WO2023178034A1 - System and method for detecting oxygen for prediction, detection, mitigation and/or prevention of peristomal skin injury - Google Patents
System and method for detecting oxygen for prediction, detection, mitigation and/or prevention of peristomal skin injury Download PDFInfo
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- WO2023178034A1 WO2023178034A1 PCT/US2023/064228 US2023064228W WO2023178034A1 WO 2023178034 A1 WO2023178034 A1 WO 2023178034A1 US 2023064228 W US2023064228 W US 2023064228W WO 2023178034 A1 WO2023178034 A1 WO 2023178034A1
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- wearable sensor
- oxygen
- peristomal skin
- oxygen consumption
- phosphorescence
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
- A61B5/0071—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence by measuring fluorescence emission
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
- A61B5/1455—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue using optical sensors, e.g. spectral photometrical oximeters
- A61B5/14551—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue using optical sensors, e.g. spectral photometrical oximeters for measuring blood gases
- A61B5/14556—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue using optical sensors, e.g. spectral photometrical oximeters for measuring blood gases by fluorescence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/48—Other medical applications
- A61B5/4842—Monitoring progression or stage of a disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
- A61B5/6801—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be attached to or worn on the body surface
- A61B5/683—Means for maintaining contact with the body
- A61B5/6832—Means for maintaining contact with the body using adhesives
- A61B5/6833—Adhesive patches
Definitions
- the present disclosure pertains to a film-like adhesive sensor applied as a liquid or gel for an ostomy system. More particularly, the present disclosure pertains to an adhesive film sensor for detecting skin oxygen consumption and inflammation on peristomal skin.
- the skin is the largest organ and functions as a part of the innate immune response by initiating mechanisms to combat toxins, pathogens, and physical stressors. It is the body’s first physical defense against external pathogens.
- the skin itself is made up of three main layers: the dermis, the epidermis, and the hypodermis.
- the epidermis can be broken down into the stratum basale, stratum spinosum, stratum granulosum, stratum lucidum, and stratum corneum.
- the stratum basale of the epidermis consists primarily of undifferentiated cells undergoing mitosis, and cells eventually differentiate from this layer to form the stratum spinosum.
- the stratum spinosum produces keratin, a structural protein that plays a role in protecting epithelial cells from damage.
- the stratum granulosum is composed of keratinocytes, which play an essential role in skin repair and re-epithelialization.
- the stratum lucidum is a smooth, seemingly translucent layer of the epidermis located just above the stratum granulosum and below the stratum corneum. This thin layer of cells is generally found in the thick skin of the palms, soles, and digits.
- the stratum corneum contains mature keratinocytes and functions to maintain body temperature, as well as prevent harmful water loss or absorption.
- the acid mantle is a term used to describe the acidic property of the stratum corneum, ranging from a pH of about 4.4-6.
- the acid mantle is part of the outermost layer of skin and, therefore, truly the first response against harmful foreign materials.
- the lipid-rich stratum corneum can also protect against transepidermal water loss by helping the skin retain moisture. However, as this layer is thin and delicate, it may be easily damaged, by mechanical or chemical means, which can subsequently leave the skin exposed and more vulnerable to infection.
- Certain medical procedures can create a cutaneous environment that is susceptible to mechanical and chemical injury.
- An ostomy is a surgery that creates an opening in the abdomen, called a stoma, that enables a connection between the small or large intestines and the skin surface.
- the stoma is created by the diversion of the intestine to the lower quartile of the abdomen and functions as an anus for the disposal of bodily waste products.
- patients After the procedure, patients generally live with an ostomy pouch that is attached to the area around the stoma through adhesion to the skin and collects waste products.
- PSC Peristomal skin complications
- a system and method for detecting oxygen levels of the skin for the prediction, mitigation, detection, and prevention of peristomal skin injury and pressure injury is provided according to various embodiments.
- a system for predicting, detecting, mitigating, and/or preventing peristomal skin injury may include a wearable sensor film adhesive.
- the wearable sensor may include phosphorescent metal loporphyrin molecules that are excited by pulses of light based on oxygen consumption.
- the system may also include a light sensor.
- the light sensor may detect phosphorescence from the wearable sensor.
- the system may further include a computing unit. The computing unit may determine a peristomal skin injury based on the detected phosphorescence.
- the wearable sensor may be mounted to peristomal skin.
- the wearable sensor adhesive film can be applied as a liquid or gel that may be affixed to the peristomal skin.
- the computing unit may detect the peristomal skin injury by measuring an oxygen consumption rate on the wearable sensor based on the detected phosphorescence.
- the system may further include a light unit.
- the light unit may output light pulses to excite the phosphorescent metalloporphyrin molecules.
- the image sensor may be attached to at least part of an area of the wearable sensor.
- the image sensor may include a handheld device.
- the wearable sensor may include an ethanol-based adhesive film applied as a liquid or gel.
- the ethanol-based adhesive film can be a gel or liquid bandage.
- the ethanol-based gel or liquid adhesive may include an esterified oxyphor solution and coumarin.
- the ethanol -based gel or liquid adhesive may be painted onto an area of peristomal skin.
- the wearable sensor may include an alginate hydrogel.
- the alginate hydrogel may include CaS0 4
- a method for detecting peristomal skin injury may be applied to a computing device or unit and may include outputting light pulses, through a light output device, onto a wearable sensor mounted on peristomal skin.
- the wearable sensor may include phosphorescent metalloporphyrin molecules that are excited by pulses of light based on oxygen consumption.
- the computing device may also obtain phosphorescence intensity levels of the phosphorescent metalloporphyrin molecules excited by the pulses of light.
- the computing device may further determine the development of or healing of a peristomal skin injury based on the phosphorescence intensity levels.
- the computing device may further measure an oxygen consumption rate on the wearable sensor based on the phosphorescence intensity levels.
- the computing device may also determine the status of a peristomal skin injury based on the oxygen consumption rate.
- the wearable sensor may include a film-like adhesive applied as a liquid .
- the consumption rate may include a constant rate during a measurement period and a rate of diffusion out of the fdm-like adhesive can be constant and directly related to the oxygen consumption rate under the fdm-like adhesive.
- the fdm-like adhesive can be painted on the peristomal skin.
- the fdm-like adhesive can be an oxygen sensing fdm.
- the computing device may also obtain a phosphorescence image of the wearable sensor.
- a computing device for detecting peristomal skin injury.
- the computing device may include one or more processors, a non- transitory computer-readable memory storing instructions executable by the one or more processors.
- the one or more processors may be configured to obtain phosphorescence intensity levels of a wearable sensor mounted on peristomal skin.
- the wearable sensor may include phosphorescent metalloporphyrin molecules.
- the one or more processors may also be configured to measure an oxygen consumption rate on the wearable sensor based on the phosphorescence intensity levels.
- the one or more processors may further be configured to determine a peristomal skin injury based on the oxygen consumption rate.
- the wearable sensor may include a film-like adhesive applied as a liquid or gel.
- the consumption rate may include a constant rate during a measurement period and a rate of diffusion out of the film-like adhesive can be constant and directly related to the oxygen consumption rate under the film-like adhesive.
- FIG. 1 is a front view of a wearable sensor attached to a user, according to an embodiment.
- FIG. 2 is a diagrammatical section view of a wearable sensor attached to a user’s peristomal skin, according to an embodiment.
- FIG. 3 is a front view of a system for detecting a peristomal skin injury, according to an embodiment.
- FIG. 4A is a front view of a user’s abdomen with a stoma and peristomal skin inflammation.
- FIG. 4B is a front view of the user’s abdomen of FIG. 4A with a wearable sensor surrounding the stoma in accordance with embodiments presented herein.
- FIG. 4C is an oxygen-sensing image of the wearable sensor of FIG. 4B.
- FIG. 5 is a graphical illustration of a prior art Jablonski diagram of the electronic states of a porphyrin interacting with an oxygen molecule.
- FIG. 6 is an illustration of a prior art Oxyphor R4 (red) and Oxyphor G4 (green).
- FIG. 7A is a graphical illustrating the curved results of oxygen consumption rate measurements.
- FIG. 7B is a graphical illustrating the linear results of oxygen consumption rate measurements.
- FIG. 8 A is a graph illustrating data produced for phosphorescence of oxyphor R4.
- FIG. 8B is a graph illustrating data produced for phosphorescence of time averaged oxyphor R4.
- FIG. 8C is a graph illustrating data produced for phosphorescence over time.
- FIG. 9A is a graph illustrating data produced for phosphorescence of oxyphor R4.
- FIG. 9B is a graph illustrating data produced for phosphorescence of time averaged oxyphor R4.
- FIG. 10A is a graph illustrating data produced for phosphorescence of oxyphor R4.
- FIG. 10B is a graph illustrating data produced for fluorescence as a function of oxygen consumption rate.
- FTG. 11 is a flow diagram illustrating a method for detecting peristomal skin injury, according to another embodiment.
- FIG. 12 is a schematic illustration of a computing environment, according to an embodiment.
- the present disclosure provides a wearable film system applied as a liquid or gel for detecting skin oxygen consumption and inflammation on peristomal skin.
- the wearable film can be part of an oxygen sensing film system that can include a wearable sensor that can allow monitoring of critical changes in oxygen consumption in the peristomal skin, as a proxy for skin damage caused by the stoma and ostomy bags.
- the wearable sensor can be a standard patient point- of-care diagnostic or indicator tool.
- the wearable sensor can allow researchers to investigate the effect of physical and chemical irritants on the skin as well as explore the oxygenation state of the occluded peristomal skin in general.
- the oxygen sensing system can include a computing unit that can provide alerts regarding impending or resolving peristomal skin conditions for user intervention.
- the peristomal skin injury can include inflamation, irritation and redness, fungal or bacterial infections, allergic reactions to an adhesive used to hold the ostomy pouch in place, pressure ulcers caused by the weight of the pouch or tight clothing, trauma from accidental removal or dislodgement of the pouch, fissures or tears in the skin caused by straining during bowel movements. Pressure ulcers can include bed sores.
- Skin injury and associated inflammation can have a significant effect on the tissue microenvironment, including increased oxygen consumption by highly metabolically active resident cells and recruited inflammatory cells. Normal wound- healing consists of four main stages — hemostasis, inflammation, proliferation, and remodeling — and sufficient oxygenation is a key component of healing. As a critical aspect of cell metabolism, oxygen prevents wounds from infection, induces angiogenesis, increases keratinocyte differentiation, migration, and re-epithelialization, enhances fibroblast proliferation and collagen synthesis, and promotes wound contraction.
- FIG. 1 illustrates a wearable sensor 14 mounted on a user.
- the wearable sensor 14 can be applied to peristomal skin around a stoma 12.
- the wearable sensor 14 can be used for transcutaneous oxygen monitoring based on phosphorescence emission of a metalloporphyrin embedded in a breathable oxygen-sensing film.
- the wearable sensor 14 can be a liquid or gel film that can be painted on the peristomal skin.
- the wearable sensor 14 can be a bandage, dressing, coating or barrier that can attach to a user’s peristomal skin.
- oxygenation monitoring can include the use of the fluorescence emissions of phosphors embedded in a thin, oxygen-permeable liquid or gel film, to measure tissue oxygenation at the skin surface.
