Ingestible capsule device

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 and remitting inflammation of the GI tract. A variety of factors, including an overreactive immune system response, genetic mutations in multiple genes, the 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, specific 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 for more effective and accurate diagnosis of 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 defining a cavity and a sampling opening formed within the capsule housing. The sampling opening may provide fluid communication between the cavity and the exterior of the capsule housing. The device may further include a luminescence substrate layer positioned within the cavity. The luminescence substrate may be configured to emit luminescence light when exposed to a sample fluid containing a luminescence trigger. The device may further include at least one additional substrate layer positioned within the cavity between the sampling opening and the luminescence 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 the luminescence light. The device may further include a biodegradable coating closing the sampling opening, and thus, degradation of the biodegradable coating may expose the sampling opening and allow fluid to flow into the cavity.

[0005] In some embodiments, a method for detecting biomarkers within a patient's gastrointestinal tract may be provided, the method including administering an ingestible device to the patient. The ingestible device may include a capsule housing defining a cavity and a sampling aperture formed within the capsule housing and providing fluid communication between the cavity and the exterior of the capsule housing. A luminescence substrate may be positioned within the cavity. The luminescence substrate may be configured to emit luminescence light when exposed to a sample fluid containing a luminescence trigger. The luminescence trigger may indicate the presence of a biomarker. A photodetector may additionally be positioned within the cavity. The photodetector may be configured to detect the luminescence 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 luminescence substrate to the sample fluid, receiving the wireless signal at a user device, and determining, based on the wireless signal, whether the biomarker is present in the sample fluid.

[0006] It should be understood that the foregoing concepts, and additional concepts discussed below, may be arranged in any suitable combination, as the present disclosure is not limited in this respect. Further, other advantages and novel features of the present disclosure will become apparent from the following detailed description of various non-limiting embodiments when considered in conjunction with the accompanying drawings.

[0007] Where this specification and the documents incorporated by reference include disclosures that are inconsistent and / or not consistent with each other, this specification shall prevail. Where two or more documents incorporated by reference include disclosures that are inconsistent and / or not consistent with each other, the document with the later effective date shall prevail.

Brief Description of the Drawings

[0008] The accompanying drawings are not intended to be drawn to scale. In the drawings, each identical or nearly identical component that is illustrated in various figures may be represented by the same numeral. For clarity, not all components may be labeled in all the drawings. In the drawings,

Figure 1

Figure 2

Figure 3

Figure 4A

Figure 4B

Figure 5A

Figure 5B

Figure 5C

Figure 5D

Figure 5E

Figure 6A

Figure 6B

Figure 7A

Figure 7B

Figure 8A

Figure 8B

Figure 8C

Figure 9A

Figure 9B

Figure 9C

Figure 9D

Figure 10A

Figure 10B

Figure 11A

Figure 11B

Figure 11C

Figure 11D

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 the levels of certain biomarkers can increase during relapse in patients suffering from IBD, cancer, or other GI conditions. These biomarkers can 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. Thus, changes in the concentration of MPO can be a useful indicator of inflammation or mucosal damage resulting from the development or relapse of IBD or cancer related to the GI tract.

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

[0013] In view of the above, the inventors recognize and understand the advantages of ingestible capsule devices for detecting and / or evaluating the condition within the GI tract. In some embodiments, the ingestible capsule devices according to the present disclosure can detect or evaluate the presence of an enzyme or other biomarker at a particular point within a patient's GI tract. For example, the ingestible capsule device can detect the presence of MPO within a patient's small intestine to monitor or diagnose IBD or cancer associated with the GI. This can enable a less invasive, non-destructive, and inexpensive diagnosis or monitoring compared to conventional methods such as endoscopic procedures, while providing a higher level of reliability and accuracy compared to methods such as fecal sampling.

[0014] Some methods and devices for detecting the condition within the GI tract can include ingestible capsule devices that include fluorescence imaging capabilities. For example, a capsule device having fluorescence imaging capabilities can be used in the diagnosis of certain GI-related cancers or other disease states. However, capsule devices that utilize fluorescence imaging may need to include an excitation light source within the capsule. The excitation light source may require a significant power source to operate, may involve a high degree of complexity in manufacturing, and may be unreliable.

[0015] In view of the above, the inventors recognize and understand the advantages of ingestible capsule devices that use luminescence or chemiluminescence for detecting and evaluating the condition within the GI tract. A capsule device having luminescence capabilities can generate and detect luminescent light in the presence of a particular condition of a substance or composition using a chemical interaction to detect or evaluate the GI condition. Such a device can operate without using an excitation light source, thereby reducing the power requirements and manufacturing complexity compared to fluorescent capsule devices.

