Intake capsule device

Abstract

The technique provides non-invasive gastrointestinal sampling. In some embodiments, an apparatus includes: a capsule housing defining a cavity; a sampling orifice formed in the capsule housing and providing fluid communication between the cavity and an exterior of the capsule housing; a luminescent substrate layer positioned within the chamber, the luminescent substrate configured to emit luminescent light upon exposure to a sample fluid comprising a luminescent initiator; and 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 configured to chemically interact with the sample fluid. The apparatus further includes a photodetector positioned within the cavity, the photodetector configured to detect the emitted light; and a biodegradable coating closing the sampling aperture such that degradation of the biodegradable coating exposes the sampling aperture to allow fluid to flow into the cavity.

Description

Technical Field

[0001] The disclosed embodiments relate to ingestible capsule devices for detecting and assessing gastrointestinal conditions and related methods of use. Background Art

[0002] Developing tools that can accurately detect certain conditions in the gastrointestinal (GI) tract can promote medical progress, such as effectively and accurately predicting and diagnosing diseases and disease progression. For example, inflammatory bowel disease (IBD) is a group of intestinal disorders that cause chronic remission and recurrent inflammation of the gastrointestinal tract. Various factors may promote the development of IBD, including the hyperresponsiveness of the immune system, genetic variations in multiple genes, intestinal microbiota and diet. In 2017, nearly 6.8 million IBD cases were reported worldwide. It is estimated that nearly 1.6 million people suffer from two common types of IBD (Crohn's disease (CD) and ulcerative colitis (UC)) in the United States alone. Therefore, it would be desirable to predict and / or diagnose IBD progression.

[0003] Conventional techniques for diagnosing IBD can include, for example, monitoring symptoms, endoscopy, colonoscopy, and capsule endoscopy. Recently, certain biomarkers have been correlated with the occurrence and recurrence of IBD. Stool sampling techniques have been developed to detect these biomarkers in patient feces. However, there is still a need to more effectively and accurately diagnose IBD and other gastrointestinal conditions. Summary of the invention

[0004] In some embodiments, a device for passively sampling the gastrointestinal tract of a patient may include a capsule housing defining a cavity and a sampling orifice formed in the capsule housing. The sampling orifice may provide fluid communication between the cavity and the outside of the capsule housing. The device may also include a luminescent substrate layer positioned in 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 also include at least one additional substrate layer positioned in the cavity between the sampling orifice 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 in the cavity. The photodetector may be configured to detect the luminescent light. The device may also include a biodegradable coating that closes the sampling orifice, so that degradation of the biodegradable coating may expose the sampling orifice to allow fluid to flow into the cavity.

[0005] In some embodiments, a method for detecting biomarkers in the gastrointestinal tract of a patient may be provided, the method comprising administering an ingestible device to the patient. The ingestible device may include a capsule housing and a sampling orifice, the capsule housing defining a cavity, the sampling orifice formed in the capsule housing and providing 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 the luminescent light and generate a detection signal. The wireless transmitter of the device may be configured to transmit a wireless signal based on the detection signal. The method may also include exposing the luminescent substrate to the sample fluid, receiving the wireless signal at the user device, and determining whether the biomarker is present in the sample fluid based on the wireless signal.

[0006] It should be appreciated that the aforementioned concepts and the additional concepts discussed below can be arranged in any suitable combination, as the present disclosure is not limited in this regard. In addition, 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] In the event that this specification and the documents incorporated by reference contain conflicting and / or inconsistent disclosures, this specification 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 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 illustrated in various figures may be represented by the same numeral. For clarity, not every component is labeled in every drawing. In the drawings:

[0009] Figure 1 shows a schematic internal view of an ingestible capsule device according to one embodiment;

[0010] Figure 2 A schematic diagram showing an ingestible capsule device operating within the gastrointestinal tract of a patient according to one embodiment;

[0011] Figure 3 A schematic diagram showing various substrate layers and photodetectors of one embodiment;

[0012] Figure 4A a graph showing luminous intensity during a time when an orifice of a capsule device according to one embodiment is kept closed;

[0013] Figure 4Ba graph showing luminous intensity during a time when an orifice of a capsule device according to one embodiment has been opened;

[0014] Figure 5A A perspective view of a threaded capsule of an ingestible capsule device according to one embodiment is shown;

[0015] Figure 5B A perspective view of a non-threaded capsule of an ingestible capsule device according to one embodiment is shown;

[0016] Figure 5C Three substrate layers of an ingestible capsule device according to one embodiment are shown;

[0017] Figure 5D shows a front view of an electronics unit of an ingestible capsule device according to one embodiment;

[0018] Figure 5E shows a top view of an electronics unit of an ingestible capsule device according to one embodiment;

[0019] Fig. 6A is a graph of luminescence intensity for various pH values ​​of a fluid sample containing MPO when exposed to luminol for one embodiment of an ingestible capsule device;

[0020] Figure 6B It is for Fig. 6A Graph of peak luminescence intensity at various pH values;

[0021] Fig. 7A An experimental setup for evaluating various concentrations of pH buffer for one embodiment of an ingestible capsule device is shown;

[0022] Figure 7B An embodiment of an ingestible capsule device is shown, which is used by Fig. 7A The pH value produced by the concentration of the setting evaluation;

[0023] Fig. 8A shows a heat map illustration of the luminescence intensity peak obtained from the interaction of UHP and luminol in the absence of MPO for one embodiment of an ingestible capsule device;

[0024] Figure 8B shows a heat map illustration of the luminescence intensity peak obtained from the interaction of UHP and luminol in the presence of MPO for one embodiment of an ingestible capsule device;

[0025] Figure 8C One embodiment of an ingestible capsule device is shown. Fig. 8A The peak intensity and Figure 8BHeat map illustration of the difference between the intensity peaks of

[0026] Fig.9A shows a time profile of the luminescence intensity generated by MPO exposed to various concentrations of luminol in one embodiment of an ingestible capsule device;

[0027] Fig. 9B For one embodiment, Fig.9A The area under each time curve of

[0028] Fig. 9C shows a time curve of the voltage generated by the photodetector in response to the luminescence generated by exposure of various concentrations of MPO to luminol in one embodiment of an ingestible capsule device;

[0029] Fig.9D For one embodiment, Fig. 9C The area under each time curve of

[0030] Fig. 10A shows a time profile of a voltage generated by a photodetector in response to luminescence generated by exposure of various biomarkers at various concentrations to luminol in one embodiment of an ingestible capsule device;

[0031] Fig. 10B For one embodiment, Fig. 10A The area under each time curve of

[0032] Fig.11A An experimental setup for an in vitro assay for evaluating MPO is shown for one embodiment of an ingestible capsule device, wherein the capsule device is prepared for insertion into a porcine small intestine;

[0033] Fig. 11B Shows Fig.11A ’s experimental setup, in which the capsule device was inserted into the pig small intestine;

[0034] Fig. 11C Shown in Fig.11A time curves of the voltage generated by the photodetector in response to luminescence generated by various concentrations of MPO in the experimental setup; and

[0035] Fig.11D For one embodiment, Fig. 11C The area under the curve at each time. DETAILED DESCRIPTION

[0036] As described above, conventional methods for detecting and evaluating the condition within the gastrointestinal tract of a patient may include monitoring symptoms, endoscopy, colonoscopy, and capsule endoscopy. As used herein, the term "condition" is intended to encompass not only disease conditions or disorders, such as IBD, but also the general state of the gastrointestinal tract, including the presence or absence of certain environments, traits, or substances (such as enzymes, biomarkers, microbiota, etc.).