- the phosphors can undergo quenching in the presence of oxygen, so tracking the lifetime and intensity of phosphorescence can correlate directly to the progression of skin inflammation over time.
- the feasibility of such a device can be proven in preliminary in vivo testing models with consistently reproducible results between devices and calibrations.
- the device can include machine learning models and remote monitoring.
- FIG. 2 illustrates a diagrammatic section view of a wearable sensor 114.
- the wearable sensor 114 can be attached to a user’s skin 112 on one side and be exposed to atmospheric oxygen 110 on the other.
- the wearable sensor 114 can be a liquid bandage or an oxygen-sensing bandage that can include phosphorescent metalloporphyrin molecules that can be excited by pulses of light.
- the liquid bandage 114 can transcutaneously monitor oxygen based on inflamed tissue 116 consuming oxygen more rapidly than healthy tissue.
- FIG. 3 illustrates a system 200 for detecting a peristomal skin injury.
- the system 200 can include a liquid or gel bandage or fdm 214, a light sensor unit 216, a sensor interface 218, and a computing unit 220.
- the liquid bandage or fdm 214 can include phosphorescent metalloporphyrin molecules that can be excited by pulses of light based on oxygen consumption.
- the light sensor unit 216 can include a phosphorimeter, a camera or other photosensitive sensors capable of detecting phosphorescence.
- the light sensor unit 216 can also include a light unit such as a light out device, LED, flashlamp, or laser that can output light pulses.
- the light sensor unit 216 can be mounted to cover an area of the liquid bandage 214.
- the light sensor unit 216 can output light pulses and measure the phosphorescent output of the covered area of the liquid bandage or fdm 214.
- the light sensor unit 216 can be placed along or adjacent an area where inflammation is most likely to occur.
- the light sensor unit 216 can be placed at an area close to the stoma (an inner ring of the liquid bandage 214), where irritation and inflammation can occur due to its proximity to stoma output.
- the light sensor unit 216 can be placed at an area below the inner ring of the oxygen sensing liquid, gel or fdm 214, near a user’s hip (where stoma output could descend due to gravity).
- the light sensor unit 216 can cover the entire oxygen sensing liquid or gel bandage 214 to measure the phosphorescent output of the entire liquid bandage 214 (FIG. 4C).
- the senor 216 can include small battery-powered systems with oxyphor-based sensor heads.
- the sensor interface 218 can comprise connecting wires that can electronically connect the sensor 216 and computing unit 220 to acquire data from the light sensor unit 216.
- the computing unit 220 can analyze the acquired data to determine oxygen consumption (see FIG. 15).
- FIG. 4A shows a user’s abdomen with a stoma 312 and inflamated peristomal skin 322.
- FIG. 4B shows the user’s abdomen of FIG. 4A with the stoma 312 and a liquid bandage 314 attached over the peristomal skin.
- FIG. 4C shows a captured image 324 of a liquid bandage 326 with a detected oxygen consumption area 328.
- the captured image 324 can be captured by a sensor (such as sensor 116) being placed in front of the liquid bandage 314.
- the sensor can be a handheld device such as a mobile phone having a camera or other image capture device/sensor.
- a patient, user or clinician can apply the liquid bandage when an ostomy bag is changed to detect inflammation while the ostomy bag is worn.
- the wearable sensor can be incorporated into a barrier adhesive and the barrier can have openings and mechanical mechanisms to expose the liquid bandage for measuring phosphorescence. This method could allow for more frequent measurements of the oxygen consumption rate.
- a computing unit could also be incorporated therein to push automatic alerts to medical professionals allowing rapid intervention if a peristomal skin condition is developing.
- the computing unit can provide haptic feedback, sound, and light alerts.
- the wearable sensor 14, 114, 214 can include an ethanol-based gel or liquid bandage (such as NEW-SKIN®), embedded with phosphorescent molecules.
- the phosphorescent molecules can include Oxyphor R2 and Coumarin 500 that may be used as a red, oxygen-sensing dye and a green reference dye, respectively.
- the excitation and emission wavelengths of the two dyes in the liquid bandage can icnclude:
- a mechanism of porphyrin phosphorescence can include Oxyphor R2.
- Oxyphor R2 may be categorized as a porphyrin molecule, which is a heterocyclic organic compound that consists of four modified pyrrole subunits, which are connected via methine bridges at the a-carbon atom.
- Metal complexes comprising porphyrins and/or metalloporphyrins occur naturally and these molecules may be found throughout the human body. For example, heme is an iron-containing porphyrin complex found in hemoglobin.
- Porphyrins may demonstrate a certain luminescent emission, phosphorescence, which is light emission similar to fluorescence, but on a longer timescale that can continue after initial excitation. After being excited by exposure to a photon, most porphyrins undergo internal conversion to an initial singlet state over a picosecond timescale. Then, the porphyrin may quickly change the configuration to form a metastable triplet state. Triplet state formation is typically very efficient in porphyrins, and certain irregular metalloporphyrins have electronic spectra that are significantly affected by their central atoms. Several Pt(II) and Pd(II) complexes display hypsochromic spectra, which means that triplet state formation enables a particularly strong emission of phosphorescence.
- Molecular triplets have a tendency to interact with other molecular triplets.
- One of the most prevalent molecular triplets in nature is oxygen.
- the excited triplet states of Pt and Pd porphyrins have been shown to be effectively quenched by molecular (triplet) oxygen both in solid- state oxygen-permeable materials and in solutions.
- Pd(II) porphyrins have lifetimes on the order of approximately 500-1000 ps, which are ten times longer than the half-lives of Pt(II) porphyrins and better-suited to measuring low oxygen levels.
- porphyrin triplets interact with oxygen triplets, they transfer energy to the oxygen molecules before the porphyrins phosphoresce.
- FIG. 5 illustrates a prior art Jablonski diagram of the electronic states of a porphyrin interacting with an oxygen molecule.
- Oxyphor R4 in particular, is a metalloporphyrin derived from phosphorescent Pd- meso-tetra-(3,5-dicarboxyphenyl)-porphyrin (PdP). This porphyrin is highly soluble in aqueous environments and is known to not permeate biological membranes.
- FIG. 6 illustrates structures of a prior art Oxyphor R4 and Oxyphor G4.
- the liquid bandage can include oxyphor that can be esterified in order to enhance the compatibility of the dye with the ethanol-based liquid bandage matrix.
- Esterified Oxyphor R2 may then be mixed with Coumarin and NEW-SK1N® liquid bandage in order to formulate the liquid bandage. This mixture can be painted onto a small area of skin and, within several minutes of air-drying, the liquid should harden into a thin film.
- the oxygen consumption rate under an oxygen sensing film applied as a liquid or gel bandage can be used as a proxy for skin inflammation. It can be assumed that this rate of consumption is constant during the measurement period, and the rate of diffusion out of the liquid bandage can be constant and directly related to the oxygen consumption rate under the bandage. In addition, there is constant O 2 content in the air in contact with the upper surface of the sensing fdm. Given a constant concentration on the exposed side and a constant diffusion rate on the other, the system can eventually reach a state of equilibrium in which the oxygen content of the bandage is constant and can be directly related to the oxygen consumption rate under it. Consequently, the equilibrium oxygen content in the liquid bandage after application on the skin can be used as a proxy for skin inflammation.
- metalloporphyrin can demonstrate measurable changes in phosphorescence emission intensity with changing oxygen content inside the bandage. Therefore, the equilibrium phosphorescence emission can be used as a proxy for skin inflammation.
- tegaderm can be used as a top layer on the liquid bandage to control oxygen levels.
- the liquid bandage can be exposed to atmospheric oxygen since the rate of oxygen consumption in the skin can be related to the partial pressure of oxygen in the bandage and thus to the phosphorescence intensity at equilibrium.
- the model can be validated by directly relating the phosphorescence intensity to known values of oxygen consumption rate, show a change in phosphorescence with inflammation, and test new formulations of the liquid bandage with different porphyrins.
- a model of oxygen consumption can be used. Solutions of cells such as yeast in different concentrations can be used. In order to relate the concentration of cells to the average rate of oxygen consumption, an oxygen meter can be used.
- the liquid bandage can be prepared using Oxyphor G4, Oxyphor R4, and Oxyphore without the control green dye (Coumarin)
- a time until the equilibration of oxygen flux between the atmosphere, the bandage, and the oxygen consuming medium underneath can be determined.
- a thin layer of liquid bandage can be solidified on a glass slide then transferred on top of the wells containing the solutions of cells with different concentrations. Measurements of the red and green emission intensities can be taken thereafter on the order of every two minutes for at least 20 minutes.
- the partial pressure of oxygen in the bandage can be calculated using the emission intensity given equation (1). This result can allow a validation of the relation between the difference in pO 2 at equilibrium and in the air and the known oxygen consumption rates. Consequently, a clear relationship between the intensity of emissions and the oxygen consumption rate can be acquired, which is a direct measure of inflammation. This calibration can also be done for new liquid bandage formulations, including Oxyphor G4, which might result in greater sensitivity.
- near-infrared (NIR) imaging of the incorporated fluorophores can be used to extract meaningful information from the liquid bandage.
- Thyristor(R) Speedlight flash units with the proper bandpass fdters can be used to excite the dyes and a NIR complementary metal-oxide-semiconductor (CMOS) camera with a macro lens and a digital delay/pulse generator to capture the resultant fluorescence.
- CMOS complementary metal-oxide-semiconductor
- IVIS in vivo imaging system
- Another potential imaging system can include an 3i Lattice Lightsheet Microscope with Bessel Beam Illumination. This microscope can include a CMOS NIR camera.
- a solidified liquid bandage of thickness containing dyes can be deposited on the skin which consumes oxygen with a constant (negative) rate Ren. skin.
- the surface of the bandage can be in contact with the air which has a constant oxygen content at a partial pressure pCh(air).
- An amount of oxygen inside the bandage given diffusion from the air into it and out of it to the skin can be calculated.
- the change in oxygen content can be described by the following mass transport equation:
- R 02 is the bulk reaction rate and is the flux of oxygene described by:
- D 02 is the diffusivity of oxygen in the material considered and v is the bulk velocity.
- BC2 flux out of the bandage equal to flux into the skin at the interface
- BC3 assume that the superficial skin layer of thickness d s is supplied by the diffusion of oxygen from the atmosphere, and beyond this depth the tissue oxygen is supplied by circulation.
- the oxygen content inside the bandage at steady-state can be directly related to the oxygen consumption rate under it.
- the oxygen content inside the bandage can also be related to the intensity of Oxyphore R4 emission using the Stern- Volmer equation, the intensity of emission can be a proxy for skin level inflammation where a greater intensity corresponds to less oxygen in the bandage, so a higher oxygen consumption rate in the skin can be representative of a higher level of inflammation.
- a yeast model can be very similar to the skin model but with slight differences.
- the yeast solution can be placed in a well with depth d w and can consume oxygen at a rate
- 3 ⁇ 4 of the well can be filled with the yeast solution (0.3mL) while the top 1 ⁇ 4 contains air which it can be assumed does not have a bulk velocity either.
- BC2 flux out of the bandage equal to flux into air 2 at the interface
- BC3 flux out of the air 2 equal flux into the yeast at the interface
- BC4 no flux at the bottom of the well
- This equation is very similar to the one obtained for the skin model. It can also demonstrate a direct relation to the oxygen consumption rate under the liquid bandage to the steady-state oxygen content of the liquid bandage. Accordingly, the model can serve as a good proof-of-concept for the functioning of the liquid bandage.
