Ingestable capsule devices

Abstract

This technology provides non-invasive gastrointestinal sampling. In some embodiments, the device includes a capsule housing that defines a cavity, a sampling aperture formed within the capsule housing that provides fluid communication between the cavity and the exterior of the capsule housing, a luminescent substrate layer positioned within the cavity, the luminescent substrate being configured to emit luminescent light when exposed to a sample fluid containing a luminescence trigger, at least one additional substrate layer positioned within the cavity between the sampling aperture and the luminescent substrate, each of the at least one additional substrate layer being configured to chemically interact with the sample fluid, a photodetector positioned within the cavity and configured to detect the luminescent light, and a biodegradable coating that closes the sampling aperture, the degradation of the biodegradable coating exposing the sampling aperture and enabling fluid to flow into the cavity.

Description

Technical Field

[0001] The disclosed embodiments relate to ingestible capsule devices for detecting and evaluating the state of the digestive tract and related methods of use.

Background Art

[0002] The development of tools that can accurately detect specific conditions within the gastrointestinal (GI) tract can facilitate medical advancements such as the effective and accurate prediction and diagnosis of diseases and disease progression. For example, inflammatory bowel disease (IBD) is a group of intestinal disorders that cause chronic, relapsing inflammation of the GI tract. A variety of factors, including hyperreactive immune responses, genetic mutations in multiple genes, gut microbiota, and diet, can contribute to the development of IBD. Nearly 6.8 million cases of IBD were reported worldwide in 2017. It is estimated that nearly 1.6 million people in the United States alone are affected by two common types of IBD, Crohn's disease (CD) and ulcerative colitis (UC). Therefore, it may be desirable to predict and / or diagnose the progression of IBD.

[0003] Conventional techniques for diagnosing IBD include, for example, symptom monitoring, endoscopy, colonoscopy, and capsule endoscopy. More recently, certain biomarkers have been correlated with the occurrence and recurrence of IBD. Fecal sampling techniques have been developed to detect these biomarkers in a patient's feces. However, there remains a need to more effectively and accurately diagnose IBD and other GI conditions.

Summary of the Invention

[0004] In some embodiments, a device for passive sampling of a patient's gastrointestinal tract may include a capsule housing that defines the boundary of a cavity and a sampling opening formed within the capsule housing. The sampling opening may provide fluid communication between the cavity and the outside of the capsule housing. The device may further include a luminescent substrate layer positioned within the cavity. The luminescent substrate may be configured to emit luminescent light when exposed to a sample fluid containing a luminescent trigger. The device may further include at least one additional substrate layer positioned within the cavity between the sampling opening and the luminescent substrate. Each of the at least one additional substrate layer may be configured to chemically interact with the sample fluid. The device may also include a photodetector positioned within the cavity. The photodetector may be configured to detect luminescent light. The device may further include a biodegradable coating closing the sampling opening, so that the decomposition of the biodegradable coating may expose the sampling opening and allow fluid to flow into the cavity.

[0005] In some embodiments, a method may be provided for detecting biomarkers in a patient's gastrointestinal tract, the method comprising administering an ingestible device to the patient. The ingestible device may include a capsule housing that defines the boundary of a cavity and a sampling opening formed within the capsule housing that provides fluid communication between the cavity and the outside of the capsule housing. A luminescent substrate may be positioned within the cavity. The luminescent substrate may be configured to emit luminescent light when exposed to a sample fluid containing a luminescent trigger. The luminescent trigger may indicate the presence of a biomarker. A photodetector may be additionally positioned within the cavity. The photodetector may be configured to detect luminescent light and generate a detection signal. A wireless transmitter of the device may be configured to transmit a wireless signal based on the detection signal. The method may further include exposing the luminescent substrate to the sample fluid, receiving the wireless signal in a user device, and determining, based on the wireless signal, whether or not a biomarker is present in the sample fluid.

[0006] The concepts described above and the additional concepts discussed below may be arranged in any preferred combination, and it should be understood that this disclosure is not limited in this respect. Furthermore, other advantages and novel features of this disclosure will become apparent from the following detailed description of various non-limiting embodiments when considered in relation to the accompanying drawings.

[0007] In the event of any conflicting and / or inconsistent disclosures between this Specified and any documents incorporated by reference, this Specified shall prevail. If two or more documents incorporated by reference contain conflicting and / or inconsistent disclosures, the document with the later effective date shall prevail. [Brief explanation of the drawing]

[0008] The attached drawings are not intended to be drawn to scale. In the drawings, identical or nearly identical components illustrated in various figures may be represented by the same number. For clarity, not all components may be labeled in all drawings. In the drawings, [Figure 1] A schematic internal diagram of an ingestible capsule device according to one embodiment is shown. [Figure 2] A schematic diagram of an ingestible capsule device that operates within the patient's GI duct, according to one embodiment, is shown. [Figure 3] A schematic diagram of various substrate layers and photodetectors according to one embodiment is shown. [Figure 4A] This shows a plot of luminescence intensity during the time the opening of the capsule device according to one embodiment remains closed. [Figure 4B] This shows a plot of luminescence intensity during the time the opening of the capsule device according to one embodiment is open. [Figure 5A] A perspective view of a threaded capsule of an ingestible capsule device according to one embodiment is shown. [Figure 5B] A perspective view of a threadless capsule of an ingestible capsule device according to one embodiment is shown. [Figure 5C] Three substrate layers of an ingestible capsule device according to one embodiment are shown. [Figure 5D] This shows a front view of the electronic unit of an ingestible capsule device according to one embodiment. [Figure 5E] This shows a top view of the electronic unit of an ingestible capsule device according to one embodiment. [Figure 6A] This is a plot of luminescence intensity at various pH values ​​of a fluid sample containing MPO upon exposure to luminol, relating to one embodiment of an ingestible capsule device. [Figure 6B] Figure 6A shows the plot of peak luminescence intensity for various pH values. [Figure 7A]This document describes an experimental setup for evaluating various concentrations of pH buffers related to one embodiment of an ingestible capsule device. [Figure 7B] The pH values ​​obtained by concentrations evaluated using the settings in Figure 7A, relating to one embodiment of an ingestible capsule device, are shown. [Figure 8A] This shows a heatmap of luminescence intensity peak values ​​obtained from the interaction of UHP and luminol in the absence of MPO, relating to one embodiment of an ingestible capsule device. [Figure 8B] This shows a heatmap of luminescence intensity peak values ​​obtained from the interaction of UHP and luminol in the presence of MPO, relating to one embodiment of an ingestible capsule device. [Figure 8C] Figure 8B shows a heatmap of the difference between the peak intensity values ​​in Figure 8A and Figure 8B for one embodiment of an ingestible capsule device. [Figure 9A] This shows time curves of luminescence intensity resulting from various concentrations of MPO exposed to luminol in one embodiment of an ingestible capsule device. [Figure 9B] This shows the area under each time curve in Figure 9A according to one embodiment. [Figure 9C] This shows a time curve of voltage generated by a photodetector in response to luminescence resulting from various concentrations of MPO exposed to luminol in one embodiment of an ingestible capsule device. [Figure 9D] The area under each time curve in Figure 9C, relating to one embodiment, is shown. [Figure 10A] This shows a time curve of voltage generated by a photodetector in response to luminescence resulting from various biomarkers at various concentrations exposed to luminol in one embodiment of an ingestible capsule device. [Figure 10B] This shows the area under each time curve in Figure 10A, relating to one embodiment. [Figure 11A]An experimental setup for evaluating ex vivo detection of MPO is shown, regarding one embodiment of an ingestible capsule device that is prepared for insertion into the porcine small intestine. [Figure 11B] The experimental setup of FIG. 11A is shown, where the capsule device is inserted into the porcine small intestine. [Figure 11C] The time curve of the voltage generated by a photodetector in response to luminescence from various concentrations of MPO in the experimental setup of FIG. 11A is shown. [Figure 11D] The area under each time curve of FIG. 11C is shown, regarding one embodiment.

