Apparatus, method and system for sampling and analyzing the gastrointestinal tract - Patent Application 20070233633

Abstract

Embodiments of the present application are directed to an improved device for sampling the digestive tract of a subject. In some embodiments, the device includes at least an ingestible capsule having two portions for housing an adjustable thread or drag material having at least a proximal and a distal segment. In some embodiments, the distal segment includes a multi-ply material that can absorb fluid and / or further include a sequestrant. In certain embodiments, the improved device of the present application includes assessing the condition of the subject's upper digestive tract, including but not limited to the subject's esophagus and stomach.

Description

[Technical field]

[0001] Embodiments of the present invention relate to devices and their uses for sampling, analyzing, testing, and diagnosing medical disorders or monitoring the health status of a subject. In certain embodiments, an improved gastrointestinal (GI) sampling device is disclosed, which includes a thread having proximal and distal segments configured for improved analyte collection in the upper GI tract with optimal deployment, reduced discomfort, and reduced cross-contamination for analysis, diagnosis, and treatment of a subject. [Background technology]

[0002] Diagnosing gastrointestinal health conditions such as severe gastroesophageal reflux disease (GERD), eosinophilic gastroenteritis (EGE), food allergic enteropathy (FAE), microbial infections, and inflammatory bowel disease (IBD) is often difficult. In certain cases, non-invasive access to the gastrointestinal (GI) tract is only available via radiography or fecal analysis, but these methods do not provide definitive diagnostic information for many GI disorders.

[0003] Currently, endoscopic analysis is used to obtain mucosal sampling for diagnosis and treatment regimens. In certain conditions, such as Crohn's disease, histopathological features can be clearly recognized. For other conditions, such as eosinophilic gastroenteritis and food allergy disorders, histopathological features are more difficult to assess and often overlap with other conditions making diagnosis more difficult.

[0004] There is a need for more efficient, effective and less invasive devices for collecting GI tract associated molecules for improved diagnosis and treatment and monitoring of health conditions. Summary of the Invention

[0005] The embodiments disclosed herein relate to devices and uses for sampling, testing, and diagnosing a medical disorder, or monitoring the health status of a subject, through GI tract analysis in the subject.

[0006] In certain embodiments, an improved gastrointestinal (GI) sampling device is disclosed, which includes a device having an ingestible and optionally digestible outer capsule, a string or drag material at least partially enclosed in the capsule for deployment within a subject during use, and a weight enclosed within the capsule.

[0007] In certain embodiments, the thread is optimally configured to deploy from the outer capsule in the GI tract of a subject during use. In some embodiments, the thread or drag material may be wound to configure for optimal containment within the outer capsule. According to these embodiments, the thread or drag material may be wound to configure in a layered loop orientation with a hole in the center, the loops remain separated from one another and do not overlap, and the proximal end of the thread is fed inward for optimal deployment in the subject. In other embodiments, the thread or drag material may be wound to configure in a layered loop orientation with a hole in the center, the loops remain separated from one another and do not overlap, and the proximal end of the thread is fed outward for optimal deployment in the subject.

[0008] In certain embodiments, the thread may include a proximal segment and a distal or sampling segment. In certain embodiments, the proximal and distal segments form a single thread, while in other embodiments, the proximal and distal segments are operably attached to form the thread. For example, in certain embodiments, an end (e.g., distal end) of the proximal segment is operably attached to an end (e.g., proximal end) of the distal segment. In some embodiments, one end (e.g., distal end) of the proximal segment may be tapered for attachment to an end (e.g., proximal end) of the distal segment, which may optionally be tapered. In certain embodiments, the ends of the proximal and distal segments may be operably attached using adhesives, thermal bonding, intertwining, weaving, or other suitable fastening methods and remain associated with one another when deployed.

[0009] In some embodiments, the outer capsule may be configured as a two-part capsule including a cap and a base, which operably fit together to enclose the thread and weight within the operably fitted cap and base.

[0010] In some embodiments, the cap of the two-part capsule can include a thread deployment opening through which a proximal end of the thread (e.g., the proximal end of the proximal segment) extends. According to these embodiments, the thread can be deployed through the opening when provided to a subject to capture an agent in the subject's GI tract.

[0011] In some embodiments, the base of the two-part capsule may include an end-fixation opening 116, and a terminal portion of the distal end of the thread (e.g., the distal end of the distal segment) extends onto the top surface of the base, along the periphery of the base, and back into the interior of the base by passing through the end-fixation opening. The portion of the thread that extends along the periphery of the base may be located between the base and the cap when the cap is operably mated to the base so as to releasably secure the distal end of the thread to the outer capsule. The cap and base may be configured such that the cap extends over the thread-fixation opening when operably mated.

[0012] In some embodiments, the outer capsule, including the cap and / or base, may be made from, but is not limited to, gelatin (e.g., bovine gelatin, vegan gelatin, kosher, halal, or equivalent materials, vegetarian grade gelatin materials), cellulose (e.g., HPMC), starch (e.g., potato starch), pullulan (e.g., tapioca), polyvinyl alcohol (e.g., copolymers), hemp, or other suitable materials that can degrade, dissolve, or pass through the subject's GI system. In certain embodiments, the outer capsule, including the cap and / or base of the device disclosed herein, may be a gelatin or cellulose material. It is contemplated that the materials for the capsule and / or drag material may be made to meet any formal requirements (e.g., dietary restrictions, and / or religious considerations) depending on the subject being treated. In certain embodiments, the capsules used herein may be about 50% to about 100% bovine pharmaceutical grade gelatin, Kosher Parvez and Halal certified, and may be made in cGMP and FDA approved facilities from BSE-free or other materials meeting specified standards.

[0013] In certain embodiments, the weights disclosed herein may be made from, but are not limited to, stainless steel (e.g., magnetic, austenitic), titanium, ceramic (e.g., alumina, zirconia), glass, cobalt chromium, gold, silver, tantalum, platinum, other suitable compounds, or combinations thereof. In certain embodiments, the weights of the devices disclosed herein may be stainless steel or titanium.

[0014] According to certain embodiments, the outer capsule may be dissolvable, partially dissolvable, or passable through the subject's system. In certain embodiments, the thread material is malleable to configure within the capsule. In some embodiments, the thread may be of various lengths for optimal deployment. In some embodiments, a portion of the proximal segment may be pulled out of the capsule prior to swallowing the device or unit, and the end of the string or drag material may be attached to the subject's cheek. In some embodiments, the string or drag material may be attached to the outside of the subject's cheek. In other embodiments, the string or drag material may be attached to the inside of the subject's cheek. After a predetermined time has elapsed, the deployed string may be removed from the subject for analysis.

[0015] In certain embodiments, the thread or drag material is configured for optimal containment within the outer capsule and optimal delivery from the capsule through the subject's GI tract. According to these embodiments, a distal segment of the thread of the device can be delivered through the esophagus and into the stomach and duodenum of the subject to collect and / or deliver an agent from / to one or more regions of the GI tract. In certain embodiments, the distal segment of the thread or drag material includes the same or different capture elements along the thread or drag material. In other embodiments, the capture elements may be positioned along the thread, string, or drag material that are directed to the GI portion to be analyzed or delivered when the thread, string, or drag material is deployed or fully deployed in the subject. In certain embodiments, the capture elements may be positioned along the string with capture elements specific for the capture agent in the esophagus that are different from those in the stomach that are different from those in the small intestine and / or large intestine and / or duodenum.

[0016] In certain embodiments, the proximal and / or distal segments of the thread, drag material, or cord are made from the same or different materials. In other embodiments, the proximal and distal segments of the thread may be made from different materials joined together for optimal sampling of the GI tract area, for example to reduce cross-contamination of agents collected and delivered for more accurate diagnosis, assessment, and treatment of the subject's GI tract. In some embodiments, the proximal and / or distal segments of the thread or drag are made from nylon materials. In other embodiments, the thread, drag material, or cord may be made from cotton, rayon, polyester, acrylic, hemp, alpaca, mohair, wool, angora, silk, or combination materials.

[0017] In some embodiments, the distal segment of the thread is made from an absorbent mesh or textured fiber in a multi-ply configuration. In some embodiments, the distal segment of the thread is made from an absorbent mesh or textured fiber in a 2-5 ply configuration. In other embodiments, the distal segment of the thread is made from a 2-3 ply material. In some embodiments, the proximal segment of the thread may be a single ply material. In other embodiments, the distal segment of the thread may be made from a 2-3-4-ply to multiple ply material (e.g., a nylon material). In certain embodiments, the proximal segment of thread material may be a single ply material and the distal segment of thread material may be a 2, 3-4 ply material.

[0018] In some embodiments, the multi-ply drag, string, or thread material disclosed herein may be configured to be the same in each ply of material making up the distal segment, or each ply may be configured differently (e.g., capture agent placement, thread charge, fingerling inclusions in the thread or drag material, etc.) to maximize sampling of a particular GI region. In other embodiments, for example, if the distal segment includes a three-ply material, each ply may be the same, two of the three may be the same, or each ply may be configured differently to maximize sampling of a GI region or regions of interest. In addition, the proximal segment may be configured similarly to the distal segment containing a particular capture agent, or may be configured to carry a different capture agent.

[0019] In certain embodiments, the distal segment of the thread may have a breaking strength of about 35 N to about 40 N when pulled at about 40-60 mm / min until breakage. In other embodiments, the distal segment of the thread can absorb fluid up to 1.05, 1.1, 1.15, 1.2, 1.25, 1.3, 1.35, 1.4, 1.45, 1.5 or more of the total weight of the distal segment when it is essentially dry or completely dry. In certain embodiments, the fluid absorbed by the distal segment includes fluid obtained from the GI tract used for analysis of a health condition in a subject.

[0020] In some embodiments, the capture elements may be provided all along the thread or drag material, or different capture elements may be positioned along the thread or drag material depending on the agent to be captured and the location in the GI tract to be sampled. According to these embodiments, the capture elements may be positioned, for example, by molecular immobilization on the thread or drag. In some embodiments, a biotin-avidin molecular connector link may be used to attach one or more capture elements. Alternatively, in certain methods, the capture elements may be provided by changing the local surface properties of the thread or drag to attract target molecules with opposite properties. According to these embodiments, for example, the local surface charge of the thread, string, or drag material may be made negative, thereby attracting positively charged molecules to that portion of the thread or drag material. Alternatively, the local surface charge of the thread, string, or drag material may be made positive, thereby attracting negatively charged molecules to that portion of the thread or drag material. In other embodiments, by coating the local surface of the thread, string, or drag material with functional elements designed to capture the target protein or peptide, or by increasing or decreasing the local surface area of ​​the thread or string to increase or decrease its propensity to rub against the epithelial and mucosal layers, thereby increasing or decreasing collection of epithelial cells and mucosa by the surface. Certain embodiments have materials selected for the distal segment of the thread or drag material, and / or multi-ply features of the distal segment of the thread or drag material, that have protrusions (e.g., indentations or raised areas along the drag material) that can rub against the GI lining, the increased surface area and / or protrusions increasing uptake of the targeted agent while reducing disruption or integrity of the GI lining compared to standard sampling methods. In some embodiments, the drag, string, or thread material of the proximal segment surface and / or distal segment surface can be inert to reduce interference with testing and provide improved delivery of targeted agents through the GI tract of the subject.In other embodiments, the drags, strings, or threads on the proximal and / or distal segment surfaces can be inert to aid in the winding configuration of the drags, strings, or threads and their unwinding from the capsule and delivery within the GI tract of a subject.

[0021] In other embodiments, the thread, string, or drag material may further include an attractant or capture agent capable of binding to agents present at various locations in the GI tract for analysis, diagnosis, and treatment as determined by a medical practitioner. In certain embodiments, microorganisms (e.g., bacteria, fungi, viruses, protozoa) or their by-products may be sampled from the GI tract for analysis, diagnosis, and preventative treatment of a subject. In some embodiments, when the GI area is contaminated with microorganisms that release proteins, by-products, and / or other molecules, the drag or thread material may be used to sample these proteins, by-products, or molecules from the microorganisms to diagnose and treat the condition. In certain embodiments, such sampling may include the mucosal layer of the GI tract in various regions such as the esophagus, stomach, or intestine. In other embodiments, the devices disclosed herein are designed to capture bile from the bile duct. According to these embodiments, sampling of bile from a subject may include sampling from healthy volunteers or subjects with a health condition, or both, for comparison and diagnosis and / or treatment. In some embodiments, the bile may be captured by an absorbent material on the distal end of the device for later analysis.