- oxygen consumption models can be tested.
- the oxygen consumption models developed for this experiment were yeast solutions of varying optical densities.
- a yeast oxygen-consumption model offers an easier and more cost-effective alternative.
- yeast undergo aerobic respiration, converting oxygen and carbohydrates into carbon dioxide and water.
- Various solutions containing different amounts of yeast can be used, such that different rates of oxygen consumption can be observed as the yeast respire.
- a first step in developing yeast oxygen consumption models can be to create sterile yeast extract, peptone, and dextrose (YPD) broth, which is a solution of yeast extract, peptone, and dextrose.
- YPD is a commonly used growth media for maintaining cultures of S. cerevisiae yeast.
- 50 g of YPD powder (Sigma-Aldrich Y135) may be dissolved in 1 L of distilled water then the solution can be autoclaved for 20 minutes. This YPD broth was cooled at room temperature.
- yeast solutions a solution of 0.1 g of yeast in 10 mL of YPD broth in a 10 mL sterile tube can be made. Next, this initial solution can be diluated by 20, and then consecutive 2-fold dilutions can be performed to create 5 more yeast solutions. To characterize a yeast densities, light scattering can be used. Using a spectrophotometer, the maximum reading can be 2.5, and the dilutions that would give several solutions with readings below about 1.5 can be used. The solutions can be left at room temperature during a characterization experiments and later during the transportation to the imaging site as well as while imaging.
- Oxygen consumption of each yeast solution can be assessed using a respiration chamber that measured the pO 2 of the yeast solutions as the organisms consumed oxygen from the solutions at a constant rate.
- the assay was conducted in a small 4 mL respiration chamber that contained a small stir bar and a Clark-type oxygen electrode.
- This electrode located at the base of the reaction chamber, consists of a platinum cathode and a silver-chloride anode.
- An electrolyte solution can be placed over the tip of the electrode and prevented from diffusing into the reaction chamber by an oxygen-permeable Teflon membrane. Oxygen can diffuse across the membrane between the electrolyte solution and the yeast solution in the chamber. Voltage measurements can be transmitted to a computer and the data was collected using the PowerLab software. For each measurement, approximately 2 mL of yeast solution can be added. The solution can be taken up in a syringe, then air can be introduced through the stopcock to fill the syringe in order to oxygenate the solution.
- the stopcock can then closed and the solution can be mixed thoroughly by swirling and tilting the syringe. This process oxygenates the solution, such that conditions are primed to observe oxygen consumption by the yeast immediately upon adding the yeast to the chamber.
- the chamber can be rinsed with deionized water multiple times between measurements.
- each yeast solution can be added to the chamber, time for the yeast to consume the oxygen can be allowed until the trace demonstrates a distinct constant slope.
- the measurements can be recorded in terms of voltages by converting them to partial pressures of oxygen. To do so, two points with known oxygen contents can be used to calibrate measurements. So, the voltage can be measured when the chamber was empty (filled with air) and set that to be equal to an atmospheric pO2 at 25°C, which is 153 mmHg. For the second point, the plateau that the voltage reached once the yeast had consumed most of the oxygen can be used. This can be set to be equal to 3 mmHg because at this level, the yeast switch to fully anaerobic respiration and they can never fully deplete the oxygen in the solution.
- FIG. 7B is a graph of the results of oxygen consumption rate measurements. Specifically, FIG. 7B shows a linear regression between the slope of the linear portions at the end of the curves in panel (a) and the optical density of the yeast solutions.
- Figure 7A shows the pO2 values of the various yeast solutions changing with time.
- the yeast solutions show a decrease in the amount of oxygen in the chamber with time.
- the rate of decrease generally increases as the optical density (OD) of the solution increases as can be expected.
- the rate of decrease of pO2 can be considered as the rate of oxygen consumption by the yeast. It is can also be significant to note that the solutions took only a short amount of time to reach a period at which the rate of oxygen consumption appears to be constant (indicated by constant slopes observed at later time points).
- a correlation of each OD600 with the corresponding rate of oxygen consumption can be done, as seen from the strong linear negative correlation established in FIG. 7B.
- OD600 can be an amount of light absorbed by the culture at a wavelength of 600 nm using a spectrophotometer.
- yeast solutions of varying concentrations can be a good model of oxygen consumption and the rate of consumption can be easily determined by the measurement of the optical density of the solution using a spectrophotometer.
- a liquid bandage and its formulation can be determined.
- a solidified liquid bandage sealed over the top of wells in a plate containing yeast solutions can be used.
- the plastic can be very sticky and stretchable.
- a sample of oxyphor R4, coumarin 500, and liquid bandage in a 10: 1 : 10 ratio can be used.
- trials with different formulations of oxyphor, coumarin, and liquid bandage on top can be done.
- a sample of oxyphor R4 (200 uM), coumarin 500 (10 mM), and liquid bandage in a 10: 1:10 ratio can be combined in a small vial, and 5 ⁇ L of this mixture can be pipetted on top of each well. Imaging can be done for 6 minutes at 2-minute intervals and the average radiant efficiency in each well can be recorded and the average background noise can be subtracted.
- FIGS. 8A-8C show data produced for a trial using 5 uL of a 10:1 : 10 mixture of liquid bandage, coumarin, and oxyphor R4 pipetted on top of the liquid bandage.
- FIG. 8A shows a phosphorescence of oxyphor R4 averaged across all images at different time points plotted against OD600. The error bars are +/- 1 standard deviation (SD).
- FIG. 8B shows a phosphorescence of time averaged oxyphor R4 phosphorescence normalized by time averaged coumarin phosphorescence averaged plotted against OD600.
- FIG. 9C shows phosphorescence over time for each OD600 sample.
- FIGS. 9A-9B shows data produced for a trial using coumarin 500 (0.24 ⁇ L), oxyphor (2.4 ⁇ L), and liquid bandage (2.4 ⁇ L) pipetted directly on top of the solidified liquid bandage.
- FIG. 9A shows phosphorescence of oxyphor R4 averaged across all images at different time points plotted against OD600.
- FIG. 9B shows phosphorescence of time averaged oxyphor R4 phosphorescence normalized by time averaged coumarin phosphorescence averaged plotted against OD600.
- a larger volume (20 ⁇ L) can be used of only Oxyphor R4 in water on top of the solidified liquid bandage covering the wells.
- the data from this trial can be visualized in FIGS. 10A and 10B.
- a clear trend in which the emission increases as the optical density of the yeast solutions increases can be obtained. This may be because as the OD increases, the oxygen consumption rate increases. This may result in less oxygen in the bandage at equilibrium as described by the mathematical model. As a result, less oxyphore may be quenched and the emission may be greater.
- the data can be transformed to show the intensity of emission as a function of the rate of oxygen consumption. Due to the linear relationship and the fact that a greater oxygen consumption rate is represented by a greater negative value, the plot can be simply a mirror image of the one as a function of OD.
- the hyperbolic shape of this emission curve can agree with the prediction of the model.
- a better proof of concept can be to compare it to the predicted curve but this may require knowingthe maximum emission of Oxyphore R4 for the Stem-Volmer equation, the diffusion coefficient of oxygen in the liquid bandage, and the thickness of the liquid bandage. Nevertheless, the lack of unreasonable assumptions in the model which agrees with the shape of this curve serves as a good proof-of- concept for the sensor.
- FIGS. 10A and 10B show data produced for a trial using only oxyphor R4 pipetted on top of the liquid bandage.
- FIG. 10A shows phosphorescence of oxyphor R4 averaged across all images at different time points plotted against OD600.
- FIG. 10B shows fluorescence as a function of oxygen consumption rate, determined using the results from the yeast model characterization results to relate OD600 to oxygen consumption rate.
- a liquid bandage can include an alginate hydrogel as an alternative to the liquid bandage.
- Two formulations of the hydrogel can be CaS0 4 or CaCl 2 as the source of bivalent positive ions for crosslinking.
- a base solution of 2% weight per volume of sodium alginate in deionized water can be used.
- 0.435 g of CaS0 4 can be added to 50 mL of alginate solution with the goal of having the number of moles of calcium in the hydrogel equal half the moles of alginate monomers in the gel.
- CaSO 4 may not dissolve easily in the alginate solutions so a large part of it settled to the bottom of the solution container.
- the supernatant of the CaSO 4 hydrogel mixture can be poured off to form relatively homogeneous solutions that can be of an acceptable consistency for a liquid bandage material.
- addition of CaCl 2 can resulted in crosslinking resulting in clumps in the solutions which may make it difficult to get a homogeneous gel.
- an alginate hydrogel can include CaSO 4 having between 0.130mL to 0.520mL.
- the alginate hydrogel can include CaCl 2 having between 0.5275mL to ImL.
- the most promising hydrogel formulation was created by first completely dissolving 0.130 g of CaS0 4 in 10 mL of deionized water, then this can be mixed with 2% weight per volume of sodium alginate in deionized water in a 1 :1 ratio (resulting in a final solution with 1% w/v alginate).
- This formulation formed a clear hydrogel that would be appropriate for imaging (FIG. 13).
- this hydrogel formulation may be characterized in order to take phosphorescence readings using Oxyphor R4 incorporated into the hydrogel.
- a paint-on liquid bandage embedded with oxygen-sensitive metalloporphyrins can offer capabilities as a transcutaneous device for tracking skin injury. The ability to develop these sorts of responsive bandages will ultimately improve patient care and the treatment of peristomal skin injuries.
- the liquid bandage solution mav not be miscible with water, but the Oxyphor R4 may only be available in aqueous solutions.
- the bandage could be composed of an alginate-based hydrogel embedded with oxyphors.
- the alginate hydrogel proves technically infeasible due to compatibility or degradation concerns, other embodiments could seek to utilize different components.
- Oxyphor R4s could either be purchased out of solution, isolated from the aqueous solution, or dissolved in ethanol as the solvent.
- the NEW-SKIN ® liquid bandage other liquid bandage formulations with fewer hydrophobic elements can be used.
- alginate hydrogel is a suitable option, a water-soluble control dye can be used.
- Coumarin 500 does not dissolve in water, but the typical solvent for Coumarin 500, ethanol, appeared to react with alginate. Therefore, neither ethanol nor water may be used in alginate hydrogels with coumarin.
- the use of alginate hydrogels may require the identification and purchase of a water soluble dye to replace Coumarin 500.
- measurements of oxygen diffusivity in the final liquid bandage, maximum oxyphore emission, and thickness of the bandage may allow a more complete proof-of-concept.
- FIG. 11 shows a method 1100 for detecting peristomal skin injury.
- the method may be applied to a computing device such as a wearable device, mobile device, personal computer or server.
- the wearable device may include the light sensor unit 216, the sensor interface 218, and the computing unit 220.
- the wearable device can output light pulses, through a light output device, onto a wearable sensor mounted on peristomal skin.
- the wearable sensor may include phosphorescent metalloporphyrin molecules that are excited by pulses of light based on oxygen consumption.
- the wearable sensor may be a liquid bandage that is painted on a user’s abdomen near a stoma. The liquid bandage, once dry, can output phosphorescence when exposed to light pulses.
- the wearable device can obtain phosphorescence intensity levels of the phosphorescent metalloporphyrin molecules excited by the pulses of light.