[0037] These conventional methods can be used to detect or assess various conditions, including IBD or related conditions. However, these methods may be time consuming, expensive, unpleasant and / or invasive, and may require skilled medical practitioners. These factors may bring challenges to patients who need regular monitoring. For example, the discomfort and pain caused by endoscopic procedures (which generally include sedation) may reduce the patient's willingness or ability to undergo the procedure. In addition, the predictive value of these methods may be very limited. Therefore, patients may need to visit a doctor frequently to reassess their condition, which may often be once every 2-4 months.

[0038] It has been appreciated that in patients with IBD, cancer or other gastrointestinal conditions, the levels of certain biomarkers may increase during a sudden attack of the disease. These biomarkers may include myeloperoxidase (MPO), tumor necrosis factor-α, interleukin (IL), C-reactive protein (CRP), calprotectin, lactoferrin and / or others. For example, studies indicate that the biomarker MPO is the main enzyme released by polymorphonuclear leukocytes that gather at the site of inflammation. Therefore, changes in MPO concentrations can be useful indicators of inflammation or mucosal damage caused by the occurrence or sudden attack of IBD or gastrointestinal related cancers.

[0039] Based on these findings, stool sampling techniques have been developed to detect and assess the presence of such biomarkers in patient feces. These stool sampling techniques can allow non-invasive diagnosis or monitoring of IBD (or related conditions), which can be accomplished with reduced costs and less interference with patients when compared to the above-mentioned traditional methods. However, although the level of biomarkers in patient feces can (to some extent) indicate the presence, absence or state of a disease state, the level of biomarkers in feces may also be highly dependent on a variety of other factors. Exemplary factors that may affect fecal biomarker levels may include, for example, the water content and disease location in the patient's diet, fecal sample. For example, ileal CD patients may have large ulcers. However, ileal disease locations may only result in very low levels of fecal biomarkers. Therefore, these stool sampling methods can provide a simple assessment of IBD, but may be imprecise or unreliable in determining the location or state of a disease state.

[0040] In view of the above, the inventors have recognized and appreciated the benefits of an ingestible capsule device for detecting and / or evaluating conditions within the gastrointestinal tract. In some embodiments, an ingestible capsule device according to the present disclosure can detect or evaluate the presence of enzymes or other biomarkers at specific points in the patient's gastrointestinal tract. For example, an ingestible capsule device can detect the presence of MPO in the patient's small intestine to monitor or diagnose IBD or gastrointestinal-related cancers. This can allow for diagnosis or monitoring that is less invasive, less destructive, and less costly than traditional methods (such as endoscopic procedures), while having greater reliability and accuracy than methods such as stool sampling.

[0041] Some methods and devices for detecting conditions in the gastrointestinal tract may include an ingestible capsule device that includes a fluorescence imaging capability. For example, a capsule device with fluorescence imaging capability may be used to diagnose certain cancers or other disease conditions related to the gastrointestinal tract. However, a capsule device that utilizes fluorescence imaging may require the inclusion of an excitation light source within the capsule. The excitation light source may require a large amount of electrical power to operate, may be associated with a high degree of complexity in manufacturing, and may be unreliable.

[0042] In view of the above, the inventors have recognized and appreciated the benefits of an ingestible capsule device that uses luminescence or chemiluminescence to detect and assess conditions within the gastrointestinal tract. A capsule device with luminescence capability can use chemical interactions to detect or assess gastrointestinal conditions to produce and detect luminescent light in the presence of certain conditions or material compositions. Such a device can operate without the use of an excitation light source, thereby reducing power requirements and manufacturing complexity compared to fluorescent capsule devices.

[0043] In some embodiments, the ingestible capsule device can use luminescence or chemiluminescence to detect or evaluate a target enzyme or other biomarker indicative of a disease condition. For example, the ingestible capsule device can include a luminescent substrate configured to emit luminescent light when exposed to a gastrointestinal fluid containing a luminescent trigger. The luminescent trigger can be a target enzyme or biomarker, or the luminescent trigger can be another chemical derived from the target enzyme or biomarker. In some embodiments, the capsule can include a photodetector configured to detect the presence, absence, or intensity of luminescent light emitted by the luminescent substrate.

[0044] In some embodiments, the target biomarkers may include myeloperoxidase (MPO), tumor necrosis factor-α, interleukin (IL), C-reactive protein (CRP), calprotectin, lactoferrin, etc. In some such embodiments, the luminescent substrate of the capsule device may be impregnated with a solution containing a luminescent agent, such as fluorescein, firefly luciferin, oxalate, lucigenin, luminol (C 8H 7 N 3 O 2 ), derivatives of luminol and / or other chemiluminescent molecules. In some embodiments, the luminescent agent can be used in combination with quantum dots or nanoparticles, which are configured to emit additional light when exposed to the luminescence emitted by the luminescent agent. In embodiments using luminol, the luminescent trigger can be an oxidant, such as hypochlorous acid (HOCl). In some such embodiments, active molecules can be included to interact with the target biomarker to produce a luminescent trigger. For example, in embodiments using luminol and wherein the target biomarker is MPO, the capsule device can include urea hydrogen peroxide (UHP). UHP can interact with MPO to produce the HOCl required for interaction with luminol. The interaction between HOCl and luminol can generate luminescent light that indicates the presence, absence or concentration of MPO in the gastrointestinal fluid sample.

[0045] The capsule device may also be configured to transmit a wireless signal. The wireless signal may relay information about the detection signal generated by the photodetector of the capsule device to a separate receiving device outside the patient's body. In some embodiments, the wireless signal may indicate the presence, absence, or intensity of luminescent light detected at a specific location within the patient's gastrointestinal tract or at a time corresponding to the specific location. The presence, absence, or intensity of luminescence may indicate the presence, absence, or concentration of a biomarker, which in turn may indicate the state of a disease or other gastrointestinal condition.