Mode for Carrying Out the Invention

[0009] As described above, conventional methods for detecting and evaluating the state within a patient's GI tract may include symptom monitoring, endoscopy, colonoscopy, and capsule endoscopy. As used herein, the term "state" is intended to include not only disease states or disorders such as IBD, but also the general state of the GI tract, including specific situations, qualities, or the presence or absence of substances such as enzymes, biomarkers, microbiota, etc.

[0010] These conventional methods can be used to detect or evaluate various states, including IBD or related states. However, these methods can be time-consuming, expensive, uncomfortable, and / or invasive, and may require a skilled physician. These factors can pose challenges for patients who require regular monitoring. For example, the discomfort and pain caused by endoscopic procedures (often with sedation) can reduce the willingness or ability of patients undergoing such procedures. In addition, the predictive value of these methods can be very limited. Thus, patients may need to visit a physician frequently, perhaps every 2 - 4 months, to re-evaluate their condition.

[0011] It is understood that levels of certain biomarkers may be elevated during relapses in patients with IBD, cancer, or other GI conditions. These biomarkers may include myeloperoxidase (MPO), tumor necrosis factor-α, interleukin (IL), C-reactive protein (CRP), calprotectin, lactoferrin, and / or others. For example, studies have shown that the biomarker MPO is a major enzyme released by polymorphonuclear leukocytes that accumulate at the site of inflammation. Therefore, changes in MPO concentration may be a useful indicator of inflammation or mucosal damage resulting from the development or relapse of cancer associated with IBD or GI.

[0012] Based on these findings, fecal sampling techniques have been developed to detect and evaluate the presence of such biomarkers in a patient's stool. These fecal sampling techniques may enable non-invasive diagnosis or monitoring of IBD (or related conditions), which can be done at a reduced cost and with less disturbance to the patient compared to the conventional methods described above. However, while the levels of biomarkers in a patient's stool may (to some extent) indicate the presence, absence, or current state of the disease state, the levels of biomarkers in the stool can also be highly dependent on a variety of other factors. Exemplary factors that may influence the levels of fecal biomarkers include, for example, the patient's diet, the water content in the stool sample, and the location of the disease. For example, a patient with ileal ileal dysplasia may have severe ulcers. However, the location of the disease in the ileum may result in only very low levels of fecal biomarkers. Therefore, while these fecal sampling methods may provide a simple assessment of IBD, they may be inaccurate or unreliable in determining the location or current state of the disease state.

[0013] In consideration of the foregoing, the inventors recognize and understand the advantages of ingestible capsule devices for detecting and / or evaluating conditions within the GI tubule. In some embodiments, the ingestible capsule devices according to the present disclosure may detect or evaluate the presence of enzymes or other biomarkers at specific points within a patient's GI tubule. For example, an ingestible capsule device may detect the presence of MPO in a patient's small intestine to monitor or diagnose IBD or GI-related cancer. This may enable a diagnosis or monitoring that is less invasive, non-destructive, and less expensive than conventional methods such as endoscopic procedures, while providing greater reliability and accuracy than methods such as fecal sampling.

[0014] Several methods and devices for detecting conditions within a GI tube may include ingestible capsule devices with fluorescence imaging capabilities. For example, capsule devices with fluorescence imaging capabilities may be used in the diagnosis of certain GI-related cancers or other disease conditions. However, capsule devices that utilize fluorescence imaging may require the inclusion of an excitation light source within the capsule. Excitation light sources may require a considerable power source to operate, may be highly complex to manufacture, and may be unreliable.

[0015] In consideration of the above, the inventors recognize and understand the advantages of ingestible capsule devices that use luminescence or chemiluminescence to detect and evaluate the state inside a GI tube. A capsule device having luminescence capability can detect or evaluate the GI state by using chemical interactions to generate and detect luminescent light in the presence of a particular state or composition of a substance. Such a device may operate without the use of an excitation light source, thereby reducing power requirements and manufacturing complexity compared to fluorescent capsule devices.

[0016] In some embodiments, the ingestible capsule device may use luminescence or chemiluminescence to detect or evaluate a target enzyme or other biomarker indicating a disease state. For example, the ingestible capsule device may include a luminescent substrate configured to emit luminescent light when exposed to a GI fluid containing a luminescent trigger. The luminescent trigger may be a target enzyme or biomarker, or it may be another chemical substance derived from the target enzyme or biomarker. In some embodiments, the capsule may include a photodetector configured to detect the presence, absence, or intensity of luminescent light emitted by the luminescent substrate.

[0017] In some embodiments, the target biomarker may include myeloperoxidase (MPO), tumor necrosis factor-α, interleukin (IL), C-reactive protein (CRP), calprotectin, lactoferrin, or others. In some such embodiments, the luminescent substrate of the capsule device may be injected with a solution containing a luminescent agent such as sea firefly luciferin, firefly luciferin, oxalate, lucigenin, luminol (C8H7N3O2), derivatives of luminol, and / or other chemiluminescent molecules. In some embodiments, the luminescent agent may be used in combination with quantum dots or nanoparticles configured to emit additional light upon exposure to luminescence released by the luminescent agent. In embodiments using luminol, the luminescence trigger may be an oxidizing agent such as hypochlorous acid (HOCl). In some such embodiments, an active molecule that interacts with the target biomarker may be included to generate the luminescence trigger. For example, in embodiments using luminol and where the target biomarker is MPO, the capsule device may contain urea peroxide (UHP). UHP may interact with MPO to produce HOCl, which is necessary for interacting with luminol. The interaction between HOCl and luminol may generate luminescent light indicating the presence, absence, or concentration of MPO in the GI fluid sample.

[0018] The capsule device may be further configured to transmit wireless signals. These wireless signals may relay information about detection signals generated by the capsule device's photodetector to a separate receiving device outside the patient. In some embodiments, the wireless signals may indicate the presence, absence, or intensity of luminescent light detected at a specific location within the patient's GI tube, or at a time corresponding to a specific location. The presence, absence, or intensity of luminescence may indicate the presence, absence, or concentration of a biomarker, and consequently, the current state of the disease or other GI condition.

[0019] In some embodiments, the ingestible capsule devices of the present disclosure may target specific regions of the GI tube (e.g., for monitoring or evaluation). For example, the capsule device may include a capsule having a sampling opening that allows GI fluid to enter the capsule for evaluation. In some embodiments, the sampling opening may be closed with one or more layers of a biodegradable or enteric coating. The enteric coating may be selected to degrade at a desired pH level, allowing the sampling opening to remain closed until the enteric coating is exposed to the desired pH level. Because the pH level of the GI tube varies along its length, the ingestible capsule device may be designed to target specific regions of the GI tube by selecting or configuring the enteric coating to degrade at a specific pH level. Multilayer enteric coatings may also be used to target specific regions of the GI tube, such as the colon. When multilayer enteric coatings are used, each layer of the enteric coating may be configured to degrade at a different pH level, thus allowing for more specific targeting of regions of the GI tube. Suitable coating materials include, but are not limited to, pH-sensitive polymer materials such as basic butylated methacrylate (EUDRAGIT EPO), polymethacrylate-co-ethyl acrylate (EUDRAGIT L 100-55), polymethacrylate-co-methyl methacrylate (EUDRAGIT L100), hydroxypropyl methylcellulose phthalate (HP-55), hypromellose phthalate (HPMCP), cellulose acetate phthalate (CAP), and polyvinyl acetate phthalate (PVAP). An exemplary ingestible sampling capsule using an enteric coating having multiple layers that degrade at different pH levels is described in further detail in U.S. Provisional Patent Application No. 63 / 320,825, filed March 17, 2022, which is incorporated herein by reference for all purposes. Similar capsules and / or multilayer enteric coatings may be used in conjunction with any of the embodiments described herein.