- the wearable device trough, for example, a phosphorimeter can detect phosphorescence and calculate phosphorescence intensity levels.
- the wearable device can determine a peristomal skin injury based on the phosphorescence intensity levels.
- the wearable device for example, can use the phosphorescence intensity levels to determine oxygen consumption levels under the wearable sensor.
- the oxygen consumption levels can include an oxygen consumption rate that can be used to determine a peristomal skin injury.
- FIG. 12 shows a computing system 1200 that can be part of the system 200 for detecting a peristomal skin injury.
- the computing system 1200 can include a computing environment 1210, a user interface 1250, a communication unit 1260.
- the computing system can further include a haptic motor and an accelerometer.
- the computing environment 1210 can include a processor 1220, a memory 1230, and an I/O interface 1240.
- the computing environment 1210 can be coupled to the user interface 1250 and communication unit 1260 through the I/O interface 1240.
- the processor 1220 can typically control the overall operations of the computing environment 1210, such as the operations associated with data acquisition, data processing, and data communications
- the processor 1220 can include one or more processors to execute instructions to perform all or some of the steps in the above-described methods.
- the processor 1220 can include one or more modules that facilitate the interaction between the processor 1220 and other components.
- the processor may be or include a central processing unit (CPU), a microprocessor, a single chip machine, a graphical processing unit (GPU) or the like.
- the memory 1230 can store various types of data to support the operation of the computing environment 1210.
- Memory 1230 can include predetermined software 1231. Examples of such data comprise instructions for any applications or methods operated on the computing environment 1210, raw data, detected data, oxygen levels, phosphorescence intensity levels, light levels, etc.
- the memory 1230 may be implemented by using any type of volatile or non-volatile memory devices, or a combination thereof, such as a static random-access memory (SRAM), an electrically erasable programmable read-only memory (EEPROM), an erasable programmable read-only memory (EPROM), a programmable read-only memory (PROM), a read-only memory (ROM), a magnetic memory, a flash memory, a magnetic or optical disk.
- SRAM static random-access memory
- EEPROM electrically erasable programmable read-only memory
- EPROM erasable programmable read-only memory
- PROM programmable read-only memory
- ROM read-only memory
- magnetic memory
- the I/O interface 1240 can provide an interface between the processor 1220 and peripheral interface modules, such as a RF circuitry, external port, proximity sensor, audio and speaker circuitry, video and camera circuitry, microphone, accelerometer, display controller, optical sensor controller, intensity sensor controller, other input controllers, keyboard, a click wheel, buttons, and the like.
- the buttons may include but are not limited to, a home button, a power button, and volume buttons.
- the user interface 1250 can include a speaker, lights, display, haptic feedback motor or other similar technologies for communicating with the user.
- Communication unit 1260 provides communication between the processing unit, an external device, mobile device, and a webserver (or cloud).
- the communication can be done through, for example, WIFI or BLUETOOTH hardware and protocols.
- the communication unit 1260 can be within the computing environment or connected to it.
- non-transitory computer-readable storage medium comprising a plurality of programs, such as comprised in the memory 1230, executable by the processor 1220 in the computing environment 1210, for performing the above- described methods.
- the non-transitory computer-readable storage medium may be a ROM, a RAM, or the like.
- the non-transitory computer-readable storage medium has stored therein a plurality of programs for execution by a computing device having one or more processors, where the plurality of programs when executed by the one or more processors, cause the computing device to perform the above-described method for motion prediction.
- the computing environment 1210 may be implemented with one or more application-specific integrated circuits (ASICs), digital signal processors (DSPs), digital signal processing devices (DSPDs), programmable logic devices (PLDs), field-programmable gate arrays (FPGAs), graphical processing units (GPUs), controllers, micro-controllers, microprocessors, or other electronic components, for performing the above methods.
- ASICs application-specific integrated circuits
- DSPs digital signal processors
- DSPDs digital signal processing devices
- PLDs programmable logic devices
- FPGAs field-programmable gate arrays
- GPUs graphical processing units
- controllers micro-controllers, microprocessors, or other electronic components, for performing the above methods.
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Abstract
A system and method detecting oxygen levels that indicate peristomal skin injury, other skin injuries, or healing. The system may include a wearable sensor. The wearable sensor may include phosphorescent metalloporphyrin molecules that are excited by pulses of light based on oxygen consumption. The system may also include a light sensor. The light sensor may detect phosphorescence from the wearable sensor. The system may further include a computing unit. The computing unit may detect a peristomal skin injury based on the detected phosphorescence.
Description
TITLE
SYSTEM AND METHOD FOR DETECTING OXYGEN FOR PREDICTION, DETECTION, MITIGATION AND/OR PREVENTION OF PERISTOMAL SKIN INJURYSYSTEM AND METHOD FOR DETECTING PERISTOMAL SKIN INJURY
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is based upon and claims priority to U.S. Provisional Applications No. 63/319,488 fried on March 14, 2022, and U.S. Provisional Patent Application No. 63/324,307 filed on March 28, 2022, the entire contents thereof are incorporated herein by reference in their entirety.
BACKGROUND
[0002] The present disclosure pertains to a film-like adhesive sensor applied as a liquid or gel for an ostomy system. More particularly, the present disclosure pertains to an adhesive film sensor for detecting skin oxygen consumption and inflammation on peristomal skin.
[0003] The skin is the largest organ and functions as a part of the innate immune response by initiating mechanisms to combat toxins, pathogens, and physical stressors. It is the body’s first physical defense against external pathogens. The skin itself is made up of three main layers: the dermis, the epidermis, and the hypodermis. The epidermis can be broken down into the stratum basale, stratum spinosum, stratum granulosum, stratum lucidum, and stratum corneum.
[0004] The stratum basale of the epidermis consists primarily of undifferentiated cells undergoing mitosis, and cells eventually differentiate from this layer to form the stratum spinosum. The stratum spinosum produces keratin, a structural protein that plays a role in protecting epithelial cells from damage. The stratum granulosum is composed of keratinocytes, which play an essential
role in skin repair and re-epithelialization. The stratum lucidum is a smooth, seemingly translucent layer of the epidermis located just above the stratum granulosum and below the stratum corneum. This thin layer of cells is generally found in the thick skin of the palms, soles, and digits. The stratum corneum contains mature keratinocytes and functions to maintain body temperature, as well as prevent harmful water loss or absorption. The acid mantle is a term used to describe the acidic property of the stratum corneum, ranging from a pH of about 4.4-6. The acid mantle is part of the outermost layer of skin and, therefore, truly the first response against harmful foreign materials. The lipid-rich stratum corneum can also protect against transepidermal water loss by helping the skin retain moisture. However, as this layer is thin and delicate, it may be easily damaged, by mechanical or chemical means, which can subsequently leave the skin exposed and more vulnerable to infection.
[0005] Certain medical procedures, such as ostomies, can create a cutaneous environment that is susceptible to mechanical and chemical injury. An ostomy is a surgery that creates an opening in the abdomen, called a stoma, that enables a connection between the small or large intestines and the skin surface. The stoma is created by the diversion of the intestine to the lower quartile of the abdomen and functions as an anus for the disposal of bodily waste products. After the procedure, patients generally live with an ostomy pouch that is attached to the area around the stoma through adhesion to the skin and collects waste products.
[0006] Repeated adhesion and removal of the ostomy bag, as well as potential leakage of intestinal contents (dejecta) onto the skin, can cause many complications in the peristomal skin. These might involve mechanical trauma from ostomy equipment and skin stripping (medical adhesive-related skin injury (MARSI)), bacterial infection, chemical trauma due to irritants in feces or urine, as well as many diseases such as pyoderma gangrenosum or psoriasis. The most
common peristomal skin condition is irritant dermatitis, caused by consistent exposure to waste effluent through leakage. In fact, the skin easily becomes irritated and inflamed (dermatitis) when in contact with the chemicals present in urine and feces. The skin can also break down from moisture buildup, causing maceration. Treatments for peristomal skin conditions range from changing pouching systems and increased skincare to the use of antibiotic medications. Early detection and mitigation of peristomal skin conditions is vital to ensuring high patient quality of life.
[0007] Peristomal skin complications (PSC) are common, occurring in up to 60% of ostomy patients. As there are an estimated 500,000 patients living in the U.S. with a stoma, PSC are a significant source of concern. In addition to contributing to patient pain and discomfort, these skin complications can reduce the ostomy pouch’s ability to attach, leading to further leakage that can be potentially debilitating. Maintaining the integrity of peristomal skin is, therefore, of critical importance to patient health and a central part of post-operative and chronic stoma care.
[0008] Accordingly, it is desirable to provide a system for determining inflammation on peristomal skin so that a user can seek early treatment to mitigate a potentially harmful peristomal skin condition.
BRIEF SUMMARY
[0009] A system and method for detecting oxygen levels of the skin for the prediction, mitigation, detection, and prevention of peristomal skin injury and pressure injury is provided according to various embodiments.
[0010] In a first aspect of the present disclosure, a system for predicting, detecting, mitigating, and/or preventing peristomal skin injury is provided. The system may include a wearable sensor
film adhesive. The wearable sensor may include phosphorescent metal loporphyrin molecules that are excited by pulses of light based on oxygen consumption. The system may also include a light sensor. The light sensor may detect phosphorescence from the wearable sensor. The system may further include a computing unit. The computing unit may determine a peristomal skin injury based on the detected phosphorescence.
[0011] In an embodiment, the wearable sensor may be mounted to peristomal skin. For example, the wearable sensor adhesive film can be applied as a liquid or gel that may be affixed to the peristomal skin.
[0012] In an embodiment, the computing unit may detect the peristomal skin injury by measuring an oxygen consumption rate on the wearable sensor based on the detected phosphorescence.
[0013] In an embodiment, the system may further include a light unit. The light unit may output light pulses to excite the phosphorescent metalloporphyrin molecules.
[0014] In an embodiment, the image sensor may be attached to at least part of an area of the wearable sensor.
[0015] In an embodiment, the image sensor may include a handheld device.
[0016] In an embodiment, the wearable sensor may include an ethanol-based adhesive film applied as a liquid or gel. For example, the ethanol-based adhesive film can be a gel or liquid bandage. In such an embodiment, the ethanol-based gel or liquid adhesive may include an esterified oxyphor solution and coumarin.
[0017] In an embodiment, the ethanol -based gel or liquid adhesive may be painted onto an area of peristomal skin.
[0018] In an embodiment, the wearable sensor may include an alginate hydrogel.
[0019] In an embodiment, the alginate hydrogel may include CaS04
[0020] In a second aspect of the present disclosure, a method for detecting peristomal skin injury is provided. The method may be applied to a computing device or unit and may include outputting light pulses, through a light output device, onto a wearable sensor mounted on peristomal skin. The wearable sensor may include phosphorescent metalloporphyrin molecules that are excited by pulses of light based on oxygen consumption. The computing device may also obtain phosphorescence intensity levels of the phosphorescent metalloporphyrin molecules excited by the pulses of light. The computing device may further determine the development of or healing of a peristomal skin injury based on the phosphorescence intensity levels.
[0021] In an embodiment, the computing device may further measure an oxygen consumption rate on the wearable sensor based on the phosphorescence intensity levels. The computing device may also determine the status of a peristomal skin injury based on the oxygen consumption rate.