[0022] In another embodiment, the capture agent may be disposed along the thread, string, or drag material. In certain embodiments, the capture agent may be disposed on a distal segment of the thread, string, or drag material. In some embodiments, the capture agent may be any agent capable of binding to the analyte through an interaction or binding sufficient to allow the agent to bind and concentrate or attract the analyte from a heterogeneous mixture of different analytes in a given region of the GI tract. According to these embodiments, the binding interaction may be mediated by an affinity region of the capture agent, by a receptor, by an alloy, by a chemical attractant, by a nucleic acid, by a peptide, or by other suitable capture agent. According to these embodiments, the capture agent may include, but is not limited to, antibodies, monoclonal antibodies, antibody fragments (e.g., eosinophil granules or other antibodies), as well as certain agents capable of attracting inflammatory markers, mucin, and / or other agents capable of capturing mucosa-associated markers for subsequent analysis and evaluation.

[0023] In some embodiments, the devices, methods, and use of the disclosed devices allow for the evaluation of GI tract inflammation in a subject. According to these embodiments, assessing inflammation in the esophagus of a subject can, for example, diagnose a health condition and assess a treatment strategy for the subject. In one embodiment, the device of the present invention can be deployed in the esophageal GI tract of a subject, where a distal segment of the device can capture an agent in the subject for diagnosis. The string, cord, or drag of the device is removed from the GI tract of the subject after a predetermined period of time, and the distal segment is analyzed, for example, for collection of esophageal diagnostic indicators, for diagnosis of a health condition, such as inflammation, microbial infection, or other health condition. It is contemplated herein that a subject can be evaluated before, during, or after a predetermined period of time, and / or periodically, and / or before, during, or after a predetermined treatment period. In some embodiments, the condition of the subject can include, but is not limited to, an esophageal disease or condition, or esophageal inflammation. For example, the present invention may be used to assess and diagnose gastroesophageal reflux disease (GERD) or complications associated with GERD, such as Barrett's esophagus or cancer. In another non-limiting embodiment, the disease may be eosinophilic esophagitis (EE). In another embodiment, the condition may be an allergy to one or more foods or food components.

[0024] In certain embodiments, the devices disclosed herein are pharma- ceutical acceptable and are further sterilized to reduce contamination, etc. In certain embodiments, the device unit, including all components of the device, may be sterilized in preparation for use with ethylene oxide (EO) or other similar agents for sterilization.

[0025] In other embodiments, the predetermined period of time for deployment of the device within the subject may be any length of time as determined by a medical professional and / or determined to be optimal for capturing an analyte from or delivering an agent to the GI tract of the subject. According to these embodiments, the predetermined period of time may be from about 15 minutes to about 1 hour, from about 15 minutes to 2 hours, and up to about 12 hours, or as needed. In some embodiments, the predetermined period of time for deployment of the string, thread, or drag material or device may be about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24 hours or more, or any increment thereof.

[0026] In other embodiments, after removal of the deployed thread, string, or drag material from the subject, the distal segment may be analyzed for diagnostic or other health indicators, or may be analyzed to ensure delivery of a particular agent. In some embodiments, the diagnostic or health indicator is absorbed into the thread for further analysis when collected from the subject. In other embodiments, one or more capture agents for one or more diagnostic or health indicators may be present on the distal segment of the thread or drag material, and the one or more diagnostic or health indicators may bind to the one or more capture agents for analysis and / or diagnosis. According to these embodiments, the distal segment, with or without capture agents, may bind to one or more analytes or agents. Analytes and agents may include, but are not limited to, microorganisms (e.g., viruses, bacteria, fungi, protozoa, flagella, etc.), cells, cell fragments, proteins, polypeptides (e.g., antigens, enzymes, etc.), antibodies, or any other captured or collected agents. Any method known in the art may be used to analyze agents, analytes, or fluids or other compounds collected from the GI tract of a subject. In certain embodiments, once the thread or drag material is collected from the subject, the thread or drag material may be stored in a refrigerator or freezer at a predetermined temperature, if desired, prior to collecting the analyte or agent. In other embodiments, the agent, analyte, compound, or other collected GI resident flora may be analyzed immediately upon removal of the thread, string, or drag material from the subject for rapid assessment and diagnosis, if desired. In certain embodiments, ELISA, cytology, mass spectrometry, gas chromatography, HPLC, blots (e.g., Western or other), Mesoscale, Licor, PCR, nucleic acid extraction, histology, immunochemistry, PCR, microbial culture, lateral flow assays, or other assays may be used to identify the presence or absence of the agent, or the microorganism or its by-products. In certain embodiments, the absence or reduced level of the agent in the GI tract may be diagnostic of a condition, such as a reduced or absent enzyme or other health indicator.

[0027] In certain embodiments, the one or more diagnostic indicators may be any factor that indicates the presence or severity of inflammation in the esophagus or other GI tract region. In some embodiments, the diagnostic indicators may be one or more eosinophil granule proteins, including but not limited to major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), and eosinophil-derived neurotoxin (EDN). In some embodiments, the diagnostic indicators may be cytokines or chemokines such as eotaxin, or other inflammatory markers such as arachidonic acid products, one or more neurotransmitters such as substance P and bradykinin, interleukins, and the like. In another embodiment, the diagnostic indicator may be a cellular infiltrate not normally found in the GI tract being sampled. In yet another embodiment, the pH of the GI region may be assessed. In yet another embodiment, the one or more diagnostic indicators may be a marker of an allergic response. According to these embodiments, these agents may include, but are not limited to, IgE, tryptase, histamine, receptor molecules (e.g., FcRI or CD23), or other allergens associated with allergies. Cellular diagnostic or health indicators contemplated herein may include cellular markers including, but not limited to, peripheral and / or plasma eosinophil counts (e.g., compared to controls without the condition), mast cells, and other inflammatory and / or immune cell markers associated with a health condition, or markers associated with the development of one or more health conditions. In other embodiments, the diagnostic indicators may include one, two, three, four, or more markers.

[0028] definition As used herein, the term "about" may indicate that a value includes the standard deviation of error for the device or method being employed to determine the value, such as + / - 10 percent.

[0029] As used herein, the term "assessing" includes any form of measurement, including determining whether an element is present or not. The terms "determining," "measuring," "evaluating," "assessing," and "assaying" are used interchangeably and can include quantitative and / or qualitative determinations.

[0030] As used herein, the term "subject" refers to any member of the animal kingdom, as well as humans. The terms "treatment", "treating", "treating" and the like as used herein refer to obtaining a desired pharmacological and / or physiological effect. The effect may be preventative in that it completely or partially prevents a disease or its symptoms, and / or may be therapeutic in that it partially or completely cures a disease and / or adverse effects caused by the disease. As used herein, "treatment" encompasses any treatment of a disease in a mammal (especially a human), including (a) preventing the disease from occurring in a subject who may be susceptible to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease (i.e., arresting its development); and (c) relieving the disease (i.e., causing regression of the disease and / or relieving one or more disease symptoms). "Treatment" is also meant to encompass the delivery of an agent to provide a pharmacological effect even when the disease or condition is not present.

[0031] Other objects, features, and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and specific examples, while indicating particular embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. [Brief description of the drawings]

[0032] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein. [Figure 1] 1 illustrates an exemplary device showing the distal segment end for a two-part capsule according to certain embodiments disclosed herein. [Figure 2-1] 2A-2J depict exemplary configurations of threads or drag material according to some embodiments disclosed herein. [Figure 2-2] Same as above. [Figure 2-3] Same as above. [Diagram 3] 3A and 3B show an exemplary embodiment of a method for threading a distal segment end of a thread, string, or drag material of an exemplary device of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0033]

[0003] The embodiments disclosed herein relate to devices and uses for sampling and testing and diagnosis of medical disorders or monitoring of health status in a subject through GI tract analysis in the subject. Referring to Figure 1, in certain embodiments, an improved gastrointestinal (GI) sampling device is disclosed that includes a device 100 having an ingestible, optionally digestible, outer capsule 102, a thread, string, or drag material 104 at least partially enclosed in the capsule for deployment within the subject during use, and a weight 106 enclosed within the capsule.

[0034] In certain embodiments, the thread may include a proximal segment and a distal or sampling segment (not shown). In certain embodiments, the proximal and distal segments form a single thread, while in other embodiments, the proximal and distal segments are operably attached to form the thread. For example, in certain embodiments, an end (e.g., distal end) of the proximal segment is operably attached to an end (e.g., proximal end) of the distal segment. In some embodiments, one end (e.g., distal end) of the proximal segment may be tapered for attachment to an end (e.g., proximal end) of the distal segment, which may optionally be tapered. In certain embodiments, the ends of the proximal and distal segments may be operably attached using adhesives, thermal bonding, intertwining, weaving, or other suitable fastening methods.

[0035] In some embodiments, the outer capsule 102 may be configured as a two-part capsule including a cap 108 and a base 110 that operably fit together to enclose the thread 104 and weight 106 inside the outer capsule 102.

[0036] In some embodiments, the cap 108 of the two-part capsule 102 can include a thread deployment opening 112, with the proximal end 114 of the thread 104 (e.g., the proximal end of the proximal segment) extending through the opening 112.

[0037] In some embodiments, the base 110 of the two-part capsule 102 may include an end-fixation opening 116, and a portion of the distal end 118 of the thread 104 (e.g., the distal end of a distal segment) extends above the top surface 120 of the base 110, along the periphery 122 of the base 110, and back into the interior of the base 110 by passing through the end-fixation opening 116. The thread extending along the periphery of the base may be located between the base and the cap when the cap is operably mated to the base so as to releasably secure the distal end of the thread to the outer capsule. The cap and base may be configured such that the cap extends over the thread-fixation opening when operably mated.

[0038] In certain embodiments, the thread 104 is optimally configured to be enclosed within the outer capsule 102 for deployment from the outer capsule in the GI tract of a subject during use. Any suitable configuration of the thread that allows for enclosure within the outer capsule as well as deployment from the outer capsule may be used in conjunction with the device of the present disclosure. In certain embodiments, the configuration provides for efficient release from the capsule 102 through the thread deployment opening 112. By way of non-limiting example, exemplary winding configurations for optimal enclosure within the outer capsule are shown in Figures 2A-2J, and any such configurations may be used in conjunction with the device of the present disclosure. For example, as shown in Figure 2A, the thread or drag material may be wound to be configured in a layered loop orientation with a hole in the center, where the loops remain separated from one another and do not overlap, and the proximal end of the thread is fed internally for optimal deployment in the subject. In another embodiment, as shown in Figure 2B, the thread or drag material may be wound to be configured in a layered loop orientation with a hole in the center, where the loops remain separated from one another and do not overlap, and the proximal end of the thread is fed externally for optimal deployment in the subject. Additional embodiments of exemplary winding configurations of the thread are shown in Figures 2C (longitudinal), 2D (random), 2E (no loop layering), 2F (thin dense longitudinal layers), 2G (twisted), 2H (internal short spool), 2I (internal long spool), and 2J (circular).

[0039] In some embodiments, the outer capsule, including the cap and / or base, may be made from, but is not limited to, gelatin (e.g., bovine gelatin, vegan gelatin, kosher, halal, or equivalent materials, vegetarian grade gelatin materials), cellulose (e.g., HPMC), starch (e.g., potato starch), pullulan (e.g., tapioca), polyvinyl alcohol (e.g., copolymers), hemp, or other suitable materials that can degrade, dissolve, or pass through the subject's GI system. In certain embodiments, the outer capsule, including the cap and / or base of the device disclosed herein, may be a gelatin or cellulose material. It is contemplated that the materials for the capsule and / or drag material may be made to meet any formal requirements (e.g., dietary restrictions, allergies, and / or religious considerations) depending on the subject being treated. In certain embodiments, the capsules used herein may be about 50% to about 100% bovine pharmaceutical grade gelatin, Kosher Parvez and Halal certified, and may be made in cGMP and FDA approved facilities from BSE-free or other materials meeting certain standards.

[0040] In certain embodiments, the weights disclosed herein may be made from, but are not limited to, stainless steel (e.g., magnetic, austenitic), titanium, ceramic (e.g., alumina, zirconia), glass, cobalt chromium, gold, silver, tantalum, platinum, other suitable compounds, or combinations thereof. In certain embodiments, the weights of the devices disclosed herein may be stainless steel or titanium.