[0046] In some embodiments, the ingestible capsule device of the present disclosure can target a specific area of ​​the gastrointestinal tract (e.g., for monitoring or evaluation). For example, the capsule device can include a capsule with a sampling orifice that allows gastrointestinal fluid to enter the capsule for evaluation. In some embodiments, the sampling orifice can be closed with one or more layers of biodegradable coating or enteric coating. The enteric coating can be selected to degrade at a desired pH level, allowing the sampling orifice to remain closed until the enteric coating is exposed to the desired pH level. Because the pH level of the gastrointestinal tract changes along the length of the gastrointestinal tract, the ingestible capsule device can be designed to target a specific area of ​​the gastrointestinal tract by selecting or configuring the enteric coating to degrade at a specific pH level. Multilayer enteric coatings can also be used to target a specific area of ​​the gastrointestinal tract, such as the colon. When using a multilayer enteric coating, each layer of enteric coating can be configured to degrade at different pH levels, thereby allowing more specific targeting of the gastrointestinal tract region. Suitable coating materials may include, but are not limited to, pH-sensitive polymeric materials such as alkaline butylated methacrylate (EUDRAGIT EPO), polymethacrylic acid-ethyl acrylate copolymer (EUDRAGIT L 100-55), polymethacrylic acid-methyl methacrylate copolymer (EUDRAGIT L 100), hydroxypropyl methylcellulose phthalate (HP-55), hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP) and polyvinyl acetate phthalate (PVAP). An exemplary ingestible sampling capsule is further described in detail in U.S. Provisional Application No. 63 / 320,825 filed on March 17, 2022 (the entire contents of which are incorporated herein by reference). Similar capsules and / or multi-layer enteric coatings are used with any of the embodiments described herein.

[0047] Turning to the drawings, specific non-limiting embodiments are described in further detail. It should be understood that the various systems, components, features, and methods described with respect to these embodiments may be used alone and / or in any desired combination, as the present disclosure is not limited to the specific embodiments described herein.

[0048] Figure 1Depicted is one 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 orifice 120 to allow fluid exchange between the cavity 122 and the surrounding environment of the device 100. The orifice 120 may be filled, covered, or otherwise closed by an orifice closure 104. The orifice 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 gastrointestinal tract. 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.

[0049] The device 100 may include one or more layers of substrate material, such as two layers, three layers, four layers, etc. In the illustrated embodiment, the device 100 may include a luminescent substrate 106, a first additional substrate layer 110 and a second additional substrate layer 112, although other embodiments may include more substrate layers or fewer substrate layers. The substrate material may include any suitable material for carrying active molecules therein, such as paper, fabric, polymer material (including polymer mesh, polymer film and others), synthetic material, composite material, hydrogel, freeze-dried hydrogel matrix, etc. In some embodiments, the substrate material may include filter paper or cellulose paper. Each layer of substrate material may include one or more active molecules. Each active molecule may be selected to produce a desired chemical interaction with the gastrointestinal fluid sample or the ingredients or components of the gastrointestinal fluid sample in the capsule device.

[0050] The luminescent substrate 106 may include a luminescent agent. The luminescent agent may be an active molecule that produces luminescent light when exposed to a luminescent initiator 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 fluorescein, firefly luciferin, oxalate, lucigenin, and / or other chemiluminescent molecules. In some embodiments, the luminescent agent may be used in conjunction with quantum dots or nanoparticles that are configured to emit additional light when exposed to luminescence emitted by the luminescent agent. The inclusion of quantum dots or nanoparticles may increase the amount of light generated in response to a given concentration of luminescent initiators, thereby increasing the sensitivity of the capsule device.

[0051] The luminescent trigger molecule can indicate the condition within the gastrointestinal tract. In some embodiments, the luminescent trigger can be an enzyme, a biomarker, a biomolecule, or other indicator of gastrointestinal condition. In other embodiments, the luminescent trigger can be an active molecule derived from an enzyme, a biomarker, a biomolecule, or other indicator of gastrointestinal condition. For example, in an embodiment using luminol as a luminescent agent, the luminescent trigger can be an oxidant, such as hypochlorous acid (HOCl). The device 100 can obtain an oxidant or other luminescent trigger from an enzyme or biomarker through a chemical interaction between a gastrointestinal fluid sample and one or more active molecules in one or more substrate layers of the capsule device. In the illustrated embodiment, the luminescent trigger can be obtained through a chemical interaction between a gastrointestinal fluid sample and one or more active molecules impregnated in the first additional substrate layer 110 and / or the second additional substrate layer 112.

[0052] For example, in the illustrated embodiment, for the device 100 configured to detect MPO in a gastrointestinal fluid sample, the second additional substrate layer can be impregnated with a solution having an appropriate concentration of UHP such that the interaction between UHP and MPO can produce HOCl. HOCl can act as an oxidant or luminescent agent to interact with the luminol of the luminescent substrate 106 to produce luminescent light to indicate the presence, absence, or concentration of MPO in the gastrointestinal fluid sample.

[0053] Additionally or alternatively, additional substrate layers may be included and configured to produce other effects in addition to obtaining luminescent triggers. In some embodiments, active molecules in additional substrate layers may be provided to adjust or change the properties of the gastrointestinal fluid sample. For example, in some embodiments, the additional substrate layer may include a pH buffer. The pH buffer may be an active molecule capable of adjusting the pH level of the gastrointestinal fluid sample. The pH buffer may include 4-(cyclohexylamino)-1-butanesulfonic acid (CABS) or similar active molecules. In the illustrated embodiment, the first substrate layer 110 may be impregnated with a solution of a pH buffer (such as CABS) having an appropriate concentration. As will be described in more detail in the example sections below, it may be desirable to adjust the pH level or other properties of the gastrointestinal fluid sample in order to optimize the luminous intensity produced by the luminescent substrate 106.

[0054] In some embodiments, the device 100 may include a translucent partition 114. The translucent partition 114 may divide the cavity 122 into a first portion 124 and a second portion 126 of the cavity 122. In addition, the translucent partition 114 may form a fluid-tight seal between the first portion and the second portion of the cavity while allowing light to pass between the first portion and the second portion. In various embodiments, the translucent partition may include glass, plastic, or any other suitable material for forming a seal within the capsule while allowing light to pass therethrough.

[0055] According to some embodiments, the ingestible capsule device may include an electronics unit 116. Some embodiments may further include a power source 118. In some embodiments, the electronics 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 emitted 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.

[0056] The signal processing module 130 may 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 otherwise process the detection signal.

[0057] The data collection and transmission module 132 can communicate with the signal processing module 130. The data collection and transmission module 132 can be configured to transmit a wireless signal containing information based at least in part on information from the detection signal. The data collection and transmission module 132 can be configured to transmit the wireless signal via any suitable communication protocol, including a radio frequency (RF) protocol, a WiFi protocol, Bluetooth, a long-range (LoRa) networking protocol, a multicast wireless sensor network (e.g., ANT), an in-vivo communication network, and / or others.

[0058] A power supply 118 may be included to provide appropriate levels of electrical power to the various components of the electronics unit 116. The power supply 118 may include a battery or any other suitable source of electrical power.

[0059] Exemplary embodiments of the electronics unit 116 according to the present disclosure are described in more detail in the Examples section below. However, it will be appreciated that the electronics unit may include any suitable one or more components for detecting the presence, absence, or intensity of emitted light and relaying information about the detected light. In this regard, the present disclosure is not limited to the specific components described below.

[0060] Now refer to Figure 2 Describe such as Figure 1Operation of the device of the ingestible capsule device shown. The device 100 can be ingested by a patient 200. When the device 100 is in the stomach 202 of the patient 200, the sampling orifice 120 can be kept closed by the orifice closure 104. In the illustrated embodiment, the orifice 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. Therefore, when the device 100 reaches the small intestine 204, the orifice closure 104 can degrade or dissolve, thereby allowing a sample of gastrointestinal fluid to pass through the orifice 120 and enter the cavity 122 of the device 100. It will be appreciated that in other embodiments, the orifice closure 104 can be configured to degrade or dissolve at another location of the gastrointestinal tract, such as the large intestine 206.