[0016] In some embodiments, an ingestible capsule device may use luminescence or chemiluminescence to detect or evaluate a target enzyme or other biomarker indicative of a disease state. For example, an ingestible capsule device may include a luminescent substrate configured to emit luminescent light when exposed to GI fluid containing a luminescence trigger. The luminescence trigger may be the target enzyme or biomarker, or the luminescence trigger 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 the luminescent light emitted by the luminescent substrate.

[0017] In some embodiments, target biomarkers 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 infused with a solution containing a luminescence agent such as coelenterazine, luciferin, oxalate, lucigenin, luminol (C8H7N3O2), derivatives of luminol, and / or other chemiluminescent molecules. In some embodiments, the luminescence agent may be used in combination with quantum dots or nanoparticles configured to emit additional light when exposed to the luminescence emitted by the luminescence 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 an embodiment using luminol and where the target biomarker is MPO, the capsule device may include urea hydrogen peroxide (UHP). UHP may interact with MPO to generate HOCl necessary to interact with luminol. The interaction between HOCl and luminol may generate luminescent light indicative of the presence, absence, or concentration of MPO in a GI fluid sample.

[0018] The capsule device may be further configured to transmit a wireless signal. The wireless signal may relay information regarding a detection signal generated by a photodetector of the capsule device to a separate receiving device external to the patient. In some embodiments, the wireless signal may indicate the presence, absence, or intensity of luminescence light detected at a particular location within the patient's GI tract or at a time corresponding to a particular location. The presence, absence, or intensity of luminescence may indicate the presence, absence, or concentration of a biomarker and, as a result, the current state of a disease or other GI condition.

[0019] In some embodiments, the ingestible capsule device of the present disclosure can target specific regions of the GI tract (e.g., for monitoring or evaluation). For example, the capsule device can include a capsule having a sampling opening that allows GI fluid to enter the capsule for evaluation. In some embodiments, the sampling opening can be closed with one or more layers of a biodegradable or enteric coating. The enteric coating can 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. Since the pH level of the GI tract varies along the length of the GI tract, the ingestible capsule device can be designed to target specific regions of the GI tract by selecting or configuring the enteric coating to degrade at a specific pH level. Multilayer enteric coatings can also be used to target specific regions of the GI tract, such as the colon. When a multilayer enteric coating is used, each layer of the enteric coating can be configured to degrade at a different pH level, thus allowing for more specific targeting of regions of the GI tract. Suitable coating materials can include, but are not limited to, pH-sensitive polymer materials such as basic butylated methacrylate (EUDRAGIT EPO), polymethacrylic acid-co-ethyl acrylate (EUDRAGIT L 100-55), polymethacrylic acid-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 more detail in U.S. Provisional Patent Application No. 63 / 320,825, filed March 17, 2022, the entire disclosure of which is incorporated herein by reference for all purposes. Similar capsules and / or multilayer enteric coatings can be used in conjunction with any of the embodiments described herein.

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

[0021] FIG. 1 shows an embodiment of an ingestible capsule device according to the present disclosure. In the illustrated 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 for 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 tract. For example, the enteric coating may be selected to degrade at a pH level corresponding to the pH level of the small intestine, such that the device 100 may be configured to evaluate a sample from the small intestine.

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

[0023] The luminescence substrate 106 may include a luminescent agent. The luminescent agent may be an active molecule that produces luminescence light when exposed to a luminescence 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 coelenterazine, 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 the luminescence emitted by the luminescent agent. Including quantum dots or nanoparticles can increase the amount of light generated in response to a given concentration of luminescence trigger, thereby increasing the sensitivity of the capsule device.

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

[0025] For example, in the illustrated embodiment, in the case of device 100 configured to detect MPO in a GI fluid sample, the second additional substrate layer can be injected with a solution having an appropriate concentration of UHP such that the interaction between UHP and MPO can generate HOCl. HOCl can function as an oxidizing agent or a luminescence agent that interacts with the luminol of the luminescence substrate 106 to generate luminescence light indicating the presence, absence, or concentration of MPO in the GI fluid sample.

[0026] Additionally or alternatively, an additional substrate layer can be included and configured to provide effects other than inducing a luminescence trigger. In some embodiments, the active molecules in the additional substrate layer can be provided to adjust or modify the properties of the GI fluid sample. For example, in some embodiments, the additional substrate layer can include a pH buffer. The pH buffer can be an active molecule capable of adjusting the pH level of the GI fluid sample. The pH buffer can include 4-(cyclohexylamino)-1-butanesulfonic acid (CABS) or a similar active molecule. In the illustrated embodiment, the first substrate layer 110 can be injected with a solution having an appropriate concentration of a pH buffer such as CABS. As will be described in more detail in the Examples section below, it may be desirable to adjust the pH level or other properties of the GI fluid sample to optimize the luminescence intensity generated by the luminescence substrate 106.