[0020] Certain non-limiting embodiments are described in further detail with reference to the drawings. Since this disclosure is not limited to the specific embodiments described herein, it should be understood that the various systems, components, features, and methods described in relation to these embodiments may be used individually and / or in any desired combination.

[0021] Figure 1 shows one embodiment of an ingestible capsule device according to the present disclosure. In the shown embodiment, the device 100 may include a capsule 102 having an internal cavity 122. The capsule 102 may also include a sampling opening 120 that allows fluid exchange between the cavity 122 and the surrounding environment of the device 100. The opening 120 may be filled, covered, or otherwise closed by an opening closure 104. The opening closure 104 may include a biodegradable material such as an enteric coating. The biodegradable material may be selected or configured to degrade at a desired point along the patient's GI tube. For example, the enteric coating may be selected to degrade at a pH level corresponding to the pH level of the small intestine, so that the device 100 may be configured to evaluate a sample from the small intestine.

[0022] Device 100 may comprise one or more layers of substrate material, such as two, three, or four layers. In the shown embodiment, device 100 may comprise a luminescent substrate 106, a first additional substrate layer 110, and a second additional substrate layer 112, but other embodiments may comprise more or fewer substrate layers. The substrate material may comprise any suitable material for supporting the active molecules therein, such as paper, textiles, polymer materials (including polymer meshes, polymer films, etc.), synthetic materials, composite materials, hydrogels, or lyophilized hydrogel matrices. In some embodiments, the substrate material may comprise filter paper or cellulose paper. Each layer of the substrate material may comprise one or more active molecules. Each active molecule may be selected to produce a desired chemical interaction with the sample of GI fluid in the capsule device, or with components or constituent materials of the GI fluid sample.

[0023] The luminescent substrate 106 may contain a luminescent agent. The luminescent agent may be an active molecule that produces luminescent light when exposed to a luminescent trigger molecule. For example, in some embodiments, the luminescent agent may be luminol. In other embodiments, the luminescent agent may be a derivative of luminol, or the luminescent agent may be sea firefly luciferin, firefly luciferin, oxalate, lucigenin, and / or other chemiluminescent molecules. In some embodiments, the luminescent agent may be used in combination with quantum dots or nanoparticles configured to emit additional light when exposed to luminescence emitted by the luminescent agent. Including quantum dots or nanoparticles may increase the amount of light generated in response to a given concentration of luminescent trigger, thereby increasing the sensitivity of the capsule device.

[0024] A luminescence trigger molecule may indicate the state within the GI tube. In some embodiments, the luminescence trigger may be an enzyme, biomarker, biomolecule, or other indicator of the GI state. In other embodiments, the luminescence trigger may be an active molecule derived from an enzyme, biomarker, biomolecule, or other indicator of the GI state. For example, in embodiments using luminol as the luminescent agent, the luminescence trigger may be an oxidizing agent such as hypochlorous acid (HOCl). Device 100 may induce an enzyme or biomarker, an oxidizing agent, or other luminescence trigger by a chemical interaction between the GI fluid sample and one or more active molecules in one or more substrate layers of the capsule device. In the shown embodiments, the luminescence trigger may be induced by a chemical interaction between the GI fluid sample and one or more active molecules injected into a first additional substrate layer 110 and / or a second additional substrate layer 112.

[0025] For example, in the embodiment shown, for device 100 configured to detect MPO in a GI fluid sample, a second additional substrate layer may be injected with a solution having an appropriate concentration of UHP so that the interaction between UHP and MPO can produce HOCl. HOCl can interact with the luminol of the luminescent substrate 106 to function as an oxidizing or luminescent agent for producing luminescent light indicating the presence, absence, or concentration of MPO in the GI fluid sample.

[0026] Additional or alternative substrate layers may be included and configured to produce effects other than inducing luminescence triggering. In some embodiments, active molecules in the additional substrate layers may be provided to tune or modify the properties of the GI fluid sample. For example, in some embodiments, the additional substrate layer may include a pH buffer. The pH buffer may be an active molecule that can adjust the pH level of the GI fluid sample. The pH buffer may include 4-(cyclohexylamino)-1-butanesulfonic acid (CABS) or a similar active molecule. In the embodiments shown, the first substrate layer 110 may be injected with a solution having an appropriate concentration of a pH buffer, such as CABS. It may be desirable to tune the pH level or other properties of the GI fluid sample to optimize the luminescence intensity produced by the luminescence substrate 106, as will be described in more detail in the Examples section below.

[0027] In some embodiments, the device 100 may include a translucent partition 114. The translucent partition 114 can separate the cavity 122 into a first portion 124 and a second portion 126 of the cavity 122. Furthermore, the translucent partition 114 can form a liquid-tight seal between the first and second portions of the cavity, while allowing light to pass between the first and second portions. In various embodiments, the translucent partition may include glass, plastic, or any other suitable material to form a seal within the capsule while allowing light to pass through it.

[0028] According to some embodiments, the ingestible capsule device may include an electronic unit 116. Some embodiments may further include a power supply 118. In some embodiments, the electronic unit 116 may include a sensor interface module 128, a signal processing module 130, and a data acquisition and transmission module 132. The sensor interface module 128 may include a photodetector 108 for detecting the presence, absence, or intensity of luminescent light. In some embodiments, the photodetector 108 may include a photodiode such as a single-photon avalanche diode (SPAD). In other embodiments, the photodetector may include a microplate reader or any other suitable type of photodetector.

[0029] The signal processing module 130 can communicate with the sensor interface module 128 and / or the photodetector 108 to receive and process the detection signal from the photodetector 108. In some embodiments, the signal processing module 130 may be configured to control the noise level of the detection signal or to process the detection signal in any other way.

[0030] The data acquisition and transmission module 132 may communicate with the signal processing module 130. The data acquisition and transmission module 132 may be configured to transmit a wireless signal containing information that is at least partially based on information from the detection signal. The data acquisition and transmission module 132 may be configured to transmit a wireless signal via any suitable communication protocol, including radio frequency (RF) protocols, WiFi protocols, Bluetooth, long-range (LoRa) networking protocols, multicast wireless sensor networks (e.g., ANT), human body communication networks, and / or others.

[0031] The power supply 118 may be included to supply appropriate levels of power to the various components of the electronic unit 116. The power supply 118 may include a battery or any other suitable power source.

[0032] Exemplary embodiments of the electronic unit 116 according to this disclosure are described in more detail in the following Examples section. However, it will be understood that the electronic unit may include any suitable one or more components for detecting the presence, absence, or intensity of luminescent light and relaying information about the detected light. In this regard, this disclosure is not limited to the specific components described below.

[0033] Next, with reference to Figure 2, the operation of an ingestible capsule device as shown in Figure 1 will be described. Device 100 can be ingested by a patient 200. While device 100 is in the stomach 202 of patient 200, the sampling opening 120 may remain closed by the opening closure 104. In the embodiment shown, the opening closure 104 may contain a biodegradable or enteric-coated material configured to decompose at a pH level corresponding to a portion of the small intestine 204. Thus, when device 100 reaches the small intestine 204, the opening closure 104 may decompose or dissolve, thereby allowing a sample of the GI fluid to pass through the opening 120 and enter the cavity 122 of device 100. In other embodiments, it will be understood that the opening closure 104 may be configured to decompose or dissolve at another location in the GI tube, such as the large intestine 206.