[0061] The sample of gastrointestinal fluid passing through the orifice 120 may contain an enzyme or other biomarker 208 indicative of a gastrointestinal condition to be monitored or evaluated. The enzyme or biomarker 208 may be a luminescent trigger, or the luminescent trigger may be chemically derived from the enzyme or biomarker 208 as described herein. When the luminescent substrate of the device 100 is exposed to the luminescent trigger, the luminescent substrate may emit luminescent light 210. As described above Figure 1 As shown, the luminescent light 210 may be detected by the photodetector 108 of the device 100. The photodetector may generate a detection signal indicating the presence, absence, or intensity of the luminescent light 210 as described above.

[0062] 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.

[0063] Now refer to Figure 3An example of an operating mode of an embodiment of a capsule device according to the present disclosure is described. In this example, the device can be configured to monitor or evaluate an IBD condition by detecting MPO in a gastrointestinal fluid sample. This exemplary embodiment may include luminol as a luminescent agent in a luminescent substrate 106. In this embodiment, the interaction between MPO and luminol can produce luminescent light that is insufficient to allow useful analysis or evaluation. Therefore, the capsule device of this embodiment can obtain a luminescent initiator from MPO through a chemical interaction with an active molecule. The luminescent initiator in this embodiment can be HOCl. The luminescent initiator can be obtained by a chemical interaction between MPO of a gastrointestinal fluid sample and an active molecule impregnated into an additional substrate layer. In this particular embodiment, the active molecule can be urea hydrogen peroxide (UHP). UHP may interact with MPO to produce HOCl. HOCl can interact with the luminol of the luminescent substrate to produce luminescent light.

[0064] Additionally, as will be further described in the example section below, the pH of the gastrointestinal fluid sample can affect the intensity of the luminescent light generated by the interaction of HOCl and luminol. Therefore, it may be desirable to adjust the pH of the gastrointestinal fluid sample. In the specific embodiments described herein, the pH can be adjusted to a desired value using a substrate layer impregnated with CABS.

[0065] While this example is intended to illustrate the principles of operation of an ingestible capsule device, it will be appreciated that these principles can be applied and adapted to produce an ingestible capsule device for any appropriate application, including monitoring or evaluating other gastrointestinal conditions by using other active molecules and / or other electronic components to detect other target biomarkers appropriate for a given application. As another example, different numbers and / or arrangements of substrates (e.g., substrates impregnated with different chemicals or combinations of chemicals) can be used according to the techniques described herein. Therefore, the present disclosure is not limited to the examples described herein that specifically target the use of luminol, UHP, and CABS pH buffers to detect MPO.

[0066] In the first stage 302, a sample of gastrointestinal fluid may contain a variety of components, including a 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.

[0067] The first substrate layer 110 can be configured to chemically interact with a sample of gastrointestinal fluid. As described above, the first substrate layer 110 can be configured to adjust the pH of the gastrointestinal fluid. In order to optimize the luminescence of the sample, this pH adjustment can be desirable. In some embodiments, the first substrate layer 110 can be a filter paper layer impregnated with a first buffer solution containing an appropriate concentration of CABS. In other embodiments, the first substrate layer 110 can include other active molecules, including other pH buffers or active molecules that adjust fluid properties (such as salinity, viscosity, conductivity and / or other) other than pH. For example, in some embodiments, the substrate layer can be impregnated with a redox buffer solution or redox buffer molecules to control the oxidation / reduction potential of the gastrointestinal fluid sample or its components. In some embodiments, the substrate layer can be impregnated with a detergent or other compounds to control the viscosity of the gastrointestinal fluid sample.

[0068] According to the presently described embodiments, at the second stage 306, the pH of the gastrointestinal fluid sample can be different from the pH of the gastrointestinal fluid sample at the first stage 302. For example, in some embodiments, the concentration of the CABS solution impregnated in the first substrate layer can be selected to raise the pH of the gastrointestinal fluid sample to a pH of 11. In other embodiments, other buffer solutions at appropriate concentrations can be used to adjust the pH to any desired level, as the present disclosure is not limited in this regard.

[0069] Thus, 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. Additionally, the concentration of the pH buffer solution may be selected to obtain a pH value that is less than or equal to 14, 12, 11, 10, and / or any other suitable pH value. Combinations of the foregoing are contemplated, including, for example, a pH value that is greater than or equal to 0 and less than or equal to 14, greater than or equal to 10 and less than or equal to 12, and / or any other suitable combination of the foregoing. Of course, while specific ranges of desired pH values ​​are provided above, it should be understood that other ranges greater than and less than both of the above ranges are also contemplated, as the present disclosure is not limited in this regard.

[0070] Additionally, in some embodiments, where CABS is used as a pH buffer to adjust the pH of a gastrointestinal 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 greater than or equal to 0.2M, 0.4M, 0.6M, 0.8M and / or any other appropriate molar concentration or concentration. Additionally, the concentration of the CABS buffer solution may be less than or equal to 1.4M, 1.2M, 1.0M, 0.8M and / or any other appropriate molar concentration or concentration. The aforementioned combinations may be expected, including, for example, a concentration greater than or equal to 0.2M and less than or equal to 1.4M, greater than or equal to 0.8M and less than or equal to 1.0M, and / or any other appropriate combination of the aforementioned. Of course, although a specific range of CABS buffer solution concentrations is provided above, it should be understood that other ranges greater than and less than both of the above ranges may also be expected, because the present disclosure is not limited in this regard.

[0071] The second substrate layer 112 can be configured to chemically interact with the gastrointestinal fluid sample from the second stage 306. In some embodiments, the second substrate layer 112 can be configured to interact with the gastrointestinal fluid to produce a luminescent trigger. For example, in some embodiments, the second substrate layer 112 can be a filter paper layer impregnated with a solution containing urea hydrogen peroxide (UHP) at an appropriate concentration. In some embodiments, the volume concentration of the UHP solution selected to obtain HOCl from MPO to interact with luminol can be greater than or equal to 0%, 0.25%, 0.5%, 1.0%, 1.5%, and / or any other appropriate concentration. Additionally, the concentration of the UHP solution can be less than or equal to 3.0%, 2.5%, 2.0%, 1.5%, 1.0%, and / or any other appropriate concentration. Combinations of the foregoing can be expected, including, for example, concentrations greater than or equal to 0% and less than or equal to 3.0%, greater than or equal to 1.5% and less than or equal to 2.5%, and / or any other appropriate combination of the foregoing. Of course, while specific ranges for UHP solution concentrations are provided above, it should be understood that other ranges both greater and less than the above-recited ranges are also contemplated, as the present disclosure is not limited in this regard.

[0072] In some embodiments, the UHP may react with the MPO of the gastrointestinal fluid to produce hypochlorous acid (HOCl). Thus, at the third stage 310, the gastrointestinal fluid sample may include a luminescent trigger. In this example, the gastrointestinal fluid sample at the third stage 310 may include HOCl.