[0022] In an embodiment, the wearable sensor may include a film-like adhesive applied as a liquid . In such an embodiment, the consumption rate may include a constant rate during a measurement period and a rate of diffusion out of the fdm-like adhesive can be constant and directly related to the oxygen consumption rate under the fdm-like adhesive.
[0023] In an embodiment, the fdm-like adhesive can be painted on the peristomal skin. The fdm-like adhesive can be an oxygen sensing fdm.
[0024] In an embodiment, the computing device may also obtain a phosphorescence image of the wearable sensor.
[0025] In a third aspect of the present disclosure, a computing device for detecting peristomal skin injury is provided. The computing device may include one or more processors, a non- transitory computer-readable memory storing instructions executable by the one or more
processors. The one or more processors may be configured to obtain phosphorescence intensity levels of a wearable sensor mounted on peristomal skin. The wearable sensor may include phosphorescent metalloporphyrin molecules. The one or more processors may also be configured to measure an oxygen consumption rate on the wearable sensor based on the phosphorescence intensity levels. The one or more processors may further be configured to determine a peristomal skin injury based on the oxygen consumption rate.
[0026] In an embodiment, the wearable sensor may include a film-like adhesive applied as a liquid or gel.
[0027] In an embodiment, the consumption rate may include a constant rate during a measurement period and a rate of diffusion out of the film-like adhesive can be constant and directly related to the oxygen consumption rate under the film-like adhesive.
[0028] The foregoing general description and the following detailed description are examples only and are not restrictive of the present disclosure.
BRIEF DESCRIPTION OF THE DRAWINGS
[0029] The benefits and advantages of the present embodiments will become more readily apparent to those of ordinary skill in the relevant art after reviewing the following detailed description and accompanying drawings, wherein:
[0030] FIG. 1 is a front view of a wearable sensor attached to a user, according to an embodiment.
[0031] FIG. 2 is a diagrammatical section view of a wearable sensor attached to a user’s peristomal skin, according to an embodiment.
[0032] FIG. 3 is a front view of a system for detecting a peristomal skin injury, according to
an embodiment.
[0033] FIG. 4A is a front view of a user’s abdomen with a stoma and peristomal skin inflammation.
[0034] FIG. 4B is a front view of the user’s abdomen of FIG. 4A with a wearable sensor surrounding the stoma in accordance with embodiments presented herein.
[0035] FIG. 4C is an oxygen-sensing image of the wearable sensor of FIG. 4B.
[0036] FIG. 5 is a graphical illustration of a prior art Jablonski diagram of the electronic states of a porphyrin interacting with an oxygen molecule.
[0037] FIG. 6 is an illustration of a prior art Oxyphor R4 (red) and Oxyphor G4 (green).
[0038] FIG. 7A is a graphical illustrating the curved results of oxygen consumption rate measurements.
[0039] FIG. 7B is a graphical illustrating the linear results of oxygen consumption rate measurements.
[0040] FIG. 8 A is a graph illustrating data produced for phosphorescence of oxyphor R4.
[0041] FIG. 8B is a graph illustrating data produced for phosphorescence of time averaged oxyphor R4.
[0042] FIG. 8C is a graph illustrating data produced for phosphorescence over time.
[0043] FIG. 9A is a graph illustrating data produced for phosphorescence of oxyphor R4.
[0044] FIG. 9B is a graph illustrating data produced for phosphorescence of time averaged oxyphor R4.
[0045] FIG. 10A is a graph illustrating data produced for phosphorescence of oxyphor R4.
[0046] FIG. 10B is a graph illustrating data produced for fluorescence as a function of oxygen consumption rate.
[0047] FTG. 11 is a flow diagram illustrating a method for detecting peristomal skin injury, according to another embodiment.
[0048] FIG. 12 is a schematic illustration of a computing environment, according to an embodiment.
DETAILED DESCRIPTION
[0049] While the present disclosure is susceptible of embodiment in various forms, there is shown in the drawings and will hereinafter be described presently preferred embodiments with the understanding that the present disclosure is to be considered an exemplification and is not intended to limit the disclosure to the specific embodiments illustrated. The words “a” or “an” are to be taken to include both the singular and the plural. Conversely, any reference to plural items shall, where appropriate, include the singular. The words “first,” “second,” “third,” and the like may be used in the present disclosure to describe various information, such information should not be limited to these words. These words are only used to distinguish one category of information from another. The directional words “top,” “bottom,” up,” “down,” front,” “back,” and the like are used for purposes of illustration and as such, are not limiting. Depending on the context, the word “if’ as used herein may be interpreted as “when” or “upon” or “in response to determining.”
[0050] The present disclosure provides a wearable film system applied as a liquid or gel for detecting skin oxygen consumption and inflammation on peristomal skin. The wearable film can be part of an oxygen sensing film system that can include a wearable sensor that can allow monitoring of critical changes in oxygen consumption in the peristomal skin, as a proxy for skin damage caused by the stoma and ostomy bags. The wearable sensor can be a standard patient point- of-care diagnostic or indicator tool. In an embodiment, the wearable sensor can allow researchers
to investigate the effect of physical and chemical irritants on the skin as well as explore the oxygenation state of the occluded peristomal skin in general. In terms of clinical research, it can be used to collect data from ostomy patients to quantify the extent of their peristomal skin injury or healing of injury. The oxygen sensing system can include a computing unit that can provide alerts regarding impending or resolving peristomal skin conditions for user intervention.
[0051] The peristomal skin injury can include inflamation, irritation and redness, fungal or bacterial infections, allergic reactions to an adhesive used to hold the ostomy pouch in place, pressure ulcers caused by the weight of the pouch or tight clothing, trauma from accidental removal or dislodgement of the pouch, fissures or tears in the skin caused by straining during bowel movements. Pressure ulcers can include bed sores. Skin injury and associated inflammation can have a significant effect on the tissue microenvironment, including increased oxygen consumption by highly metabolically active resident cells and recruited inflammatory cells. Normal wound- healing consists of four main stages — hemostasis, inflammation, proliferation, and remodeling — and sufficient oxygenation is a key component of healing. As a critical aspect of cell metabolism, oxygen prevents wounds from infection, induces angiogenesis, increases keratinocyte differentiation, migration, and re-epithelialization, enhances fibroblast proliferation and collagen synthesis, and promotes wound contraction.
[0052] However, as a result of vascular disruptions and enhanced metabolic and inflammatory processes during chronic inflammation, profound decreases in skin oxygen levels can occur, often leading to chronic localized tissue hypoxia that can worsen disease progression and lead to extended hospitalization. In chronic wounds, transcutaneous tissue oxygen levels have been measured from 5 to 20 mm Hg, compared with levels between 30 and 50 mm Hg in control tissues. The combined effect of neutrophil and monocyte recruitment with high proliferation of
lymphocytes leads to high rates of oxygen metabolism on and around the site of ongoing inflammation. Given that inflamed tissues consume transcutaneous oxygen more rapidly than normal tissues, quantitative measurements of skin oxygenation levels can reveal the severity and healing processes of injury over time.
[0053] Turning now to the figures, FIG. 1 illustrates a wearable sensor 14 mounted on a user. According to example embodiments shown schematically in FIG. 1, the wearable sensor 14 can be applied to peristomal skin around a stoma 12. The wearable sensor 14 can be used for transcutaneous oxygen monitoring based on phosphorescence emission of a metalloporphyrin embedded in a breathable oxygen-sensing film. In an embodiment, the wearable sensor 14 can be a liquid or gel film that can be painted on the peristomal skin. In another embodiment, the wearable sensor 14 can be a bandage, dressing, coating or barrier that can attach to a user’s peristomal skin. [0054] In an embodiment, oxygenation monitoring can include the use of the fluorescence emissions of phosphors embedded in a thin, oxygen-permeable liquid or gel film, to measure tissue oxygenation at the skin surface. The phosphors can undergo quenching in the presence of oxygen, so tracking the lifetime and intensity of phosphorescence can correlate directly to the progression of skin inflammation over time. The feasibility of such a device can be proven in preliminary in vivo testing models with consistently reproducible results between devices and calibrations. In an embodiment, the device can include machine learning models and remote monitoring.
[0055] FIG. 2 illustrates a diagrammatic section view of a wearable sensor 114. According to example embodiments shown schematically in FIG 2, the wearable sensor 114 can be attached to a user’s skin 112 on one side and be exposed to atmospheric oxygen 110 on the other. The wearable sensor 114 can be a liquid bandage or an oxygen-sensing bandage that can include phosphorescent metalloporphyrin molecules that can be excited by pulses of light. The liquid bandage 114 can
transcutaneously monitor oxygen based on inflamed tissue 116 consuming oxygen more rapidly than healthy tissue. Due to hypoxic conditions in areas of skin inflammation, a result of damage to local vasculature and the presence of oxygen-consuming pathogens, oxygen consumption could feasibly be used as a proxy for tracking the degree of tissue inflammation across a certain area of skin.
[0056] FIG. 3 illustrates a system 200 for detecting a peristomal skin injury. According to example embodiments shown schematically in FIG. 3, the system 200 can include a liquid or gel bandage or fdm 214, a light sensor unit 216, a sensor interface 218, and a computing unit 220. The liquid bandage or fdm 214 can include phosphorescent metalloporphyrin molecules that can be excited by pulses of light based on oxygen consumption. The light sensor unit 216 can include a phosphorimeter, a camera or other photosensitive sensors capable of detecting phosphorescence. The light sensor unit 216 can also include a light unit such as a light out device, LED, flashlamp, or laser that can output light pulses. The light sensor unit 216 can be mounted to cover an area of the liquid bandage 214. The light sensor unit 216 can output light pulses and measure the phosphorescent output of the covered area of the liquid bandage or fdm 214.
[0057] In an embodiment, the light sensor unit 216 can be placed along or adjacent an area where inflammation is most likely to occur. For example, the light sensor unit 216 can be placed at an area close to the stoma (an inner ring of the liquid bandage 214), where irritation and inflammation can occur due to its proximity to stoma output. In another example, the light sensor unit 216 can be placed at an area below the inner ring of the oxygen sensing liquid, gel or fdm 214, near a user’s hip (where stoma output could descend due to gravity). In an embodiment, the light sensor unit 216 can cover the entire oxygen sensing liquid or gel bandage 214 to measure the phosphorescent output of the entire liquid bandage 214 (FIG. 4C). In an embodiment, the sensor
216 can include small battery-powered systems with oxyphor-based sensor heads. The sensor interface 218 can comprise connecting wires that can electronically connect the sensor 216 and computing unit 220 to acquire data from the light sensor unit 216. The computing unit 220 can analyze the acquired data to determine oxygen consumption (see FIG. 15).
[0058] FIG. 4A shows a user’s abdomen with a stoma 312 and inflamated peristomal skin 322. FIG. 4B shows the user’s abdomen of FIG. 4A with the stoma 312 and a liquid bandage 314 attached over the peristomal skin. FIG. 4C shows a captured image 324 of a liquid bandage 326 with a detected oxygen consumption area 328. In an embodiment, the captured image 324 can be captured by a sensor (such as sensor 116) being placed in front of the liquid bandage 314. For example, the sensor can be a handheld device such as a mobile phone having a camera or other image capture device/sensor.