[0034] A sample of GI fluid passing through the opening 120 may contain an enzyme or other biomarker 208 indicating a GI state to be monitored or evaluated. The enzyme or biomarker 208 may be a luminescence trigger, or the luminescence trigger may be chemically derived from the enzyme or biomarker 208 as described herein. When the luminescence substrate of device 100 is exposed to the luminescence trigger, the luminescence substrate may emit luminescence light 210. The luminescence light 210 may be detected by the photodetector 108 of device 100, as shown in Figure 1 above. The photodetector may generate a detection signal as described above, which indicates the presence, absence, or intensity of the luminescence light 210.

[0035] The capsule device 100 may transmit a wireless signal 212 to an external receiving device 214. The receiving device 214 may be any device capable of receiving the wireless signal 212 from the capsule device. The receiving device may be monitored by a user or a medical professional. Alternatively or additionally, the receiving device 214 may be configured to store information from the wireless signal 212 for subsequent analysis.

[0036] Next, an example of an operating mode of an embodiment of the capsule device according to the present disclosure will be described with reference to Figure 3. In this example, the device may be configured to monitor or evaluate the IBD state by detecting MPO in a GI fluid sample. This exemplary embodiment may contain luminol as a luminescent agent within the luminescent substrate 106. In this embodiment, the interaction between MPO and luminol may produce luminescent light insufficient to enable useful analysis or evaluation. Therefore, the capsule device of this embodiment may induce a luminescent trigger from MPO by chemical interaction with an active molecule. The luminescent trigger in this embodiment may be HOCl. The luminescent trigger may be induced by a chemical interaction between the MPO in the GI fluid sample and an active molecule injected into an additional substrate layer. The active molecule in this particular embodiment may be urea peroxide (UHP). UHP may interact with MPO to produce HOCl. HOCl may interact with luminol in the luminescent substrate to produce luminescent light.

[0037] In addition, as will be further explained in the Examples section below, the pH value of the GI fluid sample can affect the intensity of the luminescence light produced by the interaction of HOCl and luminol. Therefore, it may be desirable to adjust the pH value of the GI fluid sample. In the specific embodiments described herein, the pH value can be adjusted to a desired value using a CABS-implanted substrate layer.

[0038] While this example is intended to illustrate the operating principles of an ingestible capsule device, it will be understood that these principles can be applied and adapted to produce ingestible capsule devices for any suitable application, including monitoring or evaluating other GI states by using other active molecules and / or other electronic components to detect other target biomarkers appropriate for a given application. As a further example, substrates of different numbers and / or arrangements (e.g., substrates injected with different chemicals or combinations of chemicals) can be used in accordance with the techniques described herein. Thus, this disclosure is not limited to the examples described herein that specifically concern the detection of MPO using luminol, UHP, and CABS pH buffer.

[0039] In the first step 302, the GI fluid sample may contain various components, including the target enzyme or other biomarker to be detected. In some embodiments, the target biomarker may be MPO. In other embodiments, the target biomarker may be tumor necrosis factor-α, interleukin (IL), C-reactive protein (CRP), calprotectin, lactoferrin, or any suitable biomarker.

[0040] The first substrate layer 110 may be configured to chemically interact with the GI fluid sample. As described above, the first substrate layer 110 may be configured to adjust the pH of the GI fluid. This pH adjustment may be desirable to optimize the sample with respect to luminescence. In some embodiments, the first substrate layer 110 may be a layer of filter paper into which a first buffer solution containing an appropriate concentration of CABS has been injected. In other embodiments, the first substrate layer 110 may contain other pH buffers or other active molecules, including active molecules that adjust fluid properties other than pH, such as salinity, viscosity, conductivity, and / or others. For example, in some embodiments, the substrate layer may be intofused with a redox buffer solution or redox buffer molecules to control the oxidation / reduction potential of the GI fluid sample or its components. In some embodiments, the substrate layer may be intofused with a detergent or other compound to control the viscosity of the GI fluid sample.

[0041] According to the embodiments described herein, the pH of the GI fluid sample may differ in the second step 306 from the pH of the GI fluid sample in the first step 302. For example, in some embodiments, the concentration of the CABS solution injected into the first substrate layer may be selected to raise the pH of the GI fluid sample to a pH value of 11. In other embodiments, other buffer solutions may be used at appropriate concentrations to adjust the pH to any desired level, and the disclosure is not limited thereto.

[0042] Accordingly, in some embodiments, the concentration of the pH buffer solution may be selected to obtain a pH value that may be greater than or equal to 0, 5, 7, 10, and / or any other suitable pH value. In addition, the concentration of the pH buffer solution may be selected to obtain a pH value that may be less than or equal to 14, 12, 11, 10, and / or any other suitable pH value. Combinations of the above are intended, and include, for example, pH values ​​of 0 or greater and 14 or less, pH values ​​of 10 or greater and 12 or less, and / or any other suitable combination of the above. Naturally, while specific ranges for desired pH values ​​are provided above, it should be understood that other ranges, both greater than and less than the above, are also intended, as this disclosure is not limited to this form.

[0043] In addition, in some embodiments in which CABS is used as a pH buffer to adjust the pH value of a GI sample containing MPO for detection by interaction with luminol, the concentration of the CABS buffer solution selected to obtain the desired pH value may be 0.2 M, 0.4 M, 0.6 M, 0.8 M and / or any other suitable molar concentration or concentration greater than or equal to 0.2 M, 0.4 M, 0.6 M, 0.8 M and / or any other suitable molar concentration or concentration less than or equal to 1.4 M, 1.2 M, 1.0 M, 0.8 M and / or any other suitable molar concentration or concentration. Combinations of the above are intended, including, for example, concentrations of 0.2 M or more and 1.4 M or less, concentrations of 0.8 M or more and 1.0 M or less, and / or any other suitable combination of any of the above. Naturally, while specific ranges for the concentration of the CABS buffer solution are provided above, it should be understood that other ranges both greater than and less than the above are also intended, as this disclosure is not limited to this form.

[0044] The second substrate layer 112 may be configured to chemically interact with the GI fluid sample from the second step 306. In some embodiments, the second substrate layer 112 may be configured to interact with the GI fluid to generate a luminescence trigger. For example, in some embodiments, the second substrate layer 112 may be a layer of filter paper injected with a solution containing a suitable concentration of urea peroxide (UHP). In some embodiments, the volume concentration of the UHP solution selected to obtain HOCl from MPO for interaction with luminol may be 0%, 0.25%, 0.5%, 1.0%, 1.5%, and / or any other suitable concentration or higher. In addition, the concentration of the UHP solution may be 3.0%, 2.5%, 2.0%, 1.5%, 1.0%, and / or any other suitable concentration or lower. Combinations of the above are intended, and include, for example, concentrations of 0% or more and 3.0% or less, concentrations of 1.5% or more and 2.5% or less, and / or any other suitable combination of any of the above. Naturally, a specific range of concentrations for the UHP solution is provided above, but please understand that this disclosure is not limited to this form, and other ranges both above and below those above are also contemplated.

[0045] In some embodiments, UHP may react with MPO in the GI fluid to produce hypochlorous acid (HOCl). Therefore, the GI fluid sample in the third step 310 may include a luminescence trigger. In this example, the GI fluid sample in the third step 310 may include HOCl.

[0046] The luminescent substrate 106 may be configured to emit luminescent light 210 when exposed to a luminescent trigger. In some embodiments, the luminescent substrate may be injected with a solution containing a luminescent agent of an appropriate concentration. The luminescent agent may be a chemiluminescent agent such as luminol (C8H7N3O2). In this example, luminol may interact with HOCl derived from MPO as described above to produce luminescent light 210.