[0073] The luminescent substrate 106 can be configured to emit luminescent light 210 when exposed to a luminescent trigger. In some embodiments, the luminescent substrate can be impregnated with a solution containing a luminescent agent at an appropriate concentration. The luminescent agent can be a chemiluminescent agent, such as luminol (C 8 H 7 N 3 O 2 ). In this example, as described above, luminol can interact with HOCl from MPO to produce luminescent light 210.

[0074] In some embodiments, the concentration of the luminol solution selected for optimizing the luminescence intensity in the presence of MPO may be greater than or equal to 1 mM, 10 mM, 15 mM, 20 mM and / or any other suitable molar concentration or concentration. Additionally, the concentration of the luminol solution may be less than or equal to 30 mM, 25 mM, 20 mM, 15 mM and / or any other suitable molar concentration or concentration. The aforementioned combinations may be expected, including, for example, a concentration greater than or equal to 1 mM and less than or equal to 30 mM, greater than or equal to 20 mM and less than or equal to 30 mM, and / or any other suitable combination of the aforementioned. Of course, although a specific range of luminol solution concentrations is provided above, it should be understood that other ranges greater than and less than the above ranges may also be expected, because the present disclosure is not limited in this regard.

[0075] It will be appreciated that although the combination of MPO, UHP and luminol is described herein as being included in one embodiment of the present disclosure, other embodiments may utilize other luminescent triggers, luminescent agents and / or buffer solutions, as the present disclosure is not limited in this regard. Additionally, luminescent agents, luminescent triggers, buffer solutions, active molecules, and combinations and concentrations thereof may be selected and optimized for detecting any appropriate enzyme or biomarker, including tumor necrosis factor-α, interleukin (IL), C-reactive protein (CRP), calprotectin, lactoferrin, etc.

[0076] Furthermore, it will be appreciated that although Figure 3 Embodiments include one luminescent substrate layer and two additional substrate layers, but other embodiments may include any suitable number of additional substrate layers. For example, it will be appreciated that in some embodiments, additional substrate layers will not be required to produce luminescent light indicating the presence of a desired enzyme or biomarker. In other embodiments, more than two additional substrate layers may be desired. Therefore, the present disclosure is not limited to any particular number of substrate layers.

[0077] The luminescent light 210 may be detected by the photodetector 108. In some embodiments, the photodetector 108 may be sensitive enough to detect only trace amounts of the 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 electronics unit of a capsule device as described herein.

[0078] Figure 4A Depicts the intensity of luminescence within some embodiments of the devices described herein during the time the capsule orifice remains closed. For example, Figure 4A The luminous intensity shown may correspond to the time when the device 100 is located in the stomach 202 of the patient 200 (eg, Figure 2 shown). Figure 4B Depicts the intensity of luminescence within some embodiments of the device as described herein during the time when the capsule orifice has been opened and a gastrointestinal fluid sample containing an enzyme or biomarker to be detected has entered the capsule. For example, Figure 4B The luminous intensity shown may correspond to when the device 100 is located in a Figure 2 Time in the small intestine 204 of patient 200 is shown. Figure 4B The increase in luminous intensity shown in 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 and wirelessly transmitted to a receiving device, as described above with respect to Figure 2 described.

[0079] Example

[0080] Design and use cases of experimental examples

[0081] One example of an experimental capsule device according to the present disclosure includes six elements: a capsule, a pH-sensitive biodegradable enteric coating, a stack of three thick filter papers, a glass cover slip, an electronics unit with a photodetector on top, and a 3-volt lithium battery. The capsule uses a two-part threaded design to facilitate assembly of the capsule device. The pH-sensitive polymer coating is used to survive the low pH gastric environment, in which the experimental capsule device is intended to remain intact.

[0082] This example is intended to evaluate the small intestine. When exposed to target inflammatory tissue in the small intestine (which has an average pH of 6.8), the enteric coating will dissolve to allow MPO (released by neutrophils at the site of inflammation) to flow into the capsule. Subsequently, the three layers of filter paper will begin to absorb MPO and perform their functions as follows: first, the filter paper impregnated with CABS will adjust the pH of the introduced sample to pH 11; next, the filter paper impregnated with UHP will interact with MPO (with pH 11) and produce hypochlorous acid (HOCl); and then, the filter paper impregnated with luminol will interact with HOCl and begin to emit blue light. At this point, the photodetector will detect the luminescence and convert the photon energy into an electrical signal, which will then be transmitted to the receiving device through the wireless transmitter of the electronics unit of the capsule device.

[0083] Exemplary Optimization of Analysis Parameters

[0084] The characteristics and intensity of the luminescence emitted by the oxidation reaction of luminol can depend on several parameters, including the pH level and concentration of the reactants. Therefore, a series of experiments were performed to optimize these parameters around the specific use case of luminol for optical detection of MPO.

[0085] Optimization of pH

[0086] First, the effect of pH on luminescence intensity was studied by exposing MPO to buffers of different pH, including buffers with pH values ​​of 6, 7, 8, 9, 10, 11, and 12. To this end, a 96-well black microtiter plate was filled with an upper gastrointestinal fluid having a pH value ranging from 6 to 12. 50 μL of UHP (250 μM) was added to each well. 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 left to incubate for 10 seconds. After the incubation period, the luminescence spectrum of each reaction was recorded for 250 seconds using a BMG microplate reader. Fig. 6A and 6B The results for each pH level are shown in Fig. 6A and 6B It can be seen that the maximum luminescence intensity was observed when the pH value was 11.

[0087] However, the pH in the small intestine region varies from 6.2 to 7.4. Fig. 6A and 6BIt can be seen that the luminescence intensity observed in this pH range is significantly less than the intensity at pH 11. Therefore, the inventors have recognized and appreciated the benefits of adjusting the pH of the gastrointestinal fluid sample in order to optimize the luminescence intensity in the disclosed capsule device. In the experimental embodiments disclosed herein, filter paper impregnated with CABS is included in the capsule to adjust the pH of the gastrointestinal fluid sample.

[0088] In order to obtain the desired pH value of 11 from the gastrointestinal fluid sample with an initial pH value between 6 and 7, the filter paper impregnated with CABS needs to be further optimized to determine the appropriate concentration of CABS in the filter paper. Several dilutions of CABS stock solution were prepared (0.2M, 0.4M, 0.6M, 0.8M, 1.0M, 1.2M and 1.4M dilutions). Each dilution was drop-cast onto a disc of thick filter paper using a fixed volume (100 μL). The resulting filter paper (with different concentrations of CABS) was placed overnight at room temperature to dry.