[0027] In some embodiments, device 100 can 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. Further, 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 can 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 source 118. In some embodiments, the electronic unit 116 may include a sensor interface module 128, a signal processing module 130, and a data collection and transmission module 132. The sensor interface module 128 may include a photodetector 108 for detecting the presence, absence, or intensity of luminescence 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 may communicate with the sensor interface module 128 and / or the photodetector 108 to receive and process detection signals 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 otherwise process the detection signal.

[0030] The data collection and transmission module 132 may communicate with the signal processing module 130. The data collection and transmission module 132 may be configured to transmit a wireless signal including information at least partially based on information from the detection signal. The data collection and transmission module 132 may be configured to transmit the 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), body communication networks, and / or others.

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

[0032] Exemplary embodiments of the electronic unit 116 according to the present disclosure are described in more detail in the Examples section below. 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 luminescence light and relaying information regarding the detected light. In this regard, the present disclosure is not limited to the specific components described below.

[0033] Next, with reference to FIG. 2, the operation of the ingestible capsule device as shown in FIG. 1 will be described. The device 100 can be ingested by the patient 200. While the device 100 is within the stomach 202 of the patient 200, the sampling aperture 120 can remain closed by the aperture closure 104. In the illustrated embodiment, the aperture closure 104 can include a biodegradable or enteric material configured to degrade at a pH level corresponding to a portion of the small intestine 204. Thus, when the device 100 reaches the small intestine 204, the aperture closure 104 can degrade or dissolve, thereby allowing a sample of GI fluid to pass through the aperture 120 and into the cavity 122 of the device 100. It will be understood that in other embodiments, the aperture closure 104 can be configured to degrade or dissolve at another location in the GI tract, such as the large intestine 206.

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

[0035] The capsule device 100 can transmit a wireless signal 212 to an external receiving device 214. The receiving device 214 can be any device capable of receiving the wireless signal 212 from the capsule device. The receiving device can be monitored by a user or a medical professional. Alternatively or additionally, the receiving device 214 can 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 FIG. 3. In this example, the device can be configured to monitor or evaluate an IBD condition by detecting MPO in a GI fluid sample. This exemplary embodiment can include luminol as a luminescence agent within the luminescence substrate 106. In this embodiment, the interaction between MPO and luminol may produce insufficient luminescence light to enable useful analysis or evaluation. Thus, the capsule device of this embodiment may induce a luminescence trigger from MPO by chemical interaction with an active molecule. The luminescence trigger in this embodiment can be HOCl. The luminescence trigger may be induced by a chemical interaction between the MPO in the GI fluid sample and the active molecule injected into the additional substrate layer. The active molecule in this particular embodiment can be urea hydrogen peroxide (UHP). UHP can interact with MPO to produce HOCl. HOCl can interact with the luminol in the luminescence substrate to produce luminescence light.

[0037] In addition, as further described 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 between HOCl and luminol. Thus, it may be desirable to adjust the pH value of the GI fluid sample. In the particular embodiments described herein, the pH value can be adjusted to a desired value using a CABS injection substrate layer.

[0038] This example is intended to illustrate the operating principles of ingestible capsule devices, but these principles can be applied and adapted to produce ingestible capsule devices for any suitable use, including the monitoring or evaluation of other GI states by the use of other active molecules and / or other electronic components for detecting other target biomarkers suitable for a given application. As a further example, different numbers and / or arrangements of substrates (e.g., substrates infused with different chemicals or combinations of chemicals) can be used in accordance with the techniques described herein. Accordingly, the present disclosure is not limited to the examples described herein that specifically target the detection of MPO using luminol, UHP, and CABS pH buffer.

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

[0040] The first substrate layer 110 can be configured to chemically interact with a sample of GI fluid. As described above, the first substrate layer 110 can 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 can be a layer of filter paper infused with a first buffer solution containing an appropriate concentration of CABS. In other embodiments, the first substrate layer 110 can contain other active molecules, including other pH buffers or active molecules that adjust fluid properties other than pH, such as salts, viscosity, conductivity, and / or others. For example, in some embodiments, the substrate layer can be infused with a redox buffer solution or redox buffer molecules to control the oxidation / reduction potential of the GI fluid sample or its constituent materials. In some embodiments, the substrate layer can be infused with a detergent or other compound to control the viscosity of the GI fluid sample.

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

[0042] Thus, in some embodiments, the concentration of the pH buffer solution can be selected to obtain a pH value that is 0, 5, 7, 10, and / or above any other suitable pH value. Additionally, the concentration of the pH buffer solution can be selected to obtain a pH value that is 14, 12, 11, 10, and / or below any other suitable pH value. Combinations of the above are contemplated and include, for example, pH values from 0 or above and 14 or below, pH values from 10 or above and 12 or below, and / or any other suitable combination of the above. Of course, specific ranges for the desired pH value are provided above, but it should be understood that the present disclosure is not limited in this manner, and other ranges both above and below the above are also contemplated.