[0047] In some embodiments, the concentration of the luminol solution selected to optimize luminescence intensity in the presence of MPO may be 1 mM, 10 mM, 15 mM, 20 mM, and / or any other suitable molar or concentration greater than or equal to 1 mM, 10 mM, 15 mM, 20 mM, 15 mM, and / or any other suitable molar or concentration less than or equal to 30 mM, 25 mM, 20 mM, 15 mM, and / or any other suitable molar or concentration greater than or equal to 30 mM. Combinations of the above are intended, including, for example, concentrations of 1 mM or greater and 30 mM or less, concentrations of 20 mM or greater and 30 mM or less, and / or any other suitable combination of the above. Naturally, while specific ranges of luminol solution concentrations are provided above, it should be understood that the disclosure is not limited to this form, and other ranges both greater and less than those above are also intended.

[0048] While the combination of MPO, UHP, and luminol is described herein as being included in one embodiment of the present disclosure, the disclosure is not limited in this respect, and it will be understood that other embodiments may utilize other luminescence triggers, luminescence agents, and / or buffer solutions. In addition, luminescence agents, luminescence triggers, buffer solutions, active molecules, and their combinations and concentrations may be selected and optimized for the detection of any suitable enzyme or biomarker, including tumor necrosis factor-α, interleukin (IL), C-reactive protein (CRP), calprotectin, lactoferrin, and the like.

[0049] Furthermore, while the embodiment in Figure 3 includes one luminescent substrate layer and two additional substrate layers, it will be understood that other embodiments may include any appropriate number of additional substrate layers. For example, it will be understood that in some embodiments, additional substrate layers are not required to generate luminescent light indicating the presence of a desired enzyme or biomarker. In other embodiments, three or more additional substrate layers may be desirable. Therefore, this disclosure is not limited to any particular number of substrate layers.

[0050] The luminescent light 210 can be detected by the photodetector 108. In some embodiments, the photodetector 108 may have sufficient sensitivity to detect only trace amounts of luminescent light 210. For example, in some embodiments, the photodetector 108 may be a single-photon avalanche diode. Upon detecting the luminescent light 210, the photodetector 108 may generate a detection signal indicating the presence, absence, or intensity of the luminescent light 210. Thus, the detection signal may indicate the presence, absence, or concentration of a luminescent trigger, or the presence, absence, or concentration of an enzyme or biomarker. The detection signal may be processed and transmitted by an electronic unit of a capsule device as described herein.

[0051] Figure 4A shows the luminescence intensity during the time the capsule opening remains closed, within the scope of several embodiments of the device as described herein. For example, the luminescence intensity shown in Figure 4A may correspond to the time when the device 100 is located in the stomach 202 of patient 200 as shown in Figure 2. Figure 4B shows the luminescence intensity during the time when the capsule opening is open and a GI fluid sample containing the enzyme or biomarker to be detected is inside the capsule, within the scope of several embodiments of the device as described herein. For example, the luminescence intensity shown in Figure 4B may correspond to the time when the device 100 is located in the small intestine 204 of patient 200 as shown in Figure 2. The increase in luminescence intensity shown in Figure 4B may be sufficient to generate a detection signal in the photodetector of the device. In some embodiments, the detection signal, or information derived therefrom, may be processed as described with respect to Figure 2 above and transmitted wirelessly to a receiving device. [Examples]

[0052] Design and use cases for experimental embodiments An example of an experimental capsule device described herein included six elements: a capsule, a pH-sensitive biodegradable enteric coating, a stack of three thick filter papers, a coverslip, an electronic unit with a photodetector on top, and a 3-volt lithium battery. The capsule utilized a two-part threaded design to facilitate the assembly of the capsule device. The pH-sensitive polymer coating used was designed to withstand a low-pH gastric environment in which the experimental capsule device was intended to remain intact.

[0053] This embodiment was intended to evaluate the small intestine. Upon exposure to target inflammatory tissue in the small intestine (having an average pH of 6.8), the enteric coating may dissolve, allowing MPO (released by neutrophils at the site of inflammation) to flow into the capsule. Subsequently, the three layers of filter paper may initiate the absorption of MPO and perform their roles as follows: First, the CABS infusion filter paper may adjust the pH of the incoming sample to pH 11. Next, the UHP infusion filter paper may interact with the MPO (having pH 11) to produce hypochlorous acid (HOCl). Then, the luminol infusion filter paper may interact with the HOCl and begin to emit blue luminescence. At this point, a photodetector may detect the luminescence, convert the photon energy into an electrical signal, which can then be transmitted to a receiving device via a wireless transmitter in the electronic unit of the capsule device.

[0054] Exemplary optimization of analysis parameters The characteristics and intensity of the luminescence released by the oxidation reaction of luminol can depend on several parameters, including pH level and reactant concentration. Therefore, a series of experiments were performed to optimize these parameters around specific use cases where luminol is used for the optical detection of MPO.

[0055] pH optimization First, the effect of pH on luminescence intensity was investigated by exposing MPO to buffers of various pH values, including pH 6, 7, 8, 9, 10, 11, and 12. For this purpose, a 96-well black microtiter plate was filled with supernatant GI fluid having pH values ​​in the range of 6–12. 50 μL of UHP (250 μM) was added to each well. Ten seconds after adding the UHP, a fixed volume of luminol was added to each well. Two seconds after adding the luminol (i.e., 12 seconds after adding the UHP), a fixed volume of MPO was added to each well. The mixture was incubated for 10 seconds. After the incubation period, the luminescence spectrum of each reaction was recorded for 250 seconds using a BMG microplate reader. The results for each pH level are shown in Figures 6A and 6B. As can be seen from Figures 6A and 6B, it was observed that the maximum luminescence intensity was produced using a pH value of 11.

[0056] However, the pH in the small intestine region varies from 6.2 to 7.4. As can be seen from Figures 6A and 6B, the luminescence intensity observed at pH values ​​in this range was significantly lower than the intensity at pH 11. Therefore, the inventors recognized and understood the advantages of adjusting the pH value of the GI fluid sample to optimize the luminescence intensity in the disclosed capsule device. In the experimental embodiments disclosed herein, CABS injection filter paper was included in the capsule to adjust the pH value of the GI fluid sample.

[0057] The inclusion of CABS-injected filter paper required further optimization to determine the appropriate concentration of CABS in the filter paper in order to obtain the desired pH value of 11 from GI fluid samples with an initial pH value of 6-7. Several dilutions of the CABS stock solution (0.2M, 0.4M, 0.6M, 0.8M, 1.0M, 1.2M, and 1.4M dilutions) were prepared. Each dilution was drop-cast onto a circular disk of thick filter paper using a fixed volume (100 μL). The resulting filter papers (containing different concentrations of CABS) were left to dry overnight at room temperature.

[0058] Using these CABS-injected, dried filter papers, we determined which dilution of the CABS stock solution best achieved the conversion of the GI fluid from an in vivo pH level of approximately 6–7 to a desired pH level of approximately 11. Three different GI fluid samples with pH levels of 5, 6, and 7, as well as a phosphate-buffered saline (PBS) buffer solution with a pH of 7.4, were used as test samples. Figure 7A shows a diagram of the experimental setup for the pH conversion experiment described above, and Figure 7B shows the obtained results. In Figure 7A, the GI fluid sample 802 or PBS buffer solutions of various pH values ​​were pipettered onto filter paper 804 injected with various dilutions of the CABS stock solution and filtered through it. The final pH of the filtered GI fluid 806 was measured using a pH meter 810.