[0089] These CABS-impregnated dried filter papers were used to determine which dilution of the CABS stock solution best achieved the conversion of gastrointestinal fluid from the in vivo pH level of about 6-7 to the desired pH level of about 11. Three different gastrointestinal fluid samples having pH levels of 5, 6, and 7 and a phosphate buffered saline (PBS) buffer solution having a pH of 7.4 were used as test samples. Fig. 7A shows a schematic diagram of the experimental setup used for the pH conversion experiment described above, and Figure 7B The obtained results are shown in Fig. 7A In the embodiment, gastrointestinal fluid samples 802 of various pH values ​​or PBS buffer solutions are pipetted onto and filtered through filter paper 804 impregnated with various dilutions of CABS stock solution. A pH meter 810 is used to measure the final pH of the filtered gastrointestinal fluid 806.

[0090] Figure 7B The results shown in indicate that filter paper impregnated with 1.0 M CABS solution was sufficient to convert the pH of each solution to the desired pH value of about 11. Therefore, 1.0 M CABS solution was selected as the appropriate concentration of CABS within the filter paper for obtaining the desired pH value of 11 from gastrointestinal fluid samples having an initial pH value between 6 and 7. Although the specific methods, parameters, and goals of these experiments led to the selection of these specific compounds, values, and concentrations, it will be appreciated that for other applications, deviations from these specific methods, parameters, and goals may result in the selection of any appropriate compound, value, or concentration for any variable discussed herein.

[0091] Optimization of the ratio of UHP and luminol concentrations

[0092] The ratio of UHP and luminol concentrations also affects the oxidation reaction of the presently described embodiment, and therefore affects the chemiluminescence intensity. Therefore, various concentrations of UHP are evaluated with various concentrations of luminol. It will be appreciated that in an in vivo environment, not all gastrointestinal fluids will contain a large amount of MPO. However, during the use of the capsule device, UHP and luminol may interact, regardless of whether the gastrointestinal fluid contains MPO. Therefore, various ratios of UHP and luminol are evaluated both in the presence of MPO and in the absence of MPO. Because the capsule device of the presently described embodiment is intended to detect MPO by evaluating the luminescence intensity generated by introducing MPO into the capsule, the difference between the luminescence in the absence of MPO and in the presence of MPO (rather than just the light intensity of the luminescence in the presence of MPO) is evaluated as an indication of the introduction of MPO.

[0093] Fig. 8A A heat map illustration of the peak luminescence intensity obtained from the interaction of UHP (horizontal axis) and luminol (vertical axis) in the absence of MPO is shown, with water as a control. It is observed that the peak luminescence intensity increases effectively with increasing concentrations of both UHP and luminol. This may be due to, for example, a strong oxidation reaction caused by excess amounts of both reactants.

[0094] Figure 8B A heat map illustration of the luminescence intensity peak obtained from the interaction of UHP and luminol in the presence of MPO (at a concentration of 7 U / mL) is shown. As described above, the effect of introducing MPO into a given ratio of UHP and luminol was evaluated by comparing the luminescence intensity peaks of the two in the presence and absence of MPO for a given ratio.

[0095] therefore, Figure 8C Shows Fig. 8A The peak intensity and Figure 8B Heat map illustration of the difference between the intensity peaks of Figure 8C As shown, the most significant increase in the peak luminescence intensity occurred at 2% UHP and 25 mM luminol concentrations. Therefore, 2% UHP and 25 mM luminol concentrations were selected for further analysis.

[0096] Exemplary Device Fabrication

[0097] like Figure 5A-5BAs shown, in one example, a capsule 102 for an ingestible device is manufactured using 3D printing. The capsule includes two parts: a main body portion 102A and a cover portion 102B. The capsule was designed using SolidWorks (Dassault Systemes). The design was 3D printed using a stereolithography (SLA) process on a Form2 printer from Formlabs Ltd. using a biocompatible resin (EN-ISO 10993-1: 2009 / AC: 2010, USP Class VI) obtained from Formlabs Ltd. The SLA process uses a layer thickness of 50 μm. After printing is completed, the capsule is washed in 99% isopropyl alcohol (IPA) for 15 minutes and cured for another 60 minutes using an ultraviolet (UV) light curing device (from Formlabs Ltd.) to complete the polymerization of the resin.

[0098] After that, using computer-controlled CO 2 The laser cuts a 6 mm diameter sampling orifice 120 in the cover portion 102B. The laser is a PLS6MW cutting and engraving system from Universal Laser, Inc. of Scottsdale, Arizona, and is set to an operating wavelength of 10.6 μm. The sampling orifice 120 is then filled with the pH sensitive coating and allowed to cure overnight at room temperature.

[0099] like Figure 5C As shown, a large sheet of filter paper is cut into small discs, each having a diameter of 5 mm. The active molecules (CABS, UHP and luminol) are impregnated into different filter paper discs, and the discs are stacked so that the UHP-impregnated paper 112 is sandwiched between the CABS-impregnated paper 110 on one side and the luminol-impregnated paper on the opposite side. The stack of discs is placed in the cover portion 102B of the capsule 102 so that the CABS-impregnated paper is closest to the sampling orifice 120.

[0100] Electronics Unit

[0101] Includes electronics unit to measure the light output of the luminaire with maximum sensitivity and provide continuous wireless luminaire measurement. Figure 5C and 5D As shown, the electronics unit 116 includes three different and modular systems combined into a single unit. The unit includes 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) are designed to accommodate the electronics. Each of the three modules is contained in a single, 8 mm diameter circular PCB. The three boards are stacked on top of each other, with the sensor interface module on one end, the signal processing module in the middle, and the data collection and transmission module at the other end.

[0102] A sensor interface module 128 is provided to interact directly with the luminescent chemical and convert the light intensity into a representative current. To achieve a wide range of functionality, a single photon avalanche diode (SPAD) array from Onsemi (MicroFC-30035-SMT) is used as a photodetector 108 to measure the light generated by the MPO reaction. The sensor is biased between -25V and -30V with an inverting DC-DC converter (LT3462) from Analog Devices. Adjustment of the bias voltage can be used as the primary method for tuning the sensitivity of the device. To allow for extended battery life when no reaction is expected, the sensor interface can be turned off by switching the enable pin on the DC-DC converter to draw a current close to zero.

[0103] The analog signal processing module 130 provides noise suppression and amplification to isolate the measurements from the sensor interface and convert them into a usable voltage. A transimpedance amplifier (TIA) is included to convert the SPAD current to a voltage between 0 and 1.8V. The TIA gain is used to balance the overall gain when adjusting the SPAD bias voltage. This will utilize the entire range of the ADC, limiting the output of the sample signal to between 0 and 1.8V. Example schematics for the bias voltage circuit and TIA can be found in the data sheets of the DC-DC converter and the SPAD.

[0104] Finally, in the data collection and transmission module 132, the microcontroller (nRF52832, ARM M4 processor) collects the analog measurements and wirelessly sends representative digital signals to an external receiving device (nRF51822, ARM M0 processor). The nRF52832 controls all the electronic components in the capsule using 1.8V digital logic and converts the TIA output voltage into a digital signal using its onboard digital-to-analog converter. The nRF52832 and nRF51822 microcontrollers provide a built-in RF communication protocol that is used to transmit the data collected from inside the gastrointestinal tract to an external system. In this example, the Raspberry Pi and nRF51822 are integrated into a single "base station" receiving device to forward the collected data to a WiFi source that can be accessed by any laptop or other WiFi-capable computing device.

[0105] The capsule active and shutdown current draws were recorded to estimate battery life. The device was powered at 3.1V and the input current was 17.5mA active and 3.1mA shutdown, recorded by an Agilent 34401A digital multimeter. Packaged with two 1.55V, 23mAh silver oxide batteries in series (producing 3.1V), the capsule electronics system was configured to actively record light for more than an hour, or sleep for more than 7 hours. It was configured to continue transmitting data through the air at a distance of 10 meters from the base station and was mounted in a standard 000 capsule.

[0106] MPO Detection Performance

[0107] Initially, the analytical performance of the sensor interface module of the electronics unit was evaluated by recording the luminescence spectra generated by different concentrations of MPO. This was done using a conventional BMG Clariostar microplate reader. Fig.9A The luminescence spectra of the oxidation reaction with various concentrations of MPO at the optimal wavelength of 425 nm are shown. Fig.9A It will be appreciated that as the MPO concentration (0–9 U / mL) increases, the luminescence intensity gradually increases, while the shape of the luminescence spectrum does not change significantly. This enhancement of luminescence with increasing MPO concentration may be due to the formation of more oxidants (HOCl) through the reaction of MPO and UHP. The increase in HOCl can further oxidize luminol and thus produce blue luminescence. Fig. 9B Various MPO concentrations and Fig.9A The graph shows the area under the corresponding luminescence curve. Fig.9A and 9B It was demonstrated that the sensor interface module is capable of detecting even trace amounts of MPO.

[0108] Subsequently, the analytical performance of the entire experimental capsule setup was also investigated. Fig. 9C A sensitivity graph showing the relationship between voltage and MPO concentration recorded by the portable device. As discussed above, the photodetector mounted on top of the electronics unit detects the increasing luminescence intensity as the MPO concentration (0-9u / mL) increases and converts the photon energy into an electrical signal which is then transmitted to a receiving device via a wireless system embedded inside the electronics unit as described above. Fig. 9C As can be well appreciated, the voltage generated by the photodetector gradually increases with increasing MPO concentration (0–9 U / mL). Fig. 9B , Fig.9D Various MPO concentrations and Fig. 9C The area under the corresponding voltage curve is plotted in the graph. Fig. 9B and 9DAs will be appreciated from the similarities between the ELISA kit and the ELISA kit, the experimental capsule device is able to detect even trace amounts of MPO.

[0109] Selectivity assay

[0110] The above results indicate that the experimental embodiments of the disclosed capsule device are capable of detecting 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 efficacy of the experimental capsule device in the presence of these biomolecules. Fig. 10A and 10B The response of the experimental capsule device in the presence of various interfering biomarkers (each at a concentration of 10 mM) is shown. Fig. 10A Indicating that in the presence of interfering biomarkers, the voltage generated by the photodetector was not significant, while the same concentration of MPO produced a relatively high output voltage signal. This may be due to the reaction of UHP and MPO forming more oxidants (HOCl) than the reaction of UHP and any interfering biomarkers. These potential interfering biomolecules produce less oxidants, resulting in low luminescence intensity and output voltage. Fig. 10B Various interfering biomarkers and Fig. 10A The area under the corresponding voltage curve is plotted between the two graphs. Fig. 10B This indicated that the experimental capsule device was selective and specific for MPO.

[0111] In vitro detection of MPO

[0112] To demonstrate the practical application of the experimental capsule device, in vitro detection of MPO was also evaluated in a physiological environment, e.g. Fig.11A and 11B Here, the porcine small intestine is divided into three segments 1100 of ~7 cm in length. Each intestinal segment 1100 receives a solution with different concentrations of MPO: 1, 5 and 9 U / mL. It is worth noting that the three test concentrations were selected to compare the analytical performance of the experimental device in both gastrointestinal fluid and buffer environments. The fully assembled device 100 is then inserted into each intestinal segment 1100 and used to detect the MPO level by recording the voltage signal generated by the photodetector. Fig. 11C and 11D Each shows the voltage signal obtained for each concentration and the area under the curve for each concentration. Fig.11D The results of the corresponding ex vivo buffer experiments are also shown. Fig. 11C and 11D The in vitro results and their similarity to the ex vivo results indicate that the experimental embodiments of the capsule device described herein are capable of determining the level of inflammation in the small intestine region by monitoring the level of MPO.

[0113] The above-mentioned embodiments of the technology described herein can be implemented in any of many 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 processor set, whether provided in a single computing device or distributed among multiple computing devices. Such a processor can be implemented as an integrated circuit, wherein one or more processors are provided in 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 in a semi-custom circuit obtained by configuring a programmable logic device. As 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, so that one or a subset of these cores can constitute a processor. However, a circuit of any suitable format can be used to implement the processor.

[0114] Furthermore, it should be appreciated that a computing device including one or more processors may be implemented in any of a variety of forms, such as a rack-mounted computer, a desktop computer, a laptop computer, or a tablet computer. Additionally, the computing device may be embedded in a device that is not typically considered a computing device but has suitable processing capabilities, including a personal digital assistant (PDA), a smart phone, a tablet computer, or any other suitable portable or fixed electronic device.

[0115] In addition, the computing device may have one or more input and output devices. These devices may be used, in particular, 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 output and a speaker or other sound generating device for auditory presentation of output. Examples of input devices that may be used for a user interface include a keyboard, individual buttons, and pointing devices, such as a mouse, a touchpad, and a digitizing tablet. As another example, the computing device may receive input information through speech recognition or in other auditory formats.

[0116] Such computing devices may be interconnected by one or more networks in any suitable form, including as a local area network or a wide area network, such as an intranet or the Internet. Such networks may be based on any suitable technology and may operate according to any suitable protocol, and may include wireless networks, wired networks, or fiber optic networks.

[0117] In addition, the various methods or processes outlined herein may be encoded as software that can be executed on one or more processors using any of a variety of operating systems or platforms. In addition, such software may be written using any of a variety of suitable programming languages ​​and / or programming or scripting tools, and may also be compiled into executable machine language code or intermediate code that is executed on a framework or virtual machine.

[0118] In this regard, the embodiments described herein may be embodied as a computer-readable storage medium (or multiple computer-readable media) encoded with one or more programs (e.g., computer memory, one or more floppy disks, compact disks (CDs), optical disks, digital video disks (DVDs), tapes, flash memory, RAM, ROM, EEPROM, circuit configurations in field programmable gate arrays or other semiconductor devices, or other tangible computer storage media), which, when executed on one or more computers or other processors, run methods that implement the various embodiments discussed above. As is apparent from the foregoing examples, computer-readable storage media may retain information long enough to provide computer-executable instructions in a non-transitory form. Such one or more computer-readable storage media may be transportable so that one or more programs stored thereon may be loaded onto one or more different computing devices or other processors to implement various aspects of the present disclosure as discussed above. As used herein, the term "computer-readable storage medium" covers only non-transitory computer-readable media that may be considered an article of manufacture (i.e., an article of manufacture) or a machine. Alternatively or additionally, the present disclosure may be embodied as a computer-readable medium other than a computer-readable storage medium, such as a propagating signal.

[0119] The term "program" or "software" is used in this article in a general sense to refer to any type of computer code or computer executable instruction set that can be used to program a computing device or other processor to implement various aspects of the present disclosure as discussed herein. Additionally, it should be appreciated that according to one aspect of this embodiment, one or more computer programs that run the methods of the present disclosure when executed do not need to reside on a single computing device or processor, but can be distributed in a modular manner among several different computers or processors to implement various aspects of the present disclosure.

[0120] Computer executable instructions may be in various forms, such as program modules, that are executed by one or more computers or other devices. Typically, program modules include routines, programs, objects, components, data structures, etc., that perform specific tasks or implement specific abstract data types. Typically, in various embodiments, the functionality of program modules may be combined or distributed as desired.

[0121] The embodiments described herein may be embodied as a method, an example of which has been provided. The actions performed as part of the method may be ordered in any suitable manner. Thus, embodiments may be constructed in which the actions are performed in a different order than shown, which may include performing some actions simultaneously, even though shown as sequential actions in the illustrative embodiments.

[0122] Additionally, some actions are described as being taken by a "user." It should be understood that a "user" need not be a single person, and in some embodiments, actions considered to be taken by a "user" may be performed by a group of individuals and / or individuals in conjunction with computer-assisted tools or other mechanisms.

[0123] Although several embodiments of the present invention have been described and illustrated herein, a person of ordinary skill in the art will readily appreciate various other devices and / or structures for operating functions and / or obtaining results and / or one or more advantages described herein, and each such variation and / or modification is considered to be within the scope of the present invention. More generally, it will be readily appreciated by those skilled in the art that all parameters, dimensions, materials, and configurations described herein are exemplary, and that the actual parameters, dimensions, materials, and / or configurations will depend on the specific application for which the present invention is used. Those skilled in the art will recognize, or will be able to determine using only routine experiments, many equivalents of the specific embodiments of the present invention described herein. Therefore, it is to be understood that the foregoing embodiments are given only as examples, and within the scope of the appended claims and their equivalents, the present invention may be implemented in a manner different from that specifically described and required. The present invention is directed to each individual feature, system, article, material, kit, and / or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and / or methods (if such features, systems, articles, materials, kits, and / or methods are not mutually contradictory) is included within the scope of the present invention.

[0124] Although the present teaching has been described in conjunction with various embodiments and examples, it is not intended that the present teaching be limited to these embodiments or examples. On the contrary, as will be appreciated by those skilled in the art, the present teaching encompasses various alternatives, modifications and equivalents. Therefore, the foregoing description and accompanying drawings are intended only as examples.

Claims

1. A device for passively sampling the gastrointestinal tract of a patient, comprising: a capsule shell defining a cavity; a sampling orifice formed in the capsule housing and providing fluid communication between the cavity and an 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 luminescent initiator; at least one additional substrate layer positioned within the chamber between the sampling orifice 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, the photodetector configured to detect luminescent light; and A biodegradable coating closes the sampling orifice such that degradation of the biodegradable coating exposes the sampling orifice to allow fluid to flow into the cavity.

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

3. The device according to claim 2, wherein: The biomarkers include myeloperoxidase (MPO).

4. The device according to any one of claims 2 to 3, wherein: The luminescent trigger includes an oxidant formed by a chemical interaction with the biomarker.

5. The device according to any one of claims 1 to 4, wherein: The luminescent substrate includes a luminescent agent, and wherein the luminescent agent interacts with the luminescent initiator to emit luminescent light.

6. The device according to claim 5, wherein: The luminescent agent includes luminol.

7. The device according to claim 1, wherein: One or more of the at least one additional substrate layer is configured to alter the pH of the sample fluid.

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

9. The device according to any one of claims 1 to 8, wherein: One or more of the at least one additional substrate layer is configured to interact with the sample fluid to form the light emitting 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 a luminescence trigger are configured to interact with the biomarkers of the sample fluid to form a luminescence trigger.

11. The device according to claim 10, wherein: The biomarkers include MPO.

12. The device according to any one of claims 10-11, wherein: The light-emitting initiator includes an oxidant.

13. The device according to any one of claims 10 to 12, wherein: One or more additional substrate layers configured to interact with the sample fluid to form a light emitting trigger comprises urea hydrogen peroxide (UHP).

14. The device according to claim 13, wherein: The one or more additional substrate layers comprising UHP are impregnated with a UHP solution comprising between 1 and 3 volume % UHP, and wherein the luminescent substrate is impregnated with a luminol solution comprising luminol at a concentration between 20 mM and 30 mM.

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 modify the pH of the sample fluid and a second additional substrate layer configured to interact with the sample fluid to form the light emitting trigger.

16. The device according to any one of claims 1-15 further includes a translucent partition positioned between the light-emitting substrate and the photodetector, wherein the translucent partition is configured to form a fluid-tight seal between the first portion of the cavity and the second portion of the cavity while allowing the emitted 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. The device according to any one of claims 1 to 17, further comprising: a signal processor in communication with the photodetector to receive a detection signal from the photodetector; a wireless transmitter in communication with the signal processor for transmitting a wireless signal, the information in the wireless signal being based at least in part on information from the detection signal; and A battery is configured to provide electrical power to at least the signal processor and the wireless transmitter.

19. The device according to any one of claims 1 to 18, wherein: The biodegradable coating includes a first coating layer and a second coating layer, the first coating layer being configured to degrade within a first pH range and the second coating layer being configured to degrade within a second pH range, the first pH range being different than the second pH range.

20. A method for detecting biomarkers in the gastrointestinal tract of a patient, the method comprising: administering to a patient an ingestible device comprising: a capsule shell defining a cavity, a sampling orifice formed in the capsule housing and providing fluid communication between the cavity and an exterior of the capsule housing, a luminescent substrate positioned within the cavity, the luminescent substrate being configured to emit luminescent light when exposed to a sample fluid containing a luminescent trigger, the luminescent trigger being indicative of the presence of the biomarker, a photodetector positioned within the cavity, the photodetector configured to detect the emitted light and generate a detection signal, and a wireless transmitter configured to transmit a wireless signal based on the detection signal; exposing the luminescent substrate to a sample fluid; receiving a wireless signal at a user device; and Based on the wireless signal, it is determined whether the biomarker is present in the sample fluid.

21. The method according to claim 20, wherein: The biomarkers include myeloperoxidase (MPO).

22. The method according to any one of claims 20-21, wherein: The luminescent substrate includes a luminescent agent, and wherein the luminescent agent interacts with the luminescent initiator to emit luminescent light.

23. The method according to claim 22, wherein: The luminescent agent includes luminol.

24. The method of any one of claims 20-23, 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 alter a pH of the sample fluid.

26. The method according to claim 25, wherein: The first additional substrate layer comprises 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 light-emitting initiator is an oxidant.

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

30. The method according to any one of claims 20 to 29, wherein: The ingestible device further comprises a biodegradable coating closing the sampling orifice, and wherein exposing the luminescent substrate to the sample fluid comprises degrading the biodegradable coating to allow fluid to flow into the cavity.

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