system, a smartphone, a smart watch, or a wearable device (e.g.
• the system for measuring the analyte of interest includes exposing the sensing material to conditions where the analyte may be present and monitoring the luminescence intensity, scattering angle, or luminescence lifetime of the light emitting material responsive to the analyte of interest.
• the scattering or reflective particles may undergo an interaction with underlying sample conditions, such as absorption of an analyte or release of a drug, that may change the optical scattering or reflective properties of the signal enhancing particles.
• the interaction may cause changes in index of refraction, absorptive properties, scattering angle, size, shape, orientation, or number of scatterers.
• a computer system may perform the analysis of luminescence intensity, scattering angle, or luminescence lifetime of the light emitting material in order to quantify an increase or decrease in these aforementioned parameters.
• the solution is cast into a mold or coated on a substrate using but not limited to techniques including spin coating, dip coating, brushing, roll coating, spraying, and flow coating.
• the scattering particles are added to the casting solution and are deposited directly into matrix material.
• the dried film is released from the mold or punched out of the substrate and is transferred on the adhesive side of a transparent film dressing, such as but not limited to Tegaderm.
• Example 2 Enhanced-signal oxygen sensing
• Emission intensity in FIG.8 was assessed using a Nikon D3400 DSLR camera equipped with 60 mm lens and two bilaterally mounted Vivitar flash units.
• ISO was set to 100. Afterwards, images were separated in red, green, and blue channels to assess the red and green signal intensity. Luminescence lifetime were measured using the an in-house optical wireless wearable readout system. Further experimental details are provided in Biomedical opt express 2020, 11, 6989– 7002, incorporated herein by reference. 21 Q B ⁇ 84790144.1

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