[0059] In another embodiment, a patient, user or clinician can apply the liquid bandage when an ostomy bag is changed to detect inflammation while the ostomy bag is worn. For example, the wearable sensor can be incorporated into a barrier adhesive and the barrier can have openings and mechanical mechanisms to expose the liquid bandage for measuring phosphorescence. This method could allow for more frequent measurements of the oxygen consumption rate. A computing unit could also be incorporated therein to push automatic alerts to medical professionals allowing rapid intervention if a peristomal skin condition is developing. For example, the computing unit can provide haptic feedback, sound, and light alerts.
[0060] In an embodiment, the wearable sensor 14, 114, 214 can include an ethanol-based gel or liquid bandage (such as NEW-SKIN®), embedded with phosphorescent molecules. The phosphorescent molecules can include Oxyphor R2 and Coumarin 500 that may be used as a red, oxygen-sensing dye and a green reference dye, respectively. The excitation and emission
wavelengths of the two dyes in the liquid bandage can icnclude:
Oxyphor R2: λex = 415nm, λem = 690nm
Coumarin 500: λex = 392nm, λem = 495nm
[0061] In an embodiment, a mechanism of porphyrin phosphorescence can include Oxyphor R2. Oxyphor R2 may be categorized as a porphyrin molecule, which is a heterocyclic organic compound that consists of four modified pyrrole subunits, which are connected via methine bridges at the a-carbon atom. Metal complexes comprising porphyrins and/or metalloporphyrins occur naturally and these molecules may be found throughout the human body. For example, heme is an iron-containing porphyrin complex found in hemoglobin.
[0062] Porphyrins may demonstrate a certain luminescent emission, phosphorescence, which is light emission similar to fluorescence, but on a longer timescale that can continue after initial excitation. After being excited by exposure to a photon, most porphyrins undergo internal conversion to an initial singlet state over a picosecond timescale. Then, the porphyrin may quickly change the configuration to form a metastable triplet state. Triplet state formation is typically very efficient in porphyrins, and certain irregular metalloporphyrins have electronic spectra that are significantly affected by their central atoms. Several Pt(II) and Pd(II) complexes display hypsochromic spectra, which means that triplet state formation enables a particularly strong emission of phosphorescence.
[0063] Molecular triplets have a tendency to interact with other molecular triplets. One of the most prevalent molecular triplets in nature is oxygen. The excited triplet states of Pt and Pd porphyrins have been shown to be effectively quenched by molecular (triplet) oxygen both in solid- state oxygen-permeable materials and in solutions. However, Pd(II) porphyrins have lifetimes on the order of approximately 500-1000 ps, which are ten times longer than the half-lives of Pt(II)
porphyrins and better-suited to measuring low oxygen levels. When porphyrin triplets interact with oxygen triplets, they transfer energy to the oxygen molecules before the porphyrins phosphoresce. This interaction converts the porphyrin triplet excited state to a singlet ground state, resulting in a lower energy level and a dimmer light emission. Therefore, more oxygen in the environment can result in a dimmer porphyrin phosphorescence emission, due to the transfer of energy between triplets. FIG. 5 illustrates a prior art Jablonski diagram of the electronic states of a porphyrin interacting with an oxygen molecule.
[0064] Dynamic quenching by oxygen and the relationship between emission intensity and oxygen concentration (pO2) can be described by the Stern- Volmer equation (1).
[0065] Where I is the phosphorescence intensity at the measured oxygen concentration pO2; 10 is the phosphorescence intensity in the absence of oxygen; and Ksv is the Stern- Volmer quenching constant.
[0066] Oxyphor R4, in particular, is a metalloporphyrin derived from phosphorescent Pd- meso-tetra-(3,5-dicarboxyphenyl)-porphyrin (PdP). This porphyrin is highly soluble in aqueous environments and is known to not permeate biological membranes. FIG. 6 illustrates structures of a prior art Oxyphor R4 and Oxyphor G4.
[0067] In an embodiment, the liquid bandage can include oxyphor that can be esterified in order to enhance the compatibility of the dye with the ethanol-based liquid bandage matrix. Esterified Oxyphor R2 may then be mixed with Coumarin and NEW-SK1N® liquid bandage in order to formulate the liquid bandage. This mixture can be painted onto a small area of skin and, within several minutes of air-drying, the liquid should harden into a thin film.
[0068] In an embodiment, the oxygen consumption rate under an oxygen sensing film applied
as a liquid or gel bandage can be used as a proxy for skin inflammation. It can be assumed that this rate of consumption is constant during the measurement period, and the rate of diffusion out of the liquid bandage can be constant and directly related to the oxygen consumption rate under the bandage. In addition, there is constant O2 content in the air in contact with the upper surface of the sensing fdm. Given a constant concentration on the exposed side and a constant diffusion rate on the other, the system can eventually reach a state of equilibrium in which the oxygen content of the bandage is constant and can be directly related to the oxygen consumption rate under it. Consequently, the equilibrium oxygen content in the liquid bandage after application on the skin can be used as a proxy for skin inflammation.
[0069] Furthermore, metalloporphyrin can demonstrate measurable changes in phosphorescence emission intensity with changing oxygen content inside the bandage. Therefore, the equilibrium phosphorescence emission can be used as a proxy for skin inflammation.
[0070] Experimental Approach:
[0071] In an embodiment, tegaderm can be used as a top layer on the liquid bandage to control oxygen levels. In another embodiment, the liquid bandage can be exposed to atmospheric oxygen since the rate of oxygen consumption in the skin can be related to the partial pressure of oxygen in the bandage and thus to the phosphorescence intensity at equilibrium.
[0072] In an embodiment, the model can be validated by directly relating the phosphorescence intensity to known values of oxygen consumption rate, show a change in phosphorescence with inflammation, and test new formulations of the liquid bandage with different porphyrins. To do so, a model of oxygen consumption can be used. Solutions of cells such as yeast in different concentrations can be used. In order to relate the concentration of cells to the average rate of oxygen consumption, an oxygen meter can be used. The liquid bandage can be prepared using
Oxyphor G4, Oxyphor R4, and Oxyphore without the control green dye (Coumarin)
[0073] A time until the equilibration of oxygen flux between the atmosphere, the bandage, and the oxygen consuming medium underneath can be determined. To do so, a thin layer of liquid bandage can be solidified on a glass slide then transferred on top of the wells containing the solutions of cells with different concentrations. Measurements of the red and green emission intensities can be taken thereafter on the order of every two minutes for at least 20 minutes.
[0074] Finally, the partial pressure of oxygen in the bandage can be calculated using the emission intensity given equation (1). This result can allow a validation of the relation between the difference in pO2 at equilibrium and in the air and the known oxygen consumption rates. Consequently, a clear relationship between the intensity of emissions and the oxygen consumption rate can be acquired, which is a direct measure of inflammation. This calibration can also be done for new liquid bandage formulations, including Oxyphor G4, which might result in greater sensitivity.
[0075] In an embodiment, near-infrared (NIR) imaging of the incorporated fluorophores can be used to extract meaningful information from the liquid bandage. In an embodiment, Thyristor(R) Speedlight flash units with the proper bandpass fdters can be used to excite the dyes and a NIR complementary metal-oxide-semiconductor (CMOS) camera with a macro lens and a digital delay/pulse generator to capture the resultant fluorescence. These materials, however, are expensive. One potential imaging system that may be suitable is the in vivo imaging system (IVIS) Spectrum as its range of excitation and emission fdters are near an image range. Another potential imaging system can include an 3i Lattice Lightsheet Microscope with Bessel Beam Illumination. This microscope can include a CMOS NIR camera.
[0076] In an embodiment, a solidified liquid bandage of thickness containing dyes can be
deposited on the skin which consumes oxygen with a constant (negative) rate Ren. skin. The surface of the bandage can be in contact with the air which has a constant oxygen content at a partial pressure pCh(air). An amount of oxygen inside the bandage given diffusion from the air into it and out of it to the skin can be calculated. The change in oxygen content can be described by the following mass transport equation:
[0078] Where D02 is the diffusivity of oxygen in the material considered and v is the bulk velocity.
[0079] Assuming no convection and that diffusion is only happening in the x direction which is perpendicular to the surface of the skin:
[0080] After a certain amount of time, a steady-state should be achieved in which the oxygen content of the bandage is constant and depends on R02,skin; this value can be used to calculate oxygen inside the bandage. Consequently, analysis at steady-state can be conducted. Hence:
[0081] This equation applies to both the change in oxygen inside the bandage and in the skin.
However, inside the bandage, there is no reaction happening so:
[0082] Thus: pO2(Jmndage) — m1 - m2 (8)
[0083] Let x = 0 be at the level of the bandage surface in contact with the air and the x direction into the skin.
[0084] The boundary conditions (BC) are then:
[0085] BC1 : constant oxygen content at the surface in contact with the air pO2(bandage, x = 0) = pO2(air)
→ m2 = pO2(air)
[0087] BC3 : assume that the superficial skin layer of thickness ds is supplied by the diffusion of oxygen from the atmosphere, and beyond this depth the tissue oxygen is supplied by circulation.
[0091] Hence, the oxygen content inside the bandage at steady-state can be directly related to the oxygen consumption rate under it.
[0092] Since the oxygen content inside the bandage can also be related to the intensity of Oxyphore R4 emission using the Stern- Volmer equation, the intensity of emission can be a proxy for skin level inflammation where a greater intensity corresponds to less oxygen in the bandage, so a higher oxygen consumption rate in the skin can be representative of a higher level of inflammation.
[0093] In an embodiment, a yeast model can be very similar to the skin model but with slight differences. The yeast solution can be placed in a well with depth dw and can consume oxygen at a rate
R02, yeast
[0094] ¾ of the well can be filled with the yeast solution (0.3mL) while the top ¼ contains air which it can be assumed does not have a bulk velocity either.
[0095] As a result, the change in oxygen inside this region containing air should also be considered, which cab be referred to as “air 2” to avoid confusion with the air that is in contact with the top surface of the bandage. Assuming also no convection in this very small volume and
no bulk reactions, a transport equations are:
[0097] The boundary conditions remain largely the same:
[0098] BC 1 : constant oxygen content at the surface in contact with the air pO2(handage,x = 0) = pO2(air) → m 2 = pO2(air)
[00106] This equation is very similar to the one obtained for the skin model. It can also demonstrate a direct relation to the oxygen consumption rate under the liquid bandage to the steady-state oxygen content of the liquid bandage. Accordingly, the model can serve as a good proof-of-concept for the functioning of the liquid bandage.
[00107] In an embodiment, oxygen consumption models can be tested. The oxygen consumption models developed for this experiment were yeast solutions of varying optical densities. As opposed to doing studies with animals or patients, a yeast oxygen-consumption model offers an easier and more cost-effective alternative. In the presence of oxygen, yeast undergo aerobic respiration, converting oxygen and carbohydrates into carbon dioxide and water. Various solutions containing different amounts of yeast can be used, such that different rates of oxygen consumption can be observed as the yeast respire.
[00108] A first step in developing yeast oxygen consumption models can be to create sterile
yeast extract, peptone, and dextrose (YPD) broth, which is a solution of yeast extract, peptone, and dextrose. YPD is a commonly used growth media for maintaining cultures of S. cerevisiae yeast. To prepare a YPD solution, 50 g of YPD powder (Sigma-Aldrich Y1375) may be dissolved in 1 L of distilled water then the solution can be autoclaved for 20 minutes. This YPD broth was cooled at room temperature.