[0043] In some embodiments where 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 can be 0.2M, 0.4M, 0.6M, 0.8M, and / or any other suitable molar concentration or higher. Additionally, the concentration of the CABS buffer solution can be 1.4M, 1.2M, 1.0M, 0.8M, and / or any other suitable molar concentration or lower. Combinations of the above are contemplated, including, for example, concentrations of 0.2M or higher and 1.4M or lower, concentrations of 0.8M or higher and 1.0M or lower, and / or any other suitable combination of the above. Of course, specific ranges for the concentration of the CABS buffer solution are provided above, but it should be understood that the present disclosure is not limited in this manner, and other ranges both above and below the above are also contemplated.

[0044] The second substrate layer 112 can be configured to chemically interact with the GI fluid sample from the second stage 306. In some embodiments, the second substrate layer 112 can be configured to interact with the GI fluid to produce a luminescence trigger. For example, in some embodiments, the second substrate layer 112 can be a layer of filter paper infused with a solution containing an appropriate concentration of urea hydrogen peroxide (UHP). In some embodiments, the volume concentration of the UHP solution selected to obtain HOCl from MPO for interaction with luminol can be 0%, 0.25%, 0.5%, 1.0%, 1.5%, and / or any other suitable concentration or higher. Additionally, the concentration of the UHP solution can be 3.0%, 2.5%, 2.0%, 1.5%, 1.0%, and / or any other suitable concentration or lower. Combinations of the above are contemplated, including, for example, concentrations of 0% or higher and 3.0% or lower, concentrations of 1.5% or higher and 2.5% or lower, and / or any other suitable combination of the above. Of course, specific ranges for the concentration of the UHP solution are provided above, but it should be understood that the present disclosure is not limited in this manner, and other ranges both above and below the above are also contemplated.

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

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

[0047] In some embodiments, the concentration of the luminol solution selected to optimize the luminescence intensity in the presence of MPO can be 1 mM, 10 mM, 15 mM, 20 mM and / or any other suitable molar concentration or above. Additionally, the concentration of the luminol solution can be 30 mM, 25 mM, 20 mM, 15 mM, and / or any other suitable molar concentration or below. Combinations of the above are contemplated, for example, concentrations of 1 mM or more and 30 mM or less, 20 mM or more and 30 mM or less, and / or any other suitable combination of the above. Of course, specific ranges for the concentration of the luminol solution are provided above, but it should be understood that the present disclosure is not limited in this manner, and other ranges both above and below the above are also contemplated.

[0048] The combination of MPO, UHP, and luminol is described herein as being included in one embodiment of the present disclosure, but the present disclosure is not limited in this regard, so it will be understood that other embodiments may utilize other luminescence triggers, luminescence agents, and / or buffer solutions. Additionally, the luminescence agent, luminescence trigger, buffer solution, active molecule, and their combinations and concentrations can 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, etc.

[0049] Furthermore, the embodiment of FIG. 3 includes one luminescence substrate layer and two additional substrate layers, but it will be understood that other embodiments may include any suitable number of additional substrate layers. For example, in some embodiments, it will be understood that no additional substrate layer is required to generate the luminescence light indicating the presence of the desired enzyme or biomarker. In other embodiments, three or more additional substrate layers may be desirable. Accordingly, the present disclosure is not limited to any particular number of substrate layers.

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

[0051] Figure 4A shows the luminescence intensity during the time when the capsule opening remains closed within the scope of some embodiments of the device as described in this specification. For example, the luminescence intensity shown in Figure 4A may correspond to the time when the device 100 is located within the stomach 202 of the patient 200 as shown in Figure 2. Figure 4B shows the luminescence intensity during the time when the capsule opening is open and the GI fluid sample containing the enzyme or biomarker to be detected enters the capsule within the scope of some embodiments of the device as described in this specification. For example, the luminescence intensity shown in Figure 4B may correspond to the time when the device 100 is located within the small intestine 204 of the patient 200 as shown in Figure 2. The increase in the 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.

Example

[0052] Design and Use Case for Experimental Embodiments An example of the experimental capsule device according to the present disclosure included six elements, namely, a capsule, a pH-sensitive biodegradable enteric coating, a stack of three thick filter papers, a cover glass, an electronic unit having a photodetector on the top, and a 3-volt lithium battery. The capsule utilized a threaded design consisting of two parts to facilitate the assembly of the capsule device. The pH-sensitive polymer coating used one that could withstand the low pH gastric environment where the experimental capsule device was intended to remain intact.

[0053] This example was intended to evaluate the small intestine. When exposed 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 initiate the absorption of MPO and may perform their roles as follows. First, the CABS injection filter paper may adjust the pH of the incoming sample to a pH of 11. Next, the UHP injection filter paper may interact with MPO (having a pH of 11) to generate hypochlorous acid (HOCl). Then, the luminol injection filter paper may interact with HOCl and begin to emit blue luminescence. At this point, the photodetector detects the luminescence, converts the photon energy into an electrical signal, and then the electrical signal may be transmitted to the receiving device via the wireless transmitter of the electronic unit of the capsule device.