[0059] The results shown in Figure 7B indicate that filter paper injected with 1.0 M CABS solution was sufficient to convert each pH to approximately the desired pH value of 11. Therefore, 1.0 M CABS solution was selected as the appropriate concentration of CABS in the filter paper to obtain the desired pH value of 11 from GI fluid samples with initial pH values ​​of 6–7. While the specific methods, parameters, and objectives of these experiments led to these specific compound, value, and concentration selections, it will be understood that deviations from these specific methods, parameters, and objectives for other applications may result in any suitable compound, value, or concentration selection for any of the variables discussed herein.

[0060] Optimization of the ratio of UHP concentration to luminol concentration The ratio of UHP concentration to luminol concentration also affects the oxidation reaction and, consequently, the chemiluminescence intensity in the embodiments described. Therefore, various concentrations of UHP were evaluated with various concentrations of luminol. It will be understood that not all GI fluids contain significant amounts of MPO in vivo. However, UHP and luminol can interact during use of the capsule device, regardless of whether the GI fluid contains MPO or not. Therefore, various ratios of UHP to luminol were evaluated both in the presence and absence of MPO. Since the capsule devices of the embodiments described aim to detect MPO by evaluating the intensity of luminescence generated by the introduction of MPO into the capsule, the difference between luminescence in the absence of MPO and luminescence in the presence of MPO (not the intensity of luminescence in the presence of MPO alone) was evaluated as indicating the introduction of MPO.

[0061] Figure 8A shows a heatmap of luminescence intensity peak values ​​obtained from the interaction of UHP (horizontal axis) and luminol (vertical axis) with water in the absence of MPO, as a control. It was observed that the luminescence intensity peaks increased effectively with increasing concentrations of both UHP and luminol. This may be due, for example, to strong oxidation reactions caused by excess amounts of both reactants.

[0062] Figure 8B shows a heatmap of luminescence intensity peak values ​​obtained from the interaction of UHP and luminol in the presence of MPO (concentration of 7 U / mL). As described above, the effect of introducing MPO to a given ratio of UHP and luminol was evaluated by comparing the luminescence intensity peak values ​​in both the presence and absence of MPO for the given ratio.

[0063] Therefore, Figure 8C shows a heatmap of the difference between the intensity peak values ​​in Figure 8A and Figure 8B. As shown in Figure 8C, the most significant increase in luminescence intensity peak values ​​occurred at a 2% UHP and 25 mM luminol concentration. Therefore, a 2% UHP and 25 mM luminol concentration was selected for further analytical investigation.

[0064] Exemplary device manufacturing As shown in Figures 5A and 5B, in one embodiment, a capsule 102 for an ingestible device was manufactured using 3D printing. The capsule consisted of two parts: a body portion 102A and a cap portion 102B. The capsule was designed using SolidWorks (Dassault Systems). The design was 3D printed using a stereolithography (SLA) printing process on a Form 2 printer manufactured by Formlabs, Inc., using biocompatible resin (EN-ISO 10993-1:2009 / AC:2010, USP Class VI) obtained from Formlabs, Inc. The SLA process used a layer thickness of 50 μm. After printing was complete, the capsule was washed in 99% isopropyl alcohol (IPA) for 15 minutes and then cured for a further 60 minutes using an ultraviolet (UV) light curing device (manufactured by Formlabs, Inc.) to complete the polymerization of the resin.

[0065] Subsequently, a 6 mm diameter sampling opening 120 was cut into the cap portion 102B using a computer-controlled CO2 laser. The laser was a PLS6MW cutting and engraving system manufactured by Universal Laser, Inc. (Scottsdale, AZ) and set to an operating wavelength of 10.6 μm. The sampling opening 120 was then filled with a pH-sensitive coating and cured overnight at room temperature.

[0066] As shown in Figure 5C, a large sheet of filter paper was cut into small circular discs, each disc having a diameter of 5 mm. Active molecules (CABS, UHP, and luminol) were injected into different filter paper discs, and the discs were stacked so that the UHP injected paper 112 was sandwiched between the CABS injected paper 110 on one side and the luminol injected paper on the opposite side. The stack of discs was placed inside the cap portion 102B of the capsule 102 so that the CABS injected paper was closest to the sampling opening 120.

[0067] Electronic unit The electronic unit was included to measure luminescence light output at maximum sensitivity and to provide continuous wireless luminescence measurements. As shown in Figures 5C and 5D above, the electronic unit 116 comprised three separate modular systems combined into a single unit. The unit included a sensor interface module 128, an analog signal processing module 130, and a data acquisition and transmission module 132. Three modular custom printed circuit boards (PCBs) were designed to house the electronics. Each of the three modules was contained within a single 8 mm diameter circular PCB. The three boards were stacked on top of each other with the sensor interface module at one end, the signal processing module in the middle, and the data acquisition and transmission module at the other end.

[0068] The sensor interface module 128 was provided to directly interact with the luminescent chemical and convert the light intensity into a representative current. To achieve a wide functional range, an Onsemi single-photon avalanche diode (SPAD) array (MicroFC-30035-SMT) was used as the photodetector 108 to measure the light produced from the MPO reaction. An Analog Devices inverting DC-DC converter (LT3462) was used to bias the sensor to -25V to -30V. Adjusting this bias voltage can serve as a primary method for adjusting the sensitivity of the device. To extend battery life when no reaction was expected, the sensor interface could be shut down to draw near-zero current by toggling the enable pin on the DC-DC converter.

[0069] The analog signal processing module 130 provided noise reduction and amplification to isolate the measurements from the sensor interface and convert them into usable voltages. A transimpedance amplifier (TIA) was included to convert the SPAD current to a voltage of 0 to 1.8V. The TIA gain was used to balance the overall gain when the SPAD bias voltage was adjusted. This utilized the full range of the ADC to limit the output of the sampled signal to 0 to 1.8V. Exemplary schematic diagrams of the bias voltage circuit and TIA can be found in the DC-DC converter and SPAD datasheets.

[0070] Finally, in the data acquisition and transmission module 132, a microcontroller (nRF52832, ARM M4 processor) collected analog measurements and wirelessly transmitted a representative digital signal to an external receiving device (nRF51822, ARM M0 processor). The nRF52832 controlled all electronic components within the capsule using 1.8V digital logic and converted the TIA output voltage into a digital signal using its onboard digital-to-analog converter. The nRF52832 and nRF51822 microcontrollers provided an internal RF communication protocol used to transmit data collected from inside the GI tube to an external system. In this example, the Raspberry Pi and nRF51822 were integrated into a single “base station” receiving device to transfer the collected data to a WiFi source accessible by any laptop or other computing device with WiFi capabilities.

[0071] Capsule active and shutdown current draws were recorded to estimate battery life. The device was powered at 3.1V, with input currents of 17.5mA active and 3.1mA shutdown, recorded with an Agilent 34401A digital multimeter. Packaged with two 1.55V, 23mAh silver oxide batteries in series (generating 3.1V), the capsule electronic system was configured to actively record light for over 1 hour or sleep for over 7 hours. It was configured to continue transmitting in the atmosphere at a distance of 10 meters from the base station and to fit within a standard 000 capsule.

[0072] MPO detection performance First, the analytical performance of the electronic unit's sensor interface module was evaluated by recording luminescence spectra generated by passing MPO at different concentrations. This was done using a conventional BMG Clariostar microplate reader. Figure 9A shows the luminescence spectra of oxidation reactions at the optimal wavelength of 425 nm with various concentrations of MPO. As can be seen from Figure 9A, the luminescence intensity gradually increased with increasing MPO concentration (0-9 U / mL) without a significant change in the shape of the luminescence spectrum. This enhancement of luminescence with increasing MPO concentration may be due to the formation of more oxidized products (HOCl) from the reaction of MPO with UHP. The increase in HOCl can further oxidize the luminol, thus producing a blue luminescence. Figure 9B shows plots between various MPO concentrations and the area under the corresponding luminescence curves in Figure 9A. Figures 9A and 9B suggest that the sensor interface module is capable of detecting even trace amounts of MPO.