[00109] To make the yeast solutions, a solution of 0.1 g of yeast in 10 mL of YPD broth in a 10 mL sterile tube can be made. Next, this initial solution can be diluated by 20, and then consecutive 2-fold dilutions can be performed to create 5 more yeast solutions. To characterize a yeast densities, light scattering can be used. Using a spectrophotometer, the maximum reading can be 2.5, and the dilutions that would give several solutions with readings below about 1.5 can be used. The solutions can be left at room temperature during a characterization experiments and later during the transportation to the imaging site as well as while imaging.
[00110] Oxygen consumption of each yeast solution can be assessed using a respiration chamber that measured the pO2 of the yeast solutions as the organisms consumed oxygen from the solutions at a constant rate. The assay was conducted in a small 4 mL respiration chamber that contained a small stir bar and a Clark-type oxygen electrode.
[00111] This electrode, located at the base of the reaction chamber, consists of a platinum cathode and a silver-chloride anode. An electrolyte solution can be placed over the tip of the electrode and prevented from diffusing into the reaction chamber by an oxygen-permeable Teflon membrane. Oxygen can diffuse across the membrane between the electrolyte solution and the yeast solution in the chamber. Voltage measurements can be transmitted to a computer and the data was collected using the PowerLab software. For each measurement, approximately 2 mL of yeast solution can be added. The solution can be taken up in a syringe, then air can be introduced through
the stopcock to fill the syringe in order to oxygenate the solution. The stopcock can then closed and the solution can be mixed thoroughly by swirling and tilting the syringe. This process oxygenates the solution, such that conditions are primed to observe oxygen consumption by the yeast immediately upon adding the yeast to the chamber. The chamber can be rinsed with deionized water multiple times between measurements.
[00112] Once each yeast solution can be added to the chamber, time for the yeast to consume the oxygen can be allowed until the trace demonstrates a distinct constant slope. The measurements can be recorded in terms of voltages by converting them to partial pressures of oxygen. To do so, two points with known oxygen contents can be used to calibrate measurements. So, the voltage can be measured when the chamber was empty (filled with air) and set that to be equal to an atmospheric pO2 at 25°C, which is 153 mmHg. For the second point, the plateau that the voltage reached once the yeast had consumed most of the oxygen can be used. This can be set to be equal to 3 mmHg because at this level, the yeast switch to fully anaerobic respiration and they can never fully deplete the oxygen in the solution.
[00113] FIG. 7A is a graph of the results of oxygen consumption rate measurements. Specifically, FIG. 7A shows a change in pO2 of the solutions in the chamber with time for yeast solutions with different optical densities. The curves were aligned such that the time at which the solutions were added was t=50s for all of them.
[00114] FIG. 7B is a graph of the results of oxygen consumption rate measurements. Specifically, FIG. 7B shows a linear regression between the slope of the linear portions at the end of the curves in panel (a) and the optical density of the yeast solutions.
[00115] Figure 7A shows the pO2 values of the various yeast solutions changing with time. Compared to the negative control, the yeast solutions show a decrease in the amount of oxygen in
the chamber with time. The rate of decrease generally increases as the optical density (OD) of the solution increases as can be expected. Given that the yeast is placed in a closed chamber, the rate of decrease of pO2 can be considered as the rate of oxygen consumption by the yeast. It is can also be significant to note that the solutions took only a short amount of time to reach a period at which the rate of oxygen consumption appears to be constant (indicated by constant slopes observed at later time points). A correlation of each OD600 with the corresponding rate of oxygen consumption can be done, as seen from the strong linear negative correlation established in FIG. 7B. OD600 can be an amount of light absorbed by the culture at a wavelength of 600 nm using a spectrophotometer.
[00116] Consequently, the yeast solutions of varying concentrations can be a good model of oxygen consumption and the rate of consumption can be easily determined by the measurement of the optical density of the solution using a spectrophotometer.
[00117] In an embodiment, after establishing a working oxygen consumption model, a liquid bandage and its formulation can be determined. A solidified liquid bandage sealed over the top of wells in a plate containing yeast solutions can be used. The plastic can be very sticky and stretchable.
[00118] In another embodiment, a sample of oxyphor R4, coumarin 500, and liquid bandage in a 10: 1 : 10 ratio can be used. After preparing the samples with the liquid bandage sealed over top of the wells, trials with different formulations of oxyphor, coumarin, and liquid bandage on top can be done. For the first trial, a sample of oxyphor R4 (200 uM), coumarin 500 (10 mM), and liquid bandage in a 10: 1:10 ratio can be combined in a small vial, and 5 μL of this mixture can be pipetted on top of each well. Imaging can be done for 6 minutes at 2-minute intervals and the average radiant efficiency in each well can be recorded and the average background noise can be
subtracted. Experiments can be conducted, and as seen in FIG. 9C, the average emission intensity from the solutions on top of wells with a given yeast density was constant throughout the measurement period. This can be a good indication that by the time imaging was started, the equilibrium between oxygen diffusing into and out of the liquid bandage had been achieved. In addition, it can show that the imaging period and imaging parameters used was not causing any significant photobleaching. Consequently, an averaging of these measurements in time for each optical density and plotted this average against the optical density. The coumarin can be used as a reference dye since its emission should not change in response to changes of oxygen concentration. Its inclusion can be for the purpose of normalizing any error or background interference that may have occurred during imaging. Using both the non-normalized (Fig. 9A) and normalized (Fig. 9B) emissions, it may be difficult to see a trend that relates the emission intensities to the yeast density- and as such to the oxygen consumption rate. This may probably be due to the immiscibility of the solutions in the mixture described earlier, which resulted in inconsistent amounts of oxyphore and coumarin in different samples of it with equal volumes.
[00119] FIGS. 8A-8C show data produced for a trial using 5 uL of a 10:1 : 10 mixture of liquid bandage, coumarin, and oxyphor R4 pipetted on top of the liquid bandage. FIG. 8A shows a phosphorescence of oxyphor R4 averaged across all images at different time points plotted against OD600. The error bars are +/- 1 standard deviation (SD). FIG. 8B shows a phosphorescence of time averaged oxyphor R4 phosphorescence normalized by time averaged coumarin phosphorescence averaged plotted against OD600. FIG. 9C shows phosphorescence over time for each OD600 sample.
[00120] In an embodiment, in order to work around the immiscibility issues, another trial can be attempted in which coumarin 500 (0.24 μL), oxyphor (2.4 μL), and liquid bandage (2.4 μL) can
be pipetted separately on top of the bandage on the wells directly This may allow for more consistent amounts of the dyes to be applied to each well. The imaging results for this trial are shown in FIGS. 9A and 9B. A relationship between the emission intensity and the yeast optical density may be difficult to obtain. These difficulties might be due to the very small volume used, which amplifies the effect of small differences in the volume pipetted.
[00121] FIGS. 9A-9B shows data produced for a trial using coumarin 500 (0.24 μL), oxyphor (2.4 μL), and liquid bandage (2.4 μL) pipetted directly on top of the solidified liquid bandage. FIG. 9A shows phosphorescence of oxyphor R4 averaged across all images at different time points plotted against OD600. FIG. 9B shows phosphorescence of time averaged oxyphor R4 phosphorescence normalized by time averaged coumarin phosphorescence averaged plotted against OD600.
[00122] Consequently, in another embodiment, a larger volume (20 μL) can be used of only Oxyphor R4 in water on top of the solidified liquid bandage covering the wells. The data from this trial can be visualized in FIGS. 10A and 10B. A clear trend in which the emission increases as the optical density of the yeast solutions increases can be obtained. This may be because as the OD increases, the oxygen consumption rate increases. This may result in less oxygen in the bandage at equilibrium as described by the mathematical model. As a result, less oxyphore may be quenched and the emission may be greater.
[00123] Using the results of the yeast oxygen consumption model in which a linear relationship between the optical density and the rate of oxygen consumption is obtained, the data can be transformed to show the intensity of emission as a function of the rate of oxygen consumption. Due to the linear relationship and the fact that a greater oxygen consumption rate is represented by a greater negative value, the plot can be simply a mirror image of the one as a function of OD. The
hyperbolic shape of this emission curve can agree with the prediction of the model. A better proof of concept can be to compare it to the predicted curve but this may require knowingthe maximum emission of Oxyphore R4 for the Stem-Volmer equation, the diffusion coefficient of oxygen in the liquid bandage, and the thickness of the liquid bandage. Nevertheless, the lack of unreasonable assumptions in the model which agrees with the shape of this curve serves as a good proof-of- concept for the sensor.
[00124] FIGS. 10A and 10B show data produced for a trial using only oxyphor R4 pipetted on top of the liquid bandage. FIG. 10A shows phosphorescence of oxyphor R4 averaged across all images at different time points plotted against OD600. FIG. 10B shows fluorescence as a function of oxygen consumption rate, determined using the results from the yeast model characterization results to relate OD600 to oxygen consumption rate.
[00125] In one or more embodiments, a liquid bandage can include an alginate hydrogel as an alternative to the liquid bandage. Two formulations of the hydrogel can be CaS04 or CaCl2 as the source of bivalent positive ions for crosslinking. In an experiment, a base solution of 2% weight per volume of sodium alginate in deionized water can be used. In a first hydrogel formulation, 0.435 g of CaS04 can be added to 50 mL of alginate solution with the goal of having the number of moles of calcium in the hydrogel equal half the moles of alginate monomers in the gel. To this formulation, 2.5 mL of ethanol can be added in order to simulate the approximate ratio of ethanol that would be added to the hydrogel via the coumarin in solution. Ethanol can react with alginate to form a precipitate, which may pose an issue because a homogeneous solution may be needed in order to image. However, because promising phosphorescence results were achieved for the trial done with only Oxyphor (no coumarin), testing hydrogel formulations were continued without the addition of the ethanol.
[00126] In an embodiment, the two hydrogel formulations, CaSO4 and CaCl2 in alginate solution can be used. These formulations with varying calcium can be used, including alginate monomer ratios. In an embodiment, CaSO4 may not dissolve easily in the alginate solutions so a large part of it settled to the bottom of the solution container. The supernatant of the CaSO4 hydrogel mixture can be poured off to form relatively homogeneous solutions that can be of an acceptable consistency for a liquid bandage material. Tn an embodiment, addition of CaCl2can resulted in crosslinking resulting in clumps in the solutions which may make it difficult to get a homogeneous gel. In an embodiment, an alginate hydrogel can include CaSO4 having between 0.130mL to 0.520mL. In another embodiment, the alginate hydrogel can include CaCl2 having between 0.5275mL to ImL.
[00127] Given the results with CaSO4, the most promising hydrogel formulation was created by first completely dissolving 0.130 g of CaS04 in 10 mL of deionized water, then this can be mixed with 2% weight per volume of sodium alginate in deionized water in a 1 :1 ratio (resulting in a final solution with 1% w/v alginate). This formulation formed a clear hydrogel that would be appropriate for imaging (FIG. 13). In another embodiment, this hydrogel formulation may be characterized in order to take phosphorescence readings using Oxyphor R4 incorporated into the hydrogel.
[00128] A paint-on liquid bandage embedded with oxygen-sensitive metalloporphyrins can offer capabilities as a transcutaneous device for tracking skin injury. The ability to develop these sorts of responsive bandages will ultimately improve patient care and the treatment of peristomal skin injuries.