[0054] Exemplary Optimization of Analysis Parameters The characteristics and intensity of the luminescence emitted by the oxidation reaction of luminol may depend on several parameters including the pH level and the concentration of the reactants. Therefore, a series of experiments were performed to optimize these parameters around the specific use case where luminol is used for the optical detection of MPO.

[0055] Optimization of pH First, the effect of pH on luminescence intensity was investigated by exposing MPO to buffer solutions 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. To each well, 50 μL of UHP (250 μM) was added. Ten seconds after the addition of UHP, a fixed volume of luminol was added to each well. Two seconds after the addition of luminol (i.e., 12 seconds after the addition of 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 FIGS. 6A and 6B. As can be seen from FIGS. 6A and 6B, it was observed that the maximum luminescence intensity was generated 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 FIGS. 6A and 6B, the luminescence intensity observed at pH values in that range was significantly lower than the intensity at a pH value of 11. Therefore, the inventors recognized and understood the advantage of adjusting the pH value of the GI fluid sample in order to optimize the luminescence intensity in the disclosed capsule device. In the experimental embodiments disclosed herein, a CABS injection filter paper was included in the capsule to adjust the pH value of the GI fluid sample.

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

[0058] Using these CABS-infused dried filter papers, it was determined which dilutions of the CABS stock solution best achieved the conversion of 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 above-described pH conversion experiment, and Figure 7B shows the results obtained. In Figure 7A, the GI fluid sample 802 or the PBS buffer solution at various pH values was pipetted onto the filter paper 804 infused 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 indicated that the filter paper infused with a 1.0 M CABS solution was sufficient to convert each pH to near the desired pH value of 11. Therefore, a 1.0 M CABS solution was selected as the appropriate concentration of CABS in the filter paper to obtain a desired pH value of 11 from GI fluid samples having an initial pH value of 6 - 7. The specific methods, parameters, and goals of these experiments led to the selection of these specific compounds, values, and concentrations, but it will be understood that deviations from these specific methods, parameters, and goals for other applications may lead to the selection of any appropriate compounds, values, or concentrations 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 of the presently described embodiments and, thus, the chemiluminescence intensity. Accordingly, various concentrations of UHP were evaluated with various concentrations of luminol. It will be understood that in an in vivo situation, not all GI fluids contain significant amounts of MPO. However, UHP and luminol can interact during the use of the capsule device regardless of whether the GI fluid contains MPO. Accordingly, various ratios of UHP to luminol were evaluated both in the presence and absence of MPO. Since the capsule device of the presently described embodiments is aimed at detecting MPO by evaluating the intensity of luminescence generated by the introduction of MPO into the capsule, the difference between the luminescence in the absence of MPO and the luminescence in the presence of MPO (not just the intensity of the luminescence in the presence of MPO) was evaluated as indicating the introduction of MPO.

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

[0062] Figure 8B shows a heat map of the peak values of luminescence intensity obtained from the interaction of UHP and luminol in the presence of MPO (at a 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 peak values of luminescence intensity in both the presence and absence of MPO for a given ratio.

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

[0064] Exemplary device manufacturing As shown in FIGS. 5A - 5B, in one embodiment, the capsule 102 for an ingestible device was manufactured using 3D printing. The capsule included two parts, namely, a body part 102A and a cap part 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 from Formlabs, Inc. using a 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 completed, the capsule was washed in 99% isopropyl alcohol (IPA) for 15 minutes and further cured for 60 minutes using an ultraviolet (UV) light curing device (from Formlabs, Inc.) to complete the polymerization of the resin.

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

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

[0067] Electronic unit The electronic unit was included to measure the luminescence light output at maximum sensitivity and provide continuous wireless luminescence measurements. As shown in FIGS. 5C and 5D above, the electronic unit 116 comprised three separate modular systems combined in a single unit. The unit included a sensor interface module 128, an analog signal processing module 130, and a data collection 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 circular PCB with a diameter of 8 mm. The three boards were stacked on top of each other with the sensor interface module at one end, the signal processing module in the center, and the data collection and transmission module at the other end.

[0068] The sensor interface module 128 was provided to directly interact with the luminescence chemical substance and convert the light intensity into a representative current. To achieve a wide functional range, a single-photon avalanche diode (SPAD) array (MicroFC-30035-SMT) manufactured by Onsemi was used as the photodetector 108 to measure the light generated from the MPO reaction. An inverting DC-DC converter (LT3462) manufactured by Analog Devices was used to apply a bias of -25V to -30V to the sensor. The adjustment of this bias voltage can function as the main method for adjusting the sensitivity of the device. To enable extending the battery life when no reaction is expected to occur, the sensor interface could be shut down to draw almost zero current by switching the enable pin on the DC-DC converter.