[0073] Next, the analytical performance of the entire experimental capsule device was investigated. Figure 9C shows a sensitivity plot relating voltage to MPO concentration when recorded via a portable device. As described above, the photodetector mounted on top of the electronic unit detected luminescence intensity that gradually increased with increasing MPO concentration (0–9 U / mL) and converted this photon energy into an electrical signal. This electrical signal was then transmitted to a receiving device via a wireless system embedded in the electronic unit, as described above. As can be clearly seen from Figure 9C, the voltage generated by the photodetector gradually increased with increasing MPO concentration (0–9 U / mL). Similar to Figure 9B, Figure 9D shows a plot between various MPO concentrations and the area under the corresponding voltage curve in Figure 9C. From the similarity between Figures 9B and 9D, it can be understood that the experimental capsule device was capable of detecting even trace amounts of MPO.

[0074] Selective assay The results above demonstrate that the experimental embodiment of the disclosed capsule device can detect MPO. However, the presence of other interfering biomarkers such as procalcitonin, c-reactive protein, and lactate may also affect the performance of the device. Therefore, further studies were conducted to evaluate the effectiveness of the experimental capsule device in the presence of these biomolecules. Figures 10A and 10B show the response of the experimental capsule device in the presence of various interfering biomarkers (each at a concentration of 10 mM). Figure 10A shows that the voltage generated by the photodetector in the presence of interfering biomarkers was not significant, but the same concentration of MPO produced a relatively high output voltage signal. This may be due to the formation of more oxidized products (HOCl) by the reaction of UHP and MPO than by the reaction of UHP with any interfering biomarker. The production of fewer oxidized products by these potentially interfering biomolecules resulted in lower luminescence intensity and output voltage. Figure 10B shows plots of various interfering biomarkers and the area under the corresponding voltage curves in Figure 10A. Figure 10B shows that the experimental capsule device was selective and specific for MPO.

[0075] Ex vivo detection of MPO To demonstrate the practical application of the experimental capsule device, ex vivo detection of MPO was also evaluated in a physiological environment, as shown in Figures 11A and 11B. Here, a pig small intestine was cut into three sections 1100, each approximately 7 cm in length. Each intestinal section 1100 was separately treated with a solution containing MPO at different concentrations, namely 1, 5, and 9 U / mL. In particular, these three test concentrations were selected to compare the analytical performance of the experimental device in both a GI fluid environment and a buffer environment. The fully assembled device 100 was then inserted into each of the intestinal sections 1100 and used to detect the MPO level by recording the voltage signal generated by the photodetector. The voltage signals obtained for each concentration and the area under each curve are shown in Figures 11C and 11D, respectively. The results of the corresponding in vitro buffer experiment are also shown in Figure 11D. The ex vivo results in Figures 11C and 11D, and their similarity to the in vitro results, demonstrate that the experimental embodiments of the capsule device described herein were able to determine the level of inflammation in the small intestinal region by monitoring the level of MPO.

[0076] The embodiments of the technology described herein can be implemented in any of a number of ways. For example, embodiments may be implemented using hardware, software, or a combination thereof. When implemented in software, the software code can run on any suitable processor or array of processors, whether provided within a single computing device or distributed across multiple computing devices. Such processors may be implemented as integrated circuits having one or more processors within an integrated circuit component, including commercially available integrated circuit components known in the art, such as CPU chips, GPU chips, microprocessors, microcontrollers, or coprocessors. Alternatively, the processor may be implemented in custom circuitry, such as ASICs, or semi-custom circuitry obtained from constituting a programmable logic device. Further alternatives include the processor being part of a larger circuit or semiconductor device, whether commercially available, semi-custom, or custom. As a specific example, some commercially available microprocessors have multiple cores such that one or a subset of their cores can constitute a processor. However, the processor may be implemented using circuitry of any suitable format.

[0077] Furthermore, it should be understood that computing devices containing one or more processors can be embodied in one of several forms, such as rack-mount computers, desktop computers, laptop computers, or tablet computers. In addition, computing devices can be incorporated into devices that are not generally considered computing devices but possess suitable processing capabilities, including personal digital assistants (PDAs), smartphones, tablets, or any other suitable portable or fixed electronic devices.

[0078] Furthermore, a computing device may have one or more input and output devices. These devices may, among other things, be used to present a user interface. Examples of output devices that may be used to provide a user interface include a display screen for visual presentation of the output and a speaker or other sound-generating device for audible presentation of the output. Examples of input devices that may be used for the user interface include a keyboard, individual buttons, and pointing devices such as a mouse, touchpad, and digitizer tablet. As another example, a computing device may receive input information through speech recognition or in other audible forms.

[0079] Such computing devices may be interconnected by one or more networks of any preferred form, including local area networks or wide area networks, such as corporate networks or the Internet. Such networks may be based on any preferred technology, operate according to any preferred protocol, and may include wireless networks, wired networks, or fiber optic networks.

[0080] Furthermore, the various methods or processes outlined herein may be coded as software executable on one or more processors using any one of various operating systems or platforms. In addition, such software may be written using any one of several suitable programming languages ​​and / or programming tools or scripting tools, and may be compiled as executable machine code or intermediate code that runs on a framework or virtual machine.

[0081] In this regard, embodiments described herein may be embodied as computer-readable storage media (or more computer-readable media) encoded in one or more programs that, when executed on one or more computers or other processors, implement the various embodiments described above (e.g., computer memory, one or more floppy disks, compact disks (CDs), optical disks, digital video disks (DVDs), magnetic tape, flash memory, RAM, ROM, EEPROM, field-programmable gate arrays or circuit configurations in other semiconductor devices, or other tangible computer storage media). As is evident from the examples above, computer-readable storage media may retain information for a sufficient amount of time to provide computer-executable instructions in a non-temporary form. One or more such computer-readable storage media may be portable, and as a result, one or more programs stored therein may be loaded onto one or more different computing devices or other processors to implement the various aspects of the present disclosure as considered above. As used herein, the term “computer-readable storage media” encompasses only non-temporary computer-readable media that can be considered to be products (i.e., manufactured goods) or machines. Alternatively or additionally, the Disclosure may be embodied in computer-readable media other than computer-readable storage media, such as propagating signals.

[0082] The terms “program” or “software” are used herein in a general sense and refer to any type of computer code or set of computer executable instructions that can be used to program a computing device or other processor to implement various aspects of the present disclosure as considered above. In addition, it should be understood that, according to one aspect of this embodiment, one or more computer programs that, when executed, implement the methods of the present disclosure do not need to reside on a single computing device or processor, but may be modularly distributed across several different computers or processors to implement various aspects of the present disclosure.

[0083] Computer executable instructions can take many forms, such as program modules, that are executed by one or more computers or other devices. Generally, program modules include routines, programs, objects, components, data structures, etc., that perform a specific task or implement a specific abstract data type. Typically, the functions of a program module may be combined or distributed as desired in various embodiments.

[0084] Furthermore, embodiments described herein can be embodied as methods, and an example thereof is provided. The actions performed as part of this method can be ordered in any preferred manner. Thus, while they are shown as sequential actions in the exemplary embodiments, embodiments can be constructed in which the actions are performed in a different order than those exemplified, which may include performing several actions simultaneously.