[0041] According to certain embodiments, the outer capsule may be dissolvable, partially dissolvable, or may pass naturally through the subject's system without issue. In certain embodiments, the thread, string, or drag material is malleable for configuration within the capsule. In some embodiments, the thread, string, or capture material may be of various lengths for optimal deployment. In some embodiments, a portion of the proximal segment may be pulled out of the capsule prior to swallowing the device or unit, and the end of the string may be attached to the subject's cheek. After a predetermined time has elapsed, the string may be removed from the subject for analysis.

[0042] In certain embodiments, the thread is configured for optimal containment within the outer capsule and optimal delivery from the capsule through the subject's GI tract. According to these embodiments, a distal segment of the thread of the device can be delivered through the esophagus and into the subject's stomach and duodenum to collect and / or deliver an agent from / to one or more regions for analysis. In certain embodiments, the distal segment of the thread or drag material includes the same or different capture elements along the thread or drag material. In other embodiments, the capture elements may be positioned along the thread or drag material that are directed to the GI portion to be analyzed or delivered when the thread or drag material is fully deployed. In certain embodiments, the capture elements may be positioned along the string, thread, or drag material that has capture elements specific for the capture agent in the esophagus that are different from those in the stomach that are different from those in the small intestine and / or large intestine and / or duodenum and / or bile duct.

[0043] In other embodiments, the thread further comprises an attractant or capture agent capable of binding to agents or molecules present at various locations in the GI tract for analysis, diagnosis, and treatment as determined by a medical professional. In certain embodiments, microorganisms (e.g., bacteria, fungi, viruses, protozoa) or their by-products can be sampled from the GI tract for subject analysis, diagnosis, and preventive treatment. In certain embodiments, pathogenic organisms can be detected in the subject's GI tract for subject diagnostic and therapeutic use.

[0044] In some embodiments, the capture elements may be provided all along the thread, string, or drag material, or different capture elements may be positioned along the thread, string, or drag material depending on the agent to be captured and the location in the GI tract to be sampled. According to these embodiments, the capture elements may be positioned, for example, by molecular immobilization on the thread, string, or drag material. In some embodiments, a biotin-avidin molecular connector link may be used to attach one or more capture elements along the string, thread, or drag material (e.g., nylon ply material). Alternatively, in certain methods, the capture elements may be provided by changing the local surface properties of the thread or drag to attract target molecules with opposite properties. According to these embodiments, for example, the local surface charge of the thread or drag material may be made negative, thereby attracting positively charged molecules to that portion of the thread, string, or drag material. Alternatively, the local surface charge of the thread, string, or drag material may be made positive, thereby attracting negatively charged molecules to that portion of the thread or drag material. In other embodiments, by coating the local surface of the thread, string, or drag with functional elements designed to capture the target protein or peptide; or by increasing or decreasing the local surface area of ​​the thread or drag to increase or decrease its propensity to rub against the epithelial and mucosal layers, thereby increasing or decreasing collection of epithelial cells and mucosa or mucosa-associated molecules by the surface. Certain embodiments are characterized in that the material selected for the distal segment of the thread, string, or drag material, and / or the multi-ply feature of the distal segment of the thread, string, or drag material, has protrusions that can rub against the GI lining (e.g., mucosal surface), and the increased surface area and / or protrusions increase uptake of the target agent while reducing disruption or integrity of the GI lining compared to standard sampling methods.In some embodiments, the drag material may be a smooth nylon material with small projections or protrusions that can interact with the mucosal surface by rubbing against the mucosal lining while maintaining its structural integrity with minimal interference upon deployment within the subject, and while doing so, absorb agents within the mucosal lining for later analysis. According to these embodiments, the distal segment of the drag or thread material may be constructed of nylon, with each ply that comprises the thread or drag comprising the same or different grades of nylon or other suitable material. In some embodiments, mucin may be collected using the devices disclosed herein to assess the condition of the small intestinal mucosa and / or large intestinal mucosa. In some embodiments, mucin indicates the condition of the subject's GI tract depending on the mucin collected and the concentration found. In some embodiments, the conditions disclosed herein may include colitis, Crohn's disease, irritable bowel syndrome (IBS or IBD), allergic reactions to foods, celiac disease, autoimmune conditions, or other factors, etc. In other embodiments, the drag material may be a coarser nylon material with an increased number of protrusions or projections that can interact with the mucosal surface by rubbing against the mucosal lining to collect an increased number of GI-related molecules while absorbing the agent within the mucosal lining for later analysis, while maintaining its structural integrity with minimal interference upon deployment within the subject.

[0045] In other embodiments, the thread, string, or drag material further comprises one or more attracting or capturing agents capable of binding to agents present at various locations in the GI tract for analysis, diagnosis, and treatment as determined by a medical practitioner. In certain embodiments, microorganisms (e.g., bacteria, fungi, viruses, protozoa) or their by-products can be sampled from the GI tract for analysis, diagnosis, and preventative treatment of a subject. In some embodiments, when the GI area is contaminated with microorganisms, such as pathogenic organisms or non-protozoa that release proteins, by-products, and / or other molecules, the drag, string, or thread material can be used to sample these proteins, by-products, or molecules produced from the microorganisms to diagnose and / or treat the condition. In certain embodiments, such sampling may include the mucosal layer of the GI tract in various regions, such as the esophagus, stomach, or intestine.

[0046] In another embodiment, the capture agent may be located on the thread or drag. In certain embodiments, the capture agent may be located on a distal segment of the thread. In some embodiments, the capture agent may be any agent capable of binding to the analyte through an interaction or binding sufficient to allow the agent to bind and concentrate or attract the analyte from a heterogeneous mixture of different analytes in a given region of the GI tract. According to these embodiments, the binding interaction may be mediated by an affinity region of the capture agent, by a receptor, by an alloy, by a chemical attractant, by a polynucleotide (e.g., mRNA, DNA, RNA molecules), by a peptide, a polypeptide, or other suitable capture agent. According to these embodiments, the capture agent may include, but is not limited to, an antibody, a monoclonal antibody, an antibody fragment (e.g., eosinophil granule or other antibody).

[0047] In certain embodiments, the proximal and / or distal segments of the thread are made from the same or different materials. In other embodiments, the proximal and distal segments of the thread may be made from different materials that are joined together for optimal sampling of the GI tract area, for example, to reduce cross-contamination of agents collected and delivered for more accurate diagnosis, assessment, and treatment of the subject's GI tract. In some embodiments, the proximal and / or distal segments of the thread or drag are made from a nylon material. In other embodiments, the thread or drag material may be made from cotton, rayon, polyester, acrylic, hemp, alpaca, mohair, wool, angora, silk, or a combination material.

[0048] In some embodiments, the distal segment of the thread is made from an absorbent mesh or textured fiber in a multi-ply configuration. In some embodiments, the distal segment of the thread is made from an absorbent mesh or textured fiber in a 2-5 ply configuration. In other embodiments, the distal segment of the thread is made from a 2-3 ply material. In some embodiments, the proximal segment of the thread may be a single ply material. In other embodiments, the distal segment of the thread may be made from a 2-3-4-ply to multiple ply material (e.g., a nylon material). In certain embodiments, the proximal segment of thread material may be a single ply material and the distal segment of thread material may be a 2, 3-4 ply material.

[0049] In some embodiments, the multi-ply drag or thread material disclosed herein may be configured to be the same in each ply of material making up the distal segment, or each ply may be configured differently (e.g., capture agent placement, thread charge, fingerling inclusions or protrusions in the thread or drag material, etc.) to maximize sampling of a particular GI region. In other embodiments, for example, if the distal segment includes three plies of material, each ply may be the same, two of the three may be the same, or each ply may be configured differently to maximize sampling of a GI region or regions of interest. Additionally, the proximal segment may be configured similarly to the distal segment containing a particular capture agent, or may be configured to carry a different capture agent.

[0050] In some embodiments, the distal segment of the thread or drag material is nylon (e.g., CORDURA nylon, nylon 6-6 fiber, nylon industrial fiber, nylon polyamide fiber, white dyeable nylon; nylon staple fiber / tow). In other embodiments, the distal segment may be 3-ply, spun, nylon 9 / 3 string, or other comparable material having a high absorbency equivalent thereof. Certain embodiments contemplate that the nylon or other material used herein may have an absorption of about 8-10 times its weight in water or other suitable liquid to increase liquid capture for analysis. According to these embodiments, the distal segment of the thread, string, or drag material may remain in the subject's GI tract and absorb diagnostic agents, health indicators, microorganisms or their by-products, or biological fluids located in the esophagus, stomach, bile duct, duodenum, intestine, or other areas of the GI tract. In some embodiments, the distal segment of the thread or drag may be any length as determined by a medical professional. In some embodiments, the distal segment may be about 500 to about 900 mm, or about 600 to about 800 mm, or other suitable length (e.g., 775 mm), depending on the subject being analyzed or the desired GI region being targeted.

[0051] In some embodiments, the proximal segment of the thread or drag material may be a single-ply parallel fiber string. In certain embodiments, the proximal segment of the thread or drag material may be a single-ply segment of nylon 6 / 6. In other embodiments, the proximal segment or drag material is selected to be a biocompatible material that is not very absorbent. In other embodiments, it is desirable for the proximal segment of the thread or drag material to not take up too much space in the capsule when wound up and to be wound and unwound as efficiently as possible. In some embodiments, the proximal segment of the thread or drag material may be about 250 to about 400 mm, or about 300 to about 400 mm, or about 356 mm. In some embodiments, the proximal segment of the thread or drag material is bonded to the distal segment and a loop is formed at the end of the proximal segment opposite the bonded portion of the proximal segment. It is contemplated that the looped end may be used to attach to a subject either inside or outside the mouth of the subject. In some embodiments, the distal and proximal interfaces are designed to reduce interference when released from the capsule. In other embodiments, the material used for the drag or thread is inert, hi other embodiments, the drag or thread has protrusions extending out from the material that minimally interfere with deployment.

[0052] In some embodiments, the distal segment of the thread or drag material may be a spun material. In some embodiments, the distal segment of the thread or drag material has high absorbency properties, unlike the proximal segment described herein. In certain embodiments, the distal segment is a 3-ply material (e.g., nylon 9 / 3 string). In some embodiments, the absorbency properties of the drag or thread material may be such that it can absorb about 5 to about 15 times, about 8 to about 12 times, or about 8 to about 10 times its weight in water. In some embodiments, when a portion of the length of the drag material has a proximal segment and a distal segment, the distal segment of the thread or drag material may be about 500 to about 900 mm in length, or about 500 to about 800 mm, or about 600 to about 800 mm, or about 775 mm in length.

[0053] In some embodiments, an adhesive may be used to bond the proximal segment of thread, string, or drag material to the distal segment. In some embodiments, the adhesive may be a silicone or other biocompatible adhesive. In other embodiments, an adhesive may be used to form a loop in the proximal segment. In some embodiments, the strength of the adhesive may be important to bond the proximal segment of thread or drag material to the distal segment. For example, the strength of the joint of the segments must be strong enough to withstand the tension caused by removing the string from the GI tract of the subject during normal use and / or to withstand the tension that would be created if the drag, string, or thread material of the device does not deploy correctly and needs to be removed from the subject. This may be the case when the capsule does not separate from the drag or thread when the device is deployed in the subject, creating more tension than if the string were to be removed alone. In certain embodiments, adhesives useful herein can withstand a tension of about 10 N to about 24 N or more.

[0054] In certain embodiments, the distal segment of the thread may have a breaking strength of about 35 N to about 40 N when pulled at about 40-60 mm / min until breakage. In other embodiments, the distal segment of the thread can absorb up to 1.05, 1.1, 1.15, 1.2, 1.25, 1.3, 1.35, 1.4, 1.45, 1.5 or more of the total weight of the distal segment when it is essentially dry or completely dry.