[0069] The analog signal processing module 130 provided noise removal and amplification to separate the measurements from the sensor interface and convert them into usable voltages. A transimpedance amplifier (TIA) was included to convert the SPAD current into 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 restricted the output of the sample signal to 0 to 1.8V by utilizing the full range of the ADC. Exemplary schematic diagrams of the bias voltage circuit and the TIA can be found in the data sheets of the DC-DC converter and the SPAD.

[0070] Finally, in the data collection and transmission module 132, a microcontroller (nRF52832, ARM M4 processor) collected analog measurement values and wirelessly transmitted representative digital signals to an external receiving device (nRF51822, ARM M0 processor). The nRF52832 controlled all the electronic components within the capsule using 1.8V digital logic and converted the TIA output voltage into a digital signal using its on-board digital-to-analog converter. The nRF52832 and nRF51822 microcontrollers provided a built-in RF communication protocol used to transmit data collected from inside the GI tube to an external system. In this example, a 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] The 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 series 1.55V, 23mAh silver oxide batteries (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 10 meters away from the base station in the atmosphere and to fit within a standard 000 capsule.

[0072] MPO detection performance First, the analytical performance of the sensor interface module of the electronic unit was evaluated by recording the luminescence spectra generated through different concentrations of MPO. This was done using a conventional BMG Clariostar microplate reader. Figure 9A shows the luminescence spectra of the oxidation reaction at the optimal wavelength of 425 nm with different concentrations of MPO. As can be seen from Figure 9A, as the MPO concentration increased (0 - 9 U / mL), the luminescence intensity gradually increased 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 oxidants (HOCl) by the reaction of MPO and UHP. The increase in HOCl can further oxidize luminol and thus generate blue luminescence. Figure 9B shows a plot between different MPO concentrations and the area under the corresponding luminescence curves in Figure 9A. Figures 9A and 9B suggest that the sensor interface module is detectable even with trace amounts of MPO.

[0073] Subsequently, the analytical performance of the entire experimental capsule device was also investigated. Figure 9C shows a sensitivity plot associating voltage with MPO concentration when recorded via the portable device. As described above, the photodetector attached to the top of the electronic unit detected the gradually increasing luminescence intensity in response to the increase in MPO concentration (0 - 9 U / mL) and converted this photon energy into an electrical signal. This electrical signal was then transmitted to the receiving device via the wireless system embedded within the electronic unit as described above. As can be well understood from Figure 9C, the voltage generated by the photodetector gradually increased with the increase in MPO concentration (0 - 9 U / mL). Similar to Figure 9B, Figure 9D shows a plot between different MPO concentrations and the area under the corresponding voltage curves in Figure 9C. From the similarity between Figures 9B and 9D, it will be understood that the experimental capsule device was detectable even with trace amounts of MPO.

[0074] Selectivity assay The above results indicate that the experimental embodiments 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 responses 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 the interfering biomarker was not significant, while the same concentration of MPO generated a relatively high output voltage signal. This may be due to the fact that more oxidants (HOCl) are formed by the reaction of UHP with MPO than by the reaction of UHP with any interfering biomarker. The generation of fewer oxidants by these potentially interfering biomolecules resulted in low luminescence intensity and output voltage. Figure 10B shows a plot between the various interfering biomarkers and the area under the corresponding voltage curve 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 actual application of the experimental capsule device, ex vivo detection of MPO was also evaluated in a physiological environment as shown in FIGS. 11A and 11B. Here, porcine small intestine was cut into three segments 1100 about 7 cm in length. Each intestinal segment 1100 was separately exposed to solutions having different concentrations of MPO, 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 GI fluid and buffer environments. The fully assembled device 100 was then inserted into each of the intestinal segments 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 respective curve are shown in FIGS. 11C and 11D, respectively. The results of the corresponding in vitro buffer experiments are also shown in FIG. 11D. The ex vivo results in FIGS. 11C and 11D, and their similarity to the in vitro results, indicate that the experimental embodiments of the capsule device described herein were able to determine the level of inflammation in the small intestine region by monitoring the level of MPO.

[0076] The above-described embodiments of the technology described in this specification can be implemented in any of a number of ways. For example, the embodiments can be implemented using hardware, software, or a combination thereof. When implemented in software, the software code can be executed on any suitable processor or collection of processors, whether provided within a single computing device or distributed among multiple computing devices. Such processors can 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 by names such as CPU chips, GPU chips, microprocessors, microcontrollers, or coprocessors. Alternatively, the processor can be implemented in a custom circuit such as an ASIC, or a semi-custom circuit obtained by configuring a programmable logic device. As yet another alternative, the processor can be 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 those cores can constitute the processor. However, the processor can be implemented using any suitable format of circuitry.