[0085] Furthermore, some actions are described as being performed by a “user.” It should be understood that the “user” does not necessarily have to be a single individual, and in some embodiments, actions attributed to a “user” may be performed by a team of individuals, and / or individuals combined with computer-aided tools or other mechanisms.

[0086] While several embodiments of the present invention have been described and illustrated herein, those skilled in the art will readily imagine a variety of other means and / or structures for performing the function and / or obtaining one or more of the results and / or advantages described herein, and each of such variations and / or modifications will be considered within the scope of the present invention. More generally, those skilled in the art will readily understand that all parameters, dimensions, materials and configurations described herein are intended to be illustrative, and that actual parameters, dimensions, materials and / or configurations will depend on one or more specific applications in which the teachings of the present invention are used. Those skilled in the art will recognize many equivalents to the specific embodiments of the present invention described herein, or can usually confirm this by using only the following experiments. Thus, it should be understood that the embodiments described herein are presented merely as examples, and within the scope of the appended claims and their equivalents, the present invention may be carried out in ways other than those specifically described and claimed. The present invention covers each of the individual features, systems, articles, materials, kits and / or methods described herein. Furthermore, any combination of two or more such features, systems, articles, materials, kits, and / or methods is included in the scope of the present invention, provided that such features, systems, articles, materials, kits, and / or methods are not mutually inconsistent.

[0087] Although these teachings have been described in conjunction with various embodiments and examples, they are not intended to be limited to such embodiments or examples. Rather, the teachings of the present invention encompass a variety of alternatives, modifications, and equivalents, as will be understood by those skilled in the art. Accordingly, the foregoing descriptions and drawings are for illustrative purposes only.

Claims

1. A device for sampling a patient's gastrointestinal tract, A capsule housing that defines a cavity inside, A sampling opening is formed within the capsule housing and provides fluid communication between the cavity and the outside of the capsule housing, A luminescent substrate layer positioned within the cavity, At least one additional substrate layer positioned within the cavity between the sampling opening and the luminescent substrate layer, each of the at least one additional substrate layer configured to chemically interact with the sample fluid flowing into the cavity through the sampling opening, A photodetector positioned within the cavity, A biodegradable coating that closes the sampling opening, wherein the decomposition of the biodegradable coating exposes the sampling opening, allowing fluid to flow into the cavity, One or more of the at least one additional substrate layers are configured to interact with the biomarker in the sample fluid to form a luminescence trigger. The luminescent substrate layer is configured to emit luminescent light when exposed to the luminescent trigger. The photodetector is a device configured to detect the luminescent light.

2. The device according to claim 1, wherein the luminescence trigger indicates the presence of the biomarker in the sample fluid.

3. The device according to claim 2, wherein the biomarker comprises myeloperoxidase (MPO).

4. The device according to any one of claims 2 to 3, wherein the luminescence trigger comprises an oxidized product formed from a chemical interaction between an active molecule injected into the additional substrate layer and the biomarker.

5. The device according to claim 1, wherein the luminescent substrate layer contains a luminescent agent, and the luminescent agent interacts with the luminescent trigger to emit the luminescent light.

6. The device according to claim 5, wherein the luminescent agent comprises luminol.

7. The device according to claim 1, wherein one or more of the at least one additional substrate layers are configured to change the pH of the sample fluid.

8. The device according to claim 7, wherein one or more additional substrate layers configured to change the pH of the sample fluid contain 4-(cyclohexylamino)-1-butanesulfonic acid (CABS).

9. The device according to claim 1, wherein the luminescence trigger includes an oxidizer.

10. The device according to claim 1, wherein one or more additional substrate layers configured to interact with the sample fluid to form the luminescence trigger contain urea peroxide (UHP).

11. The device according to claim 10, wherein one or more additional substrate layers containing UHP are injected with a UHP solution containing 1% to 3% by volume of UHP, and the luminescent substrate layer is injected with a luminol solution containing luminol at a concentration of 20 mM to 30 mM.

12. The device according to claim 1, wherein the at least one additional substrate layer includes a first additional substrate layer configured to alter the pH of the sample fluid and a second additional substrate layer configured to interact with the sample fluid to form the luminescence trigger.

13. The device according to claim 1, further comprising a translucent partition positioned between the luminescent substrate layer and the photodetector, wherein the translucent partition is configured to form a fluid seal between the first portion of the cavity and the second portion of the cavity, while allowing the luminescent light to pass from the first portion of the cavity to the second portion of the cavity.

14. The device according to claim 1, wherein the photodetector includes an avalanche photodiode.

15. A signal processor that communicates with the photodetector and receives a detection signal from the photodetector, A wireless transmitter that communicates with the signal processor and transmits a wireless signal, wherein the information in the wireless signal is at least partially based on the information from the detection signal, The device according to claim 1, further comprising a battery configured to supply power to at least the signal processor and the wireless transmitter.

16. The device according to claim 1, wherein the biodegradable coating comprises a first coating layer and a second coating layer, the first coating layer is configured to decompose within a first pH range, and the second coating layer is configured to decompose within a second pH range, and the first pH range is different from the second pH range.

17. A method for detecting biomarkers in a patient's gastrointestinal tract, To the patient, A capsule housing that defines a cavity inside, A sampling opening is formed within the capsule housing and provides fluid communication between the cavity and the outside of the capsule housing, One or more layers located within the cavity, configured to form a luminescence trigger indicating the presence of the biomarker through interaction with the sample fluid flowing into the cavity through the sampling opening, A luminescent substrate positioned within the cavity, wherein the luminescent substrate is configured to emit luminescent light when exposed to the luminescent trigger, A photodetector positioned within the cavity, configured to detect the luminescent light and generate a detection signal, Administering an ingestible device, which includes a wireless transmitter configured to transmit a wireless signal based on the aforementioned detection signal, Passing the sample fluid through one or more layers of the suctionable device, Exposing the luminescent substrate to the sample fluid passed through one or more layers, The user device receives the wireless signal, A method comprising determining whether or not the biomarker is present in the sample fluid based on the wireless signal.

18. The method according to claim 17, wherein the biomarker comprises myeloperoxidase (MPO).

19. The method according to any one of claims 17 to 18, wherein the luminescent substrate contains a luminescent agent, and the luminescent agent interacts with the luminescent trigger to emit the luminescent light.

20. The method according to claim 19, wherein the luminescent agent comprises luminol.

21. The method according to claim 17, further comprising passing the sample fluid through at least one additional substrate layer of the suctionable device, wherein the at least one additional substrate layer comprises one or more layers, each additional substrate layer configured to chemically interact with the sample fluid.

22. The at least one additional substrate layer further comprises a first additional substrate layer, separate from the one or more layers. The method according to claim 21, wherein passing the sample fluid through the at least one additional substrate layer of the suctionable device includes passing the sample fluid through a first additional substrate layer to change the pH of the sample fluid.

23. The method according to claim 22, wherein the first additional substrate layer contains 4-(cyclohexylamino)-1-butanesulfonic acid (CABS).

24. The at least one additional substrate layer includes a second additional substrate layer as one or more layers. The method according to claim 21, wherein passing the sample fluid through the at least one additional substrate layer of the suctionable device is to pass the sample fluid through the second additional substrate layer to form the luminescence trigger.

25. The method according to claim 24, wherein the luminescence trigger is an oxidized form.

26. The method according to claim 24, wherein the second additional substrate layer contains urea peroxide (UHP).

27. The method according to claim 17, wherein the ingestible device further comprises a biodegradable coating that closes the sampling opening, and the exposure of the luminescent substrate to the sample fluid causes the biodegradable coating to decompose, allowing the fluid to flow into the cavity.

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