[00129] Specifically, issues with miscibility between the liquid bandage and oxyphor sensors can be encountered. The liquid bandage solution mav not be miscible with water, but the Oxyphor
R4 may only be available in aqueous solutions. To counter this issue, the bandage could be composed of an alginate-based hydrogel embedded with oxyphors. Alternatively, if the alginate hydrogel proves technically infeasible due to compatibility or degradation concerns, other embodiments could seek to utilize different components. Oxyphor R4s could either be purchased out of solution, isolated from the aqueous solution, or dissolved in ethanol as the solvent. Instead of the NEW-SKIN® liquid bandage, other liquid bandage formulations with fewer hydrophobic elements can be used. These adjustments could result in a bandage that has greater structural integrity. If the alginate hydrogel is a suitable option, a water-soluble control dye can be used. Coumarin 500 does not dissolve in water, but the typical solvent for Coumarin 500, ethanol, appeared to react with alginate. Therefore, neither ethanol nor water may be used in alginate hydrogels with coumarin. The use of alginate hydrogels may require the identification and purchase of a water soluble dye to replace Coumarin 500. Finally, measurements of oxygen diffusivity in the final liquid bandage, maximum oxyphore emission, and thickness of the bandage may allow a more complete proof-of-concept.
[00130] FIG. 11 shows a method 1100 for detecting peristomal skin injury. The method may be applied to a computing device such as a wearable device, mobile device, personal computer or server. For example, the wearable device may include the light sensor unit 216, the sensor interface 218, and the computing unit 220.
[00131] In step 1110, the wearable device can output light pulses, through a light output device, onto a wearable sensor mounted on peristomal skin. The wearable sensor may include phosphorescent metalloporphyrin molecules that are excited by pulses of light based on oxygen consumption. For example, the wearable sensor may be a liquid bandage that is painted on a user’s abdomen near a stoma. The liquid bandage, once dry, can output phosphorescence when exposed
to light pulses.
[00132] In step 1120, the wearable device can obtain phosphorescence intensity levels of the phosphorescent metalloporphyrin molecules excited by the pulses of light. The wearable device, trough, for example, a phosphorimeter can detect phosphorescence and calculate phosphorescence intensity levels.
[00133] In step 1130, the wearable device can determine a peristomal skin injury based on the phosphorescence intensity levels. The wearable device, for example, can use the phosphorescence intensity levels to determine oxygen consumption levels under the wearable sensor. The oxygen consumption levels can include an oxygen consumption rate that can be used to determine a peristomal skin injury.
[00134] FIG. 12 shows a computing system 1200 that can be part of the system 200 for detecting a peristomal skin injury. According to example embodiments shown schematically in FIG. 12, the computing system 1200 can include a computing environment 1210, a user interface 1250, a communication unit 1260. The computing system can further include a haptic motor and an accelerometer. The computing environment 1210 can include a processor 1220, a memory 1230, and an I/O interface 1240. The computing environment 1210 can be coupled to the user interface 1250 and communication unit 1260 through the I/O interface 1240.
[00135] The processor 1220 can typically control the overall operations of the computing environment 1210, such as the operations associated with data acquisition, data processing, and data communications The processor 1220 can include one or more processors to execute instructions to perform all or some of the steps in the above-described methods. Moreover, the processor 1220 can include one or more modules that facilitate the interaction between the processor 1220 and other components. The processor may be or include a central processing unit
(CPU), a microprocessor, a single chip machine, a graphical processing unit (GPU) or the like.
[00136] The memory 1230 can store various types of data to support the operation of the computing environment 1210. Memory 1230 can include predetermined software 1231. Examples of such data comprise instructions for any applications or methods operated on the computing environment 1210, raw data, detected data, oxygen levels, phosphorescence intensity levels, light levels, etc. The memory 1230 may be implemented by using any type of volatile or non-volatile memory devices, or a combination thereof, such as a static random-access memory (SRAM), an electrically erasable programmable read-only memory (EEPROM), an erasable programmable read-only memory (EPROM), a programmable read-only memory (PROM), a read-only memory (ROM), a magnetic memory, a flash memory, a magnetic or optical disk.
[00137] The I/O interface 1240 can provide an interface between the processor 1220 and peripheral interface modules, such as a RF circuitry, external port, proximity sensor, audio and speaker circuitry, video and camera circuitry, microphone, accelerometer, display controller, optical sensor controller, intensity sensor controller, other input controllers, keyboard, a click wheel, buttons, and the like. The buttons may include but are not limited to, a home button, a power button, and volume buttons.
[00138] The user interface 1250 can include a speaker, lights, display, haptic feedback motor or other similar technologies for communicating with the user.
[00139] Communication unit 1260 provides communication between the processing unit, an external device, mobile device, and a webserver (or cloud). The communication can be done through, for example, WIFI or BLUETOOTH hardware and protocols. The communication unit 1260 can be within the computing environment or connected to it.
[00140] In some embodiments, there is also provided a non-transitory computer-readable
storage medium comprising a plurality of programs, such as comprised in the memory 1230, executable by the processor 1220 in the computing environment 1210, for performing the above- described methods. For example, the non-transitory computer-readable storage medium may be a ROM, a RAM, or the like.
[00141] The non-transitory computer-readable storage medium has stored therein a plurality of programs for execution by a computing device having one or more processors, where the plurality of programs when executed by the one or more processors, cause the computing device to perform the above-described method for motion prediction.
[00142] In some embodiments, the computing environment 1210 may be implemented with one or more application-specific integrated circuits (ASICs), digital signal processors (DSPs), digital signal processing devices (DSPDs), programmable logic devices (PLDs), field-programmable gate arrays (FPGAs), graphical processing units (GPUs), controllers, micro-controllers, microprocessors, or other electronic components, for performing the above methods.
[00143] From the foregoing it will be observed that numerous modifications and variations can be effectuated without departing from the true spirit and scope of the novel concepts of the present disclosure. It is to be understood that no limitation with respect to the specific embodiments illustrated is intended or should be inferred. The disclosure is intended to cover by the appended claims all such modifications as fall within the scope of the claims.
Claims
1. A system for detecting oxygen at a skin surface, indicating peristomal skin injury, other skin injury, and/or injury or wound healing comprising: a wearable sensor, wherein the wearable sensor comprises phosphorescent metalloporphyrin molecules that are excited by pulses of light based on oxygen consumption; a light sensor, wherein the light sensor can detect phosphorescence from the wearable sensor; and a computing unit, wherein the computing unit determines a peristomal skin injury based on the detected phosphorescence.
2. The system of claim 1, wherein the wearable sensor is mounted to peristomal skin.
3. The system of claim 1, wherein the computing unit determines the peristomal skin injury by measuring an oxygen consumption rate on the wearable sensor based on the detected phosphorescence.
4. The system of claim 1, further comprising: a light unit, wherein the light unit outputs light pulses to excite the phosphorescent metalloporphyrin molecules.
5. The system of claim 1, wherein the light sensor is attached to at least part of an area of
the wearable sensor.
6. The system of claim 1, wherein the light sensor comprises a handheld device.
7. The system of claim 1, wherein the wearable sensor comprises an ethanol-based gel or liquid adhesive.
8. The system of claim 7, wherein the ethanol-based gel or liquid adhesive comprises an esterified oxyphor solution and coumarin.
9. The system of claim 8, wherein the ethanol-based gel or liquid bandage is painted onto an area of peristomal skin.
10. The system of claim 1, wherein the wearable sensor comprises an alginate hydrogel.
11. The system of claim 10, wherein the alginate hydrogel comprises CaSO4.
12. A method for detecting peristomal skin injury comprising: outputting light pulses onto a wearable sensor mounted on peristomal skin, wherein the wearable sensor comprises phosphorescent metalloporphyrin molecules that are excited by pulses of light based on oxygen consumption; obtaining phosphorescence intensity levels of the phosphorescent metalloporphyrin molecules excited by the pulses of light; and
determining a development of a peristomal skin injury based on the phosphorescence intensity levels.
13. The method of claim 12, wherein determining the peristomal skin injury comprises: measuring an oxygen consumption rate on the wearable sensor based on the phosphorescence intensity levels; and determining a status of the peristomal skin injury based on the oxygen consumption rate.
14. The method of claim 13, wherein the wearable sensor comprises a film-like adhesive applied as a liquid.
15. The method of claim 14, wherein the oxygen consumption rate comprises a constant rate during a measurement period and a rate of diffusion out of the film-like adhesive can be constant and directly related to the oxygen consumption rate under the film-like adhesive.
16. The method of claim 14, wherein the fdm-like adhesive is painted on the peristomal skin.
17. The method of claim 12, wherein obtaining phosphorescence intensity levels comprises obtaining a phosphorescence image of the wearable sensor.
18. A computing device for detecting peristomal skin injury comprising: one or more processors;
a non-transitory computer-readable storage medium storing instructions executable by the one or more processors, wherein the one or more processors are configured to: obtaining phosphorescence intensity levels of a wearable sensor mounted on peristomal skin, wherein the wearable sensor comprises phosphorescent metalloporphyrin molecules; measuring an oxygen consumption rate on the wearable sensor based on the phosphorescence intensity levels; and determining a peristomal skin injury based on the oxygen consumption rate.
19. The computing device of claim 18, wherein the wearable sensor comprises a film-like adhesive applied as a liquid or gel.
20. The computing device of claim 19, wherein the oxygen consumption rate comprises a constant rate during a measurement period and a rate of diffusion out of the film-like adhesive can be constant and directly related to the oxygen consumption rate under the film-like adhesive.
Applications Claiming Priority (4)
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| US202263319488P | 2022-03-14 | 2022-03-14 | |
| US63/319,488 | 2022-03-14 | ||
| US202263324307P | 2022-03-28 | 2022-03-28 | |
| US63/324,307 | 2022-03-28 |
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| PCT/US2023/064228 Ceased WO2023178034A1 (en) | 2022-03-14 | 2023-03-13 | System and method for detecting oxygen for prediction, detection, mitigation and/or prevention of peristomal skin injury |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6362175B1 (en) * | 1991-09-20 | 2002-03-26 | The Trustees Of The University Of Pennsylvania | Porphyrin compounds for imaging tissue oxygen |
| EP3019854B1 (en) * | 2013-07-10 | 2021-01-06 | The General Hospital Corporation | Compounds, systems, and methods for monitoring and treating a surface of a subject |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6362175B1 (en) * | 1991-09-20 | 2002-03-26 | The Trustees Of The University Of Pennsylvania | Porphyrin compounds for imaging tissue oxygen |
| EP3019854B1 (en) * | 2013-07-10 | 2021-01-06 | The General Hospital Corporation | Compounds, systems, and methods for monitoring and treating a surface of a subject |
Non-Patent Citations (1)
| Title |
|---|
| LI ZONGXI ET AL: "Sensing, monitoring, and release of therapeutics: the translational journey of next generation bandages", JOURNAL OF BIOMEDICAL OPTICS, SPIE, 1000 20TH ST. BELLINGHAM WA 98225-6705 USA, vol. 24, no. 2, 1 February 2019 (2019-02-01), pages 21201, XP060137964, ISSN: 1083-3668, [retrieved on 20181227], DOI: 10.1117/1.JBO.24.2.021201 * |
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