[0077] Furthermore, it should be understood that a computing device including one or more processors can be embodied in any of several forms, such as a rack-mounted computer, a desktop computer, a laptop computer, or a tablet computer. Additionally, the computing device can be incorporated into a device that is not generally considered a computing device, such as a personal digital assistant (PDA), a smartphone, a tablet, or any other suitable portable or fixed electronic device having suitable processing capabilities.

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

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

[0080] Also, the various methods or processes outlined herein may be coded as software executable on one or more processors using any one of a variety of operating systems or platforms. Additionally, such software can be described using any of several suitable programming languages and / or programming tools or scripting tools, and can be compiled as executable machine language code or intermediate code to be executed on a framework or virtual machine.

[0081] In this regard, the embodiments described herein may be embodied as one or more computer-readable storage media (or a plurality of computer-readable media) (e.g., computer memory, one or more floppy disks, compact discs (CDs), optical discs, digital video discs (DVDs), magnetic tapes, flash memories, RAMs, ROMs, EEPROMs, circuit configurations within field programmable gate arrays or other semiconductor devices, or other tangible computer storage media) encoded with one or more programs that implement a method of implementing the various embodiments described above when executed on one or more computers or other processors. As is apparent from the foregoing examples, a computer-readable storage media can hold information for a sufficient time to provide computer-executable instructions in a non-transitory form. One or more such computer-readable storage media may be removable, such that one or more programs stored thereon may be loaded onto one or more different computing devices or other processors to implement the various aspects of the present disclosure as discussed above. As used herein, the term "computer-readable storage media" encompasses only non-transitory computer-readable media that can be considered a manufacture (i.e., a manufactured article) or a machine. Alternatively or additionally, the present disclosure may be embodied as a computer-readable media other than a computer-readable storage media, such as a propagated signal.

[0082] As used herein, the terms "program" or "software" are used 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 the various aspects of the present disclosure as discussed above. Additionally, it should be understood that according to one aspect of this embodiment, one or more computer programs that implement the methods of the present disclosure when executed need not be present on a single computing device or processor, but may be distributed in a modular fashion among several different computers or processors to implement the various aspects of the present disclosure.

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

[0084] Also, the embodiments described herein can be embodied as a method, and an example thereof is provided. The acts performed as part of this method can be ordered in any suitable way. Thus, although shown as sequential acts in the exemplary embodiments, embodiments can be constructed in which acts are performed in a different order than that shown, including performing some acts simultaneously.

[0085] Furthermore, some operations are described as being made by a "user". It should be understood that the "user" need not be a single individual, and that in some embodiments, operations attributable to the "user" can be performed by a team of individuals and / or an individual in combination with computer-aided tools or other mechanisms.

[0086] Although several embodiments of the present invention have been described and illustrated in this specification, those skilled in the art can readily envision various other means and / or structures for performing the functions and / or obtaining the results and / or one or more of the advantages described herein, and each such variation and / or modification is considered to be 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 exemplary, and that the 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 will be able to ascertain such equivalents using only routine experimentation. Accordingly, the foregoing embodiments are presented by way of example only, and it is to be understood that the present invention may be practiced otherwise than as specifically described and claimed within the scope of the appended claims and their equivalents. The present invention is directed to each individual feature, system, article, material, kit, and / or method described herein. Furthermore, any combination of two or more of such features, systems, articles, materials, kits, and / or methods is included within the scope of the present invention if such features, systems, articles, materials, kits, and / or methods are not mutually inconsistent.

[0087] Although the present teachings have been described in conjunction with various embodiments and examples, it is not intended that the present teachings be limited to such embodiments or examples. On the contrary, the teachings of the present invention include various alternatives, modifications, and equivalents as will be understood by those skilled in the art. Accordingly, the foregoing description and drawings are for example only.

Claims

**Claim 1** A device for passive sampling of a patient's gastrointestinal tract, comprising: A capsule housing defining a cavity; A sampling opening formed within the capsule housing to provide fluid communication between the cavity and the exterior of the capsule housing; A luminescence substrate layer positioned within the cavity, the luminescence substrate being configured to emit luminescence light when exposed to a sample fluid containing a luminescence trigger; At least one additional substrate layer positioned within the cavity between the sampling opening and the luminescence 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, the photodetector being configured to detect the luminescence light; A biodegradable coating closing the sampling opening, decomposition of the biodegradable coating exposing the sampling opening and allowing fluid to flow into the cavity. **Claim 2** The device of claim 1, wherein the luminescence trigger indicates the presence of a biomarker in the sample fluid. **Claim 3** The device of claim 2, wherein the biomarker comprises myeloperoxidase (MPO). **Claim 4** The device according to any one of claims 2 to 3, wherein the luminescence trigger comprises an oxidized form formed from a chemical interaction with the biomarker. **Claim 5** The device according to any one of claims 1 to 4, wherein the luminescence substrate contains a luminescence agent, and the luminescence agent interacts with the luminescence trigger to emit the luminescence light. **Claim 6** The device of claim 5, wherein the luminescence agent comprises luminol. **Claim 7** The device of claim 1, wherein one or more of the at least one additional substrate layer are configured to change the pH of the sample fluid. **Claim 8** The device of claim 7, wherein the one or more additional substrate layers configured to change the pH of the sample fluid contain 4-(cyclohexylamino)-1-butanesulfonic acid (CABS). **Claim 9** The device according to any one of claims 1 to 8, wherein one or more of the at least one additional substrate layer are configured to interact with the sample fluid to form the luminescence trigger.