[0055] In some embodiments, the capsule, including the cap and / or base, may be made from, but is not limited to, gelatin, cellulose (e.g., HPMC), starch (e.g., potato starch), pullulan (e.g., tapioca), polyvinyl alcohol (e.g., copolymers), hemp, or other suitable materials that can degrade, dissolve, or pass through the GI system of a subject. In certain embodiments, the capsule, including the cap and / or base of the device disclosed herein, may be a gelatin or cellulose material. In certain embodiments, the two-part capsule or the device capsule may be made from non-vegetarian gelatin. In some embodiments, for ease of manufacturing, the capsule may be a single size for any subject. In other embodiments, for sample subjects, such as livestock or other animals, the capsule and other components of the device may be tailored for optimal sampling of any animal or mammal, such as horses, cows, dogs, cats, or other animals, for diagnostic purposes or to assess the health of the animal.

[0056] In other embodiments, holes may be introduced into the capsule (e.g., by perforation or punching), for example, to facilitate assembly and function of the capsule. In certain embodiments, one or more holes may be created (e.g., drilled) at the end of the capsule cap, and one or more holes may be created at the base or body of the capsule. In certain embodiments, one or more holes may be introduced into the side of the base or body of the capsule. In some embodiments, the diameter of the one or more holes is about 0.5 mm to about 3 mm. In other embodiments, the diameter of the one or more holes is about 1.5 mm to about 2.5 mm or about 2.0 mm in diameter. In some embodiments, holes located at the end of the capsule should be relatively smooth with little or no cracks around the entire diameter. In other embodiments, holes located at the base or body of the capsule, such as the side, do not need to be relatively smooth, but have little or no cracks around the diameter of the hole.

[0057] In certain embodiments, the weights of the devices disclosed herein may be made from, but are not limited to, stainless steel (e.g., magnetic, austenitic), titanium, ceramic (e.g., alumina, zirconia), glass, cobalt chrome, gold, silver, tantalum, platinum, other suitable compounds, or combinations thereof. In certain embodiments, the weights of the devices disclosed herein may be stainless steel or titanium. In some embodiments, the weights may be stainless steel balls. In other embodiments, the stainless steel balls may be made from 316 grade stainless steel. According to these embodiments, the balls may be treated to remove any contaminants or debris. In certain embodiments, the size of the balls may be about 1.59 mm to about 9.53 mm (about 1 / 16 to about 3 / 8 inches) (e.g., 2 to about 8 mm). In other embodiments, the size of the balls may be about 3 / 16 inches (about 4 to about 5 mm) in diameter to fit into the base or bottom of the body of the capsule.

[0058] In certain embodiments, the device herein may include about six different components as disclosed herein. According to these embodiments, the proximal and distal segments may be glued together using an adhesive and a loop may be created on the proximal segment end that is not glued. Once the adhesive has cured, a drag or thread may be wound up and inserted into the base of the capsule (e.g., gelatin capsule or other capsule) onto the top of a weight placed at the end of the capsule. To glue the proximal and distal strings together, both strings may be fanned out as the adhesive is applied, so that the strands of the proximal and distal segments are intertwined together during the bonding process. It is noted that simply overlapping the strings as with a lap solder joint would not be able to meet the strength requirements of this joint. Intertwining the proximal segment end with the distal segment end increases the strength of the joint between the two segments and allows the weight to be attached without loosening the ends.

[0059] In other embodiments, adhering the weight to the inner capsule with an adhesive creates a non-sterile surface that may expose the subject to a non-sterile surface as the weight remains in the capsule during sterilization. In some embodiments, the weight does not include an adhesive so that it is freely sterilizable. In some embodiments, the thread or drag may be wound in a specific configuration to accommodate deployment and separation of the thread from the capsule (see Figures 2A-2J). In other embodiments, the thread, string, or drag may be configured such that winding begins at the proximal string. The proximal string may be wound in multiple layers. When wound, in some embodiments, 2-5 layers or 3-4 layers of the proximal segment remain after completing this part of the winding process. In other embodiments, the interface between the proximal and distal segments of the string may be wrapped around the outside of the wrapped proximal segment. In some embodiments, this positioning can facilitate deployment of the proximal segment inside the interface and allow the interface to expand outside of the capsule without impeding deployment of the distal portion of the thread or drag material. In some embodiments, the distal segment of the thread or drag may be wound. According to these embodiments, the distal segment of the thread or drag material may be wound side-by-side and then back on itself about 2 to about 4.5 times or about 3.5 times. It is noted that this winding configuration provided consistently low deployment force values. Additionally, in certain embodiments, this winding configuration was designed to reduce interference when the thread or drag is in the process of deploying from the capsule. In some embodiments, the proximal segment winding and the proximal / distal segment interface may create issues with the deployment of the thread or drag material. According to these embodiments, the interface between the proximal and distal segments may be intertwined to reduce separation while providing minimal deployment interference. In certain embodiments, the adhesive may be smooth, unhindered, and may impede deployment of the string with low force, and must be carefully titrated to ensure a smooth withdrawal. Similarly, knots may also impede easy removal of the string from the capsule.In an embodiment, adhesive can be used to join the segments while minimizing interference by applying only what is needed to join the segments without any excess adhesive, hi an embodiment, the distal segment windings can be placed within the base or body of the capsule and wound in a configuration sufficient for consistent deployment.

[0060] In some embodiments, the weight (e.g., weighted ball) of the GI device disclosed herein may include one or more of the following features: It may be made of a porous material, may include surface modifications, may be tethered to a small portion of the thread or drag material, may include active elements such as sensing elements (e.g., pH, temperature, pressure), may include visual features (e.g., camera or scope), may also include embedded power such as a battery or radio frequency antenna for receiving power by remote telemetry or a combination of these features. In certain embodiments, the weight may be a stainless steel ball with protrusions for capture agents or a rough or raised surface. In some embodiments, the weight of the device disclosed herein may be collected from the subject's waste, bowel movements, etc., and analyzed for agents located in the captured mucosa or other agents. In certain embodiments, the weight (e.g., ball) may be located at the most distal end of the distal segment and attached to the distal thread or drag material by press-fit or dissolvable adhesive, etc. In some embodiments, the weight is glued to the distal segment of the thread or drag without the use of wax, such as beeswax, to reduce interference and to ensure that the weight is separated and / or expelled from the thread or drag material. In certain embodiments, an MRI or other diagnostic tool can be used once the weight is expelled from the subject. According to these embodiments, the weight of the device of the present disclosure may be used for additional sampling while avoiding fecal contamination based on the material used and the configuration of the weight relative to the drag or thread material. According to these embodiments, upper and lower GI sampling is possible using a single device disclosed herein. For example, sampling the proximal and distal segments, as well as analyzing the weighted components expelled from the subject after exposure to the subject's lower GI tract (e.g., mucosal regions of the lower small intestine and large intestine) and rectum.

[0061] In other embodiments, as the thread or drag is wound, the capsule body or base may be slid over the outside of the string. While sliding the capsule body over the thread or drag material, the end of the distal segment may be positioned within the hole in the capsule body (see, e.g., FIG. 3A and FIG. 3B). In some embodiments, this positioning of the distal segment allows the end of the thread or drag to be sandwiched between the capsule cap and body when the cap is placed over the open end of the capsule body. In some embodiments, as shown in FIG. 1 and FIG. 3A and FIG. 3B, about 2 to about 8 mm of the end of the drag or thread is contained within the base secured by the capsule cap. In some embodiments, the assembled device may be sealed in a pouch (e.g., a Tyvek / polypeel pouch that is 3×4 inches in size), the pouch being permeable to sterilization (e.g., by ethylene oxide gas).

[0062] In other embodiments, the devices disclosed herein allow for the assessment of GI tract inflammation in a subject. According to these embodiments, assessing inflammation in the esophagus of a subject can, for example, diagnose a health condition and assess a treatment strategy for the subject. In one embodiment, the device of the present invention can be deployed in the esophageal GI tract of a subject, and a distal segment of the device can capture an agent in the subject for diagnosis. The thread of the device is removed from the GI tract of the subject after a predetermined period of time, and the distal segment is analyzed for diagnosing a health condition such as inflammation, infection, or other conditions, for example, for collection of esophageal diagnostic indicators. It is contemplated herein that the subject can be evaluated before, during, or after a predetermined period of time, and / or periodically, and / or before, during, or after a predetermined treatment period. In some embodiments, the subject's condition can include, but is not limited to, a disease of the esophagus, which can include esophageal inflammation. For example, the present invention can be used to assess and diagnose gastroesophageal reflux disease (GERD) or complications associated with GERD, such as Barrett's esophagus or cancer. In another non-limiting embodiment, the disease can be eosinophilic esophagitis (EE). In another embodiment, the condition can be an allergy to one or more foods or food components.

[0063] In certain embodiments, the devices disclosed herein are sterilized to be pharma- ceutically acceptable, to reduce contamination, to prepare for delivery to a subject, and for other considerations. In certain embodiments, the device unit, including all components of the device that are introduced into a subject, may be sterilized by ethylene oxide (EO) or other similar agents for sterilization without affecting the integrity of the device or device components.

[0064] Kits are contemplated for the devices and other materials disclosed herein. In certain embodiments, each device may be placed in a pouch for delivery in the kit. In some embodiments, a peel pouch may be used to house the devices disclosed herein. In other embodiments, the device assemblies disclosed herein may be packaged with a combination of Tyvek 1073B and polyester. In some embodiments, the pouch may house the device, or several pouches in the kit may each house a single device. In some embodiments, the device is sterilized and stored in a sealed pouch. According to these embodiments, the pouch may be about 6 mm by about 12 mm or larger. In some embodiments, the pouch may be pre-sealed on three sides of the pouch. One end of the pouch may further include a chevron that allows the pouch to be opened more easily by the user. Once the device is placed in the pouch, the fourth side may be sealed. According to these embodiments, the seal on the fourth side may not be designed to be easily peeled, but may be peelable. The pouches contemplated herein may be designed to provide a sterile barrier: the other three sides may be sealable, prefabricated and presealed to provide a sterile barrier, and easily peelable.

[0065] In some embodiments, the kits contemplated herein may include one or more devices for deployment in a subject. In certain embodiments, the kits may include home kits or kits for use by medical practitioners. In some embodiments, the kits may include instructions on how to use the devices disclosed herein, and / or instructions for testing and / or sampling and analyzing captured agents, mucosa, pH, microbiome, specific proteins, polypeptides, microorganisms or agents associated therewith captured by the devices. In certain embodiments, instructions and / or scoring of single or multiple plies of drag material for diagnosing and / or treating a subject may be included. In some embodiments, the kits may be stored for long periods of time at room temperature or by refrigeration or in a freezer for later use.

[0066] In certain embodiments, the predetermined period of time for deploying the device within the subject may be any length of time as determined by a medical professional and / or determined to be optimal for capturing an analyte from or delivering an agent to the GI tract of the subject. According to these embodiments, the predetermined period of time may be from about 15 minutes to about 1 hour, from about 15 minutes to 2 hours, and up to about 12 hours, or as needed. In some embodiments, the predetermined period of time may be about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24 hours or more, or any increment thereof.

[0067] In other embodiments, after removing the deployed thread or drag material from the subject, the distal segment may be analyzed for diagnostic or other health indicators, or may be analyzed to ensure delivery of a particular agent. In some embodiments, when a diagnostic or health indicator is collected from the subject, it is absorbed into the thread for further analysis. In other embodiments, one or more capture agents for one or more diagnostic or health indicators may be present on the distal segment of the thread or drag material, and the one or more diagnostic or health indicators may bind to the one or more capture agents for analysis and / or diagnosis. According to these embodiments, the distal segment, with or without a capture agent, may bind to one or more analytes or agents. Analytes and agents may include, but are not limited to, microorganisms (e.g., viruses, bacteria, fungi, protozoa, flagella, etc.), cells, cell fragments, proteins, polypeptides (e.g., antigens, enzymes, etc.), antibodies, or any other captured or collected agents. Any method known in the art may be used to analyze agents, analytes, or fluids or other compounds collected from the GI tract of a subject. In certain embodiments, once the thread or drag material is collected from the subject, the thread or drag material may be stored in a refrigerator or freezer at a predetermined temperature prior to collecting the analyte or agent. In other embodiments, the agent, analyte, compound, or other collected GI resident flora may be analyzed immediately upon removal of the thread or drag material from the subject for rapid assessment and diagnosis as needed. In certain embodiments, ELISA, cytology, mass spectrometry, gas chromatography, HPLC, blot (e.g., Western or other), Mesoscale, Licor, PCR, nucleic acid extraction, histology, immunochemistry, microbial culture, lateral flow assay, or other assays may be used to identify the presence or absence of the agent. In certain embodiments, the absence of the agent in the GI tract may be diagnostic of a condition, such as a reduction or absence of enzymes, a reduction or absence of natural microflora or microbiome indicators, or other health indicators.

[0068] In certain embodiments, the one or more diagnostic indicators may be any factor that indicates the presence or severity of inflammation in the esophagus or other GI tract region. In some embodiments, the diagnostic indicators may be one or more eosinophil granule proteins, including but not limited to major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), and eosinophil-derived neurotoxin (EDN). In some embodiments, the diagnostic indicators may be cytokines or chemokines such as eotaxin, or other inflammatory markers such as arachidonic acid products, one or more neurotransmitters such as substance P and bradykinin, interleukins, and the like. In another embodiment, the diagnostic indicator may be a cellular infiltrate not normally found in the GI tract being sampled. In yet another embodiment, the pH of the GI region may be assessed to diagnose one or more conditions. In yet another embodiment, the one or more diagnostic indicators may be markers of an allergic reaction. According to these embodiments, these agents may include, but are not limited to, IgE, tryptase, histamine, receptor molecules (e.g., FcRI or CD23), or other allergens associated with allergy. Cellular diagnostic or health indicators contemplated herein may include, but are not limited to, peripheral and / or plasma eosinophil counts (e.g., compared to controls without the condition), mast cells, and other inflammatory and / or immune cells associated with a health condition, or cellular markers including markers associated with the development of one or more health conditions. In other embodiments, diagnostic indicators of a condition may include one, two, three, four, or more markers associated with one or more health conditions.

[0069] In some embodiments, the captured agent or analyte may be used to diagnose a disease or condition of the upper GI tract of a subject. The evaluation may include an assessment of the presence or absence of an indicator that allows for the diagnosis of a disease or condition. For example, if the sample shows evidence of an inflammatory response or condition (e.g., the presence of inflammatory cytokines), this may indicate the presence of eosinophilic esophagitis (EE). Alternatively, the level or concentration of the indicator may be evaluated to diagnose or evaluate the level or severity of a disease or condition or treatment regimen. For example, an increase in the level of eosinophil granule protein in a sample compared to a control sample may indicate the presence of EE. In other embodiments, an increase in inflammatory cytokine expression or activity, such as an increase in IL-6 and / or IL-8 compared to a control sample, may be associated with the presence of GERD. In certain embodiments, indicators collected from the GI tract using the devices disclosed herein may include, but are not limited to, e-cadherin for detection of GERD or other related conditions; biomarkers for identifying the presence of Crohn's disease or other related inflammatory bowel disease; biomarkers for identifying the presence of colitis or other related conditions; biomarkers for identifying the presence of Intestinal Bowel Disease (IBD) or other related conditions; biomarkers or indicators of infectious agents, such as Helicobacter pylori (H. pylori), Escherichia coli (E. coli), esophageal candidiasis, or other bacterial or viral infectious agents.

[0070] In one embodiment, a device and method for measuring esophageal inflammation is described, comprising deploying a device in the GI tract of a subject, removing the device after a predetermined period of time, analyzing the device for diagnostic indicators of esophageal inflammation, and evaluating the diagnostic indicators to diagnose esophageal inflammation. In another embodiment, the device and its method of use may further comprise quantifying the diagnostic indicators or other agents. In accordance with these methods, quantification may be performed by any method known to those skilled in the art. In certain embodiments, quantification may be performed by ELISA. In another embodiment, quantification of the captured indicators may be performed by Mesoscale. In other embodiments, treatment of a disease or condition may be applied based on the analysis of one or more captured agents, indicators, or pH levels of a sample obtained by the device disclosed herein. Additionally, a treatment regimen may be monitored and adjusted as needed by sampling the GI tract of a subject before, during, and after a given treatment regimen.

[0071] In some embodiments, the diagnostic indicator or captured agent may be any agent or factor that indicates the presence or severity of GI tract infection, inflammation, and / or immune disorders or other health conditions. In some embodiments, the captured agent may be eosinophil granule proteins, including major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), or eosinophil-derived neurotoxin (EDN). In some embodiments, the diagnostic indicator is a cytokine or chemokine, such as eotaxin. In another embodiment, the diagnostic indicator is cellular infiltrate or pH. In yet another embodiment, the diagnostic indicator is a marker of allergic response, such as IgE, tryptase, receptor molecules (e.g., FcRI or CD23), or allergens. Other inflammatory markers that may be examined may include, for example, arachidonic acid products, and neurotransmitters such as substance P and bradykinin. Other diagnostic indicators include peripheral and plasma eosinophil counts, mast cells, including leukotrienes. In other embodiments, the diagnostic indicator may include one, two, or more markers (if present, decreased or increased) associated with a health condition.

[0072] In some embodiments, the use of the devices in the methods disclosed herein provides a minimally invasive method for assessing and diagnosing esophageal disease. In some embodiments, the distinction between GERD and EE in a subject can be determined using the devices and methods disclosed herein.

[0073] In addition to using the devices disclosed herein to capture and analyze agents found in different upper GI compartments, some embodiments disclosed herein relate to delivering agents, such as drugs or biological agents on the device threads, strings, or drags, to the upper GI tract of a subject to treat or improve a condition. It is contemplated that any biological or chemical agent may be associated with the threads, strings, or drags of the devices disclosed herein via an interaction agent, such as biotin-avidin or similar molecules, or by charge attraction. In other embodiments, delivery of agents to the GI tract may be more effectively delivered to specific GI tract locations, such as the esophagus, stomach, upper intestine, and mucosa thereof.

[0074] In other embodiments, the devices disclosed herein may be designed to capture bile from the bile duct. According to these embodiments, the sampling of the bile of a subject may include sampling from healthy volunteers or subjects with a healthy condition, or both, for comparison and diagnosis and / or treatment. According to these embodiments, the sampling of bile may be used to diagnose conditions associated with changes in bile and compare these to healthy adults, or to assess the presence of agents that indicate conditions, such as changes in bile pH, color, etc. In some embodiments, the assessment of the bile of a subject may be used in pharmaceutical clinical trial studies, such as absorption, distribution, metabolism, and excretion (ADME) studies, evaluation of drug-drug interaction studies, or other studies related to the identification of target markers indicative of drug resistance and drug efficacy, or other analyses.

[0075] In some embodiments, a bound-captured agent may refer to one or more agents that are attached to a distal segment of the thread, string, or drag material for analysis by a medical professional or other. According to these embodiments, the bound-captured agent is essentially immobilized on the surface of the drag, string, or thread material while the device is deployed and for a period of time after the device is retrieved from the subject.

[0076] The predetermined period of time can be of various lengths of time. For example, the predetermined period of time for capturing samples collected from the devices disclosed herein can be from about 15 minutes to about 12 hours. In some embodiments, the predetermined period of time for capturing samples collected from the devices disclosed herein can be about 15 minutes, about 30 minutes, about 45 minutes, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24 hours or more, or any increment thereof, after deployment of the device in the subject. In one embodiment, the predetermined period of time can be about 15 minutes. In another embodiment, the predetermined period of time can be about 1 hour. In other embodiments, the predetermined period of time can be about 12 hours after deployment of the device.

[0077] In some embodiments, after the device is swallowed, the end or distal end of the distal segment of the thread, string, or drag material may reach the lumen of the small intestine. In certain embodiments, the GI tract location of the distal segment may be confirmed by the presence or absence of various agents, or by a pH indicator associated with the drag or thread material, or by detection of the weight in the subject. A boundary may be identified, for example, by the presence or absence of an agent or analyte, and / or between an acidic and an alkaline portion of the drag, string, or thread material. In some embodiments, after the device is swallowed, a trace of the drag, string, or thread may be left in its path through the esophagus, stomach, and into the duodenum. Within a predetermined time, the thread, string, or drag material may be fully deployed and, if desired, may remain attached to the capsule, for example, as shown in FIG. 1. In some embodiments, the capsule dissolves and the weight is expelled by normal processes. According to these embodiments, once the capsule has dissolved, the ends of the drag, string, or thread material may be left free in the duodenum for a predetermined period of time (e.g., 15 minutes to 12 hours) to assess one or more health conditions of the subject.

[0078] In some embodiments, the drag or thread material may be collected or removed from the subject after a predetermined period of time. According to these embodiments, collection or removal of the device from the esophagus may be without capsule. In some embodiments, the thread or drag may be stored for later analysis, for example, by refrigeration, or by freezing by quick freezing and flat storage (e.g., flash freezing). In other embodiments, the thread, string, or drag segment may be analyzed immediately after collection or immediately after collection. In other embodiments, the thread, string, or drag material may be sectioned according to where the capture element was placed or according to the segment of the GI tract that is sampled. When storing the thread, string, or drag material after collection, the proximal segment may be partially or completely removed as needed, for example, to reduce cross-contamination. In some embodiments, the captured agent or analyte may be adsorbed to a distal segment of the thread. In other embodiments, the captured agent or analyte binds to an outer portion of the distal segment. In certain embodiments, the captured agent or analyte may be physically scraped off or introduced into a medium for part or all of the thread for analysis. In still further embodiments, fluids, secretions, or other compositions found within the GI tract may adhere to the distal segment of the thread, string, or drag material. The presence and analysis of secretions, polypeptides, enzymes, microorganisms, and / or cells may be examined by several different techniques well known in the art. In certain embodiments, the presence of inflammatory proteins, cytokines, enzymes, polynucleotides, cells or microorganisms, or their by-products, may be analyzed within the contents removed from the thread for analysis and diagnostic and / or treatment regimens. In other embodiments, the thread, string, or drag material may be analyzed for the level, presence, or absence of one or more diagnostic indicators. Analysis may be performed by several methods, including, but not limited to, ELISA, cytology, mass spectrometry, gas chromatography, HPLC, sequence analysis, PCR, Western blot, Mesoscale, Licor, RNA and DNA extraction, immunohistochemical analysis, and microbial culture and staining.In certain embodiments, the diagnostic indicator may be any factor, polypeptide, or other agent that indicates the presence or severity of a condition in a subject. In some embodiments, the diagnostic indicator may be a marker of eosinophil granule proteins, cytokines or chemokines, cellular infiltrates, pH, or allergic response. Other diagnostic indicators include, but are not limited to, peripheral and plasma eosinophil counts, mast cells, leukotrienes, other immune markers. In other embodiments, the diagnostic indicator may be a microorganism or its by-product. In yet other embodiments, the captured agent may include a marker related to the health of the subject, such as a sampling of the subject's microbiome. It is contemplated herein that one, two, three, four, five or more or a panel of captured agents or markers may be collected for analysis of the subject's GI tract, health assessment, diagnosis, and treatment.

[0079] As disclosed herein, eosinophil granule proteins can be obtained and used to analyze the condition of a subject. Eosinophil granule proteins include, but are not limited to, major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), and eosinophil-derived neurotoxin (EDN). These proteins can be secreted upon eosinophil stimulation and induce an inflammatory response. Eosinophil granule proteins can include, but are not limited to, other biologically active products, including bacterial penetration protein (BPP) and antimicrobial proteins. The secretion and extracellular deposition of eosinophil granule proteins in tissues affected by inflammatory diseases suggests that MBP, ECP, EPO, and EDN may be involved in the pathogenesis of the inflammatory process. Further evidence has demonstrated that topical application of MBP is associated with tracheal smooth muscle contraction and ion secretion.

[0080] In certain embodiments, the subject may be a subject that is part of a clinical trial. In some embodiments, the subject is a participant in a clinical trial of a new pharmaceutical product, such as an absorption, distribution, metabolism, and excretion (ADME) study associated with the new pharmaceutical product. According to these embodiments, the pharmaceutical product can be tested in the subject, and the device disclosed herein can be used to obtain a sample from the subject for analysis.

[0081] Other embodiments include harvesting and analyzing the deployed and collected drag, string, or thread for the presence or absence of cytokines or chemokines. In some embodiments, cytokines and / or chemokines may be harvested and analyzed from the deployed and collected drag, string, or thread material for assessment of a health condition in a subject. In certain embodiments, cytokines may include, but are not limited to, interleukins. Cytokines may include, but are not limited to, interleukin-1 alpha (IL-1α), IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-32) and interferons. In other embodiments, the diagnostic agent may be a Th2 cytokine (e.g., IL-4, IL-5, IL-13). Chemokines may include, but are not limited to, the eosinophil-specific chemokines eotaxin-1, -2, -3.

[0082] Other embodiments include detection of allergic reaction markers or indicators of inflammation in areas of the GI tract, such as the esophagus. As used herein, an "allergic reaction" can be a disorder in which the host's immune response to a particular antigen is disproportionate to a control that has no such response, leading to an adverse reaction. Allergies resulting from allergic reactions can include, but are not limited to, allergies to pollen, ragweed, shellfish, pollutants, any food, domestic animals (e.g., cats and dogs), gluten, lactose, B-poison, and other allergens. In certain cases, some allergic reactions result in asthma. In some embodiments, the markers of allergic reactions can be, but are not limited to, immunoglobulin E (IgE), tryptase, receptors (FcRI, CD23), or other allergens. Other inflammatory markers that can be captured and analyzed from GI samples can include, but are not limited to, arachidonic acid products, and neurotransmitters such as substance P and bradykinin.

[0083] In certain embodiments, the agents captured using the devices disclosed herein may be used to assess, diagnose, or monitor a disease or condition of the GI tract of a subject, such as the esophagus, stomach, duodenum, or other areas within the accessibility of the deployed thread or drag of the devices disclosed herein. According to these embodiments, the assessment of the captured agents or indicators may include, but is not limited to, the presence, level, or absence of a sought agent or indicator that allows for the diagnosis of a disease, condition, or health condition of the subject. For example, if the agents captured from the esophagus indicate the presence of inflammation, this may be an indicator of eosinophilic esophagitis. Alternatively, the level of the agent or indicator may indicate a diagnosis or severity of a disease or condition, or even represent a health level or prediction of developing a condition that does not yet exist (e.g., a microbiome assessment of a healthy subject). In certain embodiments, the eosinophil granule protein levels assessed in a subject may indicate the presence of or risk of developing eosinophilic esophagitis (EE). In other embodiments, increases or decreases in cytokines known in the art to be indicative of disease or other health conditions of the GI tract can be isolated on the distal segments of the threads or drag materials disclosed herein and used to diagnose and / or treat a condition or to assess the health of a subject. According to these embodiments, by way of example, cytokines can include, but are not limited to, IL-6, found in the esophagus or other GI region of a subject, as an indicator of the presence or risk of developing gastroesophageal reflux disease (GERD). In certain embodiments, diagnostic markers or indicators or other agents may be evaluated to assess treatment of the disease and whether further treatment or changes in the dietary regimen are required.

[0084] In certain embodiments disclosed herein, the condition may be GERD. GERD includes chronic symptoms or mucosal damage caused by abnormal reflux in the esophagus. Symptoms may include heartburn, inflammation of the esophageal lining, stenosis, dysphagia and chronic chest pain, or other symptoms. Treatment of GERD may include dietary and lifestyle modifications, positional therapy, drug therapy, and surgery. The devices disclosed herein may be used to assess, diagnose, and treat GERD or complications associated with GERD, such as Barrett's esophagus, or cancer of the GI tract associated with GERD.

[0085] In other embodiments, the disease or condition disclosed herein may include EE. EE is an eosinophilic gastrointestinal disease (EGID) that accounts for approximately 50% of dysphagia and food impaction. It has been proposed that food allergy is the underlying etiology of EE. Recent translational studies have demonstrated that skin prick testing (SPT) is a tool used to identify triggering food allergens, and that over 90% of patients respond to dietary intervention, humoral (IgE) and / or cell-mediated food allergy. Esophageal mast cells have been observed to be significantly increased in EE compared to normal controls and gastroesophageal reflux disease (GERD). EE is a disorder of the esophagus characterized by esophageal and / or upper gastrointestinal symptoms associated with normal pH monitoring and esophageal mucosal biopsy specimens containing large amounts of intraepithelial eosinophils within the esophageal squamous epithelium or deep tissue levels. EE affects more men than women, and the diagnosis is typically made in adults between the third and fourth decades of life, although it may be diagnosed at later ages. In children, diagnosis occurs after infancy through adolescence, with no recognized peak age of onset. Symptoms may include, but are not limited to, chest pain, heartburn, dysphagia, food impaction, and lack of response to acid-reducing medications. Treatment of EE typically involves administration of corticosteroids or elemental diets, but typically does not involve surgery.

[0086] Standard treatment for patients with EE currently includes esophageal endoscopy with biopsy to determine the number of epithelial eosinophils (≦15 / hpf is diagnostic). Because the consequences of chronic eosinophilic inflammation in EE may include esophageal remodeling with subsequent esophageal narrowing, trachealization, and strictures, therapeutic efforts are typically directed at inducing clinical as well as histological remission. Although relatively safe overall, esophageal endoscopy is associated with procedural risks, is expensive, time-consuming, and is limited to obtaining a 3 mm sample. To date, serological, fecal, or noninvasive tests have not provided durable or reliable results that correlate with histological evidence of disease progression or remission in EE. The current state of esophageal inflammation in subjects with EE is assessed using invasive endoscopy.

[0087] In certain embodiments, the devices disclosed herein may be used to assess the presence or severity of EE in a subject. In other embodiments, the devices disclosed herein may be used to assess EE in a subject, using collection of agents or diagnostic markers identified on the distal segment of the thread or drag material, for continued treatment and monitoring, if necessary.

[0088] In some embodiments, the devices disclosed herein may be used to assess food allergy status in a subject in a non-invasive or minimally invasive manner. According to these embodiments, adults or children may be diagnosed and / or monitored for food allergies using the devices disclosed herein. It is noted that studies show support for a close relationship between EE and food allergic disorders. Additionally, it is also noted that subjects with EE often have symptoms after ingestion of certain foods. Elimination of food triggers may result in clinical pathological remission in EE. Mucosal biopsies from subjects with EE have been demonstrated to have significantly increased numbers of mucosal mast cells compared to those from subjects with gastroesophageal reflux disease (GERD) or normal subjects, suggesting their involvement in the pathogenesis of this disease. Additionally, previous studies suggest that subjects with eosinophilic gastrointestinal disease (EGID) and food allergies exhibit increased expression of CD23 on intestinal epithelial cells and in fecal samples. Although the exact role of CD23 in food allergic reactions is uncertain, recent studies suggest that human CD23a isoform is involved as a bidirectional transporter of both free IgE and IgE / antigen complexes, potentially delivering IgE and its bound allergens across intestinal epithelial cells to induce mast cell activation. These observations provide strong evidence supporting the role of food allergic reactions (including those mediated by IgE) in the pathogenesis of EE. In certain embodiments, diagnosing food allergies in subjects using the disclosed devices can be an efficient method with reduced cost and discomfort to the subject. In some embodiments, diagnosing a subject with food allergy using one or more agents captured by the devices disclosed herein can provide early intervention and reduce the development of EE or more severe food allergies in the subject.

[0089] EE is characterized by symptoms including abdominal pain, regurgitation, feeding intolerance, food impaction, and dysphagia. It is noted that esophageal biopsies often contain numerous intraepithelial eosinophils, with eosinophilic microabscesses and luminal stratification. These advanced symptoms of EE are non-responsive to acid blockade, such as proton pump inhibition, but still respond to elimination (or basal) diets and corticosteroids. EE does not affect the columnar epithelium of the stomach or small intestine. If a subject has persistent symptoms associated with esophageal epithelial eosinophilia, as well as normal gastric and duodenal mucosa, and gastroesophageal reflux disease (GERD) and other causes of eosinophilia have been ruled out, a diagnosis of EE can be made with confidence. In certain embodiments, the devices disclosed herein may be used for deployment in subjects for early and accurate diagnosis of EE. According to these embodiments, diagnostic markers of EE may be captured on the devices disclosed herein, including but not limited to cellular, cytokine, and other markers. For example, the presence of Th1 or Th2 mediated immune responses, mast cells (e.g., induction), and IgE mediated responses, the presence or absence of eotaxin-3; the presence or absence or levels of eosinophil derived granule proteins (major basic protein 1 (MBP1), eosinophil peroxidase (EPX), eosinophil derived neurotoxin (EDN), eosinophil cationic protein (ECP), Charcot Leyden crystal protein (CLC / Galectin-10), IL-3, IL-4, IL-5, IL-10, and other agents can be assessed. In certain embodiments, identifying a Th2 phenotype instead of a Th1 phenotype using the devices disclosed herein may be indicative of a GI inflammatory condition or a GI infection by a microorganism. In certain embodiments, these GI related conditions may be diagnosed and monitored in a subject using the devices and methods of use disclosed herein.

[0090] Limitations of state-of-the-art methods, including endoscopy with biopsy, include, but are not limited to, the problem that these methods provide assessment of <0.001% of the total esophageal surface area. Endoscopy is costly and, as mentioned above, is often not covered by insurance companies when repeated. Other proposed methods for analyzing the esophageal mucosa include symptom monitoring, radiological studies, and serum or fecal analysis, but these are also limited. To date, serological or fecal analysis has not provided reliable and durable findings that correlate with and consistently predict histological evidence of disease remission or progression. These findings indicate that minimally invasive, inexpensive, safe, reliable, and accurate methods for direct measurement of GI tract status are needed for the diagnosis, treatment, and monitoring of the conditions disclosed herein.

[0091] In some embodiments, the devices disclosed herein can be used as simple, cost-effective, and reliable devices for diagnosis or assessment of a subject's GI tract health. In some embodiments, the devices disclosed herein include proximal and distal segments that are linked together using intertwined silicone adhesive ends for improved retrieval of the device from the subject. In other embodiments, the wrapping of the thread or drag is designed for internal or external delivery, and the remaining thread or drag material is looped for optimal deployment. In certain embodiments, the weight may be placed in a two-part capsule separate from the thread for secure transport within the subject's GI tract. In other embodiments, the devices disclosed herein may be sterilized in a pouch, and the entire device, including the weight, may be sterilized for storage and use, reducing contamination concerns. In some embodiments, devices sterilized by the compositions and methods disclosed herein may be stored for 2-3 days, 2-3 weeks, 2-3 months, several months, or years. In some embodiments, the proximal segment of the device comprises one ply nylon, while the distal segment of the device comprises three plies of nylon, with the proximal segment nylon having reduced absorption and the distal nylon having increased absorption. In certain embodiments, the proximal and distal segments are tapered toward the joining ends. In some embodiments, the adhesion of the proximal and distal segment thread components may comprise a silicone adhesive, and optionally the proximal and distal segment ends are intertwined and bonded to one another to improve resistance to separation when deployed and / or collected from a subject.

[0092] According to these embodiments, the thread, string, or drag material may be wound, for example, as shown in FIG. 2A or FIG. 2B, and the base of the gelatinous capsule may be placed over the wound thread, string, or drag material. In other embodiments, once the thread or drag is placed in the base of the capsule, the distal end of the drag, string, or distal segment of the thread may be placed between the cap and the base of the capsule. In some embodiments, the weight may be placed away from the exit of the thread, string, or drag (e.g., away from the hole in the cap and / or the side of the device) to reduce interference with the deployment of the thread or drag. In some embodiments, the weight may be a ball (e.g., steel). In other embodiments, the proximal segment of the thread or drag is secured to the cheek or secured outside the subject's mouth and essentially remains within the subject's mouth or oral cavity. In other embodiments, the distal segment of the thread or drag may be deployed and remain for a predetermined period of time within the GI tract, including, for example, the esophagus, stomach, duodenum, upper small intestine region, etc. of the subject.

[0093] In some embodiments, the capsule is made of a dissolvable material that dissolves upon deployment or after a period of time within the subject, and the distal end of the distal segment is released from the capsule remaining in the subject's duodenum or small intestine. At a predetermined time period, the thread or drag material may be removed from the subject's GI tract by pulling at a predetermined pace to provide optimal collection of captured agents and / or indicators and / or delivery of therapeutic agents. Once collected, in certain embodiments, the distal segment of the thread, string, or drag material may be analyzed for the presence or absence or levels of agents or diagnostic indicators, or combinations thereof.

[0094] In some embodiments, advantages of the devices disclosed herein include, but are not limited to, ease of use - no preparation / anesthesia required, inexpensive, improved versatility in assessing a subject's GI tract condition, improved adhesive strength, improved safety in administration and use due to pre-sterilization of the device, and / or improved winding, reduced snagging, and improved deployment upon delivery.

[0095] The various biochemical and molecular biology methods referred to herein are well known in the art and are contemplated for use herein. EXAMPLES

[0096] The following examples are included to demonstrate specific embodiments of the present invention. It should be understood by those skilled in the art that the techniques disclosed in the following examples represent techniques that the inventors have discovered to function well in the practice of the present invention, and therefore may be considered to constitute preferred modes for its practice. However, those skilled in the art should understand in light of this disclosure that many changes can be made in the specific embodiments disclosed and still obtain the same or similar results without departing from the spirit and scope of the present invention.

[0097] Example 1 The features of the device disclosed in these embodiments include an ingestible capsule that includes a stainless steel weighted ball and a bimodal string (proximal and distal portions). When the capsule is swallowed by a patient, the string, which is secured to the patient's exterior at a proximal end, is deployed along the gastroesophageal tract. After a relatively short time in the stomach, the string separates from the capsule, the stainless steel ball passes through the GI tract for natural elimination by the body, and the deployed string collects biological fluids, such as esophageal fluid, cells, and proteins. After a period of time, the string is retracted from the esophagus and the biological fluids adsorbed and captured by the string are analyzed.

[0098] Some functions: The capsule disclosed herein is intended to be a biological sample transport device that collects samples or delivers agents to the patient's GI tract for diagnosis and / or treatment. The capsule does this by deploying a string along the patient's esophagus. The string, once deployed, has absorbent properties that allow the string to absorb fluid from the esophagus. Once the capsule is swallowed by the patient, the looped end of the proximal string is taped to the patient's check using, for example, Tegaderm dressing tape. This relaxes the patient and eliminates the need to hold the proximal string end during the entire swallowing and deployment process.

[0099] Components Gelatin capsule The gelatin capsule is made from non-vegetarian gelatin or vegetarian gelatin. It is a standard #1 size capsule. During the assembly process, two holes are drilled in the capsule to facilitate the assembly and function of the assembly. One hole is drilled in the end of the capsule cap and one hole is drilled in the side of the body of the capsule. Both these holes are about 2.0 mm in diameter. The hole in the end of the capsule should be smooth and should not have any cracks around the entire diameter. The hole in the side of the capsule does not need to be smooth but should not have any cracks around the diameter of the hole.

[0100] Proximal cord The proximal string is a single-ply parallel fiber string made of nylon 6 / 6. This string was selected for the proximal string because it is not very absorbent and nylon is known to be a biocompatible material. Also, this parallel fiber string does not take up much space within the capsule when rolled up. This string is cut to a length of approximately 356 mm before being attached to the distal string, and a loop is made at the end opposite the proximal string.

[0101] Distal cord In this example, the distal string is a 3-ply spun nylon 9 / 3 string. This string is highly absorbent. Past absorption tests have shown that this string will absorb approximately 8-10 times its weight in water. This section of string is intended to be placed in the patient's esophagus and collect biological fluids. The distal string is cut to a length of approximately 775 mm.

[0102] Silicone Adhesive An exemplary silicone adhesive is used to bond the two types of strings together as well as form a loop at the end of the proximal string. The strength of the adhesive is important for the strength of the interface between the two types of strings. However, it is not important for the strength of the loop. The strength of the interface needs to be strong enough to withstand the tension caused by removing the string from the patient's esophagus during normal use. However, it is also intended to withstand the tension that would be created if the capsule does not deploy correctly and needs to be prematurely removed from the subject. This means that the capsule is still attached to the end of the string, which can create more tension than if the string were removed alone. The predicted tension was less than 10N during the previous project. The minimum strength allowed during testing is 23N. This allows for a safety factor of greater than 2 for this application.

[0103] Stainless Steel Ball The stainless steel (SS) balls are made from 316 grade stainless steel. These balls are passivated to remove any contaminants that may be present outside of the material. They are approximately 4.77 mm (3 / 16 inch) in diameter and fit into the bottom of the body of the gelatin capsule. The stainless steel balls are used within the assembly to help gravity pull the capsule down into the GI tract during surgery.

[0104] Peel Pouch An exemplary peel pouch in which the capsule assembly is packaged is a combination of Tyvek 1073B and polyester. The pouch is 3" x 4" and is pre-sealed on three sides of the pouch. One end of the pouch contains a chevron that allows the pouch to be opened more easily by the user. The fourth side is intended to be sealed after the capsule assembly is placed in the pouch. The fourth side seal is not designed to be easily peeled away. It is primarily designed to ensure a sterility barrier. The other three seals are made at the manufacturer and are designed to provide a sterile barrier and be easily peeled away.

[0105] Assembly Configuration These exemplary capsules have the six distinct components mentioned in the previous section. The proximal and distal are glued together using silicone adhesive and a loop is made at the other end of the proximal string. Once cured, the string is rolled up and inserted into the gelatin capsule over the stainless steel ball at the end of the gelatin capsule. In this example, the stainless steel ball is within the capsule but is not attached to the string, thread, or drag material.

[0106] To bond the proximal and distal strings together, both strings are spread apart as the adhesive is applied so that all of the strands of the two strings are intermingled together during the bonding process for improved interaction and durability during deployment. Simply overlapping the strings, as with a lap solder joint, would not meet the strength requirements of this joint. However, when all the strands are intermingled, the strength of the joint is greatly increased, allowing for full deployment and removal without separation.

[0107] In one example, during a previous development project, the SS ball was glued inside the capsule, creating a surface that would be exposed to the patient after the gelatin capsule dissolved. The gelatin capsule prevented this surface from being exposed to EtO gas during the sterilization process. The adhesive was removed from the SS ball only for ease of assembly. With the adhesive, the SS ball would not fall out of the capsule while handling the assembly.

[0108] Many different winding configurations were tested during the initial development project for this device (see, for example, Figure 2). Certain configurations gave the most consistent and lowest deployment force values. These configurations were designed so that no portion of the string would interfere with the string in the process of deploying from the capsule. During the early stages of development, the proximal string and interface sections caused the most problems with deployment. The distal string deployed with consistent low deployment values, but the combined string ends had a more optimal winding configuration as shown.

[0109] Packaging and sterilization Once the string is rolled up and placed into a gelatin capsule, the assembly is placed into a Tyvek / PET peel pouch that allows EtO gas to permeate the Tyvek side during sterilization, preparing the device for use.

[0110] Example 2 Design Elements

[0111] [Table 1]

[0112] [Table 2]

[0113] [Table 3]

[0114] Example 3 In one exemplary method, the device is composed of proximal and distal nylon strings attached to each other using an adhesive that complies with FDA standards (CFR Title 21, Chapter I, Subchapter C, Parts 210-211; cGMP Drugs / Finished Pharmaceuticals), a pharmaceutical grade gelatin capsule, and a stainless steel ball that is generally recognized as safe for the digestive system. Morphological and functional tests were performed on state of the art devices and the devices disclosed herein. Details of the various tests are also provided.

[0115] equipment design

[0116] [Table 4]

[0117] [Table 5]

[0118] Example 4. Water absorption data As shown below in Table 6, the exemplary devices absorbed fluid at levels sufficient for key functional requirements, for example, for mucosal sampling in the esophagus or other regions of the GI tract.

[0119] [Table 6]

[0120] The device was tested for sterilization with ethylene oxide sterilization and was successfully used as a pharma- ceutical acceptable device. Apparatus and methods, Figures 2A-2J show winding configurations for the thread or drag material used herein. In certain exemplary apparatus and methods, Figures 2A and 2B show winding configurations with improved compartmentalization within the capsule, improved deployment with reduced snagging.

[0121] Example 5 Performance Test - Bench Bench testing was performed to optimize materials, interweave design, winding configuration within the capsule, fluid absorption, pull-out force, and interface separation force to generate optimal device design characteristics. For force metrics, optimal values ​​were developed based on analysis of the biomechanics of capsule swallowing and capsule movement within the gastrointestinal system via peristalsis. For fluid absorption, optimal values ​​were developed based on evaluation of mucosal fluid rheology and the ability of the strings to maximize volumetric capture of fluid.

[0122] Maximum deployment force The maximum deployment force test measures the force (in Newtons) required to pull the string out of the capsule without separating it from the capsule. An optimal value of less than 2.0 N was required to ensure that the string would emerge smoothly from the capsule without snagging or otherwise interfering with its intended performance. A lower maximum deployment force correlates to the ability to more easily pull the string out of the capsule. Clinically, this force should be as small as possible.

[0123] A force gauge is used to record the maximum force required to pull the string out of the capsule. A handheld gauge is hooked onto the string loop extending from the capsule. The operator pulls on the capsule until the entire length of the string is deployed from the capsule without separating the string from the capsule. The maximum force displayed on the force gauge is recorded as the maximum deployment force. Twenty post-sterilization samples were measured and the mean and standard deviation were calculated (see Table 7). The upper tolerance limit was then calculated using normal tolerance limit calculations. Thus, the population performs as well as or better than a legal predicate device for maximum deployment force with 90% Confidence and 95% Reliability.

[0124] [Table 7]

[0125] maximum separation force The maximum separation force test measures the force (in Newtons) required to separate the string from the capsule after it has been deployed from the capsule. This ensures that the capsule actually releases from the string within the digestive system and that the capsule is not pulled back as the string is withdrawn. Pulling the capsule back through the throat with the string can damage the esophagus and vocal cords. Keeping this force as low as possible ensures safe and reliable performance. A maximum separation force of less than 4N was considered optimal.

[0126] After the maximum spreading force test has been performed on the capsule, still attached to the force gauge (tared), the capsule is pulled again until the string is pulled out of the capsule. The maximum force displayed on the force gauge is recorded as the maximum spreading force. Twenty post-sterilization samples were measured and the mean and standard deviation calculated (see Table 8). The upper tolerance limit was then calculated using normal tolerance limit calculations. Thus, the population will perform the same or better for the maximum separation force with 90% confidence and 95% confidence.

[0127] [Table 8]

[0128] Joint breakage strength The interface break strength test measures the force required to break the seal at the lace interface (the portion of the lace where the proximal lace is bonded to the distal lace). The proximal and distal lace sections need to remain attached throughout the deployment and removal process to ensure safe and reliable operation of the device. A minimum interface break strength of >23N was considered optimal.

[0129] A load frame force gauge is used to measure the peak tension in Newtons. Loops large enough to fit into the jaws of the pull frame are tied on both the proximal and distal strings. Tension is applied to the string joint by the load frame until failure is noted at the string joint, after which tension is stopped. The force displayed on the force gauge is recorded as the splice failure strength. Twenty post-sterilization samples were measured and the mean and standard deviation were calculated (see Table 9). The lower acceptance limit was then calculated using normal acceptance limit calculations. Thus, the population performs as well as or better than legally commercially available devices for splice failure strength with 90% confidence and 95% confidence.

[0130] [Table 9]

[0131] Liquid absorption rate The liquid absorbency test measures the ability of the distal cord to absorb liquid and thereby accomplish its intended function of sampling fluid from the gastrointestinal system. Water was used as a surrogate for gastrointestinal fluids to measure this function. An absorbency rate of >2 was considered optimal.

[0132] This is assessed by comparing the weight of the water absorbed by the string to the weight of the dry string using a ratio. A 24 inch (61 cm) length of string is measured, cut, and placed in a tared 20 ml vial on a balance and the weight is recorded. The vial is then filled with DI water and allowed to absorb for approximately 3 hours. The water is then drained from the vial and the string is removed using tweezers to stop the dripping. A new empty vial is tared and the wet string is placed in the new vial and weighed. The ratio of the weight of the water absorbed by the string to the weight of the dry string is recorded as the water absorption rate. Twenty post-sterilization samples were measured and the mean and standard deviation were calculated (see Table 12). The lower tolerance limit was then calculated using the usual tolerance limit calculations. Thus, the population performs as well as or better than a legally commercially available device for water absorption rate with 90% confidence and 95% confidence.

[0133] [Table 10]

[0134] Storage period The device pouch in this example is a Tyvek heat seal pouch (approximately 4" x 9") for use in EO gas sterilization (SPS Medical Supply, THP-282). The chevron seal is meant to be opened by the user, so failure of this seal is the most likely cause of pouch failure. SPS Medical offers a 3 year pouch shelf life from the date of sterilization. Preliminary heat seal strength testing of 20 samples was performed in-house. Data showed seal strength to be greater than 1 lb force using a lower tolerance analysis.

[0135] Example 6 In another exemplary device and method, Figures 3A and 3B show the device (100, shown in Figure 1) and the placement of the distal end of a distal segment of thread or drag material (302) as contemplated herein. Figure 3 shows the capsule base placed over a wound thread or drag (302) with the distal end extending out from the capsule base (left panel, 3A), and then the distal end of the distal segment is placed into a thread-fixing opening (304) in the side wall of the base before the capsule cap is placed over the capsule base (right panel, 3B). Figure 1 shows the distal proximal end of the proximal segment of thread or drag protruding through the thread deployment opening of the capsule cap, while the distal end of the distal segment of thread or drag is shown releasably fixed into the base through the thread-fixing opening of the base.

[0136] Example 7 DNA Isolation and Purification. The distal segment of the thread or drag can be incubated in a lysis buffer to lyse the bacteria isolated by the device. Total DNA can be purified and analyzed for the presence or absence of organisms such as bacteria, viruses, fungi, or other microorganisms such as pathogenic organisms.

[0137] Example 8 In some exemplary methods, the presence or level of proteins or antibodies can be measured using standard techniques such as ELISA, and the thread or drag material can be harvested by blotting to dryness, boiled in a sample buffer (e.g., SDS-PAGE), and analyzed by SDS-PAGE and / or western blotting for the presence, level, or absence of diagnostic indicators such as cytokines or other indicators of GI tract status or disease.

[0138] Example 9 In other exemplary methods, the distal segment of the thread or drag material is analyzed for the presence, level, or absence of diagnostic indicator cells, such as, for example, mast cells, or the presence of other infiltrates indicative of infection or cancer. In some methods, trypsin / EDTA can be used to remove captured cells for further analysis and identification by methods well known in the art. In certain methods, eosinophils and associated factors for diagnosis of a disease or condition can be detected.

[0139] Experimental design and methods In certain methods, the thread or drag material after deployment for a predetermined period of time may be removed and cut into pieces according to anatomical location, e.g., mouth, esophagus, stomach, duodenum. Within the packaging of each device is a pH indicator that, when applied to the thread or drag, marks the thread or drag with a color change that allows identification of the portion of the GI tract where the thread or drag was present. For example, the stomach portion of the string changes to orange (acidic environment) and the esophageal portion is blue-green (alkaline environment). The indicator is typically only applied to a small (<1 mm) portion of the string, and these portions are not included in the analysis to avoid any interference with the desired assay. The length of the string from the lips to the proximal oropharynx may be measured to determine the oral portion. The sections after cutting may be placed into tubes or trays with either sample elution buffer for protein analysis or TRIZOL reagent for RNA isolation, or other media or buffers for analysis. Samples may be analyzed immediately or frozen and processed in batches of 10-20 to eliminate day-to-day variability in isolation techniques and stored at -80 °C for final analysis.

[0140] Protein Analysis Proteins may be analyzed by methods well known in the art and may include antibody assays to determine the presence of a protein of interest. Statistical Analysis. Samples can be compared to control samples of healthy and / or diseased subjects for the assessment of a given subject, as well as known statistical analysis techniques used to diagnose and / or treat the subject.

[0141] Cytokine Panel. In certain exemplary methods, cytokine panel assays can be used to detect the presence, level, or absence of a particular cytokine or panel of cytokines, which can be measured in healthy and / or diseased subjects for analysis and treatment. In some methods, detection of IL-8 mRNA expression and / or translation can be measured alone or in combination with other cytokine markers to assess a condition such as GERD, and, for example, a particular treatment regimen. It is contemplated that any treatment for GERD can be assessed for effectiveness in subjects who have or are at risk of developing GERD (e.g., food elimination diets or corticosteroids) using the devices disclosed herein.

[0142] Exemplary Lateral Flow and Protein Analysis for the Devices Disclosed Herein ELISA - Most targets have commercially available ELISAs. The ELISA or source of the antibodies are noted here: CD23 (BD ​​Bioscience), FcεRI (ELISA), Eotaxin-1,2,3 (R&D Systems), Tryptase (R&D Systems).

[0143] Mesoscale - Mesoscale™ technology (Gowan et al., 2007) is a multiplex quantification system for the analysis of up to 12 target proteins in a single well of a 96-well plate. The technology requires only 2 μL of sample / well, and the 96-well format allows for high-throughput sampling and analysis. Data is provided in quantitative format as pg protein per mL. For the study, a standardized Th1 / Th2 template is used to assess the presence of Th1 (IL-2, TNF-α, IFN-γ) and Th2 (IL-4, IL-5, and IL-13) cytokines.

[0144] Immunohistochemistry - Tissue sections undergo immunohistochemical analysis using specific antibodies as described above; antibodies for ELISA are also available for immunohistochemical analysis as previously described (Walsh et al., 1999; Desai et al., 2005; Teitelbaum et al., 2002). Briefly, all specimens are formalin fixed, paraffin embedded, serially sectioned, stained with hematoxylin and eosin, or used for immunohistochemical studies. For immunohistochemical staining, sections are dewaxed, rehydrated, quenched for peroxidase activity, blocked, and incubated with primary and then secondary antibodies. The color reaction is then developed using the diaminobenzidine method, counterstained with hematoxylin, dehydrated, and mounted. Appropriate positive and negative controls are included in each staining reaction. Quantification of positively stained cells for each of the selected antibodies is performed.

[0145] RNA analysis. Tissues were homogenized with TRIZOL reagent to isolate total RNA, which was then subjected to reverse transcription and Q-PCR analysis using a BIORAD Real-Time iCycler PCR instrument. Primers for Th1 (IL-2, TNF-α, IFN-γ) and Th2 (IL-4, IL-5, and IL-13) cytokines were purchased from Invitrogen.

[0146] Statistical analysis. Linear regression is used to model the percent change in the amount of histological eosinophilic inflammation with changes in marker levels. Multiple linear regression is used to simultaneously assess the relationship between multiple markers and pathological outcomes.

[0147] All of the methods and devices disclosed and claimed herein can be made and executed without undue experimentation in light of this disclosure. Although the compositions and methods of the present invention have been described with reference to specific embodiments, it will be apparent to those skilled in the art that modifications can be made to the methods and devices described herein and to the steps or sequence of steps of the methods without departing from the concept, spirit and scope of the present invention. More specifically, it is apparent that certain agents that are both chemically and physiologically related may be substituted for the agents described herein while still achieving the same or similar results. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the present invention as defined by the appended claims.

Claims

1. 1. A device for sampling from or delivery to the gastrointestinal tract of a subject, comprising: a two-part ingestible capsule having a string or drag material deployment opening; a thread or drag material enclosed within the capsule, the thread or drag material having a proximal segment and a distal segment, the distal end of the proximal segment being operably connected to the proximal end of the distal segment; a weighted component enclosed within the capsule away from the line or drag material deployment opening; the thread or drag material is configured for optimal delivery through the thread or drag material deployment opening of the capsule when deployed in the gastrointestinal tract of a subject; A device, wherein the thread or drag material comprises one or more trapping agents capable of trapping or delivering one or more active substances within the gastrointestinal tract of the subject.

2. The device of claim 1 , wherein the proximal segment is at least one of thinner and shorter than the distal segment and remains outside of the subject's esophagus.

3. 3. The device of claim 2, wherein the distal segment of the thread or drag material is capable of binding to at least one of a protein, a polypeptide, a chemical, a polynucleotide, a microorganism or its by-product, a cell, a liquid composition, other agent or analyte located in the gastrointestinal tract.

4. 4. The device of claim 1, wherein at least a portion of the proximal segment passes through the string or drag deployment opening of the ingestible capsule, and the proximal segment outside the ingestible capsule is capable of being secured in or outside the subject's mouth.

5. The device of any one of claims 1 to 4, wherein the thread or drag material comprises a distal segment comprising a drag material comprising absorbent fibers, mesh fibers, or textured fibers.

6. The apparatus of claim 5 , wherein the drag material comprises nylon.

7. The device according to any one of claims 1 to 6, wherein the capsule is dissolvable.

8. 10. The device of claim 1, wherein the two-part ingestible capsule comprises a cap and a base configured to operably fit together to form an interior of the capsule, and the thread or drag material comprises a pre-configured thread for insertion into the interior of the capsule.

9. 10. The device of claim 8, wherein the cap further comprises a transparent portion that includes a window for viewing the contents of the base of the two-part ingestible capsule.

10. 10. The device of claim 9, wherein the center location of the window is a distance of about 2.5 to about 7.5 mm from the edge of the open end of the base of the ingestible capsule.

11. The apparatus of any one of claims 1 to 10, wherein the distal segment of the thread or drag material comprises three plies of material.

12. 12. The device of claim 11, wherein each ply of the three-ply material may be similarly or differently configured for sampling the GI tract of a subject.

13. 11. The device of any one of claims 1 to 10, wherein the distal segment of the line or drag material comprises a breaking strength of 35N to 40N or more when pulled at about 40mm / min to about 60mm / min until failure.

14. 4. The device of claim 3, wherein the one or more capture agents comprise an antibody, an antibody fragment, an antigen, a cytokine, a chemokine, a polynucleotide, a pharmaceutical, a receptor, a diagnostic or health indicator, a sensitivity or resistance indicator, a ligand or other agent, a chemical, an alloy, a metal, or a combination thereof.

15. 15. The device of claim 14, wherein the one or more capture agents are associated with one or more indicators in the GI tract, the one or more indicators comprising one or more of major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), eosinophil derived neurotoxin (EDN), CLC / Gal-10, other eosinophil granule proteins, interleukin-6 (IL-6), IL-8, IL-1β, IL-5, interferon gamma (INF-γ), other GI associated cytokines, chemokines, cellular infiltrates, pH, IgE, tryptase, other markers of allergic response, receptor molecules, allergens, arachidonic acid products, other inflammatory markers of the GI tract, substance P, bradykinin, other neurotransmitters of the GI tract, leukotrienes, mast cells, other GI associated cells, bacteria, yeast, viruses, other microorganisms, metals, or combinations thereof.

16. The device of claim 1 , wherein the proximal and distal segments include an adhesive compound for connecting the proximal segment to the distal segment of the thread or drag material.

17. The device of claim 1 , wherein the weighted component further comprises an adhesive compound for associating the weighted component with the ingestible capsule.

18. The device of claim 1 , wherein the distal proximal end of the proximal segment comprises a loop.

19. 10. The device of claim 1, wherein the device comprising the ingestible capsule, the string or drag material, and the weighted component comprises a unit, and the unit is sterilized.

20. 20. The apparatus of claim 19, wherein sterilizing the unit comprises sterilizing the unit using ethylene oxide (EO) or other similar sterilant.

21. The line or drag material is a layered loop orientation with a hole in the center, where the loops remain separated from one another and do not overlap, and the proximal end of the thread or drag material is fed inward; a layered loop orientation with a hole in the center, where the loops remain separate from one another and do not overlap, and the proximal end of the thread or drag material is fed outward; Longitudinal loop orientation, Random winding configuration, A spiral winding configuration with a hole in the center and no layering of loops; A multiple fold configuration with thin dense longitudinal layers of small loops throughout the fold configuration; Twisted configuration, Internal short spool configuration, Internal length spool configuration, and Circular Configuration 21. The device of any one of claims 1 to 20, wound in a winding configuration selected from the group consisting of:

22. A kit comprising a device according to any one of claims 1 to 21 and at least one container.

23. 22. A device according to any one of claims 1 to 21 for use in a method for analyzing the digestive tract of a subject, the method comprising the steps of deploying the device into the digestive tract of the subject, retrieving the thread or drag material, and analysing the distal segment of the thread or drag material of the device for diagnostic agents or health indicators captured from the digestive tract of the subject.

24. 24. The apparatus of claim 23, wherein the microbiota of the subject is analyzed.

25. The apparatus of claim 23 or 24, wherein the method further comprises assessing a condition of the subject based on the presence or absence of the captured diagnostic agent or health indicator.

26. 26. The device of claim 25, wherein the health indicator comprises an agent indicative of pharmaceutical sensitivity or resistance for the treatment of a gastrointestinal condition.

27. ​​The apparatus of claim 23, wherein bile from a subject is analyzed for one or more health conditions in a subject that is a control subject or a patient with one or more health conditions.

28. 24. The apparatus of claim 23, wherein the subject is a participant in a clinical trial of a new pharmaceutical product, such as an absorption, distribution, metabolism, and excretion (ADME) study associated with the new pharmaceutical product.

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