10. The device according to claim 9, wherein the one or more additional substrate layers configured to interact with the sample fluid to form the luminescence trigger are configured to interact with a biomarker of the sample fluid to form the luminescence trigger.

11. The device according to claim 10, wherein the biomarker comprises MPO.

12. The device according to any one of claims 10 to 11, wherein the luminescence trigger comprises an oxidized form.

13. The device according to any one of claims 10 to 12, wherein the one or more additional substrate layers configured to interact with the sample fluid to form the luminescence trigger contain urea peroxide (UHP).

14. The one or more additional substrate layers containing UHP are injected with a UHP solution containing 1% to 3% by volume of UHP, and the luminescence substrate is injected with a luminol solution containing luminol at a concentration of 20 mM to 30 mM. The device according to claim 13.

15. The device according to any one of claims 1 to 6, wherein the at least one additional substrate layer includes a first additional substrate layer configured to change the pH of the sample fluid and a second additional substrate layer configured to interact with the sample fluid to form the luminescence trigger.

16. The device according to any one of claims 1 to 15, further comprising a translucent partition positioned between the luminescence substrate and the photodetector, the translucent partition being configured to form a fluid-tight seal between the first portion of the cavity and the second portion of the cavity while allowing the luminescence light to pass from the first portion of the cavity to the second portion of the cavity.

17. The device according to any one of claims 1 to 16, wherein the photodetector includes an avalanche photodiode.

18. 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 to transmit a wireless signal, wherein the information in the wireless signal is at least partially based on the information from the detection signal, and the wireless transmitter; The device according to any one of claims 1 to 17, further comprising a battery configured to supply power to at least the signal processor and the wireless transmitter.

19. The biodegradable coating includes a first coating layer and a second coating layer, the first coating layer is configured to decompose within a first pH range, 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. The device according to any one of claims 1 to 18.

20. A method for detecting a biomarker in a patient's gastrointestinal tract, comprising: administering to the patient a ingestible device comprising: a capsule housing defining a cavity; a sampling aperture formed within the capsule housing and providing fluid communication between the cavity and the exterior of the capsule housing; a luminescence substrate positioned within the cavity, the luminescence substrate being configured to emit luminescence light when exposed to a sample fluid containing a luminescence trigger, the luminescence trigger indicating the presence of the biomarker; and a photodetector positioned within the cavity and configured to detect the luminescence light and generate a detection signal; transmitting a wireless signal based on the detection signal; exposing the luminescence substrate to the sample fluid; receiving the wireless signal at a user device; and determining whether the biomarker is present in the sample fluid based on the wireless signal.

21. The method according to claim 20, wherein the biomarker comprises myeloperoxidase (MPO).

22. The method according to any one of claims 20 to 21, wherein the luminescence substrate contains a luminescence agent, and the luminescence agent interacts with the luminescence trigger to emit the luminescence light.

23. The method according to claim 22, wherein the luminescence agent contains luminol.

24. The method according to any one of claims 20 to 23, further comprising passing the sample fluid through at least one additional substrate layer of the ingestible device, each additional substrate layer being configured to chemically interact with the sample fluid.

25. The method according to claim 24, wherein passing the sample fluid through the at least one additional substrate layer of the ingestible device includes passing the sample fluid through a first additional substrate layer to change the pH of the sample fluid.

26. The method according to claim 25, wherein the first additional substrate layer contains 4-(cyclohexylamino)-1-butanesulfonic acid (CABS).

27. The method according to any one of claims 24 to 26, wherein passing the sample fluid through the at least one additional substrate layer of the ingestible device includes passing the sample fluid through a second additional substrate layer to form the luminescence trigger.

28. The method according to claim 27, wherein the luminescence trigger is an oxidized form.

29. The method according to any one of claims 27 to 28, wherein the second additional substrate layer contains urea hydrogen peroxide (UHP).

30. The method according to any one of claims 20 to 29, wherein the ingestible device further includes a biodegradable coating that closes the sampling opening, and exposing the luminescence substrate to the sample fluid includes decomposing the biodegradable coating to allow fluid to flow into the cavity